Diagnostics & Mitigation

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.

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