Diagnostics & Mitigation

COVID-19 Diagnostics

COVID-19 tests are used for diagnosis of two basic aspects of the infection: detecting active SARS-CoV-2 infection or testing for past SARS-CoV-2 infection. Active infection indicates that the tested patient could infect others due to the presence of active replicating virus. previous infection refers to an individual who has already recovered from the virus and has no replicating virus in the sample.

Active infections  are diagnosed by antigen or molecular tests. The molecular tests are also referred to as nucleic acid amplification tests (NAAT). This category of diagnostic test includes polymerase chain reaction (PCR) tests, loop-mediated isothermal amplification (LAMP), and clustered, regularly interspaced short palindromic repeat (CRISPR)-based assays. The real time quantification RT-PCR (qRT-PCR) is the routine confirmation test recommended by WHO. It is considered as the gold standard for SARS-CoV-2 identification. These tests detect current infection and directs healthcare providers  on further treatment or isolation procedures to reduce spread.

Antigen tests are rapid and detect the presence of SARS-CoV-2 antigens in samples, typically providing results in under 30 min. This typically avoids extraction and amplification steps. The Spike (S) and Nucleocapsid (N) are the two main antigenic targets of SARS-CoV-2.

Serology tests are used to detect past infection and look for the presence of antibodies produced  by the body as a specific response to SARS-CoV-2 infection. Detection of antibodies specific to SARS-CoV-2 indicates that the subject is currently seropositive. With specific reagents, individual antibody types, like IgG, IgM, and IgA, can be determined. Antibody detection in vivo acts as a supplement to molecular methods. However, these tests require seroconversion of an individual and cannot be applied during early stages of infection.

A combination of molecular and serological tests is needed to improve the diagnostic accuracy of COVID-19. Laboratory-based tests both for molecular and serology tests are not suitable for point-of-care diagnosis due to time-consuming, expensive equipment and biosafety requirements. Point-of-care tests are rapid, accurate, sometimes portable, and have low cost and non-specific device requirements.

As per the U. S. FDA, there are following types of COVID-19 related In vitro diagnostic (IVD) devices:

  • Diagnostic Tests – Tests that detect parts of the SARS-CoV-2 virus and can be used to diagnose infection with the SARS-CoV-2 virus. These include molecular tests and antigen tests.
  • Serology/Antibody Tests – Tests that detect antibodies (e.g., IgM, IgG) to the SARS-CoV-2 virus. Serology/antibody tests cannot be used to diagnose a current infection.
  • Tests for Management of COVID-19 Patients – Beyond tests that diagnose or detect SARS-CoV-2 virus or antibodies, there are also tests that are authorized for use in the management of patients with COVID-19, such as to detect biomarkers related to inflammation. Once patients are diagnosed with COVID-19 disease, these additional tests can be used to inform patient management decisions.

As of June 14, 2021, 384 tests and sample collection devices are authorized by the FDA under emergency use authorizations (EUAs). These include 275 molecular tests and sample collection devices, 81 antibody and other immune response tests, and 28 antigen tests. There are 52 molecular authorizations and one antibody authorization that can be used with home-collected samples. There is one molecular prescription at-home test, three antigen prescription at-home tests, five antigen over-the-counter (OTC) at-home tests, and two molecular OTC at-home tests. The FDA has authorized 11 antigen tests and 4 molecular tests for serial screening programs.


  • Sensitive detection and quantification of SARS-CoV-2 in saliva [Link] (06/14/21)
  • High-throughput quantitation of SARS-CoV-2 antibodies in a single-dilution homogeneous assay [Link] (06/14/21)
  • Saliva can be more effective than nasopharyngeal swabs for COVID-19 testing [Link] (06/14/21)
  • A novel RT-LAMP workflow for rapid salivary diagnostics of COVID-19 and effects of age, gender and time from symptom onset [Link] (06/14/21)
  • SalivaDirect and Ubiquitome Deliver Cost-Effective, Mobile SARS-CoV-2 Tests [Link] (06/10/21)
  • Improved diagnosis of SARS-CoV-2 by using Nucleoprotein and Spike protein fragment 2 in quantitative dual ELISA tests [Link] (06/10/21)
  • Thermo Fisher Scientific Launches Ion AmpliSeq SARS-CoV-2 Insight Research Assay for SARS-CoV-2 Surveillance [Link] (06/10/21)
  • Digital CRISPR-based method for the rapid detection and absolute quantification of nucleic acids [Link] (06/10/21)
  • Sub-Picomolar Detection of SARS-CoV-2 RBD via Computationally-Optimized Peptide Beacons [Link] (06/10/21)
  • Diagnostic value of cutaneous manifestation of SARS-CoV-2 infection [Link] (06/10/21)
  • Complementary methods for SARS-CoV-2 diagnosis in times of material shortage [Link] (06/07/21)
  • A Comparison of Four Commercially Available RNA Extraction Kits for Wastewater Surveillance of SARS-CoV-2 in a College Population [Link] (06/07/21)
  • Eurofins Launches a New Multiplex PCR Assay for Rapid Detection of the B.1.617 “India” SARS-CoV-2 Variant [Link] (06/07/21)
  • Whole blood-based measurement of SARS-CoV-2-specific T cell responses reveals asymptomatic infection and vaccine efficacy in healthy subjects and patients with solid organ cancers [Link] (06/07/21)
  • Covid-19 diagnosis by combining RT-PCR and pseudo-convolutional machines to characterize virus sequences [Link] (06/07/21)
  • Performance of Self-Collected Saliva Testing Compared with Nasopharyngeal Swab Testing for the Detection of SARS-CoV-2 [Link] (06/07/21)
  • Real-time, selective, and low-cost detection of trace level SARS-CoV-2 spike-protein for cold-chain food quarantine [Link] (06/02/21)
  • Negative antigen RDT and RT-PCR results do not rule out COVID-19 if clinical suspicion is strong [Link] (06/02/21)
  • IDSA Guidelines on the Diagnosis of COVID-19: Antigen Testing [Link] (06/02/21)
  • Multiplexed Detection of COVID-19 with Single-Molecule Technology [Link] (06/02/21)

SELECT COVID-19 DIAGNOSTIC KITS/ASSAYS ARE HIGHLIGHTED BELOW.

ANTIGEN TESTS:

TYPE: Antigen Test

TECHNOLOGY: Lateral flow tests (LFTs)

TARGET: Nucleocapsid protein

TIME: 15 min

BRIEF DESCRIPTION: Rapid, portable Ag test with complementary phone app that can be used for mass testing

SENSITIVITY (PPA): 84.6%

SPECIFICITY (NPA): 98.5%

SAMPLES FOR PPA & NPA: PPA = 117 patients; NPA= 343 patients

LIMIT OF DETECTION (LoD): 140.6 TCID50/mL

DETAILS: The BinaxNOW COVID-19 Ag Card is an assay for the qualitative detection of specific antigens to COVID-19 in the human nasal cavity. A simple nasal swab is used to collect specimens from people suspected of having an active infection. No equipment is required to process samples or read test results. BinaxNOW uses proven Abbott lateral flow technology, making it a reliable and familiar format for frequent mass testing through their healthcare provider. BinaxNOW COVID-19 Ag Card is for use by healthcare professionals and can be used in point-of-care settings that are qualified to have the test performed and are operating under a CLIA (Clinical Laboratory Improvement Amendments) Certificate.

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TEST CLASSIFICATION: Ag; PoC

TYPE: Antigen Test

TECHNOLOGY: Chromatographic immunoassay

TARGET: Nucleocapsid protein

TIME: 15 min

BRIEF DESCRIPTION: Portable chromatographic immunoassay for the direct and qualitative detection of SARS-CoV-2 antigens in nasal swabs from patients with signs and symptoms who are suspected of COVID-19

SENSITIVITY (PPA): 84%

SPECIFICITY (NPA): 100%

SAMPLES FOR PPA & NPA: PPA = 31 direct nasal swabs; NPA= 195 swabs

LIMIT OF DETECTION (LoD): 140 TCID50/mL

DETAILS: The BD Veritor System for Rapid Detection of SARS-CoV-2 is a rapid (approximately 15 minutes) chromatographic digital immunoassay for the direct detection of the presence or absence of SARS-CoV-2 antigens in respiratory specimens taken from patients with signs and symptoms who are suspected of COVID-19, or taken from asymptomatic individuals and is designed to detect the presence or absence of SARS-CoV-2 nucleocapsid proteins. The test is intended for interpretation in both laboratory and near patient testing environments only with the BD Veritor Plus Analyzer Instrument.

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TEST CLASSIFICATION: Ag, PoC; Instrumented Read

TYPE: Antigen Test

TECHNOLOGY: Lateral flow immunoassay

TARGET: Nucleocapsid protein

TIME: 15 min

BRIEF DESCRIPTION: Over the counter at home qualitative detection of SARS-CoV-2 nucleocapsid antigens

SENSITIVITY (PPA): 95%

SPECIFICITY (NPA): 97%

SAMPLES FOR PPA & NPA: PPA = 37 samples; NPA= 161 samples

LIMIT OF DETECTION (LoD): 6310 TCID50/ml

DETAILS: The Ellume COVID-19 Home Test respectively is the first FDA EUA authorized non-prescription fully at-home COVID-19 detecting test that can be completely performed at home with the patient to detect or follow up on the infection. This test employs fluorescent LFIA for the detection of N antigen of SARS-CoV-2 and requires a smartphone as the readout instrument to report the results

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TEST CLASSIFICATION: At-home test

TYPE: Antigen Test

TECHNOLOGY: High Throughput FMIA

TARGET: Spike; Nucleocapsid

TIME: 96 samples in < 3h

BRIEF DESCRIPTION: Test is a multiplex, microsphere-based, highly sensitive and specific assay that detects the presence or absence of antibodies against three different SARS‑CoV‑2 antigens.

SENSITIVITY (PPA): 96.2%

SPECIFICITY (NPA): 99.2%

SAMPLES FOR PPA & NPA: PPA = 96.2% (53 serum samples, 14 days) & 96.6% (29 Plasma samples, 14 days); NPA= 99.2 % (182 plasma samples) & 100% (419 serum samples)

LIMIT OF DETECTION (LoD):

DETAILS: The xMAP SARS-CoV-2 Multi-Antigen IgG Assay is a multiplex, microsphere-based assay intended for qualitative detection of IgG antibodies to SARS-CoV-2 in human serum and plasma (dipotassium EDTA). The xMAP SARS-CoV-2 Multi-Antigen IgG Assay is intended for use as an aid in identifying individuals with an adaptive immune response to SARS-CoV-2, indicating recent or prior infection. It detects IgG antibodies against 3 SARS‑CoV‑2 antigens, providing comprehensive results: S1 subunit of the spike protein; Receptor binding domain (RBD) of the spike protein; Nucleocapsid protein.

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TEST CLASSIFICATION: Serology; Immunoanalyzer; ELISA

TYPE: Antigen Test

TECHNOLOGY: Microfluidic immunofluorescence assay

TARGET: Nucleocapsid protein antigen

TIME: 12 min

BRIEF DESCRIPTION: Test is a microfluidic immunofluorescence assay for the direct and qualitative detection for rapid results at the point of care

SENSITIVITY (PPA): 97.6%

SPECIFICITY (NPA): 96.6%

SAMPLES FOR PPA & NPA: PPA = 83 NPS; NPA= 174 NPS

LIMIT OF DETECTION (LoD): 32 TCID50/mL.

DETAILS: The LumiraDx SARS-CoV-2 Ag Test is a microfluidic immunofluorescence assay for the direct and qualitative detection of nucleocapsid protein antigen in nasal and nasopharyngeal swab specimens from individuals suspected of COVID-19 or asymptomatic individuals. Used with the LumiraDx Platform the test delivers rapid results at the point of care.

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TEST CLASSIFICATION: Ag, PoC; Instrumented Read

TYPE: Antigen Test

TECHNOLOGY: Chemiluminescent immunoassay

TARGET: Nucleocapsid protein

TIME: 48 min (130 tests per hour)

BRIEF DESCRIPTION: Low-cost, high throughput testing for asymptomatic detection

SENSITIVITY (PPA): 86.2%

SPECIFICITY (NPA): 97.7%

SAMPLES FOR PPA & NPA: PPA = 65 NPS; NPA= 87 NPS

LIMIT OF DETECTION (LoD): 500 TCID50/mL CDC VTM

DETAILS: The VITROS Immunodiagnostic Products SARS-CoV-2 Antigen Reagent Pack, when used in combination with the VITROS Immunodiagnostic Products SARS-CoV-2 Antigen Calibrator, is a chemiluminescent immunoassay intended for the qualitative detection of SARS-CoV-2 nucleocapsid protein antigens in nasopharyngeal (NP) and anterior nasal swab.

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TEST CLASSIFICATION: Ag, PoC; Instrumented Read

TYPE: Antigen Test

TECHNOLOGY: Paramagnetic microbead-based immunoassay

TARGET: Nucleocapsid protein

TIME: 80 min

BRIEF DESCRIPTION: Immunoassay for the qualitative detection of the nucleocapsid protein (N protein) antigen

SENSITIVITY (PPA): 97.5%

SPECIFICITY (NPA): 100%

SAMPLES FOR PPA & NPA: PPA = 135 serum & plasma samples; NPA= 100 serum & plasma samples, 7 days post onset, Cross-reaction with SARS-CoV

LIMIT OF DETECTION (LoD): 0.31 TCID50/mL (NPS)

DETAILS: The Simoa SARS-CoV-2 N Protein Antigen Test is an automated paramagnetic microbead-based immunoassay intended for the qualitative detection of the nucleocapsid protein (N protein) antigen from SARS-CoV-2 in nasopharyngeal swab specimens collected in Huachenyang iClean Viral Transport Medium (VTM), CDC’s formulation of VTM, normal saline, or phosphate buffered saline (PBS) from individuals who are suspected of COVID-19 by their healthcare provider within 14 days of symptom onset.

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TEST CLASSIFICATION: Ag, PoC; Instrumented Read

TYPE: Antigen Test

TECHNOLOGY: Immunofluorescence-based LFT

TARGET: Nucleocapsid protein antigen

TIME: 15-20 min

BRIEF DESCRIPTION: The Sofia SARS Antigen Fluorescent Immunoassay (FIA) provides automated and objective results in 15 minutes, allowing for testing of patients suspected of COVID-19

SENSITIVITY (PPA): 96.7%

SPECIFICITY (NPA): 100%

SAMPLES FOR PPA & NPA: PPA = 30 samples; NPA= 179 samples (direct anterior nasal swabs)

LIMIT OF DETECTION (LoD): 113 TCID50/mL

DETAILS: The Sofia SARS Antigen Fluorescent Immunoassay (FIA) uses advanced immunofluorescence-based lateral flow technology in a sandwich design for qualitative detection of nucleocapsid protein from SARS-CoV-2. The Sofia SARS Antigen FIA, with the Sofia 2 and Sofia analyzers, provides automated and objective results in 15 minutes, allowing for testing of patients suspected of COVID-19/2019-nCoV in near-patient testing environments.

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TEST CLASSIFICATION: Ag, PoC; Instrumented Read

TYPE: Antigen Test

TECHNOLOGY: Lateral flow immunoassay

TARGET: Nucleocapsid protein antigen

TIME: 10 min

BRIEF DESCRIPTION: Rapid, portable, instrument free Ag test can be used for mass testing

SENSITIVITY (PPA): 96.6%

SPECIFICITY (NPA): 99.3%

SAMPLES FOR PPA & NPA: PPA = 57 samples; NPA= 137 samples

LIMIT OF DETECTION (LoD): 7570 TCID50

DETAILS: The QuickVue SARS Antigen Test detects SARS-CoV-2 antigens directly from anterior nares swab specimens. The QuickVue SARS Antigen Test provides accurate and reliable results in 10 minutes, allowing for testing of patients suspected of COVID-19/2019-nCoV in near-patient testing environments.

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TEST CLASSIFICATION: Ag, PoC; Instrument Free; Prescription & OTC

TYPE: Antigen Test

TECHNOLOGY: FIA (LF immunofluorescent sandwich assay)

TARGET: Nucleocapsid protein

TIME: 15 min

BRIEF DESCRIPTION: Sofia 2 Flu + SARS Antigen FIA is an automated test reporting the results of influenza A, influenza B and COVID-19 in a POC setting in 15 min.

SENSITIVITY (PPA): 95.2%

SPECIFICITY (NPA): 100%

SAMPLES FOR PPA & NPA: PPA = 42 NPS; NPA= 122 NPS

LIMIT OF DETECTION (LoD): 91.7 copies/mL

DETAILS: The Sofia 2 Flu + SARS Antigen FIA employs immunofluorescence technology in a sandwich design that is used with Sofia 2. Sofia 2 Flu + SARS Antigen FIA is intended for the simultaneous qualitative detection and differentiation of the nucleocapsid protein antigens from SARS-CoV-2, influenza A and influenza B in direct nasopharyngeal (NP) and nasal (NS) swab specimens from individuals suspected of respiratory viral infection

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TEST CLASSIFICATION: Ag, PoC; Instrumented Read; Multi-Analyte

MOLECULAR TESTS:

TYPE: Molecular

TECHNOLOGY: Isothermal nucleic acid amplification

TARGET: RdRp Gene

TIME: 5 min (13 min negative)

BRIEF DESCRIPTION: The ID NOW COVID-19 rapid test delivers high-quality molecular positive results in as little as 5 minutes, targeting the coronavirus (COVID-19) RdRp Gene.

SENSITIVITY (PPA): 94.7%

SPECIFICITY (NPA): 98.6%

SAMPLES FOR PPA & NPA: PPA = 29 subjects; NPA= 227 subjects; NPA= Mean 4.1 days days from onset

LIMIT OF DETECTION (LoD): 125 copies/mL

DETAILS: Qualitative detection of nucleic acid from the SARS-CoV-2 virus in direct nasal, nasopharyngeal or throat swabs from individuals who are suspected of COVID-19 by their healthcare provider within the first seven days of the onset of symptoms.

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TEST CLASSIFICATION: PoC; Rapid; No nucleic acid purification

TYPE: Real-time RT-PCR

TECHNOLOGY: Real-time RT-PCR

TARGET: Spike protein

TIME: < 115 min time to first results (12 results), 12 more results 16 min thereafter

BRIEF DESCRIPTION: The Alinity m SARS-CoV-2 assay is a real-time reverse transcriptase (RT) polymerase chain reaction (PCR) test intended for the qualitative detection

SENSITIVITY (PPA): 100%

SPECIFICITY (NPA): 100%

SAMPLES FOR PPA & NPA: PPA = 40 NPS; NPA= 31 NPS

LIMIT OF DETECTION (LoD): 100 copies/mL

DETAILS: The Alinity m SARS-CoV-2 assay is a real-time reverse transcriptase (RT) polymerase chain reaction (PCR) test intended for the qualitative detection of nucleic acid from SARS-CoV-2 in nasal, nasopharyngeal (NP) and oropharyngeal (OP) swabs, and bronchoalveolar lavage (BAL) specimens collected from individuals suspected of COVID-19 by their healthcare provider (HCP), as well as nasal, NP and OP swabs collected from any individual, including individuals without symptoms or other reasons to suspect COVID-19 infection. This test is also for the qualitative detection of nucleic acid from the SARS-CoV-2 in pooled samples containing up to 5 individual upper respiratory specimens

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TEST CLASSIFICATION: High throughput systems; Fully instrumented; Reference labs/hospitals

TYPE: Molecular

TECHNOLOGY: RT-PCR + Microarray

TARGET: ORF1ab, N1, and N2 genes

TIME: NA

BRIEF DESCRIPTION: This assay combines RT-PCR and microarray technologies to target SAES-CoV-2 ORF1ab, N1, and N2 genes

SENSITIVITY (PPA): 100%

SPECIFICITY (NPA): 93.33%

SAMPLES FOR PPA & NPA: PPA = 30 NPS; NPA= 30 NPS

LIMIT OF DETECTION (LoD): 250 and 1000 copies/mL (Zymo and Qiagen extraction)

DETAILS: The Alimetrix SARS-CoV-2 RT-PCR Assay is a reverse transcription polymerase chain reaction (RT-PCR) test with microarray detection intended for the qualitative detection of nucleic acid from SARS-CoV-2 in nasopharyngeal, oropharyngeal, anterior nasal and mid-turbinate nasal swab specimens, as well as nasopharyngeal washes/aspirates or nasal aspirates and bronchoalveolar lavage (BALs) specimens from individuals suspected of COVID-19 by their healthcare provider.

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TEST CLASSIFICATION: DNA Microarray

TYPE: Real-time RT-PCR

TECHNOLOGY: Real-time RT-PCR, Nested multiplex PCR

TARGET: Spike protein (S) gene; Membrane protein (M) gene

TIME: 45 min

BRIEF DESCRIPTION: The BioFire RP2.1-EZ Panel (EUA) is a syndromic test with the ability to identify 15 viral and 4 bacterial respiratory pathogens. As the name implies, it’s easy and takes just one nasopharyngeal swab and two minutes of hands-on time, with results in about 45 minutes.

SENSITIVITY (PPA): 98%

SPECIFICITY (NPA): 100%

SAMPLES FOR PPA & NPA: PPA = 49 NPS; NPA= 49 NPS

LIMIT OF DETECTION (LoD): 500 copies/mL

DETAILS: BioFire RP2.1-EZ Panel uses a syndromic approach to accurately detect and identify a wide range of pathogens – including SARS-CoV-2 (19 respiratory targets in one multiplex PCR test, with results in about 45 minutes). The BioFire RP2.1-EZ Panel is designed to run on the CLIA-waived BioFire FilmArray  2.0 EZ Configuration System.

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TEST CLASSIFICATION: Multi-Analyte; Respiratory panel; PoC

TYPE: Real-time RT-PCR

TECHNOLOGY: Real-time RT-PCR, Nested multiplex PCR

TARGET: Spike protein (S) gene; Membrane protein (M) gene

TIME: ~45 min

BRIEF DESCRIPTION: BioFire RP2.1 Panel is a frontline test to help clinicians quickly diagnose respiratory infections, including COVID-19, influenza, RSV, and many others (22 Targets, ~45 Minutes)

SENSITIVITY (PPA): 98%

SPECIFICITY (NPA): 100%

SAMPLES FOR PPA & NPA: PPA = 49 NPS; NPA= 49 NPS

LIMIT OF DETECTION (LoD): 300 copies/ml

DETAILS: Fast and comprehensive BioFire RP2.1 Panel offers a run time of about 45 minutes, enabling high efficiency and throughput on the BioFire FilmArray 2.0 and the BioFire FilmArray Torch Systems.

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TEST CLASSIFICATION: Multi-Analyte; Respiratory panel

TYPE: Real-time RT-PCR

TECHNOLOGY: Real-time RT-PCR

TARGET: N2 (nucleocapsid gene) & E (envelope protein gene)

TIME: 25 min

BRIEF DESCRIPTION: Rapid Single PoC Test for SARS-CoV-2, Flu A, Flu B, and RSV

SENSITIVITY (PPA): 97.9%

SPECIFICITY (NPA): 100%

SAMPLES FOR PPA & NPA: PPA = 46 samples; NPA= 194 samples

LIMIT OF DETECTION (LoD): 131 copies/mL

DETAILS: Cepheid has developed an automated molecular test for the qualitative detection of SARS-CoV-2. The test can provide rapid detection of the current coronavirus SARS-CoV-2 in as soon as 25 minutes for positive results and provide results for all four pathogens in just 36 minutes with less than a minute of hands-on time.

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TEST CLASSIFICATION: Multi-Analyte; PoC

TYPE: Real-time RT-PCR

TECHNOLOGY: Real-time RT-PCR

TARGET: ORF1ab; Spike gene

TIME: 1 h

BRIEF DESCRIPTION: The Simplexa COVID-19 Direct kit allows for fast results directly from nasal swab, nasopharyngeal swab, nasal wash/aspirate, and BAL specimens, eliminating traditional RNA extraction steps.

SENSITIVITY (PPA): 100%

SPECIFICITY (NPA): 100%

SAMPLES FOR PPA & NPA: PPA = 100% in 30 Nasal swabs, 52 NPS, 11 BAL and 96.7% in 30 Nasal Wash/Aspirates; NPA= 100% in 30 Nasal swabs, 7 NPS, 56 BAL and 30 Nasal Wash/Aspirates

LIMIT OF DETECTION (LoD): 500 copies/mL (NPS, NW), 242 copies/mL (NS)

DETAILS: The DiaSorin Molecular Simplexa COVID-19 Direct real-time RT-PCR assay is intended for use on the LIAISON  MDX instrument for the in vitro qualitative detection of nucleic acid from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in nasopharyngeal swabs (NPS), nasal swabs (NS), nasal wash/aspirate (NW) or bronchoalveolar lavage (BAL) specimens from individuals suspected of COVID-19 by their healthcare provider.

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TEST CLASSIFICATION: High throughput systems; Fully instrumented; Reference labs/hospitals

TYPE: Molecular

TECHNOLOGY: NGS

TARGET: Detects 98 targets on SARS-CoV-2

TIME: 1536 to 3072 results on the NovaSeq 6000 in 12 h

BRIEF DESCRIPTION: This high-throughput, next-generation sequencing test detects SARS-CoV-2 in patients suspected of COVID-19 and enables virus genome analysis in research use.

SENSITIVITY (PPA): 97.5%

SPECIFICITY (NPA): 97.7%

SAMPLES FOR PPA & NPA: PPA = 40 NPS; NPA= 44 NPS

LIMIT OF DETECTION (LoD): 1000 copies/mL

DETAILS: The Illumina COVIDSeq Test is intended for detection of SARS-CoV-2 virus RNA in authorized countries and virus genome analysis for research use. Insight into the SARS-CoV-2 strain present in the sample enables tracking of virus strains.  This amplicon-based NGS test includes 2019-nCoV primers designed to detect RNA from the SARS-CoV-2 virus in nasopharyngeal, oropharyngeal, and mid-turbinate nasal swabs from patients with signs and symptoms of infection who are suspected of COVID-19. The Illumina COVIDSeq Test can be scaled up or down to accommodate different numbers of samples. 1536 to 3072 results can be processed on the NovaSeq 6000 system in 12 hours using two SP or S4 reagent kits, or 384 results in 12 hours using the NextSeq 2000 or the NextSeq 500/550/550Dx (in RUO mode) HO reagent kit.

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TEST CLASSIFICATION: Sequencing based

TYPE: Real-time RT-PCR

TECHNOLOGY: Real-time RT-PCR

TARGET: Nucleocapsid (N) gene

TIME: 24 h

BRIEF DESCRIPTION: RT-PCR Test to permit testing of samples self-collected by patients at home using LabCorp’s Pixel by LabCorp COVID-19 Test home collection kit.

SENSITIVITY (PPA): 100%

SPECIFICITY (NPA): 100%

SAMPLES FOR PPA & NPA: PPA = 40 NPS/BAL; NPA= 50 NPS/BAL. 98.08 PPA for 624 positive upper respiratory specimens

LIMIT OF DETECTION (LoD): 6.25 copies/uL (NP swabs) and 12.5 copies/uL (BAL)

DETAILS: This test is authorized for qualitative detection of nucleic acid from SARS-CoV-2 in individual anterior nasal swab specimens, in upper and lower respiratory specimens, in pooled samples using a matrix pooling strategy from individuals suspected of COVID-19 by their healthcare provider

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TEST CLASSIFICATION: Self-collection (home collection); Pooling

TYPE: Real-time RT-PCR

TECHNOLOGY: RT-LAMP (Reverse Transcriptase loop-mediated isothermal amplification)

TARGET: Nucleocapsid (N) gene

TIME: 30 min

BRIEF DESCRIPTION: The kit is designed to deliver PCR quality molecular accuracy in 30 minutes or less at home

SENSITIVITY (PPA): 91.7%

SPECIFICITY (NPA): 98.2%

SAMPLES FOR PPA & NPA: PPA = 132 samples; NPA= 272 samples

LIMIT OF DETECTION (LoD): 900 copies/mL

DETAILS: The Lucira CHECK-IT COVID-19 Test Kit is a molecular diagnostic test for the qualitative detection of nucleic acid from SARS-CoV-2 in anterior nasal (nasal) swab specimens. The Lucira CHECK-IT COVID-19 Test Kit is intended for use in individuals aged 14 and older (self-collected) or individuals ≥2 years (collected by an adult) with or without symptoms or other epidemiological reasons to suspect COVID-19. It is authorized for nonprescription home use. LUCIRA CHECK IT COVID-19 test kit is now available on Amazon.com in the US. Each LUCIRA CHECK IT test kit provides a PCR quality test result at home in 30 minutes or less. After testing, users can also receive a free, text based digital LUCI PASS verified test result on their phone for work or travel. The product costs $55 and includes free standard shipping.

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TEST CLASSIFICATION: At-home test; without nucleic acid purification

TYPE: Molecular

TECHNOLOGY: RT-LAMP + CRISPR/Cas12

TARGET: N2 (nucleocapsid gene) & E (envelope protein gene)

TIME: 30-40 min

BRIEF DESCRIPTION: Rapid (<40 min), easy-to-implement and accurate CRISPR–Cas12-based lateral flow assay for detection of SARS-CoV-2 from respiratory swab RNA extracts.

SENSITIVITY (PPA): 95%

SPECIFICITY (NPA): 100%

SAMPLES FOR PPA & NPA: PPA = 40 NPS; NPA= 62 NPS

LIMIT OF DETECTION (LoD): 20-30 copies/µL

DETAILS: CRISPR-based SARS-CoV-2 DNA Endonuclease-Targeted CRISPR Trans Reporter (DETECTR) assay is a rapid (<40 min), easy-to-implement and accurate CRISPR–Cas12-based lateral flow assay for detection of SARS-CoV-2 from respiratory swab RNA extracts. This assay performs simultaneous reverse transcription and isothermal amplification using loop-mediated amplification (RT–LAMP) for RNA extracted from nasopharyngeal or oropharyngeal swabs in universal transport medium (UTM), followed by Cas12 detection of predefined coronavirus sequences, after which cleavage of a reporter molecule confirms detection of the virus.

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TEST CLASSIFICATION: CRISPR/Cas

TYPE: Molecular

TECHNOLOGY: PCR (OSCillating Amplification Reaction)

TARGET: Nucleocapsid (N) gene

TIME: 30 min

BRIEF DESCRIPTION: Easy and fast, qualitative, rapid PCR-based test provides visual results within ~ 30 minutes.

SENSITIVITY (PPA): 95.8%

SPECIFICITY (NPA): 100%

SAMPLES FOR PPA & NPA: PPA = 24 nasal swabs; NPA= 26 nasal swabs (retrospective study). 100% NPA & 100% PPA in clinical study with 48 & 4 pediatric nasal swabs

LIMIT OF DETECTION (LoD): 150 copies/ml

DETAILS: The Accula SARS-CoV-2 Test, which has received an Emergency Use Authorization (EUA) from the U.S Food and Drug Administration (FDA), is performed on the Accula Dock or the Silaris Dock and is a molecular in vitro diagnostic test utilizing polymerase chain reaction (PCR) and lateral flow technologies for the qualitative, visual detection of the coronavirus SARS-CoV-2 viral RNA.

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TEST CLASSIFICATION: PoC; No nucleic acid purification

TYPE: Real-time RT-PCR

TECHNOLOGY: Real-time RT-PCR

TARGET: Nucleocapsid gene (N1 & N3)

TIME: 1 h

BRIEF DESCRIPTION: Qualitative Real-Time RT-PCR aids in the detection of SARS-CoV-2 RNA and diagnosis COVID-19 and is a real-time reverse transcription polymerase chain reaction test.

SENSITIVITY (PPA): 100%

SPECIFICITY (NPA): 100%

SAMPLES FOR PPA & NPA: PPA = 30 NP/OP samples; NPA= 30 NP/OP samples

LIMIT OF DETECTION (LoD): 136 copies/mL

DETAILS: The Quest Diagnostics SARS-CoV-2 RNA, Qualitative Real-Time RT-PCR (“Quest SARS-CoV-2 rRT-PCR”) is a real-time RT-PCR test intended for the qualitative detection of nucleic acid from the SARS-CoV-2 in upper and lower respiratory specimens (such as nasopharyngeal or oropharyngeal swabs, sputum, tracheal aspirates, and bronchoalveolar lavage) collected from individuals suspected of COVID-19 by their healthcare provider. This test is also for use with nasal swab specimens that are self-collected at home or in a healthcare setting by individuals using an authorized home-collection kit when determined to be appropriate by a healthcare provider. This test is for the qualitative detection of nucleic acid from the SARS-CoV-2 in pooled samples containing up to four of the individual upper respiratory swab specimens.

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TEST CLASSIFICATION: High throughput systems; Fully instrumented; Reference labs/hospitals

TYPE: Molecular

TECHNOLOGY: Real-time RT-PCR

TARGET: ORF1 a/b non-structural region; Nucleocapsid protein gene

TIME: 20 min

BRIEF DESCRIPTION: Test that detects and differentiates SARS-CoV-2, influenza A and influenza B from a single nasal sample and in just one test.

SENSITIVITY (PPA): 100%

SPECIFICITY (NPA): 100%

SAMPLES FOR PPA & NPA: PPA = 56 NPS; NPA= 229 NPS

LIMIT OF DETECTION (LoD): 0.0079 [Live] & 0.12 [Inactivated] TCID50/mL

DETAILS: The cobas SARS-CoV-2 & Influenza A/B Nucleic acid test for use on the cobas Liat System is a multiplex real-time polymerase chain reaction (PCR) test that detects and differentiates SARS-CoV-2, influenza A and influenza B in 20 minutes from a single nasal sample and in just one test.

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TEST CLASSIFICATION: PoC; Rapid; Multi-Analyte

TYPE: Molecular

TECHNOLOGY: RT-LAMP + CRISPR/Cas

TARGET: Nucleocapsid gene; ORF1ab gene

TIME: 1 h

BRIEF DESCRIPTION: The Sherlock CRISPR SARS-CoV-2 kit is the first FDA authorized CRISPR-based EUA diagnostic test.

SENSITIVITY (PPA): 100%

SPECIFICITY (NPA): 100%

SAMPLES FOR PPA & NPA: PPA = 30 NP samples; NPA= 30 NP samples

LIMIT OF DETECTION (LoD): 6.75 copies/µL VTM (ORF1ab) &  1.35 copies/µL VTM (N)

DETAILS: The Sherlock CRISPR SARS-CoV-2 kit is the first EUA CRISPR based diagnostic test intended for the qualitative detection of nucleic acid from SARS-CoV-2. This kit provides specific and sensitive detection of the SARS-CoV-2 virus in upper respiratory tract and bronchoalveolar lavage specimens from individuals suspected of COVID-19 by their healthcare provider. Step one is RT-LAMP where targeted SARS-CoV-2 genomic RNA is reverse transcribed to DNA then amplified by a strand-displacing DNA polymerase. Step two transcribes the amplified DNA to activate collateral cleavage activity of a CRISPR complex programmed to the target RNA sequence.

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TEST CLASSIFICATION: PoC; CRISPR/Cas

TYPE: Molecular

TECHNOLOGY: Real-time RT-PCR

TARGET: Nucleocapsid gene (N1 region)

TIME: ~2h

BRIEF DESCRIPTION: This assay is a RNA-extraction free, dualplex RT-qPCR method for SARS-CoV-2 detection and is authorized for use with the SalivaDirect At-Home Collection Kit

SENSITIVITY (PPA): 94.6%

SPECIFICITY (NPA): 100%

SAMPLES FOR PPA & NPA: PPA = 37 saliva specimens; NPA= 30 saliva specimens

LIMIT OF DETECTION (LoD): 6000 copies/mL

DETAILS: SalivaDirect is a real-time reverse transcription polymerase chain reaction (rRT-PCR) test intended for the qualitative detection of nucleic acid from SARS-CoV-2 in saliva collected without preservatives in a sterile container in the presence of a trained observer (adult trained on how to collect saliva samples) from individuals suspected of COVID-19 by their healthcare provider. This test is also for use with saliva specimens that are self-collected by individuals 18 years of age or older unsupervised at home, and dropped off at a collection site, using the SalivaDirect Unsupervised Collection Kit.

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TEST CLASSIFICATION: At-home collection; Saliva testing; Extraction-free; Pooling

SEROLOGY TESTS:

TYPE: Immunoassay (IgG)

TECHNOLOGY: High Throughput CLIA

TARGET: Spike protein

TIME: 25 min

BRIEF DESCRIPTION: Semi-quantitative assay that measures patient’s relative level of antibodies

SENSITIVITY (PPA): 100%

SPECIFICITY (NPA): 99.6%

SAMPLES FOR PPA & NPA: PPA = 192 samples (18 days after PCR); NPA=1400 samples

LIMIT OF DETECTION (LoD): 2.0 AU/mL

DETAILS: The Access SARS-CoV-2 IgG Assay is a qualitative immunoassay that detects IgG antibodies directed to the receptor binding domain of the spike protein. The assay uses immobilized virus antigens on magnetic particles to capture IgG antibodies from patient blood or serum samples and reveals them using labeled anti-IgG antibodies.

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TEST CLASSIFICATION: Serology; High performance

TYPE: Immunoassay (Pan-Ig)

TECHNOLOGY: Enzyme Immunoassay (EIA)

TARGET: Nucleocapsid protein

TIME: 120 min

BRIEF DESCRIPTION: Blood-based immunoassay for rapid, detection of IgM, IgA and IgG in one test

SENSITIVITY (PPA): 98%

SPECIFICITY (NPA): 99.3%

SAMPLES FOR PPA & NPA: PPA = 50 patients; NPA= 600 (up to 8 days after symptom onset, 100% after)

LIMIT OF DETECTION (LoD): 0.8 for Specimen OD / CutOff control OD

DETAILS: This assay will help to determine those who have been exposed to the SARS-CoV-2 and who have developed an immune response. In areas with low prevalence of COVID-19, a highly specific test is essential for COVID-19 surveillance and epidemiological applications.

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TEST CLASSIFICATION: Serology; Immunoanalyzer; ELISA

TYPE: Immunoassay (IgG/IgM)

TECHNOLOGY: Lateral flow immunoassay

TARGET: Spike; Nucleocapsid

TIME: 15-20 min

BRIEF DESCRIPTION: Antibody Rapid Test, is for the qualitative detection and differentiation of IgM and IgG antibodies in serum, plasma, or whole blood from individuals suspected of COVID-19

SENSITIVITY (PPA): 93.8%

SPECIFICITY (NPA): 96%

SAMPLES FOR PPA & NPA: PPA = 250 serum or plasma samples; NPA= 128 serum or plasma samples

LIMIT OF DETECTION (LoD):

DETAILS: The Cellex qSARS-CoV-2 IgG/IgM Rapid Test is a lateral flow chromatographic immunoassay which can detect antibodies against the SARS-CoV-2 virus. The test cassette consists of: 1) a burgundy colored conjugate pad containing SARS-CoV-2 recombinant antigens (S and N proteins) conjugated with colloidal gold (SARS-CoV-2 conjugates) and rabbit IgG-gold conjugates; 2) a nitrocellulose membrane strip containing an IgG line (G Line) coated with anti-human IgG, an IgM line (M Line) coated with anti-human IgM, and the control line (C Line) coated with goat anti-rabbit IgG.

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TEST CLASSIFICATION: Quantitative LF; Low performance

TYPE: Immunoassay (IgG)

TECHNOLOGY: High Throughput CMIA

TARGET: Spike (S1 & S2)

TIME: 35 min (170 results/hour)

BRIEF DESCRIPTION: Fully automated quantitative solution for the detection of IgG antibodies against S1/S2 antigens of SARS-CoV-2

SENSITIVITY (PPA): 97.4%

SPECIFICITY (NPA): 98.5%

SAMPLES FOR PPA & NPA: PPA = 39 samples (>15 days); NPA= 1000 samples

LIMIT OF DETECTION (LoD): 12 AU/mL

DETAILS: The LIAISON SARS-CoV-2 S1/S2 IgG is a chemiluminescent immunoassay (CLIA) intended for the qualitative detection of IgG antibodies to SARS-CoV-2 in human serum, and plasma (sodium heparin, lithium heparin, and potassium EDTA) from individuals with current or prior COVID-19 infection. It is a fully automated qualitative solution for the detection of IgG antibodies against S1/S2 antigens of SARS-CoV-2. Random access with up to 170 results/hour on LIAISON XL and 35 minutes to first result.

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TEST CLASSIFICATION: High throughput systems; Fully instrumented; PoC

TYPE: Immunoassay (IgG)

TECHNOLOGY: 2-Step ELISA

TARGET: Spike protein

TIME: < 1h

BRIEF DESCRIPTION: Two serial direct Enzyme-Linked Immunosorbent Assays (ELISA) for the qualitative detection of human IgG antibodies in serum and plasma specimens

SENSITIVITY (PPA): 92.5%

SPECIFICITY (NPA): 100%

SAMPLES FOR PPA & NPA: PPA = 37 samples; NPA= 74 samples (21 days)

LIMIT OF DETECTION (LoD): 0.15 at OD490

DETAILS: The COVID-19 ELISA IgG Antibody Test consists of two serial direct Enzyme-Linked Immunosorbent Assays (ELISA) for the qualitative detection of human IgG antibodies in serum and plasma specimens collected from individuals suspected of prior infection with the virus that causes COVID-19.

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TEST CLASSIFICATION: Serology; Immunoanalyzer; ELISA (lab developed)

TYPE: Immunoassay (IgG)

TECHNOLOGY: High Throughput CLIA

TARGET: Spike protein

TIME: 48 min

BRIEF DESCRIPTION: Test qualitatively measures total (ALL) antibodies to the SARS-CoV-2 virus (IgG, IgM, IgA and other isotypes)

SENSITIVITY (PPA): 90%

SPECIFICITY (NPA): 100%

SAMPLES FOR PPA & NPA: PPA = 36 samples; NPA= 407 samples

LIMIT OF DETECTION (LoD):

DETAILS: VITROS Anti-SARS-COV-2 Total test qualitatively measures total (ALL) antibodies to the SARS-CoV-2 virus (IgG, IgM, IgA and other isotypes) and therefore has the widest clinical utility to measure immune response. This antibody test can be used to aid in the diagnosis of acute or past infection in conjunction with other laboratory tests and or clinical information. In addition, this test may be used in population surveillance for viral exposure.

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TEST CLASSIFICATION: Serology; High performance

TYPE: Immunoassay (Pan-Ig)

TECHNOLOGY: High Throughput ECLIA

TARGET: Nucleocapsid protein

TIME: 18 min, 300 tests per hour

BRIEF DESCRIPTION: Immunoassay for the in-vitro qualitative detection of antibodies (including IgG) in human serum and plasma.

SENSITIVITY (PPA): 99.5%

SPECIFICITY (NPA): 99.8%

SAMPLES FOR PPA & NPA: PPA = 185 samples (14+ days); NPA= 10453 samples

LIMIT OF DETECTION (LoD): 0.35 U/mL

DETAILS: The test is an immunoassay for the in-vitro qualitative detection of antibodies (including IgG) in human serum and plasma. The high specificity of the test is crucial to determine reliably if a person has been exposed to the virus and if the patient has developed antibodies

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TEST CLASSIFICATION: Serology; High performance

TYPE: Immunoassay (Pan-Ig)

TECHNOLOGY: High Throughput ELISA

TARGET: Spike protein

TIME: 10 min

BRIEF DESCRIPTION: Rapid testing for IgM and longer-lasting IgG antibodies, can be used with a full range of Siemens Healthineers systems

SENSITIVITY (PPA): 100%

SPECIFICITY (NPA): 99.8%

SAMPLES FOR PPA & NPA: PPA = 79 (14 or more days from onset); NPA= 1529

LIMIT OF DETECTION (LoD): 1000 QUAL units

DETAILS: The COV2T assay detects both IgM and longer-lasting IgG antibodies with high sensitivity of recent and prior infection. This allows for identification of patients who have developed an adaptive immune response, which indicates recent infection or prior exposure.

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TEST CLASSIFICATION: Serology; High performance

TYPE: Immunoassay (Pan-Ig)

TECHNOLOGY: ELISA

TARGET: Spike protein

TIME:

BRIEF DESCRIPTION: Total Antibody ELISA test is designed for total antibody detection, thus capturing the body’s production of IgA, IgM, and IgG all in one well.

SENSITIVITY (PPA): 100%

SPECIFICITY (NPA): 100%

SAMPLES FOR PPA & NPA: PPA = 27 patients; NPA= 162 NPS (15 or more days after symptom onset)

LIMIT OF DETECTION (LoD):

DETAILS: The OmniPATH COVID-19 Total Antibody ELISA test is designed for total antibody detection, thus capturing the body’s production of IgA, IgM, and IgG all in one well.1 By measuring for isotypes produced throughout the entire cycle of infection, from acute to recovered, the test can detect immunological response to SARS-CoV-2 within the first eight days of symptom onset in some patients, reaching 100% sensitivity by 15 days after symptom onset.

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TEST CLASSIFICATION: Serology; Immunoanalyzer; ELISA

Updated: 14 June, 2021.

Following is the list of all SARS-CoV-2 tests commercially available or in development for the diagnosis of COVID-19 collated by the Foundation for Innovative New Diagnostics (FIND), which is information directly submitted by test suppliers or obtained from publicly available sources.

An Overview of Coronavirus (COVID-19) Vaccine Candidates

Over the past 18 years, Severe Acute Respiratory Syndrome (SARS), Middle East Respiratory Syndrome (MERS), and now COVID-19 (SARS-CoV-2) have caused unimaginable distress, mortality, morbidity, social disturbances, and economic disruptions [1]. To mitigate the consequences of COVID-19 and to protect from future pandemics, vaccines are urgently needed. Since the pandemic started, scientists worldwide have been evaluating different approaches at unprecedented speed with novel paradigms and accelerated development to trigger the immune system to produce effective neutralizing antibodies and enough T-cells that can fight COVID-19, in hopes of inducing the kind of responses that maybe associated with protection and minimal adverse events. The World Health Organization (WHO) maintains a working document that includes most of the vaccines in development.

As of May 13, 2021, there were 100 candidate vaccines in clinical testing and 184 candidate vaccines in preclinical evaluation as per the continually updated published draft vaccine landscape by WHO [2] (Figure1).

Figure 1: Vaccine development data from WHO [2].

Figure 2 shows at least eight different approaches that have been explored for the development of a vaccine. Most of the platforms aim to induce neutralizing antibodies against the SARS-CoV-2 Spike protein (S). These antibodies are expected to prevent uptake through the human ACE-2 receptor, thereby limiting viral entrance. The platforms include Whole virus vaccines (Weakened or Inactivated form), Viral-vector vaccines (Replicating or Non-replicating), Genetic forms (RNA, DNA), Protein-based vaccines (Subunit or Virus-like Particles).

Figure 2. An overview of different approaches to vaccine development. Image for illustration purpose only.

The first candidates to enter Phase 3 clinical trials were developed using the nucleic acid platforms, non-replicating viral vectored platforms, inactivated virus, or recombinant subunit vaccines. These are known to be faster development platforms (Ebola, HepB). The traditional strategies that use platforms like attenuated virus need more time but are historically more successful (Oral Polio, Yellow fever, Chickenpox, Mumps) [3].

As per the WHO data [2], the candidates in clinical phase as well as the in preclinical stages are visualized based on the platform technology used for their development as seen in Figure 3.

Figure 3: Visualization of candidates in various phases based on the platform technology used for their development.

Vaccine Development Timelines

Steps and timelines for traditional and pandemic vaccine development are shown in Figure 4. The traditional vaccine testing process begins with the Preclinical trials (in labs, and then in animals if it shows potential) followed by  the Phase 1 safety trials (20-100 healthy volunteers), the expanded Phase 2 trials (several hundred enrolled for observing common short-term side effects and dosing responses), and then Phase 3 efficacy trials (hundreds or thousands of volunteers). Vaccinated people are compared with people who have received a placebo or another vaccine so researchers can learn more about the test vaccine’s safety and effectiveness and identify common side effects.  Once a vaccine is successfully passed these requirements, the approval process is followed [4, 5]. A decade or longer is more typical for the completion of a successful candidate.

However, in a pandemic situation, a vaccine may receive Emergency Use Authorization (EUA) before getting any kind of formal approval, Phases II and III may be combined to shorten the time for development, and the Human challenge trials (controlled human infection model) can be skipped. The current speed with which vaccines are being developed is remarkable, from the first deciphering of the SARS-CoV-2 genome published on 11 January 2020 through Phase III trials in 6 months, as compared with a typical timeline of 2 to 10 years. It should be noted that several companies had already pursued large scale manufacturing of vaccines before establishing the vaccine safety, efficacy and/or receiving the final regulatory approval.

Figure 4. Timelines for traditional and pandemic models of vaccine development

On February 17, the United Kingdom approved the world’s first COVID-19 human challenge trial. Researchers will expose up to 90 young, healthy people to the virus in order to study how it affects the human body; as of March 25, the first three volunteers have been exposed [6].

As of May 13, 2021, as per the WHO dashboard [2], there were among the 100 clinical stage trials, 23 candidates had already moved into the final stages (4 trials in Phase 4 and 19 trials in Phase 3). In an unprecedented move, the vaccine candidate from CanSino Biologics was approved for limited use on June 25, 2020. Later, on August 11, the vaccine candidate Sputnik V from Gamaleya Research Institute, part of Russia’s Ministry of Health, was conditionally approved before Phase 3 trials. Another candidate from Russia, EpiVacCorona from the Vector Institute was granted regulatory approval. On September 14, the U.A.E. government, following intermediate results from ongoing trials, provided emergency approval for Sinopharm’s vaccine to be used on health care workers as a priority.

Moderna Inc., and the National Institute of Allergy and Infectious Diseases (NIAID) collaborated to produce a candidate that entered clinical trials in just 63 days after the genome sequencing of SARS-CoV-2.  On December 2, 2020, the United Kingdom gave emergency authorization to Pfizer and BioNTech’s vaccine, becoming the first Western country to give such an approval to a coronavirus vaccine.

Several vaccine candidates are now in the final stages of their development, including receiving of approvals as well as Emergency Use Authorization (EUA). Pfizer/BioNTech and Moderna vaccines are already under EUA in the U. S. and people are being vaccinated. The adenovirus vector vaccine from Oxford/AstraZeneca has been now approved by the UK authorities as well as in India and Argentina. Indian authorities also approved the inactivated vaccine Covaxin from Bharat Biotech following a double-bind, randomized, multi-center phase 2 clinical trial and an ongoing phase 3 trial. The Sinopharm candidate has been approved in China, U.A.E., and Bahrain while the Sinovac candidate has been approved for limited use in China, both currently in Phase 3 [7].

The WHO on May 7, 2021, listed the Sinopharm COVID-19 vaccine for emergency use, giving the green light for this vaccine to be rolled out globally. WHO has also listed the Pfizer/BioNTech, Astrazeneca, Janssen and Moderna vaccines for emergency use [8]. On May 10, 2021 the US FDA. expanded the authorization for Pfizer to children as young as 12 [9].

As an example, for development and pace of the process that ensued, a second candidate mRNA platform was the BNT162b2 developed by Pfizer and BioNTech. Four modified mRNA-based (modRNA) vaccine candidates were designed to be administered 3-weeks apart to instruct the immune cells to make several copies of the full-length SARS-CoV-2 Spike (S) protein. After positive preclinical trials for intramuscularly administered doses of one of the candidates, BNT162b2 [10], the Phase 1 trial soon after supported the selection of BNT162b2 for advancement to a pivotal phase 2-3 safety and efficacy evaluation. The BNT162b2 vaccine candidate fully protected the lungs of immunized rhesus macaques from infectious SARS-CoV-2 challenge. In both younger and older adults, the two vaccine candidates elicited similar dose-dependent SARS-CoV-2–neutralizing geometric mean titers, which were similar to or higher than the geometric mean titer of a panel of SARS-CoV-2 convalescent serum samples (ClinicalTrials.gov number, NCT04368728) [11]. The Phase 3 portion of the clinical trial was designed to determine if the BNT162b2 vaccine candidate is safe and effective in preventing COVID-19 disease. This part of the trial began July 27 2020 and a total of 43,548 participants underwent randomization. A two-dose regimen of BNT162b2 conferred 95% protection against Covid-19 in persons 16 years of age or older [12]. On 6 October, BioNTech and Pfizer initiated a rolling submission to European Medicines Agency for the candidate BNT162b2 and plan to work with the EMA’s Committee for Medicinal Products for Human Use (CHMP) to complete the rolling review process to facilitate the final Marketing Authorization Application (MAA) [13]. On December 08, 2020 the FDA released their independent analysis of the clinical trials. They determined that the Comirnaty (BNT162b2) had an efficacy rate of 95%. Soon after, on December 10, 2020 Pfizer announced that the US FDA voted 17 to 4 in support of the FDA granting Emergency Use Authorization (EUA) for the companies’ mRNA vaccine [14].

Table 1 summarizes the most advanced candidates that have successful approvals in several countries and are being used to vaccinate the population in huge numbers.

Table 1. Snapshot of the advanced vaccine candidates (as on May 13, 2021) [ref. 15-34].

*Pricing ($ / $$ / $$$) are comparisons based on some US market reports and may not truly reflect all regions and distributors. The efficacy measures have been derived based on different standards used in respective clinical trials and may not always be comparable.

Repurposed (Pre-existing) Vaccines

Given the imperative for scale and speed, epidemiological investigations have suggested a strong correlation among countries with universal vaccination policies and the severity of COVID-19. Findings suggested that countries with universal vaccination policies against Bacillus Calmette-Guerin  (BCG, Tuberculosis) and/or against MMR (Measles, Mumps and Rubella) showed a significant reduction of mortality and infection rates [35-37]. Authors suggest that such pre-existing vaccines may boost an individual’s immune response, reduce the severity of COVID-19, and alleviate the symptoms associated with COVID-19. Multiple such studies have revealed interesting associations with COVID-19 severity and vaccination coverage in the population [37, 38]. Despite the initiation of clinical trials (NCT04327206; NCT04357028), the WHO does not recommend such re-purposed vaccines until scientific evidence is provided [40]. As cautioned by the WHO and while still in the middle of this pandemic, COVID-19 cases and deaths continue to increase over time in some BCG-using countries (e.g. Brazil, India, and Mexico) [39, 41].

Several laboratories and pharma companies worldwide are in the race to develop effective vaccines against COVID-19 using different platforms, even as leading candidates are being granted emergency approvals. The WHO said vaccination alone would not stop transmission entirely, and preventive health measures such as social distancing, mask-wearing and hand washing must continue [42]. Most of SARS-CoV-2 vaccines under development require a prime-boost regimen. Massive vaccination campaigns would therefore require billions of doses to satisfy global demand, even as pharma companies are scaling up at risk production. Studies are ongoing to define the what the correlates of protection against COVID-19 infection are, including those on exact antibody titers, response duration and waning, responses in children, immunocompromised populations and pregnant women, better routes of administration as well as ability to confer sterilizing immunity. Finally, overcoming vaccine hesitancy is also of prime importance.

There are currently more than 280 vaccine candidates under development, with a number of these already receiving EUAs within less than a year since the first report of a SARS-CoV-2 infection. The durability of the immune response induced by these candidates as well as other aspects of the nature of immune responses that follow will emerge as bigger populations get vaccinated.

Regular updates and details on promising vaccine candidates are outlined in our “Highlights” tab (Dashboard).

Prepared by: Sudheer Krishna. Updated : 13 May 2021.

References

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  41. COVID-19 Dashboard by the Center for Systems Science and Engineering (CSSE) at Johns Hopkins University (JHU). Accessed 12-May-21. Johns Hopkins University and Medicine. https://coronavirus.jhu.edu/map.html
  42. WHO reviewing Seychelles COVID-19 data after fully vaccinated people test positive. 11-May-21. Reuters. https://www.reuters.com/article/ozatp-uk-health-coronavirus-seychelles-idAFKBN2CS1U0-OZATP
  • Novavax COVID-19 Vaccine Demonstrates 90% Overall Efficacy and 100% Protection Against Moderate and Severe Disease in PREVENT-19 Phase 3 Trial [Link] (06/14/21)
  • Safety, Immunogenicity, and Efficacy of a COVID-19 Vaccine (NVX-CoV2373) Co-administered With Seasonal Influenza Vaccines [Link] (06/14/21)
  • Novavax Announces Positive Data from Three Complementary Studies of COVID-19 Beta (B.1.351) Variant Strain Vaccine [Link] (06/14/21)
  • Ocugen Faces Major Slowdown for COVID-19 Vaccine as FDA Recommends BLA [Link] (06/14/21)
  • Moderna Files for Emergency Use Authorization for its COVID-19 Vaccine in Adolescents in the United States [Link] (06/14/21)
  • MigVax’s Subunit Oral COVID-19 Vaccine Preclinical Trial Demonstrates Effectivity as a Booster [Link] (06/14/21)
  • Poor antibody response to BioNTech/Pfizer COVID-19 vaccination in SARS-CoV-2 naïve residents of nursing homes [Link] (06/14/21)
  • Neutralizing antibodies elicited by the Ad26.COV2.S COVID-19 vaccine show reduced activity against 501Y.V2 (B.1.351), despite protection against severe disease by this variant [Link] (06/14/21)
  • Single-dose mRNA vaccine effectiveness against SARS-CoV-2, including P.1 and B.1.1.7 variants: a test-negative design in adults 70 years and older in British Columbia, Canada [Link] (06/14/21)
  • Immunogenicity and In vivo protection of a variant nanoparticle vaccine that confers broad protection against emerging SARS-CoV-2 variants [Link] (06/14/21)
  • Sinovac, Pfizer/BioNtech COVID-19 vaccines prove highly effective in Uruguay -government [Link] (06/10/21)
  • Bharat Biotech Plans Phase IV Study of Covaxin While Ocugen Eyes US EUA [Link] (06/10/21)
  • MCRI’s BCG vaccine trial joins global race to better understand COVID-19 variants [Link] (06/10/21)
  • Icosavax Initiates Phase 1/2 Trial of COVID-19 VLP Vaccine Candidate [Link] (06/10/21)
  • INOVIO Expands Partnership with Advaccine to Conduct Global Phase 3 Efficacy Trial of COVID-19 DNA Vaccine Candidate, INO-4800 [Link] (06/10/21)
  • Pfizer COVID vaccine: Next phase of trials in young children to begin [Link] (06/10/21)
  • China to offer COVID-19 vaccine to children as young as three [Link] (06/10/21)
  • Moderna Files for Authorization with Health Canada for its COVID-19 Vaccine in Adolescents [Link] (06/10/21)
  • Moderna Files for Conditional Marketing Approval for its COVID-19 Vaccine in Adolescents in the European Union [Link] (06/10/21)
  • Applied DNA Reports Veterinary COVID-19 Vaccine Candidate Induces Neutralizing Antibodies in 100% of Trial Cohort Against B.1.1.7, P1, and B.1.526 Variants and Sets August 2021 Mink Challenge Trial Launch [Link] (06/10/21)
  • Covaxin commences Covid-19 vaccine clinical trials in children [Link] (06/10/21)
  • Safety and Efficacy of Single-Dose Ad26.COV2.S Vaccine against Covid-19 [Link] (06/10/21)
  • The ChAdOx1 vectored vaccine, AZD2816, induces strong immunogenicity against SARS-CoV-2 B.1.351 and other variants of concern in preclinical studies [Link] (06/10/21)
  • Immunogenicity of Ad26.COV2.S vaccine against SARS-CoV-2 variants in humans [Link] (06/10/21)
  • Optimizing vaccine allocation for COVID-19 vaccines shows the potential role of single-dose vaccination [Link] (06/10/21)
  • Decreases in COVID-19 Cases, Emergency Department Visits, Hospital Admissions, and Deaths Among Older Adults Following the Introduction of COVID-19 Vaccine — United States, September 6, 2020–May 1, 2021 [Link] (06/10/21)
  • Assessment of Effectiveness of 1 Dose of BNT162b2 Vaccine for SARS-CoV-2 Infection 13 to 24 Days After Immunization [Link] (06/10/21)
  • Immunogenicity and safety of a severe acute respiratory syndrome coronavirus 2 inactivated vaccine in healthy adults: randomized, double-blind, and placebo-controlled phase 1 and phase 2 clinical trials [Link] (06/10/21)
  • Necessity of COVID-19 Vaccination in Previously Infected Individuals: A Retrospective Cohort Study [Link] (06/07/21)
  • Valneva Completes Phase 3 Trial Recruitment for its Inactivated COVID-19 Vaccine Candidate [Link] (06/07/21)
  • Ocugen Expands COVAXIN Commercialization Rights to Include Canada [Link] (06/07/21)
  • Evaxion Biotech Reports Preclinical Proof of Concept Data for Evaxion’s AI-powered Vaccine Platform RAVEN for the Design of a Next Generation SARS-CoV-2 Vaccine [Link] (06/07/21)
  • Vaxxas Covid-19 vaccine patch outshines injectable jab in pre-clinical study [Link] (06/07/21)
  • Thromboembolic Events in the South African Ad26.COV2.S Vaccine Study [Link] (06/07/21)
  • Vaccine effectiveness of the BNT162b2 mRNA COVID-19 vaccine against RT-PCR confirmed SARS-CoV-2 infections, hospitalisations and mortality in prioritised risk groups [Link] (06/07/21)
  • Sinovac’s Covid-19 shot lowers deaths by 95% in first mass trial [Link] (06/07/21)
  • Aurobindo and Vaxxinity seek DCGI approval for Covid-19 vaccine trial [Link] (06/07/21)
  • Safety and immunogenicity of a recombinant DNA COVID-19 vaccine containing the coding regions of the spike and nucleocapsid proteins: Preliminary results from an open-label, phase 1 trial in healthy adults aged 19-55 years [Link] (06/07/21)
  • NIH clinical trial evaluating mixed COVID-19 vaccine schedules begins [Link] (06/07/21)
  • Heterologous ChAdOx1 nCoV-19 and BNT162b2 prime-boost vaccination elicits potent neutralizing antibody responses and T cell reactivity [Link] (06/07/21)
  • Immunization with RBD-P2 and N protects against SARS-CoV-2 in nonhuman primates [Link] (06/07/21)
  • Reactogenicity and Immunogenicity of BNT162b2 in Subjects Having Received a First Dose of ChAdOx1s: Initial Results of a Randomised, Adaptive, Phase 2 Trial (CombiVacS) [Link] (06/07/21)
  • WHO validates Sinovac COVID-19 vaccine for emergency use and issues interim policy recommendations [Link] (06/02/21)
  • Moderna Announces Initiation of Rolling Submission of Biologics License Application (BLA) with U.S. FDA for the Moderna COVID-19 Vaccine [Link] (06/02/21)
  • Moderna Announces Agreement with Thermo Fisher Scientific for Fill/Finish Manufacturing of Moderna’s COVID-19 Vaccine [Link] (06/02/21)
  • Heterologous ChAdOx1 nCoV-19 and BNT162b2 prime-boost vaccination elicits potent neutralizing antibody responses and T cell reactivity [Link] (06/02/21)
  • Complete protection by a single dose skin patch delivered SARS-CoV-2 spike vaccine [Link] (06/02/21)
  • The indirect effect of mRNA-based Covid-19 vaccination on unvaccinated household members [Link] (06/02/21)
  • Effectiveness of BNT162b2 and mRNA-1273 COVID-19 vaccines against symptomatic SARS-CoV-2 infection and severe COVID-19 outcomes in Ontario, Canada [Link] (06/02/21)
  • One-dose Janssen COVID-19 vaccine approved by the MHRA [Link] (06/02/21)
  • CoronaVac reduces mortality by 97 percent: Uruguay study [Link] (06/02/21)
  • CureVac’s First-Generation COVID-19 Vaccine Candidate, CVnCoV, Continues Toward Phase 2b/3 Efficacy Readout in Variant-rich Environment Following DSMB Recommendation [Link] (06/02/21)
  • Lipid Nanoparticle RBD-hFc mRNA Vaccine Protects hACE2 Transgenic Mice against a Lethal SARS-CoV-2 Infection [Link] (06/02/21)
  • Reverse vaccinology approach to design a novel multi-epitope vaccine candidate against COVID-19: an in silico study [Link] (06/02/21)

Select promising vaccine candidates currently in clinical trials are detailed below.

Candidate: Four BNT162 Vaccines – BNT162 a1, b1, b2, and c2, BNT162b2 in Phase 3 and now approved, also known as COMIRNATY.

Sponsors/Developers: Pfizer | BioNTech RNA Pharmaceuticals GmbH | Fosun Pharma

Location: Germany, U. S.

Trial identifier: NCT04368728 (Phase1/2/3); NCT04380701 (Phase 1/2)

Description: The phase 1 clinical trials began in the U.S. and Germany in April and were designed to evaluate the safety, tolerability, and potential efficacy of up to four mRNA vaccine candidates and to select which vaccine candidate and dose should be taken forward for future clinical study. The BNT162b2 candidate, at a 30-µg dose level in a two vaccination course was selected for phase 2/3 and also received U.S. Food and Drug Administration Fast Track designation.

The two lipid nanoparticle–formulated nucleoside-modified RNA (modRNA) vaccine candidates against SARS-CoV-2 were evaluated in the phase 1 portion of the trial in the United States. One of these candidates, BNT162b1, encodes the SARS-CoV-2 receptor–binding domain, trimerized by the addition of a T4 fibritin foldon domain to increase its immunogenicity through multivalent display.  The other candidate, BNT162b2, encodes the SARS-CoV-2 full-length spike, modified by two proline mutations to lock it in the prefusion conformation and more closely mimic the intact virus with which the elicited virus-neutralizing antibodies must interact.

BNT162b2, which encodes a prefusion stabilized membrane-anchored SARS-CoV-2 full-length spike was selected over BNT162b1, which encodes a secreted trimerized RBD for Phase 2/3. Additional safety and immunogenicity data were presented from the US Phase 1 trial that supported selection of the vaccine candidate advanced to a pivotal Phase 2/3 safety and efficacy evaluation. BNT162b2 was associated with less systemic reactogenicity, particularly in older adults. In both younger and older adults, the 2 vaccine candidates elicited similar dose-dependent neutralizing titers , higher than convalescent sera.

Immunization of mice with a single dose of BNT162b2 induced dose level-dependent increases in pseudovirus neutralization titers. Prime-boost vaccination of rhesus macaques elicited authentic SARS-CoV-2 neutralizing geometric mean titers 10.2 to 18.0 times that of a SARS-CoV-2 convalescent human serum panel. BNT162b2 generated strong TH1 type CD4+ and IFNg+ CD8+ T-cell responses in mice and rhesus macaques. The BNT162b2 vaccine candidate fully protected the lungs of immunized rhesus macaques from infectious SARS-CoV-2 challenge.

The Phase 3 portion of the clinical trial was designed to determine if the BNT162b2 vaccine candidate is safe and effective in preventing COVID-19 disease. If successful, the next step will be to seek regulatory review and emergency use authorization or approval. In September 2020, Pfizer expanded the enrollment of its Phase 3 pivotal COVID-19 vaccine trial to approximately 44,000 participants. This allowed for the enrollment of new populations, including adolescents as young as 16 years of age and people with chronic, stable HIV (human immunodeficiency viruses), Hepatitis C, or Hepatitis B infection. In October 2020, Pfizer received permission from the FDA to enroll adolescents as young as 12. The Phase 3 clinical trial of BNT162b2 has enrolled 43,538 participants to date, 38,955 of whom have received a second dose of the vaccine candidate as of November 8, 2020.

On 6 October, BioNTech and Pfizer initiated a rolling submission to European Medicines Agency for the candidate BNT162b2 and plan to work with the EMA’s Committee for Medicinal Products for Human Use (CHMP) to complete the rolling review process to facilitate the final Marketing Authorization Application (MAA).

On November 09, 2020, following an interim phase 3 efficacy analysis, Pfizer and BioNTech announced that the mRNA-based vaccine candidate, BNT162b2 was found to be more than 90% effective in preventing COVID-19 in participants without evidence of prior SARS-CoV-2 infection in the first interim efficacy analysis. Analysis evaluated 94 confirmed cases of COVID-19 in trial participants.

A final analysis of the Phase 3 trial  shows it was 95% effective in preventing infections, even in older adults, and caused no serious safety concerns, the company said on November 18, 2020. The company counted 170 cases of coronavirus infection among volunteers who took part in the trial. It said 162 infections were in people who got placebo, or plain saline shots, while eight cases were in participants who got the actual vaccine. That works out to an efficacy of 95%, Pfizer said. Data demonstrate vaccine was well tolerated across all populations with over 43,000 participants enrolled; no serious safety concerns observed; the only Grade 3 adverse event greater than 2% in frequency was fatigue at 3.8% and headache at 2.0%. The companies expect to produce globally up to 50 million vaccine doses in 2020 and up to 1.3 billion doses by the end of 2021. Pfizer is confident in its vast experience, expertise and existing cold-chain infrastructure to distribute the vaccine around the world.

On December 08, 2020 the FDA released their independent analysis of the clinical trials. They determined that the Comirnaty has an efficacy rate of 95%.

On December 10, 2020 Pfizer announced that the US FDA voted 17 to 4 in support of the FDA granting Emergency Use Authorization (EUA) for the companies’ COVID-19 mRNA vaccine (BNT162b2). The Phase 3 data demonstrated a vaccine efficacy rate of 95% in participants without prior SARS-CoV-2 infection (first primary objective) and in participants with and without prior SARS-CoV-2 infection (second primary objective), in each case measured from 7 days after the second dose. On December 21, 2020 the European Commission (EC) granted a conditional marketing authorization (CMA) to Pfizer and BioNTech for BNT162b2, for active immunization to prevent COVID-19 in individuals 16 years of age and older. This follows the European Medicines Agency’s (EMA) Committee for Medicinal Products for Human Use (CHMP) positive opinion to authorize the vaccine earlier.

Pfizer announced they will supply an additional 100 million doses of COMIRNATY to the 27 European Union (EU) member states in 2021. This agreement brings the total number of doses to be delivered to the EU to 300 million.

The study reports that the D614G mutation modestly reduced (1.7–2.4-fold) SARS-CoV-2 neutralization by BNT162b2 vaccine-elicited mouse, rhesus, and human sera, concurring with the 95% vaccine efficacy observed in clinical trial.

On April 01, 2021, Study published in the peer reviewed journal; Between Jan 11 and Feb 25, 2021, 170 patients who were being treated with immune checkpoint inhibitors were offered the vaccine and surveyed. Data support the short-term safety of the BNT162b2 mRNA COVID-19 vaccine in patients with cancer being treated with immune checkpoint inhibitors. Because no vaccine-related or immune checkpoint inhibitor-related severe adverse events were observed in this cohort of 134 patients who received two doses of the vaccine, it is unlikely that any common side-effects were missed.

Status: On April 18, 2021, A new study at Tel Aviv University found that the British variant (termed: B.1.1.7) of Covid-19 is 45% more contagious than the original virus. Despite a 45% increased transmission of the B.1.1.7 SARS-CoV-2 variant, the Israeli vaccination program with BNT162b2 vaccine curtails its spread in elderly populations

References:

  • Preprint: Phase 1/2 Study to Describe the Safety and Immunogenicity of a COVID-19 RNA Vaccine Candidate (BNT162b1) in Adults 18 to 55 Years of Age: Interim Report. medRxiv (07/01/20).
  • Press Release: Pfizer and BioNTech Granted FDA Fast Track Designation for Two Investigational mRNA-based Vaccine Candidates Against SARS-CoV-2. Businesswire (07/13/20).
  • Preprint: Concurrent human antibody and TH1 type T-cell responses elicited by a COVID-19 RNA vaccine. medRxiv (07/20/20).
  • Press Release: PFIZER and BIONTECH announce agreement with the United Kingdom for 30 million doses of mRNA-based vaccine candidate against SARS-COV-2. Pfizer (07/20/20).
  • Press Release: Pfizer and BioNTech Choose Lead mRNA Vaccine Candidate Against COVID-19 and Commence Pivotal Phase 2/3 Global Study. BioNTech (07/27/20).
  • Publication: Phase 1/2 study of COVID-19 RNA vaccine BNT162b1 in adults. Nature (08/12/20).
  • Publication: RNA-Based COVID-19 Vaccine BNT162b2 Selected for a Pivotal Efficacy Study. medRxiv (08/21/20).
  • Preprint: A prefusion SARS-CoV-2 spike RNA vaccine is highly immunogenic and prevents lung infection in non-human primates. bioRxiv (09/19/20).
  • Press Release: PFIZER AND BIONTECH PROPOSE EXPANSION OF PIVOTAL COVID-19 VACCINE TRIAL. Pfizer (09/12/20).
  • Reuters: Pfizer says Covid-19 vaccine showed moderate side effects. Reuters (09/16/20).
  • Publication: COVID-19 vaccine BNT162b1 elicits human antibody and TH1 T-cell responses. Nature (09/30/20).
  • Press Release: BioNTech and Pfizer Initiate Rolling Submission to European Medicines Agency for SARS-CoV-2 Vaccine Candidate BNT162b2. BioNtech (10/06/20).
  • Press Release: PFIZER AND BIONTECH ANNOUNCE VACCINE CANDIDATE AGAINST COVID-19 ACHIEVED SUCCESS IN FIRST INTERIM ANALYSIS FROM PHASE 3 STUDY. Pfizer (11/09/20).
  • Press Release: PFIZER AND BIONTECH CONCLUDE PHASE 3 STUDY OF COVID-19 VACCINE CANDIDATE, MEETING ALL PRIMARY EFFICACY ENDPOINTS. Pfizer (11/18/20).
  • Press Release: PFIZER AND BIONTECH RECEIVE AUTHORIZATION IN THE EUROPEAN UNION FOR COVID-19 VACCINE Pfizer (12/21/20).
  • Press Release: PFIZER AND BIONTECH RECEIVE FDA ADVISORY COMMITTEE VOTE SUPPORTING POTENTIAL FIRST EMERGENCY USE AUTHORIZATION FOR VACCINE TO COMBAT COVID-19 IN THE U.S. Pfizer (12/10/20).
  • Press Release: PFIZER AND BIONTECH TO SUPPLY THE EUROPEAN UNION WITH 100 MILLION ADDITIONAL DOSES OF COMIRNATY. Pfizer (12/29/20).
  • Preprint: BNT162b vaccines are immunogenic and protect non-human primates against SARS-CoV-2. bioRxiv (12/11/20).
  • Preprint: BNT162b2 induces SARS-CoV-2-neutralising antibodies and T cells in humans. medRxiv (12/11/20).
  • Publication: Safety and Immunogenicity of Two RNA-Based Covid-19 Vaccine Candidates. NEJM (12/17/20).
  • Publication: Safety and Efficacy of the BNT162b2 mRNA Covid-19 Vaccine. NEJM (12/30/20).
  • Publication: The effect of SARS-CoV-2 D614G mutation on BNT162b2 vaccine-elicited neutralization. Nature (03/25/21).
  • Publication: Short-term safety of the BNT162b2 mRNA COVID-19 vaccine in patients with cancer treated with immune checkpoint inhibitors. The Lancet Oncology (04/01/21).
  • Publication: BNT162b2 Vaccination Effectively Prevents the Rapid Rise of SARS-CoV-2 Variant B.1.1.7 in high risk populations in Israel. Cell (04/18/21).

Candidate: Adenovirus type 26 based vaccine Ad26.COV2.S.

Sponsors/Developers: Janssen Vaccines & Prevention B.V (Johnson & Johnson), Beth Israel Deaconess Medical Center.

Location: United States, United Kingdom, Belgium, Brazil, Japan, Others

Trial identifier: NCT04509947 (Phase 1); NCT04436276 (Phase1/2); NCT04614948 (Phase 3, ENSEMBLE 2); EudraCT Number: 2020-001483-28 (Phase 1/2a); EudraCT Number: 2020-002584-63 (Phase 2a)

Description: Ad26 vector encoding for a membrane-bound stabilized S protein with a wild type signal peptide.

The company’s large-scale, pivotal, multi-country Phase 3 trial (ENSEMBLE) for its COVID-19 vaccine candidate, JNJ-78436735 was initiated following positive interim results from the Company’s Phase 1/2a clinical study, which demonstrated that the safety profile and immunogenicity after a single vaccination were supportive of further development. Based on these results and following discussions with the U.S. Food and Drug Administration (FDA), ENSEMBLE will enroll up to 60,000 volunteers across three continents and will study the safety and efficacy of a single vaccine dose versus placebo in preventing COVID-19.

The Janssen COVID-19 vaccine candidate leverages the Company’s AdVac technology platform, which was also used to develop and manufacture Janssen’s European Commission approved Ebola vaccine and construct its Zika, RSV, and HIV vaccine candidates. Janssen’s AdVac technology platform has been used to vaccinate more than 100,000 people to date across Janssen’s investigational vaccine programs. With Janssen’s AdVac technology, the vaccine, if successful, is estimated at launch to remain stable for two years at -20 °C and at least three months at 2-8° C.

The Phase 3 ENSEMBLE study of the single-dose regimen continues to enroll and vaccinate study participants. ENSEMBLE is proceeding to enroll up to 60,000 participants worldwide. In addition to the single-dose regimen ENSEMBLE study, Janssen has now initiated the two-dose regimen ENSEMBLE 2 trial. ENSEMBLE 2 is a complementary, planned, pivotal, large-scale, multi-country Phase 3 trial that will study the safety and efficacy of a two-dose regimen of the investigational Janssen vaccine candidate for the prevention of COVID-19 in up to 30,000 participants worldwide. The ENSEMBLE and ENSEMBLE 2 trials will run in parallel.

On January 19, 2021, interim Results of a Phase 1–2a Trial of Ad26.COV2.S Covid-19 Vaccine was published. After the administration of the first vaccine dose in 805 participants in cohorts 1 and 3 and after the second dose in cohort 1, the most frequent solicited adverse events were fatigue, headache, myalgia, and injection-site pain. The most frequent systemic adverse event was fever. Systemic adverse events were less common in cohort 3 than in cohort 1 and in those who received the low vaccine dose than in those who received the high dose. Reactogenicity was lower after the second dose. Neutralizing-antibody titers against wild-type virus were detected in 90% or more of all participants on day 29 after the first vaccine dose, regardless of vaccine dose or age group, and reached 100% by day 57 with a further increase in titers in cohort 1a. Titers remained stable until at least day 71. A second dose provided an increase in the titer by a factor of 2.6 to 2.9.

Status: Johnson & Johnson announced on February 27, 2021 that the U.S. Food and Drug Administration (FDA) has issued Emergency Use Authorization (EUA) for its single-dose COVID-19 vaccine, developed by the Janssen Pharmaceutical Companies of Johnson & Johnson, to prevent COVID-19 in individuals 18 years of age and older. This decision was based on the totality of scientific evidence, including data from the Phase 3 ENSEMBLE study that demonstrated the vaccine was 85 percent effective in preventing severe disease across all regions studied, and showed protection against COVID-19 related hospitalization and death, beginning 28 days after vaccination.

On March 11, 2021, The EMA also announced that it has recommended granting a conditional marketing authorization for the Janssen COVID-19 vaccine from Johnson & Johnson, to be used in people 18 and older. It is the fourth COVID-19 vaccine recommended for use in Europe.

References:

  • Press release: Johnson & Johnson Announces Acceleration of its COVID-19 Vaccine Candidate; Phase 1/2a Clinical Trial to Begin in Second Half of July. Johnson & Johnson (06/10/20).
  • Publication: Ad26 vector-based COVID-19 vaccine encoding a prefusion-stabilized SARS-CoV-2 Spike immunogen induces potent humoral and cellular immune responses. Nature (09/28/20).
  • Publication: Ad26 vaccine protects against SARS-CoV-2 severe clinical disease in hamsters. Nature (09/03/20).
  • Publication: Single-shot Ad26 vaccine protects against SARS-CoV-2 in rhesus macaques. Nature (07/30/20).
  • Press Release: Johnson & Johnson Initiates Pivotal Global Phase 3 Clinical Trial of Janssen’s COVID-19 Vaccine Candidate. JnJ (09/23/20).
  • Preprint: Safety and immunogenicity of the Ad26.COV2.S COVID-19 vaccine candidate: interim results of a phase 1/2a, double-blind, randomized, placebo-controlled trial. medRxiv (09/25/20).
  • Preprint: Immunogenicity of one- and two-dose regimens of the Ad26.COV2.S COVID-19 vaccine candidate in adult and aged rhesus macaques. bioRxiv (11/17/20).
  • Press Release: Johnson & Johnson Initiates Second Global Phase 3 Clinical Trial of its Janssen COVID-19 Vaccine Candidate. Johnson & Johnson (11/15/20).
  • Protocol: A Randomized, Double-blind, Placebo-controlled Phase 3 Study to Assess the Efficacy and Safety of Ad26.COV2.S for the Prevention of SARS-CoV-2-mediated COVID-19 in Adults Aged 18 Years and Older. Janssen Vaccines (09/15/20).
  • Press release: Johnson & Johnson COVID-19 Vaccine Authorized by U.S. FDA For Emergency Use – First Single-Shot Vaccine in Fight Against Global Pandemic. Johnson & Johnson (02/27/21).
  • Publication: Interim Results of a Phase 1–2a Trial of Ad26.COV2.S Covid-19 Vaccine. NEJM (01/19/21).
  • Press release: EMA recommends COVID-19 Vaccine Janssen for authorisation in the EU. EMA (03/11/21).

Candidate: Non-Replicating Viral Vector AZD1222 (ChAdOx1)

Sponsors/Developers: The University of Oxford, The Jenner Institute | AstraZeneca; BARDA; UK Ministry of Health

Location: UK, Brazil, United States, South Africa, Others.

Trial Identifier: NCT04400838 (COV002, Phase 2/3); ISRCTN: 15281137; NCT04516746 (Phase 2/3); NCT04536051 and ISRCTN89951424 (Phase 3, COV003); NCT04324606 (Phase 1/2); NCT04444674 (Phase 1/2); NCT04540393 (Phase 3); NCT04568031 (Phase 1/2)

Description: ChAdOx1 nCoV-19 (AZD1222) is a replication-defective chimpanzee adenovirus-vectored vaccine expressing the full-length SARS-CoV-2 spike glycoprotein gene (GenBank accession number MN908947). It uses a replication-deficient chimpanzee viral vector based on a weakened version of a common cold virus (adenovirus) that causes infections in chimpanzees and contains the genetic material of the SARS-CoV-2 virus spike protein. After vaccination, the surface spike protein is produced, priming the immune system to attack the SARS-CoV-2 virus if it later infects the body.

Vaccination of rhesus macaques with a single dose of ChAdOx1 nCoV-19 generates humoral and cellular immune responses and protects from lower respiratory infection after subsequent challenge with SARS-CoV-2. AZD1222 was co-invented by the University of Oxford and its spin-out company, Vaccitech.

Preliminary results of a phase 1/2 clinical trial of ChAdOx1 nCoV-19 in adults aged 18-55 years show that the vaccine is well tolerated and generates robust neutralising antibody and cellular immune responses against the spike glycoprotein.

The vaccine platform will also be tested in inhaled form alongside the candidate from Imperial College London.

After an interim safety review, the company on 23 October announced that clinical trials for the AZD1222 have resumed across the world with regulators in the US, UK, Brazil, South Africa and Japan confirming that it was safe to do so.

In the phase 2 component of a single-blind, randomised, controlled, phase 2/3 trial (COV002), healthy adults aged 18 years and older were enrolled at two UK clinical research facilities, in an age-escalation manner, into 18-55 years, 56-69 years, and 70 years and older immunogenicity subgroups. The Phase II trial reported a total of 560 healthy volunteers, with 160 aged 18-55 years, 160 aged 56-69 years, and 240 aged 70 or over. Article published on November 18, 2020 in The Lancet showed ChAdOx1 nCoV-19 appeared to be better tolerated in older adults than in younger adults and has similar immunogenicity across all age groups after a boost dose. Antibody responses against the SARS-CoV-2 spike protein were induced in all age groups and were boosted and maintained at 28 days after booster vaccination, including in the 70 years and older group. Cellular immune responses were also induced in all age and dose groups, peaking at day 14 after vaccination. Local and systemic reactions were more common in participants given ChAdOx1 nCoV-19 than in those given the control vaccine, and similar in nature to those previously reported (injection-site pain, feeling feverish, muscle ache, headache), but were less common in older adults (aged ≥56 years) than younger adults.

“The robust antibody and T-cell responses seen in older people in our study are encouraging,” said Maheshi Ramasamy, a consultant and co-lead investigator at the Oxford Vaccine Group. Late-stage, or Phase III, trials are ongoing to confirm the findings, researchers said, and to test whether the vaccine protects against infection with SARS-CoV-2 in a broad range of people, including people with underlying health conditions.

On 23rd November, the company announced that the AZD1222 vaccine met primary efficacy endpoint in preventing COVID-19.Positive high-level results from an interim analysis of clinical trials of AZD1222 in the UK and Brazil showed the vaccine was highly effective in preventing COVID-19, the primary endpoint, and no hospitalizations or severe cases of the disease were reported in participants receiving the vaccine. There was a total of 131 COVID-19 cases in the interim analysis. One dosing regimen (n=2,741) showed vaccine efficacy of 90% when AZD1222 was given as a half dose, followed by a full dose at least one month apart, and another dosing regimen (n=8,895) showed 62% efficacy when given as two full doses at least one month apart. The combined analysis from both dosing regimens (n=11,636) resulted in an average efficacy of 70%. All results were statistically significant (p<=0.0001). The Company will seek an Emergency Use Listing from the World Health Organization for an accelerated pathway to vaccine availability in low-income countries. In parallel, the full analysis of the interim results is being submitted for publication in a peer-reviewed journal.

Safety and efficacy of the ChAdOx1 nCoV-19 vaccine (AZD1222) data against SARS-CoV-2 was published in the Lancet on December 8, 2020. It was an interim analysis of four randomised controlled trials in Brazil, South Africa, and the UK. Participants aged 18 years and older were randomly assigned (1:1) to ChAdOx1 nCoV-19 vaccine or control. 23848 participants were enrolled and 11636 participants (7548 in the UK, 4088 in Brazil) were included in the interim primary efficacy analysis. In participants who received two standard doses, vaccine efficacy was 62·1% and in participants who received a low dose followed by a standard dose, efficacy was 90·0%. Overall vaccine efficacy across both groups was 70·4%. From 21 days after the first dose, there were ten cases hospitalised for COVID-19, all in the control arm; two were classified as severe COVID-19, including one death. There were 74341 person-months of safety follow-up: 175 severe adverse events occurred in 168 participants, 84 events in the ChAdOx1 nCoV-19 group and 91 in the control group. Three events were classified as possibly related to a vaccine: one in the ChAdOx1 nCoV-19 group, one in the control group, and one in a participant who remains masked to group allocation.

WHO on February 10, 2021 has announced Interim recommendations for use of the AZD1222 (ChAdOx1-S [recombinant]) vaccine against COVID19 developed by Oxford University and AstraZeneca based on the results obtained.

On March 6, 2021, Oxford–AstraZeneca have published the report of the updated primary efficacy results for the ChAdOx1 nCoV-19 (AZD1222) vaccine from three single-blind, randomised controlled trials. The study was based on an updated analysis of 17178 participants, 83.9% aged 18–55 years, 10·4% aged 56–69 years and 5·7% aged 70 years or older, conducted in Brazil, South Africa, and the UK. The pooled results from these trials showed an overall vaccine efficacy against symptomatic COVID-19 more than 14 days after the second dose of 66·7%. Vaccine efficacy was 63·1% in those who received two standard doses and 80·7% in those who received the low dose plus standard dose. Notably, in exploratory analyses, vaccine efficacy after a single standard dose was 76·0% (59·3–85·9) from day 22 to day 90, and antibody levels were maintained during this period with minimal waning. Supporting a longer-interval immunisation strategy, vaccine efficacy was significantly higher at 81·3% after two standard doses given at an interval of 12 weeks or longer, compared with 55·1% when given less than 6 weeks apart.

On March 16, 2021, Result published in the peer reviewed journal of a multicenter, double-blind, randomized, controlled trial to assess the safety and efficacy of the ChAdOx1 nCoV-19 vaccine (AZD1222) in people not infected with the human immunodeficiency virus (HIV) in South Africa. Study enrolled 2026 HIV-negative adults (median age, 30 years); 1010 and 1011 participants received at least one dose of placebo or vaccine, respectively. A two-dose regimen of the ChAdOx1 nCoV-19 vaccine did not show protection against mild-to-moderate Covid-19 due to the B.1.351 variant (Efficacy of 21.9%). Vaccine efficacy against this variant, analyzed as a secondary end point, was 10.4%. The incidence of serious adverse events was balanced between the vaccine and placebo groups.

On March 30, 2021, Study published in the peer reviewed journal, a post-hoc analysis of the efficacy of the adenoviral vector vaccine, ChAdOx1 nCoV-19 (AZD1222), against the B.1.1.7 (U K variant). 401 swabs from 311 participants were successfully sequenced. ChAdOx1 nCoV-19 showed reduced neutralisation activity against the B.1.1.7 variant compared with a non-B.1.1.7 variant in vitro, but the vaccine showed efficacy against the B.1.1.7 variant of SARS-CoV-2. Clinical vaccine efficacy against symptomatic NAAT positive infection was 70.4% for B.1.1.7 and 81.5% for non-B.1.1.7 lineages.

Status: On April 16, 2021, Article reports findings in 23 patients who presented with thrombosis and thrombocytopenia 6 to 24 days after receiving the first dose of the ChAdOx1 nCoV-19 vaccine (AstraZeneca). On the basis of their clinical and laboratory features, it identifies a novel underlying mechanism and address the therapeutic implications. In the absence of previous prothrombotic medical conditions, 22 patients presented with acute thrombocytopenia and thrombosis, primarily cerebral venous thrombosis, and 1 patient presented with isolated thrombocytopenia and a hemorrhagic phenotype. Testing for antibodies to platelet factor 4 (PF4) was positive in 22 patients (with 1 equivocal result) and negative in 1 patient. Study concluded that a pathogenic PF4-dependent syndrome, unrelated to the use of heparin therapy, can occur after the administration of the ChAdOx1 nCoV-19 vaccine. Rapid identification of this rare syndrome is important because of the therapeutic implications.

References:

  • Preprint: A single dose of ChAdOx1 MERS provides broad protective immunity against a variety of MERS-CoV strains. bioRxiv (04/13/20).
  • Preprint: ChAdOx1 nCoV-19 vaccination prevents SARS-CoV-2 pneumonia in rhesus macaques. bioRxiv (05/13/20).
  • Publication: Safety and immunogenicity of the ChAdOx1 nCoV-19 vaccine against SARS-CoV-2: a preliminary report of a phase 1/2, single-blind, randomised controlled trial. Lancet (07/20/20).
  • Publication: ChAdOx1 nCoV-19 vaccine induced antigen-specific antibody and T cells responses after a single dose and enhanced responses after a booster immunization in mice and pigs. Nature (07/27/20).
  • Publication: ChAdOx1 nCoV-19 vaccine prevents SARS-CoV-2 pneumonia in rhesus macaques. Nature (07/30/20).
  • Publication: A single-dose intranasal ChAd vaccine protects upper and lower respiratory tracts against SARS-CoV-2. Cell (08/19/20).
  • STAT News: Covid-19 vaccine trial participant had serious neurological symptoms, but could be discharged today, AstraZeneca CEO says. STAT (09/09/20).
  • Reuters, NYT: AstraZeneca puts leading COVID-19 vaccine trial on hold over safety concern (09/09/20).
  • Oxford Univ: University of Oxford resumes vaccine trial (09/09/20).
  • News: Vaccine Trial Illness Unlikely to Be Linked to Shot, Oxford Says. (09/16/20).
  • Imperial College: Landmark coronavirus study to trial inhaled Imperial and Oxford vaccines. (09/14/20).
  • Press Release: FDA authorises restart of the COVID-19 AZD1222 vaccine US Phase III trial. Astrazeneca (10/23/20).
  • Protocol: A Phase III Randomized, Double-blind, Placebo-controlled Multicenter Study in Adults to Determine the Safety, Efficacy, and Immunogenicity of AZD1222, a Non-replicating ChAdOx1 Vector Vaccine, for the Prevention of COVID-19. AstraZeneca (09/17/20).
  • News: AstraZeneca COVID-19 vaccine shows promise in elderly, trial results by Christmas. Reuters (11/18/20).
  • Press Release: AZD1222 vaccine met primary efficacy endpoint in preventing COVID-19. Astrazeneca (11/23/20).
  • Publication: Safety and efficacy of the ChAdOx1 nCoV-19 vaccine (AZD1222) against SARS-CoV-2: an interim analysis of four randomised controlled trials in Brazil, South Africa, and the UK. Lancet (12/08/20).
  • Press Release: Interim recommendations for use of the AZD1222 (ChAdOx1-S (recombinant)) vaccine against COVID-19 developed by Oxford University and AstraZeneca. WHO (02/10/21).
  • Publication: Single-dose Oxford–AstraZeneca COVID-19 vaccine followed by a 12-week booster.  Lancet (03/06/21).
  • Publication: Efficacy of the ChAdOx1 nCoV-19 Covid-19 Vaccine against the B.1.351 Variant.  NEJM (03/16/21).
  • Publication: Efficacy of ChAdOx1 nCoV-19 (AZD1222) vaccine against SARS-CoV-2 variant of concern 202012/01 (B.1.1.7): an exploratory analysis of a randomised controlled trial. NEJM (03/30/21).
  • Publication: Pathologic Antibodies to Platelet Factor 4 after ChAdOx1 nCoV-19 Vaccination. NEJM (04/16/21).

Candidate: Lipid nanoparticle (LNP) encapsulated mRNA (mRNA-1273)

Sponsors/Developers: Moderna, Inc. | National Institute of Allergy and Infectious Diseases (NIAID); Funding from the Biomedical Advanced Research and Development Authority (BARDA); Kaiser Permanente Washington Health Research Institute

Location: U.S.

Trial identifier: NCT04283461 (Phase 1) NCT04405076 (Phase 2), NCT04470427 (COVE, Phase 3)

Description: mRNA-1273 is an mRNA vaccine encoding for a prefusion stabilized form of the Spike (S) protein, which was selected by Moderna in collaboration with investigators from Vaccine Research Center (VRC) at the NIAID. This vaccine encodes a stabilized version of the SARS-CoV-2 full-length spike glycoprotein trimer, S-2P, which has been modified to include two proline substitutions at the top of the central helix in the S2 subunit. The mRNA is encapsulated in lipid nanoparticles at a concentration of 0.5 mg per milliliter and diluted with normal saline to achieve the final target vaccine concentrations. The first clinical batch, which was funded by the Coalition for Epidemic Preparedness Innovations, was completed on February 7, 2020 and underwent analytical testing; it was shipped to NIH on February 24, 42 days from sequence selection. The first participant in the NIAID-led Phase 1 study of mRNA-1273 was dosed on March 16, 63 days from sequence selection to Phase 1 study dosing.

On May 12, the FDA granted mRNA-1273 Fast Track designation. On May 29, the first participants in each age cohort: adults ages 18-55 years (n=300) and older adults ages 55 years and above (n=300) were dosed in the Phase 2 study of mRNA-1273. On July 8, the Phase 2 study completed enrollment.

Results from the second interim analysis of mRNA-1273 in the 56-70 and 71+ age groups were published on September 29 in The New England Journal of Medicine. On July 28, results from a non-human primate preclinical viral challenge study evaluating mRNA-1273 were published in The New England Journal of Medicine. On July 14, an interim analysis of the original cohorts in the NIH-led Phase 1 study of mRNA-1273 was published in The New England Journal of Medicine.

Interim results were published in The New England Journal of Medicine of interim results from older adult age cohorts in Phase 1 Study. mRNA-1273 induced consistently high levels of pseudovirus neutralization antibody titers in all participants in the 56-70 (n=10) and 71+ (n=10) age cohorts. Potent neutralization responses were confirmed by 3 different live virus assays. mRNA-1273 elicited Th1-biased CD4 T cell responses in the 56-70 and 71+ age cohorts. Neutralizing antibody titers and T cell responses in the 56-70 and 71+ age cohorts were consistent with those reported in younger adults. At the 25 ug and 100 ug dose levels, mRNA-1273 was generally well-tolerated in all age cohorts.

The Phase 3 COVE study was designed in collaboration with the FDA and NIH to evaluate Americans at the highest risk of severe COVID-19 disease. As of today, the COVE study includes more than 7,000 Americans over the age of 65. It also includes more than 5,000 Americans who are under the age of 65 but have high-risk chronic diseases that put them at increased risk of severe COVID-19, such as diabetes, severe obesity and cardiac disease. These medically high-risk groups represent 42% of the total participants in the Phase 3 COVE study.

Moderna on October 22 announced that it has completed enrollment of 30,000 participants for the Phase 3 COVE study of mRNA-1273. And that more than 25,650 participants have received their second vaccination. Moderna will determine whether to submit a dossier to FDA requesting Emergency Use Authorization based on an assessment of whether the potential benefit of the vaccine outweighs the potential risks once the 2 months of median safety follow-up have accrued. As on November 11, Moderna has seen a significant increase in the rate of case identification across sites in the last week. As a result, the Company expects the first interim analysis will include substantially more than 53 cases, the targeted trigger point for the analysis. The data on these cases is being prepared for submission to the independent Data Safety Monitoring Board (DSMB) for analysis and recommendation. Moderna remains blinded to whether these participants received vaccine or placebo.

Moderna on 16 November 2020 announced that the independent DSMB for the Phase 3 study has informed that the trial has met the statistical criteria pre-specified in the study protocol for efficacy, with a vaccine efficacy of 94.5%. The primary endpoint of the Phase 3 COVE study is based on the analysis of COVID-19 cases confirmed and adjudicated starting two weeks following the second dose of vaccine. This first interim analysis was based on 95 cases, of which 90 cases of COVID-19 were observed in the placebo group versus 5 cases observed in the mRNA-1273 group, resulting in a point estimate of vaccine efficacy of 94.5% (p <0.0001). The 95 COVID-19 cases included 15 older adults (ages 65+) and 20 participants identifying as being from diverse communities (including 12 Hispanic or LatinX, 4 Black or African Americans, 3 Asian Americans and 1 multiracial). Moderna also announced that the vaccine candidate is now expected to remain stable at standard refrigerator temperatures of 2° to 8°C (36° to 46°F) for 30 days, up from previous estimate of 7 days. Statement also mentioned shipping and long-term storage conditions at standard freezer temperatures of -20°C (-4°F) for 6 months.

Primary efficacy analysis of the Phase 3 COVE study of mRNA-1273 involving 30,000 participants included 196 cases of COVID-19, of which 30 cases were severe. Vaccine efficacy against COVID-19 was 94.1%; vaccine efficacy against severe COVID-19 was 100%. mRNA-1273 continues to be generally well tolerated; no serious safety concerns identified to date. Phase 3 COVE Study has exceeded 2 months of median follow-up post vaccination as required by the U.S. FDA for Emergency Use Authorization (EUA).

On December 18, 2020 the US FDA authorized the emergency use of mRNA-1273, Moderna’s vaccine against COVID-19 in individuals 18 years of age or older. The Moderna COVID-19 Vaccine is now authorized for distribution and use under an Emergency Use Authorization (EUA). On January 6th, 2021 the European Commission granted a conditional marketing authorization (CMA), allowing vaccination programs using the Moderna vaccine to be rolled out across the European Union. Followign this, on January 8, 2021 UK’s Medicines and Healthcare products Regulatory Agency (MHRA) has approved the mRNA vaccine against COVID-19 for use under Regulation 174. The temporary authorization permits the supply of COVID-19 Vaccine Moderna in Great Britain and is based upon the advice of the UK Commission on Human Medicines. The UK is the fifth jurisdiction to authorize COVID-19 Vaccine Moderna, following US, Canada, Israel, and the European Union.

On March 31, 2021, NIH clinical trial evaluating Moderna COVID-19 variant vaccine begins; The vaccine, known as mRNA-1273.351, developed by ModernaTX, Inc. has been designed to protect against the B.1.351 SARS-CoV-2 variant is to be administered as part of a new Phase 1 clinical trial evaluating the vaccine candidate’s safety and immunogenicity in adult volunteers. The trial will enroll approximately 210 healthy adult volunteers at four clinical research sites in the United States that are part of the NIAID-funded Infectious Diseases Clinical Research Consortium (IDCRC). The variant vaccine candidate differs from the currently-authorized Moderna vaccine in that it delivers instructions for making the SARS-CoV-2 spike that incorporates key mutations in the B.1.351 virus variant. In addition to the Phase 1 clinical trial, investigators at NIAID’s Vaccine Research Center are collaborating with Moderna to evaluate mRNA-1273.351 in animal models.

The mRNA vaccines (Pfizer/BioNTech and Moderna) were 90% effective at preventing SARS-CoV-2 infection after full immunization (at least 14 days after second dose) and 80% after partial immunization (at least 14 days after first dose but before second dose), according to interim estimates among 3,950 healthcare personnel, first responders, and other essential and frontline workers in multiple locations across the US. Study participants completed weekly SARS-CoV-2 testing for 13 consecutive weeks, from December 14-18, 2020 to March 13, 2021.

Status: On April 6, 2021, Interim results from a phase 3 trial of the Moderna mRNA-1273 SARS-CoV-2 vaccine indicated 94% efficacy in preventing Covid-19. Study describes mRNA1273-elicited binding and neutralizing antibodies in 33 healthy adult participants in an ongoing phase 1 trial, stratified according to age, at 180 days after the second dose of 100 μg (day 209). Antibodies that were elicited by mRNA-1273 persisted through 6 months after the second dose, as detected by three distinct serologic assays. Ongoing studies are monitoring immune responses beyond 6 months as well as determining the effect of a booster dose to extend the duration and breadth of activity against emerging viral variants.

References:

  • Publication: An mRNA Vaccine against SARS-CoV-2 – Preliminary Report. NEJM (07/14/20).
  • Preprint: mRNA-1273 induces both potent neutralizing antibody and CD8 T cell responses and protects against SARS-CoV-2 infection in lungs and noses of mice without evidence of immunopathology. bioRxiv (06/11/20).
  • Press Release: Moderna Announces Expansion of BARDA Agreement to Support Larger Phase 3 Program for Vaccine (mRNA-1273) Against COVID-19. Moderna (07/26/20).
  • Publication: Evaluation of the mRNA-1273 Vaccine against SARS-CoV-2 in Nonhuman Primates. NEJM (07/28/20).
  • Press Release: Moderna says its coronavirus vaccine shows promising results in small trial of elderly patients. Moderna (08/27/20).
  • Website: Additional COVE Study Information. Moderna (Accessed 09/25/20).
  • Publication: Safety and Immunogenicity of SARS-CoV-2 mRNA-1273 Vaccine in Older Adults. NEJM (09/29/20).
  • Press Release: Moderna Completes Enrollment of Phase 3 COVE Study of mRNA Vaccine Against COVID-19 (mRNA-1273). Moderna (10/22/20).
  • Press Release: Moderna Has Completed Case Accrual for First Planned Interim Analysis of its mRNA Vaccine Against COVID-19 (mRNA-1273). Moderna (11/11/20).
  • Press Release: Moderna’s COVID-19 Vaccine Candidate Meets its Primary Efficacy Endpoint in the First Interim Analysis of the Phase 3 COVE Study. Moderna (11/16/20).
  • Press Release:  Moderna Announces Longer Shelf Life for its COVID-19 Vaccine Candidate at Refrigerated Temperatures. Moderna (11/16/20).
  • Press Release: European Medicines Agency Begins Rolling Review of Moderna’s mRNA Vaccine Candidate Against COVID-19 (mRNA-1273). Moderna (11/17/20).
  • Press Release: Moderna Announces Primary Efficacy Analysis in Phase 3 COVE Study for Its COVID-19 Vaccine Candidate and Filing Today with U.S. FDA for Emergency Use Authorization. Moderna (11/30/20).
  • Press Release: Moderna Announces FDA Authorization of Moderna COVID-19 Vaccine in U.S. Moderna (12/18/2020).
  • Publication: Efficacy and Safety of the mRNA-1273 SARS-CoV-2 Vaccine. NEJM (12/30/2021).
  • Press Release: European Commission Authorizes COVID-19 Vaccine Moderna in Europe. Moderna (01/06/2021).
  • Press Release: United Kingdom Medicines and Healthcare products Regulatory Agency Authorizes Use of COVID-19 Vaccine Moderna. Moderna (01/08/2021).
  • Press Release: NIH clinical trial evaluating Moderna COVID-19 variant vaccine begins. NIH (03/31/2021).
  • Press Release: Interim Estimates of Vaccine Effectiveness of BNT162b2 and mRNA-1273 COVID-19 Vaccines in Preventing SARS-CoV-2 Infection Among Health Care Personnel, First Responders, and Other Essential and Frontline Workers — Eight U.S. Locations, December 2020–March 2021. CDC MMWR (03/29/2021).
  • Publication: Antibody Persistence through 6 Months after the Second Dose of mRNA-1273 Vaccine for Covid-19. NEJM (04/06/2021).

Candidate: Protein subunit; NVX-CoV2373; Full-length recombinant SARS COV-2 glycoprotein nanoparticle vaccine adjuvanted with Matrix M

Sponsors/Developers: Novavax, Inc.

Location: Australia; South Africa; U. K.

Trial identifier: NCT04368988 (Phase 2); NCT04533399 (Phase 2)

Description: NVX-CoV2373 is a stable, prefusion protein made using Novavax’ proprietary nanoparticle technology.

NVX-CoV2373 was created using Novavax’ recombinant nanoparticle technology to generate antigen derived from the coronavirus spike (S) protein and contains Novavax’ patented saponin-based Matrix-M™ adjuvant to enhance the immune response and stimulate high levels of neutralizing antibodies. NVX-CoV2373 contains purified protein antigen and cannot replicate, nor can it cause COVID-19. In preclinical trials, NVX-CoV2373 demonstrated induction of antibodies that block binding of spike protein to receptors targeted by the virus, a critical aspect for effective vaccine protection. In the Phase 1 portion of its Phase 1/2 clinical trial, NVX-CoV2373 was generally well-tolerated and elicited robust antibody responses numerically superior to that seen in human convalescent sera. NVX-CoV2373 is also being evaluated in a Phase 3 trial in the UK and two ongoing Phase 2 studies that began in August; a Phase 2b trial in South Africa, and a Phase 1/2 continuation in the U.S. and Australia. Novavax has secured $2 billion in funding for its global coronavirus vaccine program, including up to $399 million in funding from the Coalition for Epidemic Preparedness Innovations (CEPI) and almost $1.7 billion from the U.S. government.

Novavax has enrolled over 5,500 participants to date in the United Kingdom (U.K.) trial, which it has expanded to 15,000 volunteers. The increased enrollment is likely to facilitate assessment of safety and efficacy in a shorter time period.

Novavax on November 09, 2020 announced that the U.S. Food and Drug Administration (FDA) has granted Fast Track Designation for NVX-CoV2373. Novavax expects to begin its pivotal Phase 3 clinical trial in the United States and Mexico by the end of November.

Novavax, on January 28, 2021 announced that NVX-CoV2373, its protein-based COVID-19 vaccine candidate, met the primary endpoint, with a vaccine efficacy of 89.3%, in its Phase 3 clinical trial conducted in the United Kingdom (UK). The study assessed efficacy during a period with high transmission and with a new UK variant strain of the virus emerging and circulating widely. It was conducted in partnership with the UK Government’s Vaccines Taskforce. Novavax also announced successful results of its Phase 2b study conducted in South Africa.

Preliminary Efficacy of the NVX-CoV2373 Covid-19 Vaccine Against the B.1.351 Variant was published in preprint on March 3, 2021. A total of 4387 participants were randomized and dosed at least once. The NVX-CoV2373 vaccine was found efficacious in preventing Covid-19, which was predominantly mild to moderate and due to the B.1.351 variant, while evidence of prior infection with the presumptive original SARS-CoV-2 did not confer protection against probable B.1.351 disease. Evaluation of a SARS-CoV-2 Vaccine NVX-CoV2373 in Younger and Older Adults was also published in preprint on March 1, 2021. The study confirmed that the two-dose regimen of 5-µg NVX-CoV2373 is highly immunogenic and well tolerated in both younger and older participants.

Status: On March 11, 2021, Novavax announced final efficacy of 96.4% against mild, moderate and severe disease caused by the original COVID-19 strain in a pivotal Phase 3 trial in the United Kingdom (U.K.) of NVX‑CoV2373, the company’s vaccine candidate. The company also announced the complete analysis of its Phase 2b trial taking place in South Africa, with efficacy of 55.4% among the HIV- negative trial participants in a region where the vast majority of strains are B1.351 escape variants. Across both trials, NVX-CoV2373 demonstrated 100% protection against severe disease, including all hospitalization and death. Both studies achieved their statistical success criteria. Efficacy was 96.4% against the original virus strain and 86.3% against the B.1.1.7/501Y.V1 variant circulating in the U.K (post hoc). The primary efficacy endpoint demonstrated an overall vaccine efficacy of 89.7%.

References:

  • Press Release: Novavax Announces $1.6 Billion Funding from Operation Warp Speed. Novavax (07/07/20).
  • Press Release: Novavax and FUJIFILM Diosynth Biotechnologies Initiate Large Scale Manufacturing of COVID-19 Vaccine Candidate. Novavax (07/23/20).
  • Press Release: Novavax Announces Positive Phase 1 Data for its COVID-19 Vaccine Candidate. Novavax (08/05/20).
  • Press Release: Novavax and Takeda Announce Collaboration for Novavax’ COVID19 Vaccine in Japan. Novavax (08/06/20).
  • Press Release: Novavax Initiates Efficacy Trial of COVID-19 Vaccine in South Africa. Novavax (08/17/20).
  • Press Release: Novavax Initiates Phase 2 Portion of Phase 1/2 Clinical Trial of COVID-19 Vaccine. Novavax (08/24/20).
  • Publication: Phase 1-2 Trial of a SARS-CoV-2 Recombinant Spike Protein Nanoparticle Vaccine. NEJM (09/02/20).
  • Press Release: Novavax Announces COVID-19 Vaccine Manufacturing Agreement with Serum Institute of India, Increasing Novavax’ Global Production Capacity to Over 2 Billion Doses Annually. Novavax (09/15/20).
  • Press Release: Novavax Initiates Phase 3 Efficacy Trial of COVID-19 Vaccine in the United Kingdom. Novavax (09/24/20).
  • Publication: SARS-CoV-2 spike glycoprotein vaccine candidate NVX-CoV2373 elicits immunogenicity in baboons and protection in mice. bioRxiv Preprint (06/30/20).
  • Publication: Structural analysis of full-length SARS-CoV-2 spike protein from an advanced vaccine candidate. Science (10/20/20).
  • Publication: NVX-CoV2373 vaccine protects cynomolgus macaque upper and lower airways against SARS-CoV-2 challenge. Vaccine (10/23/20).
  • Press Release: Novavax Provides Phase 3 COVID-19 Vaccine Clinical Development Update. Novavax (10/27/20).
  • Press Release: Novavax COVID-19 Vaccine Granted Fast Track Designation by U.S. FDA. Novavax (11/09/20).
  • Press release: Novavax COVID-19 Vaccine Demonstrates 89.3% Efficacy in UK Phase 3 Trial. Novavax (01/28/21).
  • Publication: Evaluation of a SARS-CoV-2 Vaccine NVX-CoV2373 in Younger and Older Adults. medRxiv (03/01/21).
  • Publication: Preliminary Efficacy of the NVX-CoV2373 Covid-19 Vaccine Against the B.1.351 Variant. medRxiv (03/03/21).
  • Press release: Novavax Confirms High Levels of Efficacy Against Original and Variant COVID-19 Strains in United Kingdom and South Africa Trials. Novavax (03/11/21).

Candidate: Whole-Virion Inactivated SARS-CoV-2 Vaccine (BBV152, Covaxin)

Sponsors/Developers: Bharat Biotech International Limited, ICMR (Indian Council of Medical Research).

Trial identifier: NCT04471519 (Phase1/2), CTRI/2020/07/026300 (Phase 1/2), CTRI/2020/11/028976 (Phase 3)

Description: COVAXIN, Indias COVID-19 vaccine by Bharat Biotech is developed in collaboration with the ICMR – National Institute of Virology (NIV). The indigenous, inactivated vaccine is developed and manufactured in Bharat Biotechs BSL-3 (Bio-Safety Level 3) high containment facility. The vaccine received DCGI approval for Phase I and II Human Clinical Trials and the trials will commence across India from July 2020.

As on August 17, Covaxin has demonstrated an encouraging safety profile in a Phase I clinical trial conducted in the country. Preliminary Phase I trial results showed that the vaccine is safe. Trial investigators are said to be collecting blood samples to analysze the vaccine’s immunogenicity. The Phase I study involves 375 volunteers at 12 sites across the country.

COVAXIN has been evaluated in ~ 1000 subjects in Phase I and Phase II clinical trials, with promising safety and immunogencity data.

The published preprint on the development and evaluation of safety and immunogenicity of this whole virion inactivated SARS-CoV-2 vaccine, adjuvanted with aluminium hydroxide gel (Algel), or a novel TLR7/8 agonist adsorbed Algel. BBV152 vaccine formulations generated significantly high antigen-binding and neutralizing antibody titers, at both concentrations (3 ug and 6 ug), in all three species (mice, rats, and rabbits) with excellent safety profiles. The inactivated vaccine formulation containing TLR7/8 agonist adjuvant-induced Th1 biased antibody responses with elevated IgG2a/IgG1 ratio and increased levels of SARS-CoV-2 specific IFN-g+ CD4 T lymphocyte response.

Bharat Biotech in September said it entered into a licensing agreement with Washington University School of Medicine in St. Louis for a novel ‘chimp-adenovirus’ (Chimpanzee adenovirus), single dose intranasal vaccine for Covid-19. Bharat Biotech also announced it will use adjuvant Alhydroxiquim-II to boost immune response and longer lasting immunity. The technology is being used under licensing agreement with Kansas-based ViroVax LLC.

Bharat Biotech has announced Phase 3 results of COVAXIN Vaccine on 3rd March, 2021. 25,800 participants received the vaccine or placebo in a 1:1 ratio showed that the vaccine candidate was well tolerated.  COVAXIN demonstrated 81% interim efficacy in preventing COVID-19 in those without prior infection after the second dose. Clinical trial to continue through to final analysis at 130 confirmed cases in order to gather further data and to evaluate the efficacy of COVAXIN in additional secondary study endpoints. The participants were in the age group of 18-98 years, including 2,433 over the age of 60 and 4,500 with comorbidities. The primary endpoint of Phase 3 clinical trial is based on the first occurrence of PCR-confirmed symptomatic (mild, moderate, or severe) COVID-19 with onset at least 14 days after the second study vaccination in serologically negative (to SARS-CoV-2) adult participants at baseline. Analysis from the National Institute of Virology indicates that vaccine-induced antibodies can neutralize the UK variant strains and other heterologous strains.

On April 21, 2021, Bharat Biotech and ICMR announced interim results from phase 3 trials of COVAXIN; The second interim results showed India’s First COVID-19 Vaccine had demonstrated strong primary efficacy against severe COVID-19 disease. Bharat Biotech announced phase 3 interim analysis results of COVAXIN. The second interim analysis is based on accruing more than 87 symptomatic cases of COVID-19. Due to the recent surge in cases, 127 symptomatic cases were recorded, resulting in a point estimate of vaccine efficacy of 78% (95%CI: 61-88) against mild, moderate, and severe COVID-19 disease. The efficacy against severe COVID-19 disease was 100% (95%CI: 60-100), with an impact on reduction in hospitalizations. The efficacy against asymptomatic COVID-19 infection was 70%, suggesting decreased transmission in COVAXIN recipients. Safety and Efficacy results from the final analysis will be available in June, and the final report will be submitted to a peer-reviewed publication. The vaccine was also found to be effective against common variants.

References:

  • Preprint: Evaluation of Safety and Immunogenicity of an Adjuvanted, TH-1 Skewed, Whole Virion Inactivated SARS-CoV-2 Vaccine – BBV152. bioRxiv (09/09/20).
  • Preprint: Immunogenicity and protective efficacy of BBV152: a whole virion inactivated SARS CoV-2 vaccine in the Syrian hamster model. Research Square (09/16/20).
  • Press release: Bharat Biotech, Thomas Jefferson University pursue a promising vaccine candidate against COVID-19. Bharat Biotech (05/10/20).
  • Press Release: COVAXIN to boost the immune response and longer-lasting immunity with ViroVax’s adjuvant. Bharat Biotech (10/05/20).
  • News: Washington University School of Medicine in St. Louis Licenses Inhalable COVID-19 Vaccine to India’s Bharat Biotech. TrialSiteNews (09/28/20).
  • Press Release: Bharat Biotech starts Phase III trials for COVAXIN. Bharat Biotech (11/16/20).
  • Press Release: Bharat Biotech Announces Phase 3 Results of COVAXIN: India’s First COVID-19 Vaccine Demonstrates Interim Clinical Efficacy of 81%. Bharat Biotech (03/03/21).
  • Press Release: Bharat Biotech and ICMR Announce Interim Results from Phase 3 trials of COVAXIN; Demonstrates overall Interim Clinical Efficacy of 78% and 100% efficacy against Severe COVID-19 disease. Bharat Biotech (04/21/21).

Candidate: Inactivated virus (CoronaVac/PiccoVac)

Sponsors/Developers: Sinovac Biotech Ltd.; Funding by Advantech Capital and Vivo Capital

Location: Brazil, Turkey, Indonesia, China

Trial identifier: NCT04456595 (Phase 3), NCT04352608 (Phase 2), NCT04508075 (Phase 3), NCT04551547 (Phase 1/2), NCT04383574 (Phase 1/2), NCT04582344 (Phase 3)

Description: CoronaVac (Sinovac Life Sciences, Beijing, China) is an inactivated vaccine candidate against COVID-19 that has shown good immunogenicity in mice, rats, and non-human primates with vaccine-induced neutralising antibodies to SARS-CoV-2, which could neutralize ten representative strains of SARS-CoV-2. Moreover, the results indicated CoronaVac provided partial or complete protection in macaques from severe interstitial pneumonia after a SARS-CoV-2 challenge, without observable antibody-dependent enhancement of infection, which support progression to clinical trials in humans.

The candidate was granted an emergency use authorisation by Chinese authorities in July 2020, before the initiation of phase 3 studies. This authorisation reportedly resulted in nearly 90% of company employees being immunised with the vaccine.

Phase 1/2 clinical trials, which enrolled healthy volunteers aged 18–59 years, have been completed (eg, NCT04352608). The phase 1 trial included 143 participants. In the phase 2 trial, 600 participants were randomly assigned to receive, in two intramuscular injections, either 3 μg per 0·5 mL or 6 μg per 0·5 mL of the trial vaccine, or placebo, either on day 0 and day 14, or on day 0 and day 28. No serious adverse events were reported. The vaccine elicited anti-RBD antibodies, as measured by ELISA, and neutralising antibodies 14 days after the second dose of vaccine in 92·4% of individuals receiving the vaccine at 0 and 14 days, and in 97·4% of those receiving the vaccine at 0 and 28 days. Importantly, neutralising antibody responses were significantly higher in younger adults (aged 18–39 years) than in older adults (aged 40–59 years), and stronger responses were noted in participants given the second dose on day 28 than in those given the second dose on day 14. A phase 3 trial was launched in Brazil and Indonesia, with the trial in Brazil aiming to enrol 9000 health-care personnel.

Sinovac announced on 23 September that CoronaVac was approved by the National Medical Products Administration (NMPA) for clinical trial in adolescents and children. This randomized, double-blinded, and placebo-controlled phase I/II clinical trial among adolescents and children between the ages of 3-17 years old was approved by the Ethics Committee of the Hebei Provincial CDC on September 11, 2020, with the trial expected to commence soon. In this clinical trial, low dosage (300SU/dose) and medium dosage (600SU/dose) with two-dose immunization scheduled at 28-day intervals will be adapted.

As per news reports, research with 50,027 volunteers in China showed that the Coronavac vaccine did not show significant adverse reactions. Among people over 60 (422 volunteers), the results showed 97% effectiveness. Instituto Butantan is conducting clinical trials of the vaccine in phase 3 in Brazil on almost 6,000 volunteers. In Brazil, the vaccine was applied to almost 5,600 volunteers with no record of serious adverse reaction.

Status: CoronaVac triggered a quick immune response but the level of antibodies produced was lower than in convalescent individuals, as per preliminary trial results published on November 17, 202o. While the early to mid-stage trials were not designed to assess the efficacy of CoronaVac, the team suggest it could provide enough protection, based on their experience with other vaccines and data from preclinical studies with macaques. The Sinovac findings, published in a peer-reviewed paper in medical journal The Lancet Infectious Diseases, came from results in Phase I and Phase II clinical trials in China involving more than 700 participants.

References:

  • News: In Coronavirus Vaccine Race, China Strays From the Official Paths. The New York Times (07/16/20)
  • Press Release: Sinovac COVID-19 Vaccine Collaboration with Butantan Receives Approval from Brazilian Regulator for Phase III Trial. Businesswire (06 July 2020).
  • Press Release: Sinovac Announces Positive Preliminary Results of Phase I/II Clinical Trials for Inactivated Vaccine Candidate Against COVID-19. Sinovac (06/13/20).
  • Press Release:  Sinovac and Butantan Join Efforts to Advance the Clinical Development of An Inactivated Vaccine for COVID-19 to Phase III (06/11/20).
  • Publication: Development of an inactivated vaccine candidate for SARS-CoV-2. Science (07/03/20).
  • Preprint: Immunogenicity and Safety of a SARS-CoV-2 Inactivated Vaccine in Healthy Adults Aged 18-59 years: Report of the Randomized, Double-blind, and Placebo-controlled Phase 2 Clinical Trial. medRxiv (08/11/20).
  • News: Sinovac’s vaccine reportedly shows low adverse events following emergency use authorization. News (08/31/20).
  • News: Brazil trials of Sinovac COVID-19 vaccine show promising results: Governor. CNBC (09/10/20).
  • Press Release: Sinovac’s Coronavac, SARS-CoV-2 Vaccine (Vero Cell), Inactivated, Announces Approval for Phase I/II Clinical Trial in Adolescents and Children. Businesswire (09/23/20).
  • News: Study of more than 50,000 volunteers in China shows Coronavac safety. Sao Paulo’s State Government (09/23/20).
  • Press Release: Sinovac’s Coronavac, SARS-CoV-2 Vaccine (Vero Cell), Inactivated, Announces Approval for Phase I/II Clinical Trial in Adolescents and Children. Businesswire (09/23/20).
  • Publication: Double-Blind, Randomized, Placebo-Controlled Phase III Clinical Trial to Evaluate the Efficacy and Safety of treating Healthcare Professionals with the Adsorbed COVID-19 (Inactivated) Vaccine Manufactured by Sinovac – PROFISCOV: A structured summary of a study protocol for a randomised controlled trial. BMC Trials (10/15/20).
  • Publication: Safety, tolerability, and immunogenicity of an inactivated SARS-CoV-2 vaccine in healthy adults aged 18–59 years: a randomised, double-blind, placebo-controlled, phase 1/2 clinical trial. The Lancet Infectious Diseases (11/17/20).

Candidate: Inactivated SARS-CoV-2 vaccine BBIBP-CorV

Sponsors/Developers: Sinopharm, Wuhan Institute of Biological Products, China National Biotec Group Company Limited, G42 Healthcare company, Abu Dhabi Health Services Company

Location: UAE, Bahrain, Peru, Morocco, Argentina

Trial identifier: ChiCTR2000034780 (Phase 3); ChiCTR2000032459 (phase 1/2); NCT04510207 (Phase 3); NCT04560881 (Phase 3); ChiCTR2000039000 (Phase 3); NCT04612972 (Phase 3)

Description: Three SARS-CoV-2 strains from the BAL samples or throat swabs of 3 hospitalized patients from the recent COVID-19 outbreak were isolated to develop preclinical in vitro neutralization and challenge models for an inactivated SARS-CoV-2 vaccine candidate (from Vero cells). The 19nCoV-CDC-Tan-HB02 (HB02) strain showed the most optimal replication and generated highest virus yields in Vero cells among three viral strains and was used for the further development of the inactivated SARS-CoV-2 vaccine (BBIBP-CorV). BBIBP-CorV induced high levels of neutralizing antibodies titers in animal models. Two-dose immunization with 2 ug/dose BBIBP-CorV efficiently protects rhesus macaques. It is efficiently produced, genetically stable, and seems to be safe in animals

The first WHO enlisted global clinical Phase III trial of Sinopharm CNBG’s inactivated vaccine to combat COVID-19 started in July in Abu Dhabi. UAE Health Authorities issued a permit for up to 15,000 volunteers to participate and G42 Healthcare and SEHA are working towards achieving a minimum of 5,000 participants for the trials. Sinopharm launched the Phase 3 trials in the UAE in July, and in Peru and Morocco the following month. Sinopharm’s chairman said in August that the vaccine could potentially be ready for public use by the end of 2020.

As on August 12, 2020, the Phase III trials of the inactivated vaccine in the UAE have reached the target of 15,000 volunteers in less than a month, with individuals from 102 nationalities participating in the program. Sinopharm Group Biological Products, noted, “The speed of these trials to date and the incredible diversity of volunteers who have been vaccinated has fully reinforced our decision that the UAE was a perfect location to test our inactivated vaccine and reach the widest demographic range of volunteers.”.

The report on the preliminary assessment of the safety outcomes 28 days and immunogenicity outcomes 14 days after 3 doses in a phase 1 trial and 2 doses in a phase 2 trial of an inactivated COVID-19 vaccine candidate in healthy adults in China was published on August 13, 2020. Patients had a low rate of adverse reactions (only 15% of people in total; fever = 3%) and demonstrated immunogenicity; the study is ongoing. Efficacy and longer-term adverse event assessment will require phase 3 trials. A phase 3 trial has been initiated (ChiCTR2000034780), which will provide information on immune persistence and efficacy.

The UAE’s phase 3 trial was fully recruited by August 30 with 31,000 people having participated altogether since July 16, with 120 nationalities. The UAE had granted an Emergency Use Authorization six weeks after late-stage studies began. The health authorities said the experimental vaccine would be administered to frontline healthcare workers who are dealing with cases of COVID-19 and are at higher risk of exposure.

Nearly one million people have taken an experimental coronavirus vaccine developed by China National Pharmaceutical Group (Sinopharm) through the country’s emergency use programme, the firm said. No serious adverse reaction has been reported from those who received the vaccine in emergency use, Sinopharm said in an article on social media WeChat, citing Chairman Liu Jingzhen from a recent media interview. The experimental vaccines are undergoing Phase 3 clinical trials overseas that have recruited nearly 60,000 people, and blood samples of more than 40,000 participants have been taken 14 days after they took the second dose, the article said.

Status: On January 6, 2021, Sinopharm, said that a vaccine candidate had an efficacy rate of 79 percent based on an interim analysis of Phase 3 trials and it had filed an application with Chinese regulators to allow the vaccine to be used broadly, and on January 7, 2021 the government said the vaccine had been granted conditional approval.

Sinopharm’s COVID-19 vaccine BBIBP-CorV remained active against South Africa variant 501Y.V2 with 10 amino acids in spike protein as published in a preprint on February 2, 2021. Global concerns have been raised for its potential to affect vaccine efficacy. The neutralization activities of the vaccine was evaluated against 501Y.V2. Encouragingly, vaccine largely preserved neutralizing titres, with slightly reduction, against 501Y.V2 authentic virus compare to their titres against both original SARS-CoV-2 and the currently circulating D614G virus. These data indicated that 501Y.V2 variant will not escape the immunity induced by the vaccine.

References:

  • Publication: Development of an Inactivated Vaccine Candidate, BBIBP-CorV, with Potent Protection against SARS-CoV-2. Cell (08/06/20).
  • Publication: Effect of an Inactivated Vaccine Against SARS-CoV-2 on Safety and Immunogenicity Outcomes: Interim Analysis of 2 Randomized Clinical Trials. JAMA (08/13/20).
  • Publication: Safety and immunogenicity of an inactivated SARS-CoV-2 vaccine, BBIBP-CorV: a randomised, double-blind, placebo-controlled, phase 1/2 trial. The Lancet Infectious Diseases (10/15/20).
  • News: World’s First Phase III Clinical Trial of COVID-19 Inactivated Vaccine Begins in UAE. Businesswire (07/17/20).
  • News: UAE’s phase III Covid-19 inactivated vaccine trial (Sinopharm) reaches milestone of 15,000 volunteers. Khaleejtimes (08/12/20).
  • News: China Sinopharm’s COVID-19 vaccine starts phase-3 clinical trials in Argentina. CGTN (08/22/20).
  • News: Bahrain starts Phase III trial of Sinopharm’s Covid-19 vaccine. Clinicaltrialsarena (08/24/20).
  • News: 31,000 volunteers take part in UAE vaccine trials. The National (08/24/20).
  • News: UAE announces emergency approval for use of COVID-19 vaccine. BioSpace (09/14/20).
  • News: China Sinopharm’s coronavirus vaccine taken by about a million people in emergency use. Reuters (11/19/20).
  • Press release: China Approves Covid-19 Vaccine as It Moves to Inoculate Millions. nytimes (01/06/21).
  • Publication: Neutralization of SARS-CoV-2 VOC 501Y.V2 by human antisera elicited by both 2 inactivated BBIBP-CorV and recombinant dimeric RBD ZF2001 vaccines. Biorxiv. (02/02/21).

Candidate: Sputnik V (Gam-COVID-Vac)

Sponsors/Developers: Gamaleya National Research Institute of Epidemiology and Microbiology

Location: Russia, a number of Middle Eastern (UAE and Saudi Arabia), and Latin American countries (Brazil and Mexico).

Trial identifier: NCT04437875 (Phase 1/2), NCT04436471 (Phase 1/2), NCT04530396 (Phase 3)

Description: Russian adenovirus vector-based vaccine was registered by the Russian Ministry of Health on August 11 and became the first registered COVID-19 vaccine on the market. The Gamaleya Center successfully developed and registered an adenoviral vector-based vaccine against Ebola. Another adenoviral vector-based vaccine against Middle East Respiratory Syndrome (MERS) is in advanced stages of clinical trials.

As per the developers, Phase 1 and 2 clinical trials of the vaccine have been completed on August 1, 2020. All the volunteers are feeling well, no unforeseen or unwanted side effects were observed. The vaccine induced strong antibody and cellular immune response. Not a single participant of the current clinical trials got infected with COVID-19 after being administered with the vaccine. The high efficacy of the vaccine was confirmed by high precision tests for antibodies in the blood serum of volunteers (including an analysis for antibodies that neutralize the coronavirus), as well as the ability of the immune cells of the volunteers to activate in response to the spike S protein of the coronavirus, which indicates the formation of both antibody and cellular immune vaccine response.

Phase 3 clinical trial involving more than 2,000 people in Russia, a number of Middle Eastern (UAE and Saudi Arabia), and Latin American countries (Brazil and Mexico) will start on August 12.

Russia has released no scientific data on its testing and experts are unable to verify the vaccine’s claimed safety or effectiveness.

On August 28, 2020, the trial was registered for Phase 3 – 40,000 participants, limited outcome measures, including adults with no upper age restriction, to be conducted in Russia.

NCT04436471 and NCT04437875: Two open, non-randomised phase 1/2 studies at two hospitals in Russia (76 participants to the two studies) – A heterologous COVID-19 vaccine consisting of two components, a recombinant adenovirus type 26 (rAd26) vector and a recombinant adenovirus type 5 (rAd5) vector, both carrying the gene for SARS-CoV-2 spike glycoprotein (rAd26-S and rAd5-S). The heterologous rAd26 and rAd5 vector-based COVID-19 vaccine has a good safety profile and induced strong humoral and cellular immune responses in participants.

Status: On February 20, 2021, in a Lancet study, Sputnik V COVID-19 vaccine candidate appears safe and effective in interim results from a phase 3 trial. The interim report of the phase 3 data presented includes results for more than 20 000 participants, 75% of whom were assigned to receive the vaccine, and the follow-up for adverse events and infection. With a planned study power of 85%, those recruited were aged 18 years and older, were about 60% male, and were almost all white. Comorbidities, a known risk for COVID-19 severity, were present in about a quarter of those who entered the trial. 62 (1·3%) of 4902 individuals in the placebo group and 16 (0·1%) of 14 964 participants in the vaccine group had confirmed SARS-CoV-2 infection from day 21 after first vaccine dose (the primary outcome). A time-resolved plot of the incidence rate in the two groups showed that the immunity required to prevent disease arose within 18 days of the first dose. Vaccine efficacy, based on the numbers of confirmed COVID-19 cases from 21 days after the first dose of vaccine, is reported as 91·6%, and the suggested lessening of disease severity after one dose is particularly encouraging for current dose-sparing strategies.

References:

  • Sputnik Vaccine official website.
  • Publication: Safety and immunogenicity of an rAd26 and rAd5 vector-based heterologous prime-boost COVID-19 vaccine in two formulations: two open, non-randomised phase 1/2 studies from Russia. Lancet (09/04/20).
  • News: The first batch of the Sputnik V coronavirus vaccine released into civil circulation Ministry of Health of the Russian Federation (09/08/20)
  • Publication: Sputnik V COVID-19 vaccine candidate appears safe and effective. The Lancet.  (02/20/21).

Candidate: Recombinant Protein Vaccine formulation 1 or 2 with adjuvant 1 or 2, or without adjuvant.

Sponsors/Developers: Sanofi Pasteur, GlaxoSmithKline.

Location: United States.

Trial Identifier: NCT04537208 (Phase 1/2)

Description: Pre-clinical studies showed promising safety and immunogenicity. The Phase 1/2 clinical trial is a randomised, double blind and placebo-controlled trial designed to evaluate the safety, reactogenicity (tolerability) and immunogenicity (immune response) of the COVID-19 vaccine candidate. A total of 440 healthy adults are being enrolled in the trial across 11 investigational sites in the United States. Pending positive Phase 1/2 data, companies aim to move into Phase 3 by end of 2020. The Companies anticipate first results in early December 2020, to support the initiation of a Phase 3 trial in December 2020.  If these data are sufficient for licensure application, it is planned to request regulatory approval in the first half of 2021. Sanofi and GSK are scaling up manufacturing of the antigen and adjuvant with the target of producing up to one billion doses in 2021.

The partners plan to supply a significant portion of total worldwide available supply in 2021/2022 to COVAX, the vaccines pillar of the ACT-Accelerator (Access to COVID‐19 Tools), a global collaboration of leaders of governments, global health organisations, businesses and philanthropies to accelerate development, production, and equitable access to COVID-19 tests, treatments, and vaccines.

Status: On 22 February, 2021, Sanofi and GSK initiate new Phase 2 study of their adjuvanted recombinant protein-based COVID-19 vaccine candidate as stated by a press release of GSK. New Phase 2 study assesses potential for refined antigen formulation to achieve optimal immune response, including in older adults. Results of the Phase 2 trial will inform the Phase 3 protocol. In parallel, development work on new SARS-CoV-2 variants underway.

References:

  • Press Relase: Sanofi and GSK initiate Phase 1/2 clinical trial of COVID-19 adjuvanted recombinant protein-based vaccine candidate (09/03/20).
  • Press Release: Sanofi and GSK to join forces in unprecedented vaccine collaboration to fight COVID-19 (04/14/20).
  • Press Relase: Sanofi and GSK initiate new Phase 2 study of their adjuvanted recombinant protein-based COVID-19 vaccine candidate.  GSK (02/22/21).

Candidate: Non-replicating viral vector (Adenovirus type 5 vector) vaccine

Sponsors/Developers: CanSino Biologics | Beijing Institute of Biotechnology (Beijing); Jiangsu Province CDC, Hubei Provincial CDC, Zhongnan Hospital, Canadian Center for Vaccinology

Location: China, Canada, Pakistan

Trial identifier: LIMITED APPROVAL (Military use only). NCT04313127 (Phase 1), NCT04398147 (Phase 2, Canada), NCT04341389 (Phase 2, China), NCT04526990 (Phase 3, Pakistan)

Description: Recombinant adenovirus type 5 (Ad5) vector expressing the SARS-CoV-2 S protein: The vaccine is a replication defective Ad5 vectored vaccine expressing the spike glycoprotein of SARS-CoV-2. An optimised full-length spike gene based on Wuhan-Hu-1 (GenBank accession number YP_009724390) was cloned with the tissue plasminogen activator signal peptide gene into an E1 and E3 deleted Ad5 vector and constructed the Ad5 vectored COVID-19 vaccine using the Admax system from Microbix Biosystem (Toronto, ON, Canada). The Ad5 vectored COVID-19 vaccine was manufactured as a liquid formulation containing 5×1010 viral particles per 0.5 mL in a vial.

On Monday, June 29, the company developing a vaccine called Ad5-nCoV, CanSino, announced it had been authorized for use in the military by the country’s Central Military Commission. On 20 July 2020, results were published for the randomized, double-blind, placebo-controlled, phase 2 trial of the candidate non-replicating adenovirus type-5 (Ad5)-vectored COVID-19 vaccine was done in a single center in Wuhan, China (ClinicalTrials.gov, NCT04341389). 508 participants were randomly assigned to receive the vaccine (1x10E11 viral particles n=253; 5x10E11 viral particles n=129) or placebo (n=126). Both doses of the vaccine induced significant neutralizing antibody responses to live SARS-CoV-2. Specific interferon gamma enzyme-linked immunospot assay responses post vaccination was observed in 227 (90%) and 113 (88%) of viral particles dose groups. Severe adverse reactions were observed in 24 (9%) participants and one (1%) participant respectively.

CanSino’s Phase 3 trial was registered on 26 August 2020, with 40000 target participants, centered out of Pakistan. On August 20, another phase 3 trial was announced by CanSino: 10,000 participants this time. This is in addition to the 5000 in Saudi Arabia, 625 in Russia and unknown number in Mexico: their goal was 40000.

The Phase III trial of the Ad5-nCoV vaccine candidate has been launched in Moscow, following health ministry authorization. CanSino will work with NPO Petrovax Pharm to conduct the trials in Russia. The Russian approval comes after CanSino and the National Research Council (NRC) of Canada terminated their collaboration on the development of the vaccine. CanSino plans to test its vaccine candidate in multiple countries globally.

Status: On February 1, 2021, CanSino announced, its COVID-19 vaccine has no serious adverse events and met efficacy criteria in interim analysis. The Chinese biopharmaceutical company will continue to advance its phase III clinical trial of the vaccine. The phase III clinical trial of Ad5-nCoV saw more than 40,000 volunteers administered with the vaccine in 78 clinical trial sites across 5 countries in 3 continents. Unlike inactivated vaccines, Cansino’s vaccine is effective with a single dose and can bring dual protection – humoral and cellular immunity – at the same time. Ad5-nCoV’s phase II and III trials all involved aged participants and saw no serious adverse reactions, demonstrating that it is safe for the elderly. The vaccine can be stored and transported at temperatures of between 2- and 8-degree C, and production does not require biosafety level three laboratories, which is the case with inactivated vaccines.

References:

  • Publication: Safety, tolerability, and immunogenicity of a recombinant adenovirus type-5 vectored COVID-19 vaccine: a dose-escalation, open-label, non-randomised, first-in-human trial The Lancet (06/13/20).
  • Preprint: A single dose of an adenovirus-vectored vaccine provides complete protection of the upper and lower respiratory tracts against SARS-CoV-2 challenge (06/18/20).
  • Publication: Immunogenicity and safety of a recombinant adenovirus type-5-vectored COVID-19 vaccine in healthy adults aged 18 years or older: a randomised, double-blind, placebo-controlled, phase 2 trial. The Lancet. (07/20/20).
  • News: CanSino has its 1st phase 3 trial Covid-19 vaccine partner (Saudi Arabia & 5,000 people) (08/10/20).
  • Publication: A single dose of an adenovirus-vectored vaccine provides protection against SARS-CoV-2 challenge. Nature (08/14/20).
  • News: Pakistan gives go-ahead to Phase 3 COVID-19 vaccine trial (08/20/20).
  • News: Russia approves Phase III trial of CanSino’s Covid-19 vaccine (09/02/20).
  • Press Relase: CanSino says its COVID-19 vaccine has no serious adverse events, meets efficacy criteria in interim analysis. Global Times (02/01/21).

Updated: 14 June, 2021.

Table: Summary of all vaccine candidates under evaluation – 100 clinical and 184 pre-clinical (as of May 13, 2021).

COVID-19 vaccine efficiencies

Vaccine efficiencies (VE) have been collected from publications and reports for the COVID-19 vaccines that are being globally rolled out on a massive scale. Efficiencies against various stages of the disease (Severe, Moderate, Mild), other determinants of severity (hospitalization, death), locations of the trial or study, dose dependencies, sample numbers as well as other relevant additional details are mentioned (Table 1).

Table 1: VE for top candidates.


The percentages of vaccine effectiveness (%) for major variants of concern (VoC) are listed in Table 2. The COVID-19 variants have been relabeled according to current WHO relabeling & definitions. According to the new naming system, the variant B.1.1.7 that was first discovered in the United Kingdom is now called Alpha, B.1.351 variant that was discovered first in South Africa is called Beta, and B.1.617.2 variant that was discovered in India is called Delta.

Table 2: VE for top candidates for WHO designated Variants of Concern (VoC).


References:

1. Publication: Safety and Efficacy of the BNT162b2 mRNA Covid-19 Vaccine. NEJM (31-Dec-20). https://doi.org/10.1056/NEJMoa2034577.

2. Publication: Efficacy and Safety of the mRNA-1273 SARS-CoV-2 Vaccine. NEJM (04-Feb-21). https://doi.org/10.1056/NEJMoa2035389.

3. PressRelease: SINOVAC: Provide vaccines for humans to eliminate diseases. Sinovac (05-Feb-21). http://www.sinovac.com/news/shownews.php?id=426.

4. Publication: Single-dose administration and the influence of the timing of the booster dose on immunogenicity and efficacy of ChAdOx1 nCoV-19 (AZD1222) vaccine: a pooled analysis of four randomised trials. ScienceDirect (19-Feb-21). https://doi.org/10.1016/S0140-6736(21)00432-3.

5. Publication: Safety and efficacy of an rAd26 and rAd5 vector-based heterologous prime-boost COVID-19 vaccine: an interim analysis of a randomised controlled phase 3 trial in Russia. ScienceDirect (20-Feb-21). https://doi.org/10.1016/S0140-6736(21)00234-8.

6. Publication: Effectiveness of the Pfizer-BioNTech COVID-19 Vaccine Among Residents of Two Skilled Nursing Facilities Experiencing COVID-19 Outbreaks — Connecticut, December 2020–February 2021. MMWR (15-Mar-21). https://www.cdc.gov/mmwr/volumes/70/wr/mm7011e3.htm.

7. News: CanSinoBIO Announces Approval for its Single-Dose COVID-19 Vaccine Convidecia in Hungary. PRNewsWire (22-Mar-21). https://www.prnewswire.com/news-releases/cansinobio-announces-approval-for-its-single-dose-covid-19-vaccine-convidecia-in-hungary-301252978.html.

8. News: Covid-19: Pfizer reports 100% vaccine efficacy in children aged 12 to 15. The BMJ (01-Apr-21). https://doi.org/10.1136/bmj.n881.

9. Publication: Interim Estimates of Vaccine Effectiveness of BNT162b2 and mRNA-1273 COVID-19 Vaccines in Preventing SARS-CoV-2 Infection Among Health Care Personnel, First Responders, and Other Essential and Frontline Workers — Eight U.S. Locations, December 2020–March 2021. MMWR (02-Apr-21). https://dx.doi.org/10.15585%2Fmmwr.mm7013e3.

10. Others: Background document on the inactivated vaccine Sinovac-CoronaVac against COVID-19. WHO (05-Apr-21). https://www.who.int/publications/i/item/WHO-2019-nCoV-vaccines-SAGE_recommendation-Sinovac-CoronaVac-background-2021.1.

11. Preprint: Effectiveness of CoronaVac in the setting of high SARS-CoV-2 P.1 variant transmission in Brazil: A test-negative case-control study. medRxiv (07-Apr-21). https://doi.org/10.1101/2021.04.07.21255081.

12. Publication: Efficacy of ChAdOx1 nCoV-19 (AZD1222) vaccine against SARS-CoV-2 variant of concern 202012/01 (B.1.1.7): an exploratory analysis of a randomised controlled trial. ScienceDirect (10-Apr-21). https://doi.org/10.1016/S0140-6736(21)00628-0.

13. Preprint: Efficacy and Safety of a COVID-19 Inactivated Vaccine in Healthcare Professionals in Brazil: The PROFISCOV Study. SSRN Preprint (14-Apr-21). http://dx.doi.org/10.2139/ssrn.3822780.

14. Publication: BNT162b2 mRNA Covid-19 Vaccine in a Nationwide Mass Vaccination Setting. NEJM (15-Apr-21). https://doi.org/10.1056/NEJMoa2101765.

15. Preprint: Performance of vaccination with CoronaVac in a cohort of healthcare workers (HCW) – preliminary report. medRxiv (15-Apr-21). https://doi.org/10.1101/2021.04.12.21255308.

16. Others: Effectiveness of the inactivated CoronaVac vaccine against SARSCoV-2 in Chile. Chile Ministry of Health (16-Apr-21). https://www.minsal.cl/wp-content/uploads/2021/04/Effectiveness-of-the-inactivated-CoronaVac-vaccine-against-SARS-CoV-2-in-Chile.pdf.

17. PressRelease: Sputnik V demonstrates 97.6% efficacy according to analysis of data from 3.8 million vaccinated persons in Russia making it the most efficient COVID-19 vaccine in the world. Official website vaccine against COVID-19 Sputnik V. (19-Apr-21). https://sputnikvaccine.com/newsroom/pressreleases/sputnik-v-demonstrates-97-6-efficacy-according-to-the-analysis-of-data-of-3-8-million-vaccinated-per/.

18. Preprint: Effectiveness of the BNT162b2 vaccine in preventing COVID-19 in the working age population – first results from a cohort study in Southern Sweden. medRxiv (21-Apr-21). https://doi.org/10.1101/2021.04.20.21254636.

19. Publication: Safety and Efficacy of Single-Dose Ad26.COV2.S Vaccine against Covid-19. NEJM (21-Apr-21). https://dx.doi.org/10.1056/NEJMoa2101544.

20. PressRelease: Bharat Biotech and ICMR Announce Interim Results from Phase 3 trials of COVAXIN; Demonstrates overall Interim Clinical Efficacy of 78% and 100% efficacy against Severe COVID-19 disease. Bharat Biotech (21-Apr-21). https://www.bharatbiotech.com/images/press/covaxin-phase3-clinical-trials-interim-results.pdf.

21. Publication: Interim findings from first-dose mass COVID-19 vaccination roll-out and COVID-19 hospital admissions in Scotland: a national prospective cohort study. ScienceDirect (23-Apr-21). https://doi.org/10.1016/S0140-6736(21)00677-2.

22. Publication: COVID-19 vaccine coverage in health-care workers in England and effectiveness of BNT162b2 mRNA vaccine against infection (SIREN): a prospective, multicentre, cohort study. ScienceDirect (23-Apr-21). https://doi.org/10.1016/S0140-6736(21)00790-X.

23. Others: WHO Evidence Assessment: Sinopharm/BBIBP COVID-19 vaccine. WHO (29-Apr-21). https://cdn.who.int/media/docs/default-source/immunization/sage/2021/april/2_sage29apr2021_critical-evidence_sinopharm.pdf.

24. Preprint: Real-world effectiveness of Ad26.COV2.S adenoviral vector vaccine for COVID-19. medRxiv (30-Apr-21). https://doi.org/10.1101/2021.04.27.21256193.

25. Publication: Effectiveness of the BNT162b2 Covid-19 Vaccine against the B.1.1.7 and B.1.351 Variants. NEJM (05-May-21). https://doi.org/10.1056/NEJMc2104974.

26. News: Indonesia study finds China’s Sinovac COVID-19 vaccine effective in medical staff. Reuters (12-May-21). https://www.reuters.com/business/healthcare-pharmaceuticals/indonesia-study-finds-chinas-sinovac-covid-19-vaccine-effective-medical-staff-2021-05-12/.

27. Publication: Effectiveness of the Pfizer-BioNTech and Oxford-AstraZeneca vaccines on covid-19 related symptoms, hospital admissions, and mortality in older adults in England: test negative case-control study. The BMJ (13-May-21). https://doi.org/10.1136/bmj.n1088.

28. Preprint: Efficacy of the NVX-CoV2373 Covid-19 Vaccine Against the B.1.1.7 Variant. medRxiv (14-May-21). https://doi.org/10.1101/2021.05.13.21256639.

29. Publication: Efficacy of the ChAdOx1 nCoV-19 Covid-19 Vaccine against the B.1.351 Variant. NEJM (20-May-21). https://doi.org/10.1056/NEJMoa2102214.

30. Publication: Efficacy of NVX-CoV2373 Covid-19 Vaccine against the B.1.351 Variant. NEJM (20-May-21). https://doi.org/10.1056/NEJMoa2103055.

31. Preprint: Effectiveness of the CoronaVac vaccine in the elderly population during a P.1 variant-associated epidemic of COVID-19 in Brazil: A test-negative case-control study. medRxiv (21-May-21). https://doi.org/10.1101/2021.05.19.21257472.

32. PressRelease: Bharat Biotech Announces Phase 3 Results of COVAXIN: India’s First COVID-19 Vaccine Demonstrates Interim Clinical Efficacy of 81%. Bharat Biotech (22-May-21). https://www.bharatbiotech.com/images/press/covaxin-phase3-efficacy-results.pdf.

33. Publication: Effectiveness of COVID-19 vaccines against the B.1.617.2 variant. medRxiv (24-May-21). https://doi.org/10.1101/2021.05.22.21257658.

34. PressRelease: Moderna Announces TeenCOVE Study of its COVID-19 Vaccine in Adolescents Meets Primary Endpoint and Plans to Submit Data to Regulators in Early June. Moderna, Inc. (25-May-21). https://investors.modernatx.com/news-releases/news-release-details/moderna-announces-teencove-study-its-covid-19-vaccine.

35. Publication: Effect of 2 Inactivated SARS-CoV-2 Vaccines on Symptomatic COVID-19 Infection in Adults: A Randomized Clinical Trial. JAMA (26-May-21). http://dx.doi.org/10.1001/jama.2021.8565.

36. Publication: Safety, Immunogenicity, and Efficacy of the BNT162b2 Covid-19 Vaccine in Adolescents. NEJM (27-May-21). https://doi.org/10.1056/NEJMoa2107456.

37. Preprint: Vaccine effectiveness of the BNT162b2 mRNA COVID-19 vaccine against RT-PCR confirmed SARS-CoV-2 infections, hospitalisations and mortality in prioritised risk groups. medRxiv (02-Jun-21). https://doi.org/10.1101/2021.05.27.21257583.

38. Publication: Assessment of Effectiveness of 1 Dose of BNT162b2 Vaccine for SARS-CoV-2 Infection 13 to 24 Days After Immunization. JAMA (07-Jun-21). http://dx.doi.org/10.1001/jamanetworkopen.2021.15985.

Updated: 09 June, 2021.

  • Celltrion announces positive top-line results from global Phase III trial of regdanvimab (CT-P59), an anti-COVID-19 monoclonal antibody treatment [Link] (06/14/21)
  • REGEN-COV Antibody Cocktail in Outpatients with Covid-19 [Link] (06/14/21)
  • Sorrento Receives Authorization From the UK Regulatory Agency to Conduct a Phase 2 Clinical Trial for COVI-DROPS in an Outpatient Setting [Link] (06/14/21)
  • Bovine Colostrum Derived Antibodies Against SARS-CoV-2 Show Great Potential to Serve as a Prophylactic Agent [Link] (06/14/21)
  • Second Generation Antibodies Neutralize Emerging SARS-CoV-2 Variants of Concern [Link] (06/14/21)
  • Intranasal administration of a monoclonal neutralizing antibody protects mice against SARS-CoV-2 infection [Link] (06/14/21)
  • Namilumab or infliximab compared to standard of care in hospitalised patients with COVID-19 (CATALYST): a phase 2 randomised adaptive trial [Link] (06/14/21)
  • Single domain shark VNAR antibodies neutralize SARS-CoV-2 infection in vitro [Link] (06/14/21)
  • Nanobodies from camelid mice and llamas neutralize SARS-CoV-2 variants [Link] (06/10/21)
  • FDA Authorizes Lower 1,200 mg Intravenous and Subcutaneous Dose of REGEN-COV (casirivimab and imdevimab) Antibody Cocktail to Treat Patients with COVID-19 [Link] (06/07/21)
  • Centivax and US Naval Medical Research Center to begin Phase I clinical trial of antibody therapeutics [Link] (06/07/21)
  • Nasal delivery of an IgM offers broad protection from SARS-CoV-2 variants [Link] (06/07/21)
  • Effect of Bamlanivimab vs Placebo on Incidence of COVID-19 Among Residents and Staff of Skilled Nursing and Assisted Living Facilities: A Randomized Clinical Trial [Link] (06/07/21)
  • Broadening a SARS-CoV-1 neutralizing antibody for potent SARS-CoV-2 neutralization through directed evolution [Link] (06/02/21)
  • Humanigen Submits Application to FDA for Emergency Use Authorization for Lenzilumab in COVID-19 [Link] (06/02/21)
  • Biomm to seek ANVISA approval for Phase III Covid-19 trials [Link] (06/02/21)
  • Early Covid-19 Treatment With SARS-CoV-2 Neutralizing Antibody Sotrovimab [Link] (06/02/21)
  • Effective prophylaxis of COVID-19 in rhesus macaques using a combination of two parentally-administered SARS-CoV-2 neutralizing antibodies [Link] (06/02/21)

Monoclonal antibodies provide an alternative avenue for the prevention of COVID-19, as the vaccine development process can take at least 12-18 months. Neutralizing mAbs to SARS-CoV-2 have the potential for both therapeutic and prophylactic applications and can help to guide vaccine design and development. Numerous research groups have isolated mAbs (most often from the B cells of patients who have recently recovered from SARS-CoV-2, and in some cases from individuals who were infected with SARS-CoV in 2003). It is also possible to generate effective mAbs by immunization of humanized mice. Modern methods allow the rapid identification of pathogen-specific B cells and recovery of immunoglobulin heavy chain and light chain genes that can be expressed to produce mAbs, usually in the form of IgG. The main target of SARS-CoV-2 neutralizing mAbs is the surface spike glycoprotein that mediates viral entry into host cells. Essentially all mAbs of interest target this protein. Viral infection is mediated by the interaction between the viral spike and the angiotensin-converting enzyme 2 (ACE 2) receptor found on numerous cell types, but neutralizing mAbs block this event. Immune system of nearly everyone who recovers from COVID-19 produces antibodies against SARS-CoV-2, the novel coronavirus that causes this easily transmitted respiratory disease. mAbs are currently used to treat a variety of conditions, including asthma, cancer, Crohn’s disease, and rheumatoid arthritis. One advantage of this class of therapeutics is that the timelines for their development, testing, and approval are typically shorter than those for drugs made of chemical compounds, called small molecules. Because of these and other factors, many experts think antibody-based therapies may offer one of the best near-term options for developing safe, effective treatments for COVID-19 [1].


Select strategies are detailed in the section below:

Candidate: REGN10933 and REGN10987

Developers: Regeneron Pharmaceuticals

Locations: United States

Clinical Trial IDs: NCT04425629 (Phase 1), NCT04426695 (Phase 1), NCT04519437 (Phase 1)

Description: REGN-COV2 comprises two mABs (REGN10933 and REGN10987) and was designed specifically by Regeneron scientists to block infectivity of SARS-CoV-2, the virus that causes COVID-19. Regeneron scientists evaluated thousands of fully-human antibodies produced by the company’s proprietary VelocImmunemice, which have been genetically-modified to have a human immune system, as well as antibodies isolated from humans who have recovered from COVID-19. They selected the two most potent, non-competing and virus-neutralizing antibodies to create REGN-COV2 and have scaled up this dual-antibody cocktail for clinical use with the company’s in-house VelociMaband manufacturing capabilities. REGN-COV2’s two antibodies bind non-competitively to the critical receptor binding domain of the virus’s spike protein, which diminishes the ability of mutant viruses to escape treatment and protects against spike variants that have arisen in the human population.

Regeneron announced the initiation of  Phase 3 trial will evaluate REGN-COV2’s ability to prevent infection among uninfected people who have had close exposure to a COVID-19 patient (such as the patient’s housemate), and is being run jointly with the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health (NIH). REGN-COV2 has also moved into the Phase 2/3 portion of two adaptive Phase 1/2/3 trials testing the cocktail’s ability to treat hospitalized and non-hospitalized (or “ambulatory”) patients with COVID-19. This clinical progress follows a positive review from the Independent Data Monitoring Committee of REGN-COV2 Phase 1 safety results in an initial cohort of 30 hospitalized and non-hospitalized patients with COVID-19. The Phase 3 prevention trial is being conducted at approximately 100 sites and is expected to enroll 2,000 patients in the U.S.; the trial will assess SARS-CoV-2 infection status. The two Phase 2/3 treatment trials in hospitalized (estimated enrollment =1,850) and non-hospitalized (estimated enrollment =1,050) patients are planned to be conducted at approximately 150 sites in the U.S., Brazil, Mexico and Chile, and will evaluate virologic and clinical endpoints, with preliminary data expected later this summer. All trials are adaptively designed, and the ultimate numbers of patients enrolled will depend on trial progress and insights from Phase 2 studies.

Recent publication from Regeneron shows that REGN-COV2, greatly reduces virus load in lower and upper airway and decreases virus induced pathological sequalae when administered prophylactically or therapeutically in both rhesus macaques and golden hamsters. The ability of REGN-COV2 to almost completely block detection of sgRNA matches or exceeds the effects recently shown in vaccine efficacy studies.

On September 14, 2020, Regeneron Pharmaceuticals, and the University of Oxford announced that RECOVERY, one of the world’s largest randomized clinical trials of potential COVID-19 treatments, will evaluate Regeneron’s investigational anti-viral antibody cocktail, REGN-COV2. The Phase 3 open-label trial in patients hospitalized with COVID-19 will compare the effects of adding REGN-COV2 to the usual standard-of-care versus standard-of-care on its own. The open-label RECOVERY trial will assess the impact of adding REGN-COV2 to the usual standard-of-care on all-cause mortality 28 days after randomization. Other endpoints include the impact on hospital stay and the need for ventilation. It is anticipated that at least 2,000 patients will be randomly allocated to receive REGN-COV2 plus usual standard-of-care, and results will be compared with at least 2,000 patients who receive standard-of-care on its own. Usual standard-of-care varies by local hospital.

Regeneron Pharmaceuticals on October 06 announced the first data from a descriptive analysis of a seamless Phase 1/2/3 trial of its investigational antibody cocktail REGN-COV2 showing it reduced viral load and the time to alleviate symptoms in non-hospitalized patients with COVID-19. REGN-COV2 also showed positive trends in reducing medical visits. The ongoing, randomized, double-blind trial measures the effect of adding REGN-COV2 to usual standard-of-care, compared to adding placebo to standard-of-care.

Regeneron Pharmaceuticals on January 26 announced positive initial results from an ongoing Phase 3 clinical trial evaluating REGEN-COV (casirivimab and imdevimab antibody cocktail) used as a passive vaccine for the prevention of COVID-19 in people at high risk of infection (due to household exposure to a COVID-19 patient). An exploratory analysis was conducted on the first approximately 400 evaluable individuals enrolled in the trial, who were randomized to receive passive vaccination with REGEN-COV (1,200 mg via subcutaneous injections) or placebo. Passive vaccination with REGEN-COV resulted in 100% prevention of symptomatic infection (8/223 placebo vs. 0/186 REGEN-COV), and approximately 50% lower overall rates of infection (symptomatic and asymptomatic) (23/223 placebo vs. 10/186 REGEN-COV).

On 25 February, 2021, Regeneron announced changes to the Phase 3 trial assessing investigational REGEN-COV (casirivimab with imdevimab) in non-hospitalized patients (“outpatients”) with COVID-19, following recommendations from the Independent Data Monitoring Committee (IDMC). The IDMC found clear clinical efficacy on reducing the rate of hospitalization and death with both the 1,200 mg and 2,400 mg doses of REGEN-COV compared to placebo and recommended stopping enrollment into the placebo group. REGEN-COV also effectively neutralizes emerging strains of the virus, which are becoming increasingly common.

Status: On 23 March, 2021, In a phase III trial, Regeneron’s antibody cocktail REGEN-COV, combining casirivimab with imdevimab, reduced hospitalization or death by 70% in nonhospitalized COVID-19 patients, the company announced today. The drug—which was tested in three different doses, all of which showed similar efficacy across all endpoints—also significantly shortened duration of symptoms by 4 days. A parallel phase II trial showed “significant and comparable viral reductions for all REGEN-COV doses tested, including as low as 300 mg,” a press release notes.

References:

  • Press Release: Phase III COVID-19 Prevention Trial with Antibody Cocktail. Regeneron (07/06/20).
  • Publication: Antibody cocktail to SARS-CoV-2 spike protein prevents rapid mutational escape seen with individual antibodies. Science (08/21/20).
  • Publication: Studies in humanized mice and convalescent humans yield a SARS-CoV-2 antibody cocktail. Science (08/21/20).
  • Preprint: REGN-COV2 antibody cocktail prevents and treats SARS-CoV-2 infection in rhesus macaques and hamsters. BioRxiv (08/03/20).
  • Press Release: Recovery covid-19 phase 3 trial to evaluate Regeneron’s REGN-COV2 investigational antibody cocktail in the UK. Regeneron (09/14/20).
  • Press Release: REGENERON’S REGN-COV2 ANTIBODY COCKTAIL REDUCED VIRAL LEVELS AND IMPROVED SYMPTOMS IN NON-HOSPITALIZED COVID-19 PATIENTS. Regeneron. (10/06/20).
  • Press Release: Regeneron Reports Positive Interim Data with REGEN-COV Antibody Cocktail used as Passive Vaccine to Prevent COVID-19. (01/26/21).
  • Press Release: Independent Data Monitoring Committee Finds Clear Efficacy for REGEN-COV (casirivimab with imdevimab) in Phase 3 COVID-19 Outpatient Outcomes Trial. (02/25/21).
  • Press Release: Phase 3 trial shows REGEN-COV (Casirivimab with Imdevimab) antibody cocktail reduced hospitalization or death by 70% in non-hospitalized COVID-19 patients. Regeneron (03/23/21).

Candidate: LY3819253 (Bamlanivimab, LY-CoV555) and LY3832479 (Etesevimab, LY-CoV016, JS016); Mono- and Combination thearapies.

Developers: Eli Lilly, AbCellera, Shanghai Junshi Biosciences, NIAID.

Locations: United States.

Clinical Trial IDs: NCT04441931 (Phase 1), NCT04411628 (Phase 1), BLAZE-2/NCT04497987 (Phase 3), BLAZE-1/NCT04427501 (Phase 2)

Description: LY-CoV555 is a potent, neutralizing IgG1 mAb directed against the spike protein of SARS-CoV-2. It is designed to block viral attachment and entry into human cells, thus neutralizing the virus, potentially preventing and treating COVID-19. Emerged from the collaboration between Lilly and AbCellera to create antibody therapies for the prevention and treatment of COVID-19. Lilly scientists rapidly developed the antibody in less than three months after it was discovered by AbCellera and tested by the scientists at the National Institute of Allergy and Infectious Diseases (NIAID) Vaccine Research Center. It was identified from a blood sample taken from one of the first U.S. patients who recovered from COVID-19.

LY-CoV016 (also known as JS016) is a recombinant fully human monoclonal neutralizing antibody, which specifically binds to the SARS-CoV-2 surface spike protein receptor binding domain with high affinity and can effectively block the binding of the virus to the ACE2 host cell surface receptor. Point mutations were introduced into the native human IgG1 antibody to mitigate effector function. A SARS-CoV-2 challenge study was conducted in rhesus macaques and showed LY-CoV016 is effective for both prophylactic and therapeutic venues against SARS-CoV-2 infection.

Lilly has successfully completed enrollment and primary safety assessments of LY-CoV555 in a Phase 1 study of hospitalized patients with COVID-19 (NCT04411628) and long-term follow-up is ongoing. Lilly has also successfully completed a Phase 1 study (NCT04441931) of LY-CoV016 in healthy U.S. volunteers to evaluate the safety, tolerability, pharmacokinetics and immunogenicity. LY-CoV016 has been well tolerated and no drug-related severe adverse events (SAEs) have been observed to date.

Preprint on Eli Lilly’s candidate mAb reported that high-throughput microfluidic screening of antigen-specific B-cells led to the identification of LY-CoV555, a potent anti-spike neutralizing antibody from a convalescent COVID-19 patient. Biochemical, structural, and functional characterization revealed high-affinity binding to the receptor-binding domain, ACE2 binding inhibition, and potent neutralizing activity. In a rhesus macaque challenge model, prophylaxis doses as low as 2.5 mg/kg reduced viral replication in the upper and lower respiratory tract.

On October 7, 2020, Lilly announced that it has submitted request for emergency use authorization (EUA) for monotherapy to U.S. FDA. New data show combination therapy met primary and secondary endpoints, reducing viral load, symptoms and hospitalizations. Lilly also plans to initiate a large open-label pragmatic study in COVID-19 outpatients in October.

In LY-CoV555 monotherapy studies there have been isolated drug-related infusion reactions or hypersensitivity that were generally mild (two reported as serious infusion reactions, all patients recovered). Treatment emergent adverse events were comparable to placebo for both LY-CoV555 monotherapy and combination therapy.

Combination therapy – Data from a new interim analysis of the BLAZE-1 (NCT04427501) clinical trial showed that combination therapy with two of Lilly’s SARS-CoV-2 neutralizing antibodies reduced viral load, symptoms and COVID-related hospitalization and ER visits. The randomized, double-blind, placebo-controlled Phase 2 study evaluated LY-CoV555 and LY-CoV016, which bind complementary regions of the SARS-CoV-2 spike protein, for the treatment of symptomatic COVID-19 in the outpatient setting. The combination cohort enrolled recently diagnosed patients with mild-to-moderate COVID-19, who were assigned to 2800 mg of each antibody (n=112) or placebo (n=156). The combination therapy significantly reduced viral load at day 11 (p=0.011), meeting the primary endpoint of the study. Most patients, including those receiving placebo, demonstrated near complete viral clearance by day 11. Combination therapy has been generally well tolerated with no drug-related serious adverse events. The BLAZE-1 clinical trial continues to enroll a confirmatory cohort of higher-risk patients who have been recently diagnosed with mild-to-moderate COVID-19.

Other ongoing clinical trials include a Phase 3 study of LY-CoV555 monotherapy for the prevention of COVID-19 in residents and staff at long-term care facilities (BLAZE-2, NCT04497987). In addition, LY-CoV555 monotherapy is being tested in the National Institutes of Health-led ACTIV-2 and ACTIV-3 studies of ambulatory and hospitalized COVID-19 patients.

On January 21, 2021, Lilly announced, Bamlanivimab (LY-CoV555) significantly reduced the risk of contracting symptomatic COVID-19 among residents and staff of long-term care facilities, Eli Lilly and Company announced. The Phase 3 BLAZE-2 COVID-19 prevention trial (BLAZE-2, NCT04497987) – conducted in partnership with the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health (NIH), and the COVID-19 Prevention Network (CoVPN) – enrolled residents and staff at skilled nursing and assisted living facilities, commonly referred to as nursing homes, across the U.S. The 965 participants (299 residents and 666 staff) were randomized to receive either 4,200 mg of bamlanivimab or placebo.

Status: On February 9, 2021, The U.S. FDA granted Emergency Use Authorization (EUA) for investigational bamlanivimab (LY-CoV555) 700 mg and etesevimab (LY-CoV016) 1400 mg together, Eli Lilly and Company announced. This therapy is authorized for the treatment of mild to moderate COVID-19 in patients aged 12 and older who are at high risk for progressing to severe COVID-19 and/or hospitalization.

On March 29, 2021, Eli Lilly, Vir Biotechnology, and GlaxoSmithKline announced topline data from the expanded Phase 2 BLAZE-4 (NCT04634409) trial studying low-risk adult patients with mild to moderate COVID-19. Results showed that investigational bamlanivimab (LY-CoV555) 700 mg co-administered with VIR-7831 (also known as GSK4182136) 500 mg demonstrated a 70 percent (p<0.001) relative reduction in persistently high viral load (> 5.27; cycle threshold value < 27.5) at day 7 compared to placebo, meeting the primary endpoint. In addition, bamlanivimab administered with VIR-7831 demonstrated a statistically significant reduction compared to placebo in the key virologic secondary endpoints of mean change from baseline to days 3, 5 and 7 in SARS-CoV-2 viral load. There were no events for the secondary endpoint of COVID-19 related hospitalization or death by day 29 in either study arm. One patient (in the treatment arm) visited the emergency room for COVID-19 related symptoms. No serious adverse events were seen with co-administration of bamlanivimab and VIR-7831.

References:

  • Press Release: Lilly Begins World’s First Study of a Potential COVID-19 Antibody Treatment in Humans. Eli Lilly (06/01/20).
  • Press Release: Lilly Initiates Phase 3 Trial of LY-CoV555 for Prevention of COVID-19 at Long-Term Care Facilities in Partnership with the National Institute of Allergy and Infectious Diseases (NIAID). Eli Lilly (08/03/20).
  • Press Release: Lilly announces proof of concept data for neutralizing antibody LY-CoV555 in the COVID-19 outpatient setting. Eli Lilly (09/16/20).
  • Preprint: LY-CoV555, a rapidly isolated potent neutralizing antibody, provides protection in a non-human primate model of SARS-CoV-2 infection. bioRxiv (10/01/20).
  • Press Release: Lilly provides comprehensive update on progress of SARS-CoV-2 neutralizing antibody programs. Eli Lilly (10/07/20).
  • Press Release: Lilly’s neutralizing antibody bamlanivimab (LY-CoV555) prevented COVID-19 at nursing homes in the BLAZE-2 trial, reducing risk by up to 80 percent for residents (01/21/21).
  • Press Release: Lilly’s bamlanivimab (LY-CoV555) administered with etesevimab (LY-CoV016) receives FDA emergency use authorization for COVID-19 (02/09/21).
  • Press Release: Lilly, Vir Biotechnology and GSK Announce Positive Topline Data from the Phase 2 BLAZE-4 Trial Evaluating Bamlanivimab with VIR-7831 in Low-Risk Adults with COVID-19. Eli Lilly (03/29/21).

Candidate: Tocilizumab (Actemra/RoActemra)

Developers: Roche, Genentech

Locations: USA, Canada, Denmark, France, Germany, Italy, Netherlands, Spain, UK.

Clinical Trial IDs: COVACTA/NCT04320615 (phase III), REMDACTA/NCT04409262 (phase III), EMPACTA/NCT04372186 (phase III)

Description: Actemra/RoActemra was the first approved anti-IL-6 receptor biologic available in both intravenous and subcutaneous formulations for the treatment of adult patients with moderate-to-severe active rheumatoid arthritis. On 19 March, Roche announced the initiation of COVACTA- a clinical trial to evaluate the safety and efficacy of intravenous Actemra/RoActemra (tocilizumab) plus SoC in hospitalised adult patients with severe COVID-19 pneumonia compared to placebo plus SoC. COVACTA is a double-blind, placebo-controlled phase III study in approximately 450 adult patients hospitalised with severe COVID-19 pneumonia. REMDACTA is a two-armed global phase III, randomised, double-blind, multicentre study to evaluate the efficacy and safety of Actemra/RoActemra plus remdesivir, versus placebo plus remdesivir in hospitalised patients with severe COVID-19 pneumonia receiving Soc.

Genentech’s EMPACTA will evaluate the efficacy and safety of tocilizumab (TCZ) compared with a placebo in combination with standard of care (SOC) in hospitalized participants with COVID-19 pneumonia. EMPACTA is the first global Phase III trial with a focus on enrolling largely underserved and minority patients.

On July 29, 2020, Roche announced that the trial did not meet its primary endpoint of improved clinical status in patients with COVID-19 associated pneumonia, or the key secondary endpoint of reduced patient mortality. The study was the first global, randomised, double-blind, placebo-controlled phase III trial investigating in this setting. Roche remains committed to continuing the clinical trial program to further explore Actemra/RoActemra in other treatment settings, including in combination with an antiviral.

In a preprint published September 12, 2020, authors reported that the COVACTA trial (NCT04320615) in hospitalized COVID-19 pneumonia patients (Overall 452 – 94 tocilizumab-treated and 144 placebo-treated), tocilizumab did not improve clinical status or mortality. Potential benefits in time to hospital discharge and duration of ICU stay are being investigated in ongoing clinical trials.

On September 17, 2020, EMPACTA became the first global Phase III trial to show efficacy with Actemra in COVID-19 associated pneumonia. There was no statistical difference in mortality between patients who received Actemra or placebo. The cumulative proportion of patients who progressed to mechanical ventilation or death by day 28 was 12.2% in the Actemra/RoActemra arm versus 19.3% in the placebo arm. The EMPACTA study did not identify any new safety signals for Actemra/RoActemra. Approximately 85% of the 389 patients were from minority racial and ethnic groups.

In a preprint published February 11, 2021, RECOVERY trial reported that, between 23 April 2020 and 25 January 2021, 4116 adults were included in the assessment of tocilizumab. 596 (29%) of the 2022 patients allocated tocilizumab and 694 (33%) of the 2094 patients allocated to usual care died within 28 days (rate ratio 0.86). Consistent results were seen in all pre-specified subgroups of patients. Patients allocated to tocilizumab were more likely to be discharged from hospital alive within 28 days. Among those not receiving invasive mechanical ventilation at baseline, patients allocated tocilizumab were less likely to reach the composite endpoint of invasive mechanical ventilation or death.

Status: On March 11, 2021, Roche announced the phase III REMDACTA trial of Actemra/RoActemra plus Veklury, compared with remdesivir alone, a combination of the monoclonal antibody tocilizumab and the antiviral remdesivir did not improve time to hospital discharge up to day 28 in patients with severe COVID-19 pneumonia.

References:

  • Publication: Subcutaneous tocilizumab treatment in patients with severe COVID-19–related cytokine release syndrome: An observational cohort study. The Lancet (07/01/20).
  • Press Release: Roche provides an update on the phase III COVACTA trial of Actemra/RoActemra in hospitalised patients with severe COVID-19 associated pneumonia. Roche (07/29/20).
  • Preprint: Tocilizumab in Hospitalized Patients With COVID-19 Pneumonia. medRxiv (9/12/20).
  • Press Release: Genentech’s Phase III EMPACTA Study Showed Actemra Reduced the Likelihood of Needing Mechanical Ventilation in Hospitalized Patients With COVID-19 Associated Pneumonia. Genentech (9/17/20).
  • Preprint: Tocilizumab in patients admitted to hospital with COVID-19 (RECOVERY): preliminary results of a randomised, controlled, open-label, platform trial. medRxiv (02/11/21).
  • Press Release: Roche provides update on the phase III REMDACTA trial of Actemra/RoActemra plus Veklury in patients with severe COVID-19 pneumonia. Roche (03/11/21).

Candidate: COV2-2196 and COV2-2130, AZD7442 (AZD8895 + AZD1061)

Developers: Astrazeneca, Vanderbilt University Medical Center, Parexel

Locations: United Kingdom

Clinical Trial IDs: NCT04507256 (Phase 1)

Description: AZD7442 is a combination of two mAbs derived from convalescent patients with SARS-CoV-2 infection. Discovered by Vanderbilt University Medical Center and licensed to AstraZeneca in June 2020, the mAbs were optimized by AstraZeneca with half-life extension and reduced Fc receptor binding. The half-life extended mAbs should afford at least six months of protection from COVID-19. The mAbs were shown preclinically to block the binding of the SARS-CoV-2 virus to host cells and protect against infection in cell and animal models of disease. The two potently neutralizing monoclonal antibodies, COV2-2196 and COV2-2130, which recognize non-overlapping sites, bound simultaneously to the S protein and neutralized wild-type SARS-CoV-2 virus in a synergistic manner.

On August 25, AstraZeneca began Phase 1 trial for mAbs combination. The trial will evaluate the safety, tolerability and pharmacokinetics of AZD7442. The trial will include up to 48 healthy participants in the UK aged 18 to 55 years and is funded by the Defense Advanced Research Projects Agency (DARPA), part of the US Department of Defense, and the Biomedical Advanced Research and Development Authority (BARDA), part of the Office of the Assistant Secretary for Preparedness and Response at the US Department of Health and Human Services.

Two trials of AZD7442 will enrol over 6,000 adults for the prevention of COVID-19 with additional trials enrolling ~4,000 adults for the treatment of SARS-CoV-2 infections. US Government is set to invest ~$486m for development and supply of up to 100,000 doses and can acquire another one million doses.

Status: On February 8, an international randomized, controlled Phase 3 clinical trial has begun evaluating the safety and efficacy of an investigational long-acting antibody combination for treating people hospitalized with COVID-19. The trial, part of a master protocol known as ACTIV-3, has an adaptive design allowing investigators to add new sub-studies of additional investigational agents. The new sub-study is evaluating AZD7442, an investigational long-acting antibody combination developed by biopharmaceutical company AstraZeneca (Cambridge, United Kingdom).

References:

  • Press Release: Vanderbilt, AstraZeneca collaborate on new COVID-19 antibody research. Astrazeneca (06/09/20).
  • Publication: Potently neutralizing and protective human antibodies against SARS-CoV-2. Nature (07/15/20).
  • Press Release: Phase I clinical trial initiated for monoclonal antibody combination for the prevention and treatment of COVID-19. Astrazeneca (08/25/20).
  • Press Release: COVID-19 Long-Acting AntiBody (LAAB) combination AZD7442 rapidly advances into Phase III clinical trials. AstraZeneca (10/09/20).
  • Press Release: Clinical trial in hospitalized COVID-19 patients evaluates long-acting antibody therapy. NIH (02/08/21).

Candidate: Adalimumab (Humira)

Developers: AbbVie Inc., University of Oxford

Locations: United Kingdom; China

Clinical Trial IDs: ISRCTN33260034 (Phase 2)

Description: Adalimumab is a human recombinant monoclonal antibody directed against the soluble and cell-bound forms of tumor necrosis factor-alpha and has been used for inflammatory conditions. It is approved for use in rheumatoid arthritis, juvenile idiopathic arthritis, ankylosing spondylitis, inflammatory bowel disease, and both the skin and joint manifestations of psoriasis. Recent studies have shown that COVID-19 patients taking anti-TNF drugs are less likely to be hospitalized, the university said.

Data from SECURE-IBD, a coronavirus and IBD database, have shown that of 116 patients on anti-TNF therapy who contracted Covid-19, 99 recovered without hospitalization and one patient died. Meanwhile, in 71 patients who were receiving only 5-aminosalicylates for their underlying inflammatory disease, half recovered without hospitalization and six patients died. This suggests that IBD patients with Covid-19 receiving anti-TNF therapy do not fare worse than those treated with other therapies.

On September 30, 2020, researchers at the University of Oxford announced the start of a new study to explore the effectiveness of the adalimumab as a treatment for patients with COVID-19 in the community, especially care homes. The AVID-CC trial, which will be conducted by Oxford Clinical Trials Research Unit (OCTRU), will enroll up to 750 patients from community care settings throughout the UK.

It is funded by the COVID-19 Therapeutics Accelerator, an initiative set up by Wellcome, the Bill and Melinda Gates Foundation and Mastercard, with support from an array of public and philanthropic donors.

“The observed potential of anti-TNF drugs has prompted us to conduct a study in patients in community care to see whether treatment with the anti-TNF drug adalimumab reduces the progression to severe or critical disease or death in COVID-19 patients,” said Prof Duncan Richards, Professor of Clinical Therapeutics, University of Oxford.

Status: On January 20, Global clinical research organisation (CRO) Pharm-Olam has been selected by the US Department of Defense (DOD) to lead and offer full-service clinical trial support of the Adalimumab COVID Therapeutic Trial. Adalimumab will be tested in the adaptive, outpatient trial as a treatment against the inflammatory response and associated complications due to Covid-19.

References:

  • Press Release: Oxford researchers start new trial on the use of anti-TNF to treat Covid-19 in care homes. University of Oxford (09/30/20).
  • News: Anti-TNF therapy could treat patients suffering from Covid-19-related ARDS (05/29/20).
  • Trial Page: Adalimumab for coronavirus in community care. OCTRU (09/30/20).
  • Press Release: Pharm-Olam to support Adalimumab COVID Therapeutic Trial. Clinical trials arena (01/20/2021).

Candidate: VIR-7831 and VIR-7832

Developers: Vir Biotechnology, GlaxoSmithKline

Locations: United States

Clinical Trial IDs: NCT04545060 (Phase 2/3)

Description: VIR-7831 is a monoclonal antibody that has demonstrated the ability to neutralize SARS-CoV-2 live virus in vitro. The antibody binds to an epitope on SARS-CoV-2 that is shared with SARS-CoV-1 (also known as SARS), indicating that the epitope is highly conserved, which may make it more difficult for escape mutants to develop. VIR-7831 has been engineered to enhance bioavailability and have an extended half-life.

VIR-7832 is a monoclonal antibody that has demonstrated the ability to neutralize SARS-CoV-2 live virus in vitro. The antibody binds to an epitope on SARS-CoV-2 that is shared with SARS-CoV-1 (also known as SARS), indicating that the epitope is highly conserved, which may make it more difficult for escape mutants to develop. VIR-7832 has been engineered to enhance bioavailability, have an extended half-life and to potentially function as a T cell vaccine.

On August 31, 2020, Vir Biotechnology and GSK announced start of Phase 2/3 study of the antibody treatment. The first patient was dosed last week in a Phase 2/3 study with VIR-7831 (also known as GSK4182136), a fully human anti-SARS-CoV-2 monoclonal antibody, for the early treatment of COVID-19 in patients who are at high risk of hospitalization. The aim of the COMET-ICE (COVID-19 Monoclonal antibody Efficacy Trial – Intent to Care Early) study, which will enroll approximately 1,300 patients worldwide who have early symptomatic infection, is to assess whether VIR-7831, as a single-dose monoclonal antibody, can prevent hospitalization due to COVID-19. Initial results may be available before the end of this year.

Vir Biotechnology is expanding its Phase III COMET-ICE study evaluating VIR-7831 for the early treatment of COVID-19 in patients who are at high risk of hospitalization.

On December 17, 2020, Vir Biotechnology and GlaxoSmithKline plc announced that the first patient has been dosed in a new sub-trial of the NIH ACTIV Program Phase 3 clinical trial. This trial is designed to evaluate the safety and efficacy of VIR-7831 for the treatment of hospitalized adults with COVID-19.

On January 27, 2021, Eli Lilly, Vir Biotechnology, and GlaxoSmithKline announced a collaboration to evaluate a combination of two COVID-19 therapies in low-risk patients with mild to moderate COVID-19. Lilly has expanded its ongoing BLAZE-4 trial to evaluate the administration of bamlanivimab (LY-CoV555) 700mg with VIR-7831 (also known as GSK4182136) 500mg, two neutralizing antibodies that bind to different epitopes of the SARS-CoV-2 spike protein. This unique collaboration marks the first time that monoclonal antibodies from separate companies will be brought together to explore potential outcomes.

Status: On March 10, 2021, Vir Biotechnology and GlaxoSmithKline  announced that an IDMC recommended that the Phase 3 COMET-ICE (COVID-19 Monoclonal antibody Efficacy Trial – Intent to Care Early) trial evaluating VIR-7831 (GSK4182136) as monotherapy for the early treatment of COVID-19 in adults at high risk of hospitalization be stopped for enrollment due to evidence of profound efficacy. The IDMC recommendation was based on an interim analysis of data from 583 patients enrolled in the COMET-ICE trial, which demonstrated an 85% (p=0.002) reduction in hospitalization or death in patients receiving VIR-7831 as monotherapy compared to placebo, the primary endpoint of the trial. VIR-7831 was well tolerated. As the trial remains ongoing and blinded with patients continuing to be followed for 24 weeks, additional results, including epidemiology and virology data, will be forthcoming once the trial is completed. Based on these results, Vir and GSK plan to submit an Emergency Use Authorization (EUA) application to the U.S. Food and Drug Administration (FDA) and for authorizations in other countries.

On March 29, 2021, Eli Lilly, Vir Biotechnology, and GlaxoSmithKline announced topline data from the expanded Phase 2 BLAZE-4 (NCT04634409) trial studying low-risk adult patients with mild to moderate COVID-19. Results showed that investigational bamlanivimab (LY-CoV555) 700 mg co-administered with VIR-7831 (also known as GSK4182136) 500 mg demonstrated a 70 percent (p<0.001) relative reduction in persistently high viral load (> 5.27; cycle threshold value < 27.5) at day 7 compared to placebo, meeting the primary endpoint. In addition, bamlanivimab administered with VIR-7831 demonstrated a statistically significant reduction compared to placebo in the key virologic secondary endpoints of mean change from baseline to days 3, 5 and 7 in SARS-CoV-2 viral load. There were no events for the secondary endpoint of COVID-19 related hospitalization or death by day 29 in either study arm. One patient (in the treatment arm) visited the emergency room for COVID-19 related symptoms. No serious adverse events were seen with co-administration of bamlanivimab and VIR-7831.

References:

  • Website: Vir Bio’s antibody pipeline (accessed 09/21/20).
  • Press Release: GSK and Vir Biotechnology enter collaboration to find coronavirus solutions. GSK (04/06/21).
  • Press Release: Vir Biotechnology and GSK Start Phase 2/3 Study of COVID-19 Antibody Treatment. Vir Biotechnology (09/14/20).
  • Press Release: Vir Biotechnology and GSK announce global expansion to Phase 3 of COMET-ICE study evaluating VIR-7831 for the treatment of COVID-19. Vir Bio (10/06/20).
  • Press Release: Vir Biotechnology and GSK Announce Start of NIH-Sponsored ACTIV-3 Trial Evaluating VIR-7831 in Hospitalized Adults with COVID-19 (12/27/20).
  • Press Release: Lilly, Vir Biotechnology and GSK announce first patient dosed in expanded BLAZE-4 trial evaluating bamlanivimab (LY-CoV555) with VIR-7831 (GSK4182136) for COVID-19 (01/27/21).
  • Press Release: Vir Biotechnology and GSK Announce VIR-7831 Reduces Hospitalization and Risk of Death in Early Treatment of Adults with COVID-19. Vir Bio (03/10/21).
  • Press Release: Lilly, Vir Biotechnology and GSK Announce Positive Topline Data from the Phase 2 BLAZE-4 Trial Evaluating Bamlanivimab with VIR-7831 in Low-Risk Adults with COVID-19. Eli Lilly (03/29/21).

Candidate: COVI-GUARD (Neutralizing Antibody – STI 1499), COVI-SHIELD (Neutralizing Antibody Cocktail), COVI-AMG (Affinity Matured COVI-GUARD Neutralizing Antibody – STI 2020), and COVIDROPS (Intranasal COVI-AMG Neutralizing Antibody – STI 2099)

Developers: Sorrento Therapeutics, Inc.

Locations: United States

Clinical Trial IDs: NCT04454398 (Phase 1)

Sorrento is developing a Neutralizing Antibody COVI-GUARD (Neutralizing Antibody – STI 1499) which binds to S1 subunit of SARS-CoV-2 Spike protein. It is also developing a Neutralizing Antibody Cocktail COVI-SHIELD (Neutralizing Antibody Cocktail) to bind to distinct epitopes on SARS-CoV-2 Spike protein. The antibody cocktail potentially creates a high barrier to emergence of resistant variants in treated individuals. Both the mAbs Fc regions are engineered to eliminate interactions with host Fc receptors, thereby decreasing risk of Antibody Dependent Enhancement of SARS-CoV-2 infection.

Sorrento is developing COVI-AMG (STI-2020; Affinity Matured COVI-Guard) neutralizing antibodies (nAbs) against SARS-CoV-2 infection.  STI-2020 has demonstrated greater than 50-fold increase in potency in in vitro experiments. In addition to the intravenous formulation of COVI-AMG neutralizing antibody, Sorrento is developing COVIDROPS which will be the intranasal formulation of COVI-AMG.

Sorrento Therapeutics is teaming up with New York City-based Mount Sinai Health System to develop COVI-SHIELD to treat COVID-19. COVI-SHIELD is expected to deliver a mixture of three antibodies that combined recognize three specific regions of the SARS-CoV-2 Spike protein.

August 19, 2020, Sorrento announced that it is filing an investigational new drug application (IND) for COVI-GUARD (STI-1499) for hospitalized COVID-19 patients. Sorrento has previously received guidance from the FDA in response to a pre-IND meeting package and believes it has addressed all questions and followed the recommendations from the agency for all sections of the IND. As Sorrento previously announced, in preclinical studies, STI-1499 demonstrated 100% neutralizing effect (in vitro) of the antibody and that a low dose prevented SARS-CoV-2 from infecting healthy cells in such preclinical in vitro studies. Animal data generated by Dr. Paessler’s laboratory at the UTMB in Syrian Golden Hamsters infected with SARS-CoV-2, justify the IND filing and continued clinical development.

The highest proposed dose (200 mg per patient) in the phase 1 safety trial is a much lower dose than currently being tested for other known antibodies in active clinical studies. The potentially higher potency of the antibody may allow for faster scaled manufacturing (availability to patients) and potentially a lower cost per dose as compared to other known antibodies currently being evaluated.

STI-1499 antibody has also been evaluated in preclinical studies against multiple strains of SARS-CoV-2, including the highly contagious D614G mutant, the current dominant strain globally. In such preclinical studies, the antibody has been 100% effective against the highly contagious D614G mutant strain at a low dose.

On September 16, 2020, Sorrento announced that phase 1 clinical trial for STI-1499 (COVI-GUARD™) in hospitalized COVID-19 patients has received FDA notice that it may proceed with patient enrollment. The initial trial is expected to enroll rapidly and is expected to be followed by large trials targeting a potential EUA submission as early as before the end of this year. Sorrento has initiated cGMP manufacturing to produce 50,000 doses in anticipation of a potential EUA.

On September 28, Sorrento released preclinical study results, both STI-1499 and STI-2020 demonstrated potent neutralizing activity against SARS-CoV-2 virus isolates, including the emerging Spike D614G variant virus. STI-1499 and STI-2020 also demonstrated protective activities against SARS-CoV-2 infection in Syrian golden hamsters. At day 5, STI-2020 at 500 ug reduced virus load in hamster lungs to undetectable levels in 100% of animals tested, whereas STI-1499 at 2,000 ug reduced virus load below the detection limit in 60% of animals tested and showed a 10-fold reduction in the remaining 40% of animals.

On November 11, 2020, Sorrento Announces IND Filing for STI-2099 (COVI-DROPS) for a phase 1 safety and pharmacokinetic study in healthy volunteers and outpatients with mild COVID-19 disease with or without a simultaneous intravenous injection of COVI-AMG™. Initial trial is expected to be followed by a phase 2 trial in both mild and moderate COVID-19 patients, either as a stand-alone nasal application or as a combination nasal and intravenous administration.

On December 9, 2020, FDA has granted clearance for the commencement of Phase 1 clinical trials of STI-2020 (COVI-AMGTM) in healthy volunteers and COVID-19 patients with mild symptoms. STI-2020, a monoclonal antibody, has been engineered for ultra-high potency, which potentially translates to a smaller IV volume required to administer an effective dose. In preclinical studies, STI-2020 demonstrated strong or stronger affinities to multiple antibody drug-resistant SARS-CoV-2 variants.

On January 19, 2021, Sorrento Therapeutics announced that it will be presenting preliminary results from an ongoing SARS-CoV-2 mutation surveillance program for its neutralizing antibodies currently in clinical and pre-clinical development for treatment of patients with COVID-19 disease. Disclosed data will provide evidence of maintained binding potency by STI-2020 in in vitro assays including the Spike amino acid changes found in SARS-CoV-2 viruses of the B.1.1.7 lineage initially identified in the United Kingdom which has since been detected in ten U.S states.Status: On March 2, 2021, FDA granted IND clearance today for the commencement of a Phase 1 safety and pharmacokinetic study for STI-2099 (COVIDROPS) in healthy volunteers and outpatients with mild COVID-19 disease with or without a simultaneous intravenous injection of STI-2020 (COVI-AMG). Initial trials are expected to be followed by a Phase 2 trial in both mild and moderate COVID-19 patients, either as a stand-alone nasal application or as a combination nasal and intravenous administration. This is the first FDA clearance of a clinical trial of intranasal administration of a neutralizing antibody against the SARS-CoV-2 virus.

References:

  • Press Release: Sorrento And Mount Sinai Health System To Jointly Develop COVI-SHIELD™ Antibody Therapy Targeting SARS-CoV-2 Infection (COVID-19). Sorrento (05/12/2020).
  • Publication: Sorrento’s antibody completely blocks Covid-19 in-vitro. Pharmaceutical-technology (05/18/20).
  • Press Release: Sorrento Announces FDA IND Filing Today for COVI-GUARD Neutralizing and High Potency Antibody Against SARS-CoV-2. Sorrento (08/19/20).
  • Press Release: Sorrento Receives US FDA Clearance to Proceed With Phase 1 Clinical Trial of STI-1499 (COVI-GUARD) Neutralizing Antibody in COVID-19 Positive Patients. Sorrento (09/16/20).
  • Press Release: Sorrento Releases Preclinical Data for STI-1499 (COVI-Guard™) and STI-2020 (COVI-AMG™), Potent Neutralizing Antibodies Against SARS-CoV-2. Sorrento (09/28/20).
  • Press Release: Sorrento Announces IND Filing for COVI-DROPS, an Intranasal Formulation of a High Potency Neutralizing Antibody Against SARS-CoV-2. Sorrento (11/11/20).
  • Press Release: Sorrento Receives US FDA Clearance to Proceed With Phase 1 Clinical Trials for STI-2020 (COVI-AMG) in Healthy Volunteers and in Newly Diagnosed COVID-19 Patients. Sorrento (12/09/20).
  • Press Release: Sorrento to Present Data Demonstrating STI-2020 Preserves Binding Against UK B.1.1.7 SARS-CoV-2 Mutated Spike Protein. Biospace (01/19/21).
  • Press Release: Sorrento Receives US FDA Clearance to Proceed With Phase 1 Study for STI-2099 (Intranasal COVIDROPS) in Healthy Volunteers and Outpatient Treatment for Newly Diagnosed COVID-19 Positive Patients. Sorrento (03/02/21).

Candidate: Lenzilumab

Developers: Humanigen

Locations: United States

Clinical Trial IDs: NCT04351152 (Phase 3)

Description: Lenzilumab is a first-in-class Humaneered recombinant mAB targeting human GM-CSF, with potential immunomodulatory activity, high binding affinity in the picomolar range, 94% homology to human germline, and has low immunogenicity. Following intravenous administration, lenzilumab binds to and neutralizes GM-CSF, preventing GM-CSF binding to its receptor, thereby preventing GM-CSF-mediated signaling to myeloid progenitor cells. Lenzilumab has been studied across 4 completed clinical trials in healthy volunteers, and persons with asthma, rheumatoid arthritis, and chronic myelomonocytic leukemia.  A total of 113 individuals received lenzilumab in these trials; lenzilumab was very well tolerated with a low frequency and severity of adverse events.  

Lenzilumab has been shown to have a protective effect against cytokine release syndrome associated with CAR-T therapy. It’s believed that Lenzilumab can aid cytokine-mediated immunopathology of lung injury and ARDS.

Early results from the first 12 patients who received lenzilumab at Mayo Clinic locations showed 11 of 12 patients (92%) had clinical improvement, with a median discharge time of 5 days. Oxygenation was also improved in patients taking lenzilumab.

Humanigen now expects to complete enrolment of the 300 subjects this month with topline results due in the fourth quarter. Statements regarding the potential that lenzilumab will receive an Emergency Use Authorization in 2020 and commence commercialization, and regarding the potential additional manufacturing capacity afforded by the collaboration beginning in 2021.

On September 1, 2020, Lenzilumab is being evaluated in an ongoing Phase III trial and was selected by the NIH for its COVID-19 Big Effect Trial. 80% reduction in relative risk of invasive mechanical ventilation and/or death in patients treated with lenzilumab compared to the control group. Median time to resolution of acute respiratory distress syndrome (ARDS) reduced to one day for patients treated with lenzilumab versus eight days in control group. Lenzilumab patients discharged from the hospital in less than half the time compared with control group. The study involved a total of 39 patients, including 12 treated with lenzilumab, and 27 contemporaneous matched control patients who received standard of care treatment.

A case report shared by Humanigen on October 06, demonstrated rapid resolution of hypoxemia and mobility and potential benefit of lenzilumab beyond the initial acute hyper-inflammatory window. After 13 weeks of hospitalization, administration of lenzilumab resulted in rapid improvement in oxygenation and subsequent discharge.

On November 6, 2020, Humanigen announced positive interim Phase III data of lenzilumab in hospitalized COVID-19 patients. They found the drug had a clinically meaningful impact on patient recovery. About 37% more recoveries were seen in the lenzilumab arm of the trial compared to standard-of-care (SOC). As a result, the company plans to increase enrollment to about 515 patients, which would increase the likelihood of hitting the primary endpoint while maintaining the power of the trial at 90%.

On January 10, 2021, Humanigen announced that they are partnering to make lenzilumab available to hospitalized and hypoxic COVID-19 patients in the event that an Emergency Use Authorization is issued from the U.S. Food and Drug Administration (FDA) and subsequent BLA.

Status: On March 29, 2021, Humanigen announced positive topline results from its Phase 3 clinical trial evaluating the efficacy and safety of lenzilumab in patients hospitalized with COVID-19. Trial results showed that patients who received lenzilumab and other treatments, including steroids and/or remdesivir, had a 54% greater relative likelihood of survival without the need for IMV compared with patients receiving placebo and other treatments. These results are statistically significant. The trial incorporated a diverse population with various comorbidities, most commonly a body mass index above 30, which is representative of a real-world, high-risk population. Company’s next step is to submit an application for Emergency Use Authorization (EUA) to the Food and Drug Administration (FDA) as soon as possible.

References:

  • Preprint: First Clinical Use of Lenzilumab to Neutralize GM-CSF in Patients with Severe COVID-19 Pneumonia. medRxiv (06/14/20).
  • Press Release Humanigen Expands Phase III Study of Lenzilumab in COVID-19 to Brazil (08/10/2020).
  • Press Release: Humanigen Reports Additional Analysis of Lenzilumab in Severe and Critical COVID-19 Patients Humanigen (06/16/2020).
  • Press Release: Lenzilumab COVID-19 Case-Control Study Published in Mayo Clinic Journal. Humanigen (09/01/2020).
  • Press Release: Humanigen says review of lenzilumab Phase 3 study of COVID-19 by data safety monitoring board gets green light to continue. Humanigen (09/14/20).
  • Press Release: Humanigen and Lonza Announce Collaboration to Expand Manufacturing of Humanigen’s COVID-19 Therapeutic Candidate Lenzilumab. Humanigen (09/15/20).
  • Press Release: Humanigen Announces COVID-19 Case Report Demonstrating Rapid Resolution and Discharge after Single IND Emergency Use Authorization of Lenzilumab. Humanigen (10/06/20).
  • Press Release Humanigen Announces Positive Interim Phase 3 Data of Lenzilumab in Patients Hospitalized with COVID-19. Humanigen (11/06/20).  
  • Press Release: Humanigen and EVERSANA Announce Partnership to Support the Launch and Commercialization of Lenzilumab for the Treatment of COVID-19 (01/10/21). 
  • Press Release : Humanigen Reports Positive Phase 3 Topline Results Demonstrating That Lenzilumab Improves Survival Without Need for Mechanical Ventilation in Hospitalized Patients With COVID-19. Humanigen (03/29/21).

Candidate: Sarilumab (Kevzara)

Developers: Sanofi, Regeneron Pharmaceuticals

Locations: Argentina, Brazil, Canada, Chile, France, Germany, Israel, Italy, Japan, Russian Federation, Spain

Clinical Trial IDs: NCT04327388 (Phase III); NCT04386239 (Phase 1)

Description: Kevzara is currently approved in multiple countries to treat adults with moderately to severely active rheumatoid arthritis who have not responded to or tolerated previous therapy. Kevzara is a fully-human mAB that inhibits the interleukin-6 (IL-6) pathway by binding and blocking the IL-6 receptor. IL-6 may play a role in driving the overactive inflammatory response in the lungs of patients who are severely or critically ill with COVID-19 infection. The role of IL-6 is supported by preliminary data from a single-arm study in China using another IL-6 receptor inhibitor.

U.S. Phase 3 trial of Kevzara (sarilumab) 400 mg in COVID-19 patients requiring mechanical ventilation did not meet its primary and key secondary endpoints when Kevzara was added to best supportive care compared to best supportive care alone (placebo). Minor positive trends were observed in the primary pre-specified analysis group (critical patients on Kevzara 400 mg who were mechanically ventilated at baseline) that did not reach statistical significance and these were countered by negative trends in a subgroup of critical patients who were not mechanically ventilated at baseline. A separate Sanofi-led trial outside of the U.S. in hospitalized patients with severe and critical COVID-19 using a different dosing regimen is ongoing.

Status: On September 1, Sanofi announced that the global Phase 3 trial investigating intravenously administered Kevzara® (sarilumab) at a dose of 200 mg or 400 mg  in severely or critically ill  patients hospitalized with COVID-19 did not meet its primary endpoint and key secondary endpoint when Kevzara was compared to placebo added to usual hospital care. The 420-patient randomized trial was conducted outside the U.S. in Argentina, Brazil, Canada, Chile, France, Germany, Israel, Italy, Japan, Russia and Spain (86 in placebo, 161 in 200 mg, and 173 in 400 mg arms).

References:

  • Publication: COVID‐19 pneumonia treated with Sarilumab: A clinical series of eight patients. J Med Virol (06/16/20).
  • Preprint: Sarilumab use in severe SARS-CoV-2 pneumonia. medrxiv (05/18/20).
  • Press Release: Sanofi provides update on Kevzara® (sarilumab) Phase 3 trial in severe and critically ill COVID-19 patients outside the U.S. Sanofi (09/01/20).

Updated: 14 June, 2021.

  • Molecular Partners Announces First Patient Dosed in COVID-19 NIH-Sponsored ACTIV-3 Trial Evaluating Antiviral Candidate Ensovibep [Link] (06/14/21)
  • MPI8 is Potent Against SARS-CoV-2 by Inhibiting Dually and Selectively the SARS-CoV-2 Main Protease and the Host Cathepsin L [Link] (06/14/21)
  • Transcriptomics-based drug repositioning pipeline identifies therapeutic candidates for COVID-19 [Link] (06/14/21)
  • Bold Therapeutics Receives Additional Funding to Support Development of BOLD-100 as a Novel Antiviral [Link] (06/14/21)
  • Selva Announces SLV213, a Potential Oral COVID-19 Treatment, Has Broad Activity Against SARS-CoV-2 Variants of Concern [Link] (06/14/21)
  • Safety and efficacy of antiviral therapy alone or in combination in COVID-19 – a randomized controlled trial (SEV COVID Trial) [Link] (06/14/21)
  • Merck (MSD) Announces Supply Agreement with U.S. Government for Molnupiravir, an Investigational Oral Antiviral Candidate for Treatment of Mild to Moderate COVID-19 [Link] (06/10/21)
  • Sunshine biopharma mice study for COVID-19 treatment progressing as planned [Link] (06/10/21)
  • Scipher Medicine and Leading Medical Researchers in Network and Data Science Compress Time to Identify COVID-19 Treatments From Years to Months [Link] (06/10/21)
  • Drug Repurposing of potential drug targets for treatment of COVID-19 [Link] (06/10/21)
  • A metabolic modeling approach reveals promising therapeutic targets and antiviral drugs to combat COVID-19 [Link] (06/07/21)
  • Lexaria’s DehydraTECH(TM)-Enabled Remdesivir and Ebastine Effectively Inhibit the COVID-19 SARS-CoV-2 Virus [Link] (06/07/21)
  • Drug repurposing screens identify chemical entities for the development of COVID-19 interventions [Link] (06/07/21)
  • Synergistic inhibition of two host factors that facilitate entry of Severe Acute Respiratory Syndrome Coronavirus 2 [Link] (06/07/21)
  • Identification of proteasome and caspase inhibitors targeting SARS-CoV-2 Mpro [Link] (06/02/21)
  • Favorable outcome on viral load and culture viability using Ivermectin in early treatment of non-hospitalized patients with mild COVID-19, A double-blind, randomized placebo-controlled trial [Link] (06/02/21)
  • Kite-shaped molecules block SARS-CoV-2 cell entry at a post-attachment step [Link] (06/02/21)
  • Bardoxolone and bardoxolone methyl, two Nrf2 activators in clinical trials, inhibit SARS-CoV-2 replication and its 3C-like protease [Link] (06/02/21)
  • ALG-097111, a potent and selective SARS-CoV-2 3-chymotrypsin-like cysteine protease inhibitor exhibits in vivo efficacy in a Syrian Hamster model [Link] (06/02/21)

Select strategies are detailed in the section below:

Candidate: Remdesivir (Veklury, GS-5734)

Sponsors/Developers: Gilead Sciences, Inc.

Location: United States

Clinical Trial IDs: NCT04501952 (Outpatient Setting, Phase 3), NCT04431453 (CARAVAN, < 18 Years, Phase 2/3), NCT04292899 (Severe COVID-19, Phase 3), NCT04292730 (Moderate COVID-19, Phase 3), NCT04323761 (expanded access)

Description: The broad-spectrum antiviral agent Remdesivir (GS-5734; Gilead Sciences, Inc) is a nucleotide analog prodrug. The US FDA issued EUA of remdesivir to allow emergency use in children and hospitalized adults. The findings from the NIAID trial of remdesivir in hospitalized patients with advanced COVID-19 have been published in a peer-reviewed medical journal. These findings support the use of remdesivir in this population, with the largest benefit observed among individuals who required oxygen supplementation but were not mechanically ventilated. The open-label phase 3 SIMPLE trial (n = 397) in hospitalized patients with severe COVID-19 disease not requiring mechanical ventilation showed similar improvement in clinical status with the 5-day remdesivir regimen compared with the 10-day regimen on day 14 (OR=0.75). The first published report concerning remdesivir compassionate use described clinical improvement in 36 of 53 hospitalized patients (68%) with severe COVID-19. At baseline, 30 patients (57%) were receiving ventilation and 4 (8%) extracorporeal membrane oxygenation (ECMO).

Coordinating closely with the U.S. FDA, Gilead has designed and will soon begin enrollment of an open-label, single-arm Phase 2/3 clinical trial that will evaluate the safety, tolerability, pharmacokinetics and efficacy of remdesivir in treating approximately 50 pediatric patients with moderate-to-severe COVID-19, including newborns through adolescents. This important trial will be conducted at more than 30 sites in the United States and Europe (Trial ID: NCT04431453).

On July 10, 2020 Gilead presented additional data -Remdesivir was associated with an improvement in clinical recovery and a 62% reduction in the risk of mortality compared with standard of care – an important finding that requires confirmation in prospective clinical trials. Traditionally marginalized racial/ethnic groups treated with Remdesivir had similar clinical outcomes as overall patient population. Compassionate use program, which demonstrated that 83% of pediatric patients (n=77) and 92% of pregnant and postpartum women (n=86) with a broad spectrum of disease severity recovered by Day 28. To further the understanding of these results in individual patient cases, Gilead recently announced the initiation of a global, open-label Phase 2/3 trial to evaluate the safety, tolerability and pharmacokinetics of remdesivir in pediatric patients from birth to less than 18 years of age. Gilead is also collaborating on a study for pregnant women.

Gilead announced on 28 August that the U.S. FDA expanded the Emergency Use Authorization (EUA) enabling use of the investigational antiviral Veklury (remdesivir) to treat all hospitalized patients with COVID-19, in addition to the previous authorization for patients hospitalized with severe COVID-19. The expanded EUA is based on results from the Phase 3 SIMPLE trial evaluating Veklury in hospitalized patients with moderate COVID-19 pneumonia, as well as results from the National Institute of Allergy and Infectious Diseases (NIAID) ACTT-1 trial in hospitalized patients with a range of disease severity.

Final results of the ACTT trial, presented in top-line form back in April, confirm that in patients hospitalized with COVID-19, remdesivir shortened the time to recovery from 15 days to 10 days compared with placebo. Mortality at days 15 and 29 was numerically lower with remdesivir.

On November 5, 2021, A randomized, open-label, phase 3 trial of remdesivir in hospitalized patients who did not require mechanical ventilation showed that there was no significant difference between a 5-day versus a 10-day course of treatment on the outcome of clinical status on a 7-point scale at day 14 in patients with confirmed SARS-CoV-2 infection. The authors note that there was no placebo control group in this study, and therefore the magnitude of benefit cannot be determined (ClinicalTrials.gov number, NCT04292899).

On November 20, 2021, WHO has issued a conditional recommendation against the use of remdesivir in hospitalized patients, regardless of disease severity, as there is currently no evidence that remdesivir improves survival and other outcomes in these patients.

On November 20, 2021, FDA’s approval of remdesivir (Veklury) was supported by the agency’s independent, in-depth analysis of data from three randomized, controlled clinical trials that included patients hospitalized with mild-to-severe COVID-19. This included the ACTT-1 trial sponsored by National Institute of Allergy and Infectious Disease (NIAID) and the “SIMPLE” trials (GS-US-540-5774 and GS-US-540-5773) sponsored by Gilead Sciences Inc. The most compelling evidence of effectiveness was provided by the NIAID-sponsored ACTT-1 trial, with its rigorous trial design.

Status: The US National Institutes of Health has announced it will study the use of the antiviral remdesivir in pregnant women with COVID-19. There is an “urgent need” to address the safety and efficacy of treatments in pregnant women. For now, the drug is approved for use in adults and children over age 12, but it has not specifically been approved in pregnancy; providers can prescribe the drug if they believe it may be of benefit.

On February 26, 2021, In a retrospective analysis of patients with moderate-to-severe COVID-19 in India (n=346), patients receiving remdesivir 9 days or less after symptom onset had significantly lower all-cause mortality compared to those who received it after 9 days (18% vs 34%). Odds of death were reduced by 37% among patients receiving remdesivir <=9 days post-symptom onset compared to those receiving it after 9 days, as published in a peer-reviewed medical journal.

References:

  • Publication: Remdesivir for the Treatment of Covid-19 – Preliminary Report. NEJM (05/22/20).
  • Publication: Remdesivir for 5 or 10 Days in Patients with Severe Covid-19. NEJM (05/27/20).
  • Publication: Clinical benefit of remdesivir in rhesus macaques infected with SARS-CoV-2. Nature (06/09/20).
  • Publication: Structural basis for inhibition of the RNA-dependent RNA polymerase from SARS-CoV-2 by remdesivir. Science (06/26/20).
  • Publication: Compassionate Use of Remdesivir for Patients with Severe Covid-19. NEJM (06/11/20).
  • Press Release: Gilead Presents Additional Data on Investigational Antiviral Remdesivir for the Treatment of COVID-19. Gilead (07/10/20).
  • Press Release: Gilead’s Investigational Antiviral Veklury (Remdesivir) Receives U.S. Food and Drug Administration Emergency Use Authorization for the Treatment of Patients With Moderate COVID-19. Gilead (08/28/20).
  • Publication: Remdesivir for the Treatment of Covid-19 – Final Report. NEJM (10/08/20).
  • Press Release: Remdesivir (Veklury) Approval for the Treatment of COVID-19-The Evidence for Safety and Efficacy. FDA (11/25/20).
  • Press Release: NIH funds study to evaluate remdesivir for COVID-19 in pregnancy. NIH (02/17/21).
  • Publication: A Shorter Symptom-Onset to Remdesivir Treatment (SORT) Interval Is Associated with a Lower Mortality in Moderate-to-Severe COVID-19: A Real-World Analysis.. International Journal of Infectious Diseases. (02/26/21).

Candidate: Favipiravir (Avigan).

Sponsors/Developers: FUJIFILM Toyama Chemical Co., Ltd.

Location: United States, Japan, China, Middle East and other countries

Clinical Trial IDs: NCT04358549 (Phase 2), NCT04373733 (Phase 3)

Description: Favipiravir is an oral antiviral approved for the treatment of influenza in Japan. It selectively inhibits RNA polymerase, which is necessary for viral replication. Japan has commenced with a phase 3 clinical trial. In the United States, a phase 2 trial will enroll approximately 50 patients with COVID-19, in collaboration with Brigham and Women’s Hospital, Massachusetts General Hospital, and the University of Massachusetts Medical School. In India, a phase 3 trial combining 2 antiviral agents, favipiravir and umifenovir, started in May 2020.

Fujifilm will team up with India’s Dr. Reddy’s Laboratories to run a 1,000-person trial on flu med Avigan in coronavirus patients in Kuwait. The trial was originally slated to run in Japan, but low patient enrollment forced Fujifilm to relocate. In early July, Fujifilm granted Dr. Reddy’s a license to produce and sell Avigan as a potential COVID-19 treatment overseas in partnership with Global Response Aid.

Indian firm Glenmark’s open-label randomized, multicenter clinical trial conducted in 150 patients, evaluated the efficacy and safety of Favipiravir plus standard supportive care versus standard supportive care alone in mild to moderate patients, randomized within a 48 h window of testing RT-PCR positive for COVID-19. Results from the Phase 3 trial showed numerical improvements for the primary efficacy endpoint with 28.6%  faster viral clearance in the overall population as measured by the median time until cessation of oral shedding of virus in the Favipiravir treatment arm compared to those in the control arm (Hazard Ratio 1.367 [95%CI 0.944,1.979]; p=0.129). 40% faster achievement of “clinical cure” defined as the physician’s assessment with a statistically significant reduction in median time to clinical cure in the Favipiravir treatment arm (3 days vs. 5 days) [HR 1.749, p=0.029). No serious adverse events (SAEs) or deaths were observed.

FujiFilm, which has licensed GRA and Dr. Reddy’s to manufacture, distribute and sell the drug globally. Clinical trials of the drug have been conducted and are underway in the United States, Japan, China, the Middle East and other countries, where it is being used to reduce fevers and shorten recovery time in patients who receive Avigan in the early stages of infection with COVID-19. In July, the Central Drugs Standard Control Organisation of India’s Directorate General of Health Services approved Favipiravir for distribution, sale and use in treatment of COVID-19 patients.

FUJIFILM  has announced that primary endpoint has been met in phase III clinical trial of “Avigan Tablet” conducted in Japan. The efficacy primary endpoint is time to negative conversion of detectable SARS-CoV 2 viral RNA in the RT-PCR assays, and to alleviation of symptoms (body temperature, oxygen saturation and chest images). FUJIFILM began a phase III clinical trial of Avigan in Japan in March 2020, for COVID-19 patients with non-severe pneumonia – a randomized, placebo-controlled, single-blind comparative study, to evaluate the efficacy and safety of Avigan. The median value of primary endpoints, using 156 individuals as analysis targets, were 11.9 days for the Avigan group and 14.7 days for the placebo group.

In a randomized, open-label, parallel-arm, multicenter, Phase 3 trial, adults (18-75 years) with RT-PCR-confirmed COVID-19 and mild-to-moderate symptoms (including asymptomatic) were randomized 1:1 to oral favipiravir (n=75) or control (n=75). Median time to cessation of viral shedding was 5 days versus 7 days, and median time to clinical cure was 3 days versus 5 days, for favipiravir and control, respectively. Adverse events were observed in 36% of favipiravir and 8% of control patients. Favipiravir may be a safe and effective treatment in mild-to-moderate COVID-19.

Appili Therapeutics Inc, announced that its Phase 3 PRESECO (PREventing SEvere COvid-19) clinical trial is actively recruiting participants in 12 out of 20 planned sites in the United States and company believes that it will reach the enrollment threshold required to provide an interim data readout by late March 2021. PRESECO is evaluating favipiravir, an oral antiviral, in the early treatment of COVID-19 in the outpatient setting.

Status: On February 17, 2021, A meta-analysis published in preprint revealed a significant clinical improvement in the Favipiravir group versus the control group during seven days after hospitalization (RR=1.24; P=0.001). Viral clearance was more in 14 days after hospitalization in the Favipiravir group than in the control group, but this finding marginally not significant (RR=1.11; P=0.094). Requiring supplemental oxygen therapy in the Favipiravir group was 7% less than the control group, (RR=0.93; P=0.664).

On March 23, 2021, A multicenter randomized open-labeled clinical trial found that adding Favipiravir to the treatment protocol for in patients with moderate to severe SARS-CoV-2 infection did not reduce the number of ICU admissions or intubations or In-hospital mortality compared to Lopinavir/Ritonavir regimen. It also did not shorten time to clinical recovery or length of hospital stay.

References:

  • Press Release: Fujifilm announces the start of a phase III clinical trial of influenza antiviral drug “Avigan Tablet” on COVID-19 and commits to increasing production. FUJIFILM (03/31/20).
  • Press Release: Fujifilm announces the start of a phase II clinical trial of its influenza antiviral drug “Avigan Tablet” for COVID-19 patients in the U.S. FUJIFILM (04/09/20).
  • News: Fujifilm to begin clinical trials testing Avigan in COVID-19 patients in Kuwait. Pharmafile (07/21/20).
  • Press Release: Glenmark Announces Top-Line Results From Phase 3 Clinical Trial of Favipiravir in Patients with Mild to Moderate COVID-19. Glenmark (07/22/20).
  • News: India Approves Avigan (Favipiravir) For COVID-19 Treatment. Business World (08/20/20).
  • Press Release: Anti-influenza drug Avigan Tablet Meets Primary Endpoint in Phase III Clinical Trial in Japan for COVID-19 patients. FUJIFILM (09/23/20).
  • Publication: Efficacy and Safety of Favipiravir, an Oral RNA-Dependent RNA Polymerase Inhibitor, in Mild-to-Moderate COVID-19: A Randomized, Comparative, Open-Label, Multicenter, Phase 3 Clinical Trial. (11/16/20).
  • Press Release: Appili Therapeutics Provides Enrollment Update for Its Phase 3 PRESECO Trial Evaluating the Oral Antiviral Favipiravir as an Early Treatment in COVID-19. Biospace (01/28/21).
  • Publication: The Efficacy and Safety of Favipiravir in Treatment of COVID-19 A Systematic Review and Meta-Analysis of Clinical Trials. (02/17/21).
  • Publication: Safety and efficacy of Favipiravir in moderate to severe SARS-CoV-2 pneumonia. International Immunopharmacology (03/23/21).

Remdesivir is the only Food and Drug Administration-approved drug for the treatment of COVID-19. In this section, the COVID-19 Treatment Guidelines Panel (the Panel) provides recommendations for using antiviral drugs to treat COVID-19 based on the available data. As in the management of any disease, treatment decisions ultimately reside with the patient and their health care provider.

Remdesivir – It is recommended for use in hospitalized patients who require supplemental oxygen. However, it is not routinely recommended for patients who require mechanical ventilation due to the lack of data showing benefit at this advanced stage of the disease.

The Panel recommends against the use of chloroquine or hydroxychloroquine with or without azithromycin for the treatment of COVID-19 in hospitalized patients and nonhospitalized patients.

The Panel recommends against the use of lopinavir/ritonavir and other HIV protease inhibitors for the treatment of COVID-19 in hospitalized patients and nonhospitalized patients. 

Ivermectin- There are insufficient data for the Panel to recommend either for or against the use of ivermectin for the treatment of COVID-19. Results from adequately powered, well-designed, and well-conducted clinical trials are needed to provide more specific, evidence-based guidance on the role of ivermectin in the treatment of COVID-19.  

 References:

  • NIH: Potential Antiviral Drugs Under Evaluation for the Treatment of COVID-19 (Last Updated: February 11, 2021).
  • NIH: Antiviral Drugs That Are Approved or Under Evaluation for the Treatment of COVID-19 (Accessed 09/21/20).

Candidate: EIDD-2801 (Molnupiravir)

Sponsors/Developers: Ridgeback Biotherapeutics, LP., Merck (MSD).

Location: United States, United Kingdom

Clinical Trial IDs: NCT04392219 (Phase 1), NCT04405739 (Phase 2), NCT04405570 (Phase 2)

Description: EIDD-2801 is an investigational, orally-bioavailable form of a potent ribonucleoside analog that inhibits the replication of multiple RNA viruses including SARS-CoV-2, the causative agent of COVID-19. In animal studies of two distinct coronaviruses (SARS-CoV-1 and MERS), EIDD-2801 has been shown to improve pulmonary function, decrease body-weight loss and reduce the amount of virus in the lung. EIDD-2801 was invented at Drug Innovations at Emory (DRIVE), LLC, a not-for-profit biotechnology company wholly owned by Emory University.

Under the agreement, announced on May 26, 2020, Merck (MSD), through a subsidiary, has acquired exclusive worldwide rights to develop EIDD-2801 and related molecules in collaboration with Ridgeback. Ridgeback will continue to fund and conduct multiple Ridgeback-sponsored Phase 1 and 2 trials and fund manufacturing campaigns for clinical supply. Going forward, the parties will collaborate on clinical development for COVID-19 and manufacturing, to be led by Merck. Consistent with the shared history and commitment to addressing global unmet needs in grievous illness, Merck and Ridgeback also plan to explore the potential for EIDD-2801 in other severe acute viral diseases, such as Ebola.

Ridgeback Biotherapeutics announces the launch of two Phase 2 clinical trials to test the efficacy of EIDD-2801 as an anti-viral treatment for COVID-19. Phase 1 trials recently determined that EIDD-2801 is safe in human doses that provide blood levels well above levels that animal models suggest should be effective against SARS-CoV-2, the virus which causes COVID-19. EIDD-2801 will be administered to patients 18 years old and over in two studies: Study 2003 will enroll recently symptomatic, newly diagnosed patients in a home, or out of hospital, setting; Study 2004 will enroll hospitalized patients with COVID-19.

Study published in nature on December 3, 2020, shows that the treatment of SARS-CoV-2 infection with a new antiviral drug, MK-4482/EIDD-2801 or Molnupiravir, completely suppresses virus transmission within 24 hours, researchers in the Institute for Biomedical Sciences at Georgia State University have discovered. Team repurposed MK-4482/EIDD-2801 against SARS-CoV-2 and used a ferret model to test the effect of the drug on halting virus spread. If these ferret-based data translate to humans, COVID-19 patients treated with the drug could become non-infectious within 24 hours after the beginning of treatment.

Study published in nature on February 9, 2021, show that therapeutic and prophylactic administration of EIDD-2801, an oral broad-spectrum antiviral currently in phase II–III clinical trials, dramatically inhibited SARS-CoV-2 replication in vivo and thus has significant potential for the prevention and treatment of COVID-19.

Status: On Marchc 6, 2021, MSD and Ridgeback Biotherapeutics announced preliminary results from Ridgeback’s Phase 2a randomized, double-blind, placebo-controlled trial to evaluate the safety, tolerability, and efficacy to eliminate SARS-CoV-2 viral RNA of molnupiravir (EIDD-2801/MK-4482), an investigational oral antiviral agent. The companies today reported findings on one secondary objective from the Phase 2a study, showing a reduction in time (days) to negativity of infectious virus isolation in nasopharyngeal swabs from participants with symptomatic SARS-CoV-2 infection, as determined by isolation in Vero cell line culture. This multi-center U.S. Phase 2a study enrolled 202 non-hospitalized adults who had signs or symptoms of COVID-19 within 7 days and confirmed active SARS-CoV-2 infection. At day 5, there was a reduction (nominal p=0.001, not controlled for multiplicity) in positive viral culture in subjects who received molnupiravir (all doses) compared to placebo: 0% (0/47) for molnupiravir and 24% (6/25) for placebo. No safety signals have been identified and of the 4 serious adverse events reported, none were considered to be study drug related.

References:

  • Press Release: Ridgeback Biotherapeutics Announces Potential COVID-19 Treatment EIDD-2801 Will Leverage Innovative Testing Platform AGILE for Phase 2 Trial. BusinessWire (07/07/20).
  • Press Release: Ridgeback Biotherapeutics Announces Launch of Phase 2 Trials Testing EIDD-2801 as Potential Treatment. Ridgeback Biotherapeutics (06/19/20).
  • Press Release: Merck and Ridgeback Bio Announce Closing of Collaboration and Licensing Transaction. BusinessWire (07/01/20).
  • Publication: Therapeutically administered ribonucleoside analogue MK-4482/EIDD-2801 blocks SARS-CoV-2 transmission in ferrets. Nature (12/03/20).
  • Publication: SARS-CoV-2 infection is effectively treated and prevented by EIDD-2801. Nature (02/09/21).
  • Press Release: Ridgeback Biotherapeutics and Merck (MSD) Announce Preliminary Findings from a Phase 2a Trial of Investigational COVID-19 Therapeutic Molnupiravir. MSD (03/06/21).

Candidate: Lopinavir/Ritonavir (Kaletra)

Sponsors/Developers: Multiple clinical trials

Location: Multiple locations

Clinical Trial IDs: NCT04330690 (Phase 2), Chinese Clinical Trial Register number ChiCTR2000029308

Description: Lopinavir/ritonavir is an inhibitor of severe acute respiratory syndrome-associated coronavirus (SARS-CoV) 3CLpro in vitro, and this protease appears to be highly conserved in SARS-CoV-2. Although lopinavir/ritonavir has in vitro activity against SARS-CoV, it is thought to have a poor selectivity index, indicating that higher than tolerable levels of the drug might be required to achieve meaningful inhibition in vivo.

In a study published in NEJM on 5July 2020, treatment was not associated with a difference from standard care in the time to clinical improvement. A total of 199 patients with laboratory-confirmed SARS-CoV-2 infection participated in this randomized, controlled, open-label trial; 99 were assigned to the lopinavir-ritonavir group, and 100 to the standard-care group. Mortality at 28 days was similar in the lopinavir–ritonavir group and the standard-care group. Treatment was stopped early in 13 patients (13.8%) because of adverse events.

WHO on July 04, 2020, accepted the recommendation from the Solidarity Trial’s International Steering Committee to discontinue the trial’s hydroxychloroquine and lopinavir/ritonavir arms. The Solidarity Trial was established by WHO to find an effective COVID-19 treatment for hospitalized patients.

The COVID-19 Treatment Guidelines Panel recommends against using lopinavir/ritonavir or other HIV protease inhibitors for the treatment of COVID-19, except in a clinical trial. The pharmacodynamics of lopinavir/ritonavir raise concerns about whether it is possible to achieve drug concentrations that can inhibit the SARS-CoV-2 proteases. In addition, lopinavir/ritonavir did not show efficacy in a moderately sized randomized controlled trial in patients with COVID-19.

Result of an Exploratory Randomized Controlled Trial on efficacy and safety of Lopinavir/Ritonavir or Arbidol in Adult Patients with Mild/Moderate COVID-19 was published in Med on December 18, 2021. Lopinavir/Ritonavir showed little benefit for improving the clinical outcome of patients hospitalized with mild/moderate COVID-19 over supportive care.

Status: On February 9, 2021, A result published for multicenter clinical study in Indonesia showed that, the administration of lopinavir/ritonavir-doxycycline, lopinavir/ritonavir-azithromycin, and azithromycin-hydroxychloroquine as a dual drug combination produced a significantly rapid PCR conversion rate to negative in three-day treatment of mild to moderate COVID-19 cases.

References:

  • Publication: A Trial of Lopinavir–Ritonavir in Adults Hospitalized with Severe Covid-19. NEJM (05/07/20).
  • News Release: WHO discontinues hydroxychloroquine and lopinavir/ritonavir treatment arms for COVID-19. WHO (07/04/20).
  • NIH guidelines: Lopinavir/Ritonavir and Other HIV Protease Inhibitors. NIH (07/17/20).
  • Publication: Efficacy and Safety of Lopinavir/Ritonavir or Arbidol in Adult Patients with Mild/Moderate COVID-19: An Exploratory Randomized Controlled Trial. Med (12/18/20).
  • Publication: A Randomized, Double-Blind, Multicenter Clinical Study Comparing the Efficacy and Safety of a Drug Combination of Lopinavir/Ritonavir-Azithromycin, Lopinavir/Ritonavir-Doxycycline, and Azithromycin-Hydroxychloroquine for Patients Diagnosed with Mild to Moderate COVID-19 Infections. BioChem (02/09/21).

Candidate: Ivermectin

Sponsors/Developers: Multiple developers.

Location: Multiple locations.

Clinical Trial IDs: NCT04422561, NCT04343092, NCT04425863 and several others.

Description: Ivermectin is a Food and Drug Administration (FDA)-approved antiparasitic drug that is used to treat several neglected tropical diseases, including onchocerciasis, helminthiases, and scabies. It is also being evaluated for its potential to reduce the rate of malaria transmission by killing mosquitoes that feed on treated humans and livestock. For these indications, ivermectin has been widely used and has demonstrated an excellent safety profile. Ivermectin acts by inhibiting the host importin alpha/beta-1 nuclear transport proteins, which are part of a key intracellular transport process that viruses hijack to enhance infection by suppressing the host antiviral response. Ivermectin is therefore a host-directed agent, which is likely the basis for its broad-spectrum activity in vitro against the viruses that cause dengue, Zika, HIV, and yellow fever.

In the ICON (Ivermectin in COvid Nineteen) study, a  retrospective cohort study of 280 consecutive hospitalized patients, Ivermectin was associated with lower mortality during treatment of COVID-19, especially in patients who required higher inspired oxygen or ventilatory support. These findings should be further evaluated with randomized controlled trials.

Add-on use of Ivermectin to hydroxychloroquine and azithromycin had better effectiveness, shorter hospital stay, and relatively safe compared with controls. however, a larger prospective study with longer follow up may be needed to validate these results.

An experimental treatment called IDEA based on four affordable drugs (ivermectin, dexamethasone, enoxaparin and aspirin ) already available on the market in Argentina showed promising results.

The COVID-19 Treatment Guidelines Panel recommends against the use of ivermectin for the treatment of COVID-19, except in a clinical trial.

Status: In a recent publication with 89 high-risk patients receiving ivermectin, the ivermectin treated patients became SARS-CoV-2 negative more quickly and fewer treated patients developed respiratory distress. Ivermectin-treated COVID-19 patients also had shorter hospital stays and was associated with a lower mortality rate in COVID-19 patients.

A french clinical-stage pharmaceutical firm MedinCell has commenced the first clinical trial of its Covid-19 prevention programme. The randomised, double-blind, exploratory phase I trial A has been designed to evaluate the pharmacokinetic profile, safety and tolerability of a continuous daily dosing regimen of Ivermectin in healthy volunteers.

According to the COVID-19 Treatment Guidelines Panel, there are insufficient data for the COVID-19 Treatment Guidelines Panel to recommend either for or against the use of ivermectin for the treatment of COVID-19. Results from adequately powered, well-designed, and well-conducted clinical trials are needed to provide more specific, evidence-based guidance on the role of ivermectin in the treatment of COVID-19.

The effect of an early treatment with ivermectin on viral load, symptoms and humoral response in patients with non-severe COVID-19 was published on January 19, 2021. A pilot, double-blind, placebo-controlled, randomized clinical trial was conducted with patients with non-severe COVID-19. Among patients with non-severe COVID-19 and no risk factors for severe disease receiving a single 400 mcg/kg dose of ivermectin within 72 h of fever or cough onset there was no difference in the proportion of PCR positives. There was however a marked reduction of self-reported anosmia/hyposmia, a reduction of cough and a tendency to lower viral loads and lower IgG titers.

Merck affirmed its position regarding use of ivermectin. They note that, to-date, analysis has identified: No scientific basis for a potential therapeutic effect against COVID-19 from pre-clinical studies; No meaningful evidence for clinical activity or clinical efficacy in patients with COVID-19 disease, and; A concerning lack of safety data in the majority of studies.

In a randomized clinical trial among patients with symptomatic, laboratory-confirmed SARS-CoV-2 infection (n=400), a 5-day course of ivermectin did not significantly improve the time to symptom resolution compared with placebo (10 vs 12 days, HR=1.07, 95%CI: 0.87-1.32). Fifteen (7.5%) patients in the ivermectin group versus 5 (2.5%) in the placebo group discontinued treatment due to an adverse event.

On March 21, 2021, EMA has reviewed the latest evidence on the use of ivermectin for the prevention and treatment of COVID-19 and concluded that the available data do not support its use for COVID-19 outside well-designed clinical trials. Ivermectin medicines are not authorised for use in COVID-19 in the EU, and EMA has not received any application for such use.

References:

  • Publication: The FDA-approved drug ivermectin inhibits the replication of SARS-CoV-2 in vitro. Antiviral Research (04/03/20).
  • NIH guidelines: NIH COVID-19 treatment guidelines. NIH (Last accessed 08/27/20).
  • Preprint: Effectiveness of Ivermectin as add-on Therapy in COVID-19 Management (Pilot Trial). medRxiv (07/08/20).
  • Preprint: ICON (Ivermectin in COvid Nineteen) study: Use of Ivermectin is Associated with Lower Mortality in Hospitalized Patients with COVID19. medRxiv (06/10/20).
  • Preprint: Safety and Efficacy of the combined use of ivermectin, dexamethasone, enoxaparin and aspirin against COVID-19. medRxiv (09/15/20).
  • Publication: Ivermectin treatment may improve the prognosis of patients with COVID-19. ScienceDirect (09/24/20).
  • Press Release: MedinCell initiates the first clinical trial of its Covid-19 prevention program(09/29/20).
  • Publication: The effect of early treatment with ivermectin on viral load, symptoms and humoral response in patients with non-severe COVID-19: A pilot, double-blind, placebo-controlled, randomized clinical trial. EClinicalMedicine (01/19/21).
  • NIH guidelines: NIH COVID-19 treatment guidelines. NIH (Last accessed 03/18/21).
  • Press Release: Merck (MSD) Statement on Ivermectin use During the COVID-19 Pandemic. Merck (MSD) (02/04/21).
  • Publication: Effect of Ivermectin on Time to Resolution of Symptoms Among Adults With Mild COVID-19. Jama (03/04/21).
  • Press Release: EMA advises against use of ivermectin for the prevention or treatment of COVID-19 outside randomised clinical trials. EMA (03/22/21).

Candidate: Lopinavir-Ritonavir

Developers: University of Oxford

Locations: United Kingdom

Clinical Trial IDs: NCT04381936 – Randomised Evaluation of COVID-19 Therapy (RECOVERY)

Description: Lopinavir–ritonavir has been proposed as a treatment for COVID-19 on the basis of in vitro activity, preclinical studies, and observational studies. Lopinavir is a HIV-1 protease inhibitor, which is combined with ritonavir to increase its plasma half-life. Lopinavir is also an inhibitor of the severe acute respiratory syndrome coronavirus (SARS-CoV) main protease, which is critical for replication and appears to be highly conserved in SARS-CoV-2.

A previous randomised trial of lopinavir–ritonavir among 199 patients admitted to hospital with COVID-19 showed no improvement in viral load, duration of hospital stays, or mortality. The trial was too small to rule out the possibility of clinically relevant benefits and commentators recommended larger randomised trials to confirm or refute the lack of effect. RECOVERY trial is a randomised trial to assess whether lopinavir–ritonavir improves clinical outcomes in patients admitted to hospital with COVID-19.

Status: Full results of the lopinavir/ritonavir arm of the randomized, controlled, open-label RECOVERY trial has now been published in the Lancet. Top-line results released at the end of June concluded that there was no benefit to the medication, which is approved for use in HIV and had showed promise in vitro against SARS-CoV-2. Among more than 1,600 patients randomized to lopinavir/ritonavir and over 3,400 patients randomized to usual care, investigators saw no differences in death at 28 days across all subgroups, and no difference in time to hospital discharge or progression to mechanical ventilation or death. “Whilst it is disappointing that there was no significant benefit from lopinavir/ritonavir for patients in hospital, these findings have allowed us to focus our efforts on other promising treatments, and have informed the way in which individual patients are treated,” RECOVERY co-chief investigator Peter Horby, MBBS, PhD, said in a press statement. Of note, no signal of increased arrhythmia was seen with this combination agent.

References:

  • Publication: A Trial of Lopinavir–Ritonavir in Adults Hospitalized with Severe Covid-19. NEJM (05/07/20).
  • News: No clinical benefit from use of lopinavir-ritonavir in hospitalised COVID-19 patients studied in RECOVERY. University of Oxford (06/29/20).
  • Publication: Lopinavir–ritonavir in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial. The Lancet (10/05/20).

Updated: 14 June, 2021.

  • SARS-CoV-2 RBD trimer protein adjuvanted with Alum-3M-052 protects from SARS-CoV-2 infection and immune pathology in the lung [Link] (06/14/21)
  • Adamis Provides Update on Clinical Trial Start-Up Progress for Tempol in the Treatment of COVID-19 [Link] (06/14/21)
  • Vicore announces FDA acceptance for pivotal phase 3 trial of C21 in COVID-19 [Link] (06/14/21)
  • Long-lasting Chlorine Dioxide (ClO2) Aqueous Solution Presented by Taiko Pharmaceutical and Kitasato University Inactivates over 99.99% of SARS-CoV-2 (COVID-19 Virus) [Link] (06/14/21)
  • Metformin inhibition of mitochondrial ATP and DNA synthesis abrogates NLRP3 inflammasome activation and pulmonary inflammation [Link] (06/14/21)
  • The local anaesthetic procaine prodrugs ProcCluster and Procaine-hydrochloride impair SARS-CoV-2 replication in vitro [Link] (06/14/21)
  • Revive Therapeutics Partners with Supriya to Pursue EUA for Bucillamine to Treat COVID in India [Link] (06/10/21)
  • RedHill Biopharma Completes Enrollment of Oral Opaganib Phase 2/3 COVID-19 Study [Link] (06/10/21)
  • India’s CSIR commences Phase II trials of Niclosamide for Covid-19 [Link] (06/10/21)
  • Screening of natural compounds from Cyperus rotundus Linn against SARS-CoV-2 main protease (Mpro): An integrated computational approach [Link] (06/10/21)
  • RECOVERY trial finds aspirin does not improve survival for patients hospitalised with COVID-19 [Link] (06/10/21) Nanotraps for the containment and clearance of SARS-CoV-2 [Link] (06/10/21)
  • Hydroxychloroquine plus standard of care compared with standard of care alone in COVID-19: a meta-analysis of randomized controlled trials [Link] (06/07/21)
  • Therapeutic versus prophylactic anticoagulation for patients admitted to hospital with COVID-19 and elevated D-dimer concentration (ACTION): an open-label, multicentre, randomised, controlled trial [Link] (06/07/21)
  • NIH researchers identify potential new antiviral drug for COVID-19 [Link] (06/07/21)
  • Polyphor’s Balixafortide Demonstrates Consistent Dual Action Anti-Viral and Anti-Inflammatory Activity in COVID-19 Preclinical Trials [Link] (06/02/21)
  • Targeting of the CD80/86 proinflammatory axis as a therapeutic strategy to prevent severe COVID-19 [Link] (06/02/21)
  • NRx Pharmaceuticals Announces Positive Results for ZYESAM (Aviptadil-acetate) and Submits Emergency Use Authorization Application to US Food and Drug Administration to Treat Critical COVID-19 in Patients Suffering from Respiratory Failure [Link] (06/02/21)
  • Adamis Pharmaceuticals Provides Business Update – Phase 2/3 clinical trial preparation initiated for Tempol [Link] (06/02/21)
  • Vitamin D and COVID-19 susceptibility and severity in the COVID-19 Host Genetics Initiative: A Mendelian randomization study [Link] (06/02/21)
  • UV-A and UV-B Can Neutralize SARS-CoV-2 Infectivity [Link] (06/02/21)
  • Omeros Announces Preliminary Results from Additional Critically Ill COVID-19 Patients Treated with Narsoplimab [Link] (06/02/21)
  • Plitidepsin has a positive therapeutic index in adult patients with COVID-19 requiring hospitalization [Link] (06/02/21)

Select strategies are detailed in the section below:

Candidate: OLUMIANT (Baricitinib, LY3009104).

Developers: Eli Lilly, Incyte, National Institute of Allergy and Infectious Diseases (NIAID), Emory University.

Clinical Trial Ids: COV-BARRIER (NCT04421027, Phase 3), ACTT-2 (Baricitinib + Remdesivir, NCT04401579, Phase 3), RECOVERY Trial (NCT04381936), ACTT-4 (Baricitinib + Remdesivir, NCT04640168, Phase 3)

Description:

Baricitinib, sold under the brand name Olumiant among others, is an oral drug for the treatment of rheumatoid arthritis in adults whose disease was not well controlled using tumor necrosis factor antagonists. It acts as an inhibitor of Janus Kinase, blocking the subtypes JAK1 and JAK2. Baricitinib can modulate downstream inflammatory responses via JAK1/JAK2 inhibition and has exhibited dose-dependent inhibition of IL-6-induced STAT3 phosphorylation. Due to increased activation of the JAK/STAT pathway in COVID-19, it is postulated that JAK-inhibitors might have a useful role in treating these patients. Baricitinib has postulated antiviral effects by blocking SARS-CoV-2 from entering and infecting lung cells. Baricitinib reduced inflammation and lung pathology in macaques infected with SARS-CoV-2 but an antiviral effect was not confirmed.

On November 19, 2020, the U. S. FDA issued an Emergency Use Authorization (EUA) for the use of baricitinib in combination with remdesivir in hospitalized adults and children aged at least 2 years with COVID-19 who require supplemental oxygen, invasive mechanical ventilation, or extracorporeal membrane oxygenation (ECMO).

The Adaptive COVID-19 Treatment Trial 2 (ACTT-2) is a multinational, randomized, placebo-controlled trial of baricitinib use in hospitalized patients with COVID-19 pneumonia. Participants (n = 1,033) were randomized 1:1 to oral baricitinib 4 mg or placebo, for up to 14 days, in combination with intravenous remdesivir, for up to 10 days. Participants who received baricitinib had a shorter time to clinical recovery than those who received placebo (median recovery time of 7 vs. 8 days, respectively). This treatment effect was most pronounced among those who required high-flow oxygen or non-invasive ventilation but were not on invasive mechanical ventilation. The difference in mortality between the treatment groups was not statistically significant.

The COV-BARRIER is a Phase 3 study evaluating baricitinib 4 mg once daily plus standard of care (SoC) versus placebo plus SoC. The trial did not meet statistical significance on the primary endpoint. Baricitinib-treated patients were 2.7% less likely than those receiving standard of care to progress to ventilation (non-invasive or mechanical) or death, a difference that was not statistically significant.

Additional research is ongoing to further evaluate the potential role of baricitinib in COVID-19, including NIAID’s ACTT-4 trial (evaluating the efficacy and safety of baricitinib or dexamethasone in combination with remdesivir in hospitalized adults with COVID-19 on supplemental oxygen), the RECOVERY trial in the UK and several investigator-initiated trials. For ACTT-4, the independent data and safety monitoring board (DSMB) found that neither treatment regimen was significantly better than the other and NIAID closed enrollment on April 13, 2021 with just more than 1,000 participants.

NIH recommendations:

There are insufficient data for the COVID-19 Treatment Guidelines Panel (the Panel) to recommend either for or against the use of baricitinib in combination with remdesivir for the treatment of hospitalized patients when corticosteroids can be used. In the rare circumstance when corticosteroids cannot be used, the Panel recommends baricitinib in combination with remdesivir in hospitalized, non-intubated patients who require oxygen supplementation. The Panel recommends against the use of baricitinib without remdesivir. There are insufficient data for the Panel to recommend either for or against the use of baricitinib in combination with corticosteroids for the treatment of COVID-19. The Panel recommends against the use of JAK inhibitors other than baricitinib for the treatment of COVID-19.

References:

  • Publication: Baricitinib as potential treatment for 2019-nCoV acute respiratory disease. The Lancet (02/15/20).
  • Publication: Baricitinib treatment resolves lower-airway macrophage inflammation and neutrophil recruitment in SARS-CoV-2-infected rhesus macaques. Cell (01/21/21).
  • Press Release: Baricitinib Receives Emergency Use Authorization from the FDA for the Treatment of Hospitalized Patients with COVID-19. Eli Lilly (11/19/20).
  • Guideline: COVID-19 Treatment Guidelines. NIH (02/11/2021).
  • Publication: Baricitinib plus Remdesivir for Hospitalized Adults with Covid-19. The New England Journal of Medicine (03/04/21).
  • Press Release: Lilly and Incyte announce results from the Phase 3 COV-BARRIER study of baricitinib in hospitalized COVID-19 patients. Eli Lilly (04/08/21).
  • News Release: Baricitinib to be investigated as a possible treatment for COVID-19 in the RECOVERY trial. RECOVERY Trial (02/02/21).

Candidate: Dexamethasone.

Clinical Trial IDs: ISRCTN50189673 (Phase II/III), EudraCT 2020-001113-21 (Phase II/III), NCT04381936 (Phase II/III).

Developers: Randomised Evaluation of COVid-19 thERapY (RECOVERY) Trial– This trial is supported by a grant to the University of Oxford from UK Research and Innovation/National Institute for Health Research (NIHR) and by core funding provided by NIHR Oxford Biomedical Research Centre, Wellcome,  the Bill and Melinda Gates Foundation, the Department for International Development, Health Data Research UK, the Medical Research Council Population Health Research Unit, and NIHR Clinical Trials Unit Support Funding.

Description:

Dexamethasone works by suppressing inflammation and the immune system, both of which are activated in the course of COVID-19 infection.

Recommendations on the use of corticosteroids for COVID-19 are largely based on data from the RECOVERY trial, a large, multicenter, randomized, open-label trial performed in the United Kingdom. The results from RECOVERY trial for hospitalized patients was published in NEJM on February 25, 2021. In this controlled, open-label trial comparing a range of possible treatments in patients who were hospitalized with Covid-19, we randomly assigned patients to receive oral or intravenous dexamethasone (at a dose of 6 mg once daily) for up to 10 days or to receive usual care alone. In patients hospitalized with Covid-19, the use of dexamethasone resulted in lower 28-day mortality among those who were receiving either invasive mechanical ventilation or oxygen alone at randomization but not among those receiving no respiratory support. Treatment with dexamethasone conferred a survival benefit among participants who required supplemental oxygen without invasive mechanical ventilation at enrollment: 23.3% of the participants in the dexamethasone group died within 28 days of enrollment compared with 26.2% in the standard of care arm (rate ratio 0.82).

In a prospective meta-analysis of 7 randomized trials that included 1703 patients of whom 647 died (including the RECOVERY trial), 28-day all-cause mortality was lower among patients who received corticosteroids compared with those who received usual care or placebo (summary odds ratio, 0.66).

In a trial of 475 patients with non-severe COVID-19 pneumonia, early, low-dose, and short-term corticosteroids therapy was associated with worse clinical outcomes.

WHO guidelines:

On 2 September 2020, WHO issued an interim guideline on the use of dexamethasone and other corticosteroids for the treatment of COVID-19. WHO strongly recommends that corticosteroids (i.e. dexamethasone, hydrocortisone or prednisone) be given orally or intravenously for the treatment of patients with severe and critical COVID-19. WHO also advises against the use of corticosteroids in the treatment of patients with non-severe COVID-19, unless the patient is already taking this medication for another condition.

NIH recommendations:

For hospitalized patients with COVID-19 who require supplemental oxygen, the NIH Panel recommends one of the three – Remdesivir, Remdesivir + Dexamethasone, or Dexamethasone alone. For hospitalized patients with COVID-19 who require invasive mechanical ventilation or ECMO, the Panel recommends the use of dexamethasone. It recommends against the use of dexamethasone or other corticosteroids in patients who are hospitalized with moderate COVID-19 but who do not require supplemental oxygen.

References:

  • Publication: Dexamethasone in Hospitalized Patients with Covid-19. The New England Journal of Medicine (02/25/21).
  • Publication: Association between administration of systemic corticosteroids and mortality among critically ill patients with COVID-19: a meta-analysis. JAMA (09/02/20).
  • Guidelines: Corticosteroids for COVID-19 – Living Guidance. WHO (09/02/20).
  • Guidelines: Therapeutic Management of Adults With COVID-19. NIH (04/21/21).
  • Publication: Efficacy Evaluation of Early, Low-Dose, Short-Term Corticosteroids in Adults Hospitalized with Non-Severe COVID-19 Pneumonia: A Retrospective Cohort Study. Infect Dis Ther. (09/02/20).

Candidate: Mesenchymal Stem Cells.

Clinical Trial IDs: NCT04728698 (Phase II), NCT04428801 (Phase II), NCT04537351 (Phase I, II) and others.

Developers: Sorrento Therapeutics, Inc. (COVI-MSC), Celltex Therapeutics Corporation (AdMSCs), Cynata Therapeutics Limited (CYP-001) and others.

Description:

Mesenchymal stem cells are multipotent adult stem cells that are present in most human tissues, including the umbilical cord. Mesenchymal stem cells can self-renew by dividing and can differentiate into multiple types of tissues (including osteoblasts, chondroblasts, adipocytes, hepatocytes, and others), which has led to a robust clinical research agenda in regenerative medicine. Research has shown that MSCs have specific cytokines that drive immunomodulation, which may be useful against SARS-CoV-2. Current efforts with MSC therapeutics are focusing on the capability of MSCs to abort or minimize the cytokine storm, thereby reducing lung damage and promoting the restoration of tissue function through their inherent reparative properties.

Data supporting the use of mesenchymal stem cells in patients who have viral infections, including SARS-CoV-2 infection, are limited to case reports and small, open-label studies.

A small clinical trial evaluated human umbilical cord mesenchymal stem cell (hUC-MSC) infusion in patients with severe COVID-19 who had not responded to standard of care therapies after 7 to 10 days of treatment. Among the 41 patients eligible to participate in the study, 12 received hUC-MSC infusion and 29 received standard of care therapies only. All 12 participants who received hUC-MSC infusion recovered without requiring mechanical ventilation and were discharged to home. Four patients who received only standard of care therapies progressed to critical illness requiring mechanical ventilation; three of these patients died. These results are not statistically significant, and interpretation of the findings is limited by the study’s lack of randomization and small sample size.

A double-blind, phase 1/2a, randomized, controlled trial was conducted at UHealth System/Jackson Health System, in Miami, Florida to determine safety and explore efficacy of umbilical cord mesenchymal stem cell (UC-MSC) infusions in 24 subjects with COVID-19 ARDS The results of this trial indicate that UC-MSC infusions in COVID-19 with ARDS are safe. Moreover, UC-MSC treatment was associated with a significant reduction in serious adverse events, mortality, and time to recovery, compared with controls. Interpretation of these results is limited by the small sample size.

In an article discussing the applicability of stem cells in treating severe SARS-CoV-2 infection with regard to ARDS therapy, a systematic review yielded several important findings including in-vitro data of ARDS where stem cell therapy has been used, derived from various sources have shown increased proliferation and migration in lung cancer cell lines. They even exhibited decreased apoptosis and neutrophil migration. Similarly, in-vivo/preclinical data demonstrated the stem cells efficacy in different models of acute lung injury. Findings very well correlated with certain case reports and clinical studies in terms of efficacy and safety profile where the capability of stem cell-based therapy to reduce the systemic inflammatory responses have been demonstrated in ARDS patients. Large and wide-scale clinical trials will be needed to properly assess the safety profile and applicability of stem cells.

Liu et al., described an approach to COVID-19 based on engineered human mesenchymal stem cells (hu-MSC), which is like a small protein antigen response device, but will be gradually cleared and degraded by body’s immune system among recognition process. They administered MSC-SARS-CoV-2-N cells in C57BL6 mice and observed antibody production in almost all the immunized mice (7/8) after 20 days in which 50% had strong positive antibody expression.

Cynata Therapeutics is all set to expand recruitment criteria in its active MEseNchymal coviD-19 (MEND) clinical trial of Cymerus mesenchymal stem cells (MSCs) in intensive care patients with respiratory failure. Sorrento Therapeutics recently announced receipt of clearance from the Brazilian regulatory agency (ANVISA) to proceed with a Phase 2 Pivotal clinical trial of COVI-MSC, an injectable infusion of mesenchymal stem cells, for the treatment of hospitalized COVID-19 patients suffering from ARDS. The Brazil study is a Phase 2 Pivotal, multi-center, randomized, controlled study to evaluate the safety and efficacy of three infusions of COVI-MSC, administered every other day, to hospitalized patients experiencing moderate or severe COVID-19 with ARDS.

NIH recommendations:

The COVID-19 Treatment Guidelines Panel recommends against the use of mesenchymal stem cells for the treatment of COVID-19, except in a clinical trial.

References:

  • Publication: Mesenchymal Stem Cells in COVID-19: A Journey from Bench to Bedside. Laboratory Medicine (07/30/20).
  • Guidelines: Cell-Based Therapy Under Evaluation for the Treatment of COVID-19. NIH (04/21/21).
  • Publication: Transplantation of ACE2(-) mesenchymal stem cells improves the outcome of patients with COVID-19 pneumonia. Aging and Disease (03/13/20).
  • Publication: Treatment of severe COVID-19 with human umbilical cord mesenchymal stem cells. Stem Cell Research & Therapy (08/18/20).
  • Publication: Umbilical cord mesenchymal stem cells for COVID-19 acute respiratory distress syndrome: A double-blind, Phase 1/2a, randomized controlled trial. Stem Cell Research & Therapy (01/05/21).
  • Publication: Stem cell therapy in COVID-19: Pooled evidence from SARS-CoV-2, SARS-CoV, MERS-CoV and ARDS: A systematic review. Biomedicine & Pharmacotherapy (05/21/21).
  • Preprint: Engineered human mesenchymal stem cells as new vaccine platform for COVID-19. BioRxiv (06/20/20).
  • Press Release: Cynata Expands MEND clinical trial in COVID-19 and Respiratory Failure. Cynata Therapeutics Limited (03/29/21).
  • Press Release: Brazilian Health Regulatory Agency (ANVISA) Authorizes Sorrento Phase 2 Pivotal Clinical Trial of COVI-MSC in Hospitalized COVID-19 Patients With Acute Respiratory Distress Syndrome. Sorrento Therapeutics (05/20/21).

Candidate: Convalescent Plasma therapy.

Clinical Trial IDs: RECOVERY Trial (ISRCTN50189673 and NCT04381936, Phase II/II), REMAP-CAP (NCT02735707, Phase 4), Mayo Clinic Expanded Access (NCT04338360), PLASM-AR trial (NCT04383535), PLACID trial (CTRI/2020/04/024775), CONCOVID Study (NCT04342182, Phase II/III) and several others.

Developers: University of Oxford, Mayo Clinic and several others.

Description:

Convalescent plasma is a blood product containing antibodies against the SARS-CoV-2 obtained from patients who have recovered from the COVID-19 disease.

On August 23, 2020, the FDA issued an Emergency Use Authorization (EUA) for COVID-19 convalescent plasma for the treatment of hospitalized patients. On February 4, 2021, the FDA revised the convalescent plasma EUA to limit the authorization to high-titer COVID-19 convalescent plasma and only for the treatment of hospitalized patients with COVID-19 early in the disease course or hospitalized patients who have impaired humoral immunity.

In a retrospective study of 3082 patients hospitalized with Covid-19 (Expanded Access study, Mayo Clinic) who were not receiving mechanical ventilation, transfusion of plasma with higher anti–SARS-CoV-2 IgG antibody levels was associated with a lower risk of death than transfusion of plasma with lower antibody levels.

In the PLASM-AR trial, a total of 228 patients were assigned to receive convalescent plasma and 105 to receive placebo. No significant differences were observed in clinical status or overall mortality between patients treated with convalescent plasma and those who received placebo.

For the PLACID trial in India, among 464 adults with confirmed moderate COVID-19, 235 were assigned to convalescent plasma with best standard of care (intervention arm) and 229 to best standard of care only. Convalescent plasma was not associated with a reduction in progression to severe covid-19 or all-cause mortality.

In another trial, a total of 160 patients underwent randomization – In the intention-to-treat population, severe respiratory disease developed in 13 of 80 patients (16%) who received convalescent plasma and 25 of 80 patients (31%) who received placebo (relative risk: 0.52, p=0.03), with a relative risk reduction of 48%. Overall results suggested early administration of high-titer convalescent plasma against SARS-CoV-2 to mildly ill infected older adults reduced the progression of Covid-19.

A review of aggregated patient outcome data from 10 randomized clinical trials, 20 matched control studies, 2 dose-response studies, and 96 case reports or case series demonstrated that patients with COVID-19 transfused with convalescent plasma exhibited a lower mortality rate compared with patients receiving standard treatments. Additional analyses showed that early transfusion (within 3 days of hospital admission) of higher titer plasma is associated with lower patient mortality.

The CONCOVID trial was halted prematurely after 86 patients were enrolled as observations caused concerns about the potential benefit of convalescent plasma in the study population and after discussion with the data safety monitoring board. No difference in mortality (p=0.95), hospital stay (p=0.68) or day-15 disease severity (p=0.58) was observed between plasma treated patients and patients on standard of care.

Among the major plasma trials, for the RECOVERY trial, 11558 (71%) of 16287 patients enrolled were eligible to receive convalescent plasma and were assigned to either the convalescent plasma group or the usual care group. There was no significant difference in 28-day mortality between the two groups: 1399 (24%) of 5795 patients in the convalescent plasma group and 1408 (24%) of 5763 patients in the usual care group died within 28 days (rate ratio 1.00; p=0.95). Allocation to convalescent plasma had no significant effect on the proportion of patients discharged from hospital within 28 days. Among those not on invasive mechanical ventilation at randomization, there was no significant difference in the proportion of patients meeting the composite endpoint of progression to invasive mechanical ventilation or death.

The REMAP-CAP trial was an international trial into the best range of treatments for people with COVID-19. It was an adaptive trial which meant different treatments could be added over time and patients could receive different treatments. The convalescent plasma treatment in this trial was for people who had been in intensive care for less than 48 hours and have tested positive for COVID-19. People who received plasma as part of their treatment had two transfusions over two days and were monitored for 21 days to see how effective this was. The initial analysis of all trial patients requiring intensive care unit support showed that convalescent plasma did not improve outcomes. The final analysis is in progress and the results of this are awaited.

NIH recommendations:

The COVID-19 Treatment Guidelines Panel recommends against the use of low-titer COVID-19 convalescent plasma for the treatment of COVID-19. Low-titer COVID-19 convalescent plasma is no longer authorized through the convalescent plasma EUA.

References:

  • News Release: FDA Issues Emergency Use Authorization for Convalescent Plasma as Potential Promising COVID–19 Treatment. FDA (08/23/20).
  • News Release: Recommendations for investigational COVID-19 convalescent plasma. FDA (02/11/21).
  • Publication: Convalescent plasma in patients admitted to hospital with COVID-19 (RECOVERY): a randomised controlled, open-label, platform trial. The Lancet (05/14/21).
  • News Release: RECOVERY trial closes recruitment to convalescent plasma treatment for patients hospitalised with COVID-19. RECOVERY (01/15/21).
  • Guidelines: Convalescent Plasma. NIH (04/21/21).
  • Preprint: Convalescent Plasma for COVID-19. A randomized clinical trial (ConCovid). medRxiv (07/03/20).
  • Publication: A Randomized Trial of Convalescent Plasma in Covid-19 Severe Pneumonia. PlasmAr ClinicalTrials. The New England Journal of Medicine (02/18/21).
  • Publication:  Convalescent plasma in the management of moderate covid-19 in adults in India: open label phase II multicentre randomised controlled trial (PLACID Trial). BMJ (10/22/20).
  • Publication: The Effect of Convalescent Plasma Therapy on Mortality Among Patients With COVID-19: Systematic Review and Meta-analysis. Mayo Clinic Proceedings (05/10/21).
  • Publication: Early administration of high-titer convalescent plasma against SARS-CoV-2 to mildly ill infected older adults reduced the progression of Covid-19. The New England Journal of Medicine (02/18/21).
  • Press Release: International Trial of SARS-CoV-2 Convalescent Plasma Pauses Enrollment of Critically Ill COVID-19 Patients. REMAP-CAP (01/11/21).

Updated: 14 June, 2021.

The table lists various ongoing treatment efforts (Antibodies, Antivirals, Cell-based therapies and others) from developers and sponsors globally to identify a safe and efficacious solution to the pandemic. Data is collated from various sources including Publications, Press releases, WHO website and Milken Institute trackers.

Updated: June 10, 2021.

COVID-19 Clinical Trials: An Overview

Researchers and clinicians all over the world have reacted to the COVID-19 pandemic and the ensuing public health crisis with a colossal worldwide effort to discover a treatment. With increasing number of global cases and fatalities, the world waits for more positive results from these ongoing trials. Several existing antivirals, traditional and alternative medicines, investigative or repurposed compounds, support devices as well as procedures, supplements are being explored in the context of SARS-CoV-2 infection.

The pandemic has changed the way trials are being conducted, with several radical changes in terms of recruitment, obtaining consent remotely, telemedical monitoring and implementation of more innovative trial designs. There is a need to make these positive changes instigated by the pandemic sustainable [1].

The World Health Organization’s International Clinical Trials Registry Platform (WHO ICTRP) ensures that “a complete view of research is accessible to all those involved in health care decision making”. Information in the WHO ICTRP comprises of structured data from several major clinical trial databases from countries or regions of the world, including but not limited to the ClinicalTrials.gov [2], Chinese Clinical Trial Registry (ChiCTR) [3], The Clinical Trials Registry- India (CTRI) [4], Iranian Registry of Clinical Trials [5], European Union Clinical Trials Register [6] and the ISRCTN register [7].

As of May 07, 2021, there are 9485 trials registered in the WHO ICRTRP database for COVID-19, with 5481 Interventional trials and rest comprising majorly of Observational studies (3485), Diagnosis tests (49), and others (Expanded Access, Basic Science, Epidemiological research etc.) [8].

Of note, is the SOLIDARITY trial [9]. Solidarity is an international clinical trial to help find an effective treatment for COVID-19, launched by the World Health Organization and partners. It is one of the largest international randomized trials for COVID-19 treatments, enrolling almost 12 000 patients in 500 hospital sites in over 30 countries. The Solidarity Trial is evaluating the effect of drugs on 3 important outcomes in COVID-19 patients: mortality, need for assisted ventilation and duration of hospital stay. compares treatment options against standard of care to assess their relative effectiveness against COVID-19. By enrolling patients in multiple countries, the Solidarity Trial aims to evaluate whether any of the drugs improve survival or reduce the need for ventilation or duration of hospital stay. Other drugs may be added based on emerging evidence. The Solidarity Trial published interim results on 15 October 2020. It found that all 4 treatments evaluated (remdesivir, hydroxychloroquine, lopinavir/ritonavir and interferon) had little or no effect on overall mortality, initiation of ventilation and duration of hospital stay in hospitalized patients. Previously, on 4 July 2020, WHO had accepted the recommendation from the Solidarity Trial’s International Steering Committee to discontinue the trial’s hydroxychloroquine and lopinavir/ritonavir arms.

Another such trial, The Randomised Evaluation of COVid-19 thERapY (RECOVERY) trial was officially launched on 23 March 2020. The trial led to the first breakthrough in the COVID-19 response within only three months – the finding that the cheap steroid dexamethasone saves the lives of hospitalized patients. Within its first year, RECOVERY also identified another beneficial treatment, the anti-inflammatory drug tocilizumab, besides ruling out four candidate therapies. In one year, it has recruited almost 40,000 patients and investigated 10 treatments. The RECOVERY Trial is currently testing some of the other suggested treatments: Regeneron’s antibody cocktail, Baricitinib, and Dimethyl fumarate (an immunomodulatory drug used in psoriasis and multiple sclerosis). The RECOVERY Trial is registered at ISRCTN50189673; EU Clinical Trials Register: EudraCT 2020-001113-21; and Clinical Trials.gov: NCT04381936. This trial is supported by a grant to the University of Oxford from UK Research and Innovation/National Institute for Health Research (NIHR) and by core funding provided by NIHR Oxford Biomedical Research Centre, Wellcome,  the Bill and Melinda Gates Foundation, the Department for International Development, Health Data Research UK, the Medical Research Council Population Health Research Unit, and NIHR Clinical Trials Unit Support Funding [10].

The US FDA has created a special emergency program for possible coronavirus therapies, the Coronavirus Treatment Acceleration Program (CTAP). As per the program guidelines, it aims to use every available method to move new treatments to patients as quickly as possible, while at the same time finding out whether they are helpful or harmful [11]. The CTAP Dashboard provides users with a snapshot of development of potential COVID-19 therapeutics. As of May 07, 2021, the CTAP dashboard lists 600+ available therapies with 440+ clinical trials reviewed, with 10 of the available therapies approved for Emergency Use. Only one among the therapies have been FDA approved so far (Figure 1).

Figure 1: Treatments reviewed by CTAP – Numbers correspond to number of safe to proceed INDs. Excludes INDs related to vaccines (Source: CTAP dashboard [11]). There were 100+ early stage trials and 330+ late stage (Phase 2-4) trials from U. S. included in the analysis.

As per FDA classification, the categories in this bar chart span several categories –

  • Antiviral drugs keep viruses from multiplying and are used to treat many viral infections (such as HIV, Herpes, Hepatitis C, and influenza). 
  • Immunomodulators are aimed at tamping down the body’s own immune reaction to the virus, in cases where the body’s reaction basically goes overboard and starts attacking the patient’s own organs.
  • Neutralizing antibody therapies may help individuals fight the virus and include manufactured antibodies, animal-sourced antibody therapies, and blood-derived products such as convalescent plasma and hyperimmune globulin, which contain antibodies taken from people who have previously had COVID-19.
  • Cell therapy products include cellular immunotherapies and other types of both autologous and allogeneic cells, such as stem cells, and related products.
  • Gene therapy products seek to modify or manipulate the expression of a gene or to alter the biological properties of living cells for therapeutic use.

The Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV) partnership [12] was announced on April 17, 2020 by  National Institutes of Health (NIH), with coordination by the Foundation for the National Institutes of Health (FNIH) involving a collaboration among government and industry partners, including FDA, to prioritize vaccine and therapeutic candidates, streamline clinical trials, and rapidly expand the clinical research resources focused on developing therapies [13]. ACTIV continues to grow and now involves several academic and industry partners (20 biopharmaceutical companies), and up to 8 different government agencies. ACTIV also works closely with other COVID-19 efforts, including FDA and BARDA’s Medical Countermeasures Task Force, the Bill & Melinda Gates Foundation, the Wellcome Trust, the European Commission, the UK government, and the World Health Organization.

The ACTIV master protocols include ACTIV-1 (Immune Modulators including infliximab), ACTIV-2 (Outpatient Monoclonal Antibodies and Other Therapies including Lilly’s LY-CoV555, Astrazeneca’s AZD7442, Synarigen’s SNG001), ACTIV-3 (Inpatient Monoclonal Antibodies and Other Therapies including Vir Biotechnology’s VIR-7831), ACTIV-4 (Antithrombotics including Aspirin), ACTIV-5 (Big Effect Trial including Humanigen’ Lenzilumab), ACTIV-6 (Outpatient Repurposed Drugs), and ACTIV-Associated (includes Convalescent Plasma, Hyperimmune Intravenous Immunoglobulin, remdesivir, baricitinib, Rebif and other combinations) [14]. Several tracker projects [15, 16, 17] classify trials based on strategies tested against COVID-19.

Analysis of major categories highlights the top treatments being investigated world-wide as shown in Figure 2.

Figure 2: A comparison of treatments as a measure of trials they are part of, as on 10 November 2020. Data was obtained from WHO ICTRP [8] and Trials Tracker Projects [15, 16, 17].

Ever since the first clinical trial was registered early in 2020, trial registrations have seen an unprecedented pace. The number of registrations daily since early January 2020 is shown in Figure 3.

Figure 3: The pandemic pace of clinical trial registrations on leading platforms, as per data obtained from WHO ICTRP [8] on May 07, 2021. Over 9400 trials were available for analysis.

For a routinely updated list of all clinical trials with details and links to the registry page, please visit the adjacent tab “List of Clinical Trials”.

References:

  1. Gaba, P., Bhatt, D.L. The COVID-19 pandemic: a catalyst to improve clinical trials. Nat Rev Cardiol (2020). https://doi.org/10.1038/s41569-020-00439-7
  2. ClinicalTrials.gov Registry. https://clinicaltrials.gov/
  3. Chinese Clinical Trial Registry (ChiCTR). http://www.chictr.org.cn/abouten.aspx
  4. The Clinical Trials Registry- India (CTRI). http://ctri.nic.in/Clinicaltrials/login.php
  5. Iranian Registry of Clinical Trials. https://www.irct.ir/
  6. European Union Clinical Trials Register. https://www.clinicaltrialsregister.eu/ctr-search/search
  7. ISRCTN register. https://www.isrctn.com/
  8. World Health Organization’s International Clinical Trials Registry Platform (WHO ICTRP). https://www.who.int/ictrp/en/
  9. “Solidarity” clinical trial for COVID-19 treatments. https://www.who.int/emergencies/diseases/novel-coronavirus-2019/global-research-on-novel-coronavirus-2019-ncov/solidarity-clinical-trial-for-covid-19-treatments
  10. The RECOVERY Trial. https://www.recoverytrial.net/
  11. Coronavirus Treatment Acceleration Program (CTAP) | FDA. https://www.fda.gov/drugs/coronavirus-covid-19-drugs/coronavirus-treatment-acceleration-program-ctap
  12. ACCELERATING COVID-19 THERAPEUTIC INTERVENTIONS AND VACCINES (ACTIV). https://www.nih.gov/research-training/medical-research-initiatives/activ
  13. NIH to launch public-private partnership to speed COVID-19 vaccine and treatment options. https://www.nih.gov/news-events/news-releases/nih-launch-public-private-partnership-speed-covid-19-vaccine-treatment-options
  14. The ACTIV trials. https://www.nih.gov/research-training/medical-research-initiatives/activ/covid-19-therapeutics-prioritized-testing-clinical-trials
  15. The Cochrane COVID-19 database. https://covid-19.cochrane.org/
  16. The TrialsTracker project dashboard. http://covid19.trialstracker.net/
  17. Global Coronavirus COVID-19 Clinical Trial Tracker. https://covidtrialstracker.org/

Updated: May 07, 2021. Prepared by: Sudheer Krishna

COVID-19 Global Funding Response

The world is facing an unprecedented challenge with communities and economies everywhere affected by the growing COVID-19 pandemic. IMF estimates suggest that, for each month the pandemic persists, $500 billion is lost from the global economy. The world is coming together to combat the COVID-19 pandemic bringing together governments, organizations and individuals from across industries and sectors to help respond to this global outbreak. The outpour of global solidarity and support sparked by this shared challenge has been phenomenal.

An analysis of data available on the Devex funding database reveals over $20.8 trillion committed to the COVID-19 response to date. Since the beginning of 2020, governments, bilateral and multilateral donors, development banks, philanthropic organizations, and the private sector have all played a role in contributing money, equipment, expertise, and more. As of May 02, 2021, investments totaling $249.8 billion have been made through 1,351 program announcements and 1,092 grants have supported $9.3 billion worth of investment. As for business opportunities, 3,087 tenders have seen $12.2 billion invested through program delivery and service partners, while 1,919 contracts have delivered $2.8 billion on the ground.

The WHO Strategic Preparedness and Response Plan outlines a funding need of at least US$675 million for critical response efforts in countries most in need of help through April 2020. People and organizations who want to help fight the pandemic and support WHO and partners can now donate through the COVID-Solidarity Response Fund for WHO at www.COVID19ResponseFund.org. Over US$250 million has already been raised as of 29 April, 2021 from more than 669,548 individuals, companies and philanthropies.

The Coalition for Epidemic Preparedness Innovations (CEPI) is a global alliance financing and coordinating the development of vaccines against emerging infectious diseases. CEPI has a $3.5 billion plan of action to substantially reduce global epidemic and pandemic risk. CEPI has already played a central role in the global response to the pandemic, creating the world’s largest portfolio of COVID-19 vaccines and helping to make 2 billion doses accessible to 190 countries through COVAX in 2021. CEPI will by the end of March 2021 also launch a Call for Proposals to provide US $200m funding for an ‘all-in-one’ vaccine that could protect against a broad range of coronaviruses, including SARS, MERS-CoV and SARS-CoV-2. CEPI has received support from founding member Norway (US$210 million), UK government (US$270 million), Government of Belgium (US$5.5 million), Government of Canada (US$28.2 million), Greece (US$1.6 million) and German Government’s Federal Ministry (US$157 million).

CEPI, alongside Gavi and the World Health Organisation, launched COVAX – the vaccines pillar of the ACT Accelerator – with the aim of ending the acute phase of the pandemic by the end of 2021. The Access to COVID-19 Tools ACT-Accelerator is a new, ground-breaking global collaboration to accelerate the development, production, and equitable access to COVID-19 tests, treatments, and vaccines. It was set up in response to a call from G20 leaders in March and launched by the WHO, European Commission, France and The Bill & Melinda Gates Foundation in April 2020. COVAX is the solution that will deliver fair, equitable access to vaccines for every country that participates. Together the aim is to produce 2 billion doses of vaccine and distribute them globally and fairly in 2021. COVAX, the vaccines pillar of the Access to COVID-19 Tools (ACT) Accelerator is co-led by the Coalition for Epidemic Preparedness Innovations (CEPI), Gavi, the Vaccine Alliance Gavi) and the World Health Organization (WHO) – working in partnership with developed and developing country vaccine manufacturers, UNICEF, the World Bank, and others. It is the only global initiative that is working with governments and manufacturers to ensure COVID-19 vaccines are available worldwide to both higher-income and lower-income countries.

To date, CEPI has secured financial support from the Bill & Melinda Gates Foundation,  Wellcome Trust, the European Commission, and the governments of Australia, Belgium, Canada, Denmark, Ethiopia, Germany, Japan, Mexico, Norway and the United Kingdom. In response to call the Governments of Austria, Australia, Belgium, Canada, European Commission, Finland, France, Greece, Germany, Iceland, Italy, Japan, Luxembourg, Kingdom of Saudi Arabia, Norway, the Netherlands, New Zealand, Serbia, Spain, Switzerland, and the United Kingdom, alongside private sector companies and donations through the UN Foundation COVID-19 Solidarity Response Fund, have pledged $1.4 billion in financial contributions.

Through the Bill and Melinda Gates Foundation, the Microsoft founder and philanthropist plan to help fund factories for promising vaccines, even before seeing conclusive data. The foundation has committed more than $350 million to support the global response to COVID-19. This includes $100 million to Gavi’s new COVID-19 Vaccine Advance Market Commitment, to support its future efforts to deliver COVID-19 vaccines to lower-income countries. In addition to the more than $350 million committed, the foundation will also leverage a portion of its Strategic Investment Fund, which addresses market failures and helps make it attractive for private enterprise to develop affordable and accessible health products. For example, the foundation is collaborating with Gavi and the Serum Institute of India to accelerate the manufacture and delivery of up to 100 million doses of COVID-19 vaccines for low- and middle-income countries. $150 million came from the Strategic Investment Fund. The Gates Foundation, along with Wellcome and Mastercard, are the founding funders of the COVID-19 Therapeutics Accelerator. The Accelerator is intended to play a catalytic role by accelerating and evaluating new and repurposed drugs to respond to COVID-19 in the immediate term, and other viruses in the longer-term – up to $50 million of the commitment will go towards supporting the COVID-19 Therapeutics Accelerator.

Biomedical Advanced Research and Development Authority (BARDA) part of the HHS Office of the Assistant Secretary for Preparedness and Response, was established to aid in securing our nation from chemical, biological, radiological, and nuclear (CBRN) threats, as well as from pandemic influenza (PI) and emerging infectious diseases (EID). BARDA supports the transition of medical countermeasures such as vaccines, drugs, and diagnostics from research through advanced development towards consideration for approval by the FDA and inclusion into the Strategic National Stockpile. BARDA has updated its Broad Agency Announcements (BAAs) to focus exclusively on addressing the COVID-19 threat. BARDA’s annual budget of $512 Million has been supplemented by an additional $3.5 billion through the recently passed Coronavirus Aid, Relief, and Economic Security (CARES) Act. The additional funding is allocated for necessary expenses of manufacturing, production, and purchase of various supplies and services. AstraZeneca recently received $1B in BARDA funding to advance vaccine. Another leading candidate, Moderna received $483 million BARDA award for vaccine development, while it awarded $450 million to Janssen Pharmaceuticals, a division of Johnson & Johnson, to develop a vaccine.

On 4 May 2020, the EU and its partners hosted an international pledging conference which has now raised €9.8 billion in pledges from donors worldwide to kick-start the global cooperation. This includes a pledge of €1.4 billion from the Commission of which €1 billion comes from Horizon 2020. The EU plays a central role is supporting and coordinating research on infectious diseases, with €4.1 billion invested from 2007 to 2019 through the 7th Framework Programme and Horizon 2020, which foresees further commitments in 2020 in addition to the €1 billion pledge for coronavirus research. This has included initiatives to coordinate European efforts to address antimicrobial resistance, as well as preparedness and emergency response to outbreaks (Ebola, Zika). From the Horizon 2020, €818 million has already been mobilised, and a further €205 million has been pledged. The funds already mobilized includes €100 million contribution to Coalition for Epidemic Preparedness Innovations (CEPI)  (€50 million were mobilised + €50 million in the final approval process).

The Board of Directors of the European Investment Bank (EIB) has agreed on the structure and business approach of the Pan-European Guarantee Fund (EGF) to tackle the economic consequences of the COVID-19 pandemic. The Fund was endorsed by the European Council as part of the overall EU COVID-19 response package. It will enable the EIB Group to scale up its support for mostly small and medium-sized European companies, providing up to €200 billion of additional financing.

The Global Fund, the largest multilateral funder of health systems worldwide, is providing immediate funding of up to US$1 billion to help countries fight COVID-19, mitigate the impacts on lifesaving HIV, TB and malaria programs, and prevent fragile health systems from being overwhelmed. Under the World Health Organization’s leadership, the Global Fund is using its experience working with partners and governments in more than 100 countries to coordinate our response on a massive global scale.

Multiple National Institutes of Health (NIH) Institutes have issued a Notice of Special Interest (NOSI) to provide funding for research topics related to COVID-19. National Institute on Aging (NIA), National Institute of Mental Health (NIMH), The National Heart, Lung, Blood Institute (NHLBI), National Institute of Allergy and Infectious Diseases (NIAID), National Institute of General Medical Sciences (NIGMS), National Center for Advancing Translational Sciences (NCATS), National Institute of Environmental Health Sciences (NIEHS), and National Institute of Drug Abuse (NIDA) are providing opportunities under the NIH.

Updated: May 07, 2021.

The following table lists funding opportunities listed on various public platforms including the NIH grants, JHU, Frontiers, and Brown University COVID-19 funding databases.

Updated: 08 May, 2021.

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