Brace for Impact: The Delta Variant
» Due to the significantly increased infectivity and pathogenicity, the World Health Organization (WHO), on May 10, 2021, designated the B.1.617.2 variant as one of “global concern”, or technically, a VOC (Variant of Concern).
» The variant B.1.617.2, first identified in India, was renamed to ‘Delta’ by the WHO. Delta is now reported from ~96 countries worldwide, rapidly replacing other dominant circulating variants in several of these countries and now makes up more than 20% of all U.S. cases.
» Delta has shown 40%-60% increased transmissibility in studies, with estimated increases in the effective reproduction number of 55%, which is higher compared to other VOCs. But what does a 60% increase mean? “It means if the previous virus was transmitting from one person to two, the Delta variant would transmit to three people.
» Based on the estimated transmission advantage of the Delta variant and modeling forecasts, an increased percentage of new SARS-CoV-2 infections are projected to be due to this variant by early August, up to 90% of infections by the end of August. Therefore, the scientific community has emphasized the paramount need to get completely vaccinated to efficiently protect everyone against the Delta VOC.
» There is growing evidence of increased variant escape against approved monoclonal antibodies and reduced vaccine effectiveness, especially in partially vaccinated individuals as well. Despite lower susceptibility to antibody-mediated neutralization, Delta variant can be effectively controlled by immunity developed in response to natural infection or vaccination.
» Health officials have advised to continue masking and following other recommended distancing and hygiene practices. This combined with improved drug and vaccine designs can overcome the resistance offered by the variant and ensure swift return to normalcy.
» Fortunately, vaccination appears to provide good protection against Delta. A detailed report on vaccine effectiveness among various developers for COVID-19 VOCs can be accessed in the Vaccines topic of the Diagnosis and Mitigation in the dashboard (Go to Vaccines).
Recent months of the pandemic have seen several variants of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) emerge with increased transmissibility, altered epidemiology as well as concerning effects on the prescribed treatments. As per the WHO, “A SARS-CoV-2 isolate is a Variant of Interest (VOI) if, compared to a reference isolate, its genome has mutations with established or suspected phenotypic implications, and either has been identified to cause community transmission/multiple COVID-19 cases/clusters, or has been detected in multiple countries; OR; is otherwise assessed to be a VOI by WHO in consultation with the WHO SARS-CoV-2 Virus Evolution Working Group.”. Among these VOI, variants that meet the following definition are designated as Variants of Concern.
– Increase in transmissibility or detrimental change in COVID-19 epidemiology; or
– Increase in virulence or change in clinical disease presentation; or
– Decrease in effectiveness of public health and social measures or available diagnostics, vaccines, therapeutics.
Under the new naming scheme, B.1.1.7, the variant first identified in Britain, will be known as Alpha and B.1.351, the variant first spotted in South Africa, will be Beta. P.1, the variant first detected in Brazil, will be Gamma and B.1.671.2, the so-called Indian variant, is Delta. Among these, of particular concern is the Delta variant . The nomenclature is as follows –
– WHO label : DELTA
– Pango lineage: B.1.617.2
– GISAID clade/lineage: G/478K.V1
– Nextstrain clade: 21A
– Earliest documented samples: India, Oct-2020.
– Date of designation: VOI On 4-Apr-2021 and VOC on 11-May-2021.
According to the latest correspondence by WHO, the weekly epidemiological update on June 29, 2021, B.1.617.2 (Delta) had been reported from 96 countries (Figure 1) .
A recently published analysis, based on analysis of 1,722,652 SARS-CoV-2 sequences uploaded to the Global Initiative On Sharing All Influenza Data (GISAID) hCoV-19 database showed that there is a statistically significant increase in the pooled mean effective reproduction number relative to non-VOC/VOI of B.1.617.2 at 97%. This value is of concern compared to that of the B.1.1.7 at 29%, B.1.351 at 25%, and P.1 at 38%.
Accordingly, there was a rapid replacement of circulating variants by VOC in nearly all the analyzed countries (52 of 64 ) and the most common being B.1.1.7 (40 countries) and B.1.617.2 (India, Singapore, United Kingdom, Australia). The rapid observed growth of B.1.617.2, with estimated increases in the effective reproduction number of 55%, suggests a clear competitive advantage compared with B.1.1.7, B.1.351 and P.1, with increases of 55%, 60% and 34% respectively .
In a study based on viral sequencing results of samples collected across the United States, Alpha VOC was rapidly being displaced. The percentage of SARS-CoV-2 positive cases that are Alpha dropped from 67% in May 2021 to 33.4% in just 5 weeks, with growth of variants Delta and Gamma as the primary drivers for this displacement .
The CDC COVID data tracker  shows the estimated biweekly proportions of the most common SARS-CoV-2 lineages circulating in the United States, based on over 175,000 collected sequences since December 2020 and grouped in 2-week intervals.
Similar data collected in the United Kingdom by Public Health England (PHE) shows that over 75% of the new cases with confirmed variants (n= 39200, data up to June 2, 2021 since previous update) are of the Delta lineage. This is in comparison to 23% for the previously dominant Alpha VOC . A PHE study with 3,765 genomically sequenced index cases in household clusters matched to 7,530 sporadic index cases provides evidence of increased household transmission of SARS-CoV-2 Delta variant, potentially explaining its success at displacing Alpha variant as the dominant strain in England. The household transmission was significantly higher for Delta cases (OR=1.64) compared to Alpha cases .
Based on sequence-confirmed Delta and Alpha cases in England tested between 29 March 2021 and 23 May 2021 and with hospitalization data up until 5 June 2021, a preliminary analysis of 43338 sequenced cases showed significantly higher risk of hospitalization (HR 2.26) for Delta cases compared to Alpha cases after adjustment for confounders. Similar results were found in Scotland, with a 1.85 HR for hospitalization for those who were S-gene positive compared with those with S gene target failure .
Round 12 of the REACT-1 (The REal-time Assessment of Community Transmision-1) study (20 May 2021 to 7 June 2021) showed that resurgence of infections in England associated with increased Delta frequency, rapidly replacing the Alpha . Sequenced data as at 15 May 2021 from the Wellcome Sanger Institute, UK, showed an increased transmissibility, growth rate, and reproduction number of the Delta VOC . An analysis of the serial interval of household transmission pairs infected with Delta showed no significant changes in the serial intervals lending further support to increased transmissibility (effective reproduction number) for the variant .
The head of WHO said the Delta VOC is “the most transmissible of the variants identified so far”. The WHO also recently advised fully vaccinated people to continue wearing masks and practice other pandemic related safety measures like being in ventilated spaces, practicing hand hygiene, physical distancing, avoid crowds as the variant continues to spread rapidly across the globe . Similar guidelines were also provided by the Los Angeles County Department of Public Health (Public Health) which strongly recommended everyone, regardless of vaccination status, wear masks indoors in public places as a precautionary measure .
Analyzing vaccine breakthrough in over 100 healthcare workers across 3 centers in India, the Delta variant was responsible for significantly greater transmission as compared to B.1.1.7 or B.1.617.1 (mean cluster size 3.2 versus 1.1, p<0.05) . Another study in Delhi, India showed 40-60% increased transmissibility of the Delta variant and 10-50% reduction in immunity elicited by prior infection. High transmissibility and evasion of prior immunity by the Delta variant, coupled to social behavior that promoted transmission, led to the overwhelming pandemic outbreak in Delhi .
Phylogenetic analysis revealed lineage B.1.617 possessing common signature mutations D111D, G142D, L452R, E484Q, D614G and P681R, in the Spike protein including within the receptor binding domain (RBD). The lineage contains two key mutations (L452R and E484Q) in the spike protein including within the RBD. The structural analysis of L452R and E484Q along with another key P681R mutation in the furin cleavage site revealed that these may possibly result in increased ACE2 binding and S1-S2 cleavage, thus leading to better transmissibility . B.1.617 variants were also observed to be highly fusogenic and formed prominent syncytia. The P681R mutation accelerates and enhances SARS-CoV-2 S-mediated fusion .
B.1.617.2 (Delta) possesses ~12 mutations in its spike protein relative to the wildtype SARS-CoV-2 first detected in Wuhan, China, in December, 2019, but lacks mutations at amino acid positions 501 or 484 in its ACE2 receptor-binding domain, commonly associated with VOCs or escape from neutralizing antibodies. The key mutations are L452R and T478K . The RBD mutation T478K in the RBD is unique to Delta and falls within the epitope region of potent neutralizing mAbs categorized as “Class 1”. This mutation at location 478 is in proximity of the well characterized E484K mutation known to facilitate antibody escape.
Delta exhibits RBD mutations L452R and T478K, T19R, G142D R158G and A222V substitutions, together with a double deletion (156-157) in the NTD and S2 substitution D950N. B.1.617.2 shares L452R and P681R with B.1.617.1, and 20% of reported sequences share T95I. Unlike B.1.617.1, B.1.617.2 (Delta) contains NTD deletions which matches a general trend of SARS-CoV-2 variants reducing the size of the NTD.
A study on Delta demonstrated increased Calu-3-lung cell entry and enhanced cell-to-cell fusion of the variant, which may contribute further to its pathogenicity and transmissibility. Pseudotyping revealed that Delta evades control by antibodies induced upon infection and Pfizer/BioNTech BNT162b2 vaccination, although with lower efficiency as compared to B.1.351. The directed expression of Spike protein from Delta caused more and larger syncytia. The quantification of cell-to-cell fusion revealed ~2.5-fold more efficiency as compared to wild-type Spike .
Various studies have examined its sensitivity to monoclonal antibodies (mAbs) and to antibodies present in sera from COVID-19 convalescent individuals or vaccine recipients, and in comparison to other viral lineages as well. Delta variant was resistant to neutralization by some anti-NTD (N-terminal domain) and anti-RBD mAbs, including Lilly’s Bamlanivimab, an mAb with emergency use authorization for COVID-19 therapy, which were impaired in binding to the B.1.617.2 Spike. Sera from convalescent patients and from the Pfizer vaccine recipients were 3-6-fold less potent against the variant as well. The recent Delta spread is associated with an escape to antibodies targeting non-RBD and RBD spike epitopes. There was no major effect on other antibodies like Etesivimab, Casirivimab, Imdevimab or Regdanvimab. In fact, the U.S. government paused distribution of the mAbs bamlanivimab and etesevimab, authorized for high-risk COVID-19 outpatients, citing poor performance against variants.
Vaccines have demonstrated good neutralization ability, albeit reductions were observed to various degrees. Reductions in neutralizing ability have been less pronounced for approved mRNA vaccines as compared to their respective partial dosing regimens and/or the ChAdOx-1 vaccine. Sera mRNA vaccine recipients have shown 2-11-fold reductions in several recent studies. Results suggest that a single dose of AstraZeneca AZD1222 vaccine is not sufficient for optimal protection against Delta variant, recipients developing lower NAbTs than Pfizer/BioNTech BNT162b2 recipients. However, most vaccines do confer sufficient protection after the second dose, emphasizing the need for complete vaccination (second/booster doses). There was no reduction in neutralization titer for the whole-virion inactivated SARS-CoV-2 vaccine (BBV152) in vitro, which was also demonstrated in the recently published Phase 3 study results, where BBV152 conferred 65.2% protection against Delta variant [15, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29].
Table 2: Summary of antibody neutralization studies on Delta VOC.
|Convalescent plasma||Convalescent plasma from previously infected individuals||2.7 to 4.6-fold reduction; 4-6-fold reduction relative to Alpha|
|A panel of potently neutralizing human mAbs||> 5-fold|
|mAbs developed for clinical use including AZD7442, REGN10987, REGN10933, LY-CoV555, LY-CoV16, ADG10, ADG20 and ADG30||~5-fold reductions|
|mAbs||Anti-NTD and Anti-RBD mAbs||Fully resistant|
|Etesivimab, Casirivimab and Imdevimab, Regdanvimab (CT-P59)||No effect|
|AstraZeneca AZD1222||4.01-fold reduction|
|AstraZeneca AZD1222||2.5-fold reduction (vs. BNT162b2)|
|AstraZeneca AZD1222 (One dose)||~Fully resistant|
|Vaccine Sera||AstraZeneca AZD2816 (Animal studies)||No effect|
|Bharat Biotech Covaxin||2.7-fold reduction|
|Pfizer/BioNTech BNT162b2||5.8-11.30-fold reduction; 3-fold reduction (vs. Alpha)|
|Vaccine sera (BNT162b2 or AZD1222)||5.11-8-fold reduction|
Using a test negative case control design in the United Kingdom, the effectiveness of vaccination against symptomatic disease was estimated for BNT162b2 and AstraZeneca AZD1222 vaccines. Effectiveness was lower after 1 dose of vaccine with Delta VOC cases (33.5%) compared to Alpha VOC cases (51.1%), with similar results for both vaccines. After the second dose, effectiveness reduced from 93.4% with Alpha to 87.9% with Delta for the BNT162b2 vaccine while it reduced from 66.1% to 59.8% for the AstraZeneca AZD1222 vaccine . In another Public Health England study of the effectiveness of vaccines against hospital admission with the Delta variant (analyzed with 14,019 symptomatic cases with Delta), findings showed high levels of protection against hospitalization with 1 or 2 doses of either vaccine . PHE will continue to evaluate this over the coming weeks for effectiveness against hospitalization and death . The Delta VOC in Scotland was found mainly in younger, more affluent groups in an observational study, with double the risk of RT-PCR confirmed symptomatic infection when compared to the Alpha VOC. The risk of hospital admission was particularly high in patients with multiple comorbidities. Both vaccines, BNT162b2 and AstraZeneca AZD1222, were effective in conferring protection against RT-PCR confirmed symptomatic infection, but at lower levels as compared to that against the Alpha VOC. The AZD1222 seemed to be less effective in comparison to the BNT162b2 . In a Pfizer funded prospective test-negative case-control study that included adults aged at least 80 years admitted to hospital in two NHS trusts in Bristol, UK (ISRCTN number 39557), the adjusted vaccine effectiveness against hospitalization was 71.4% and 80.4% for BNT162b2 and AZD1222 respectively . Published final analysis of Phase 3 studies of BBV152 as well as other mass vaccination campaign results show benefits and the need for complete vaccination  (Table 3).
Table 3: Summary of vaccine effectiveness studies on the Delta VOC [30-35].
|AstraZeneca AZD1222||Dose 1||Symptomatic||n=51392; Scotland; 28+ d||18.00%|
|AstraZeneca AZD1222||Dose 1||Symptomatic||n=25897; England; Test negative case control design||32.90%|
|AstraZeneca AZD1222||Dose 1||Hospitalization||n=14019; United Kingdom||71.00%|
|AstraZeneca AZD1222||Dose 1||Symptomatic||n=14019; United Kingdom||30%|
|AstraZeneca AZD1222||Dose 2||Symptomatic||n=32719; Scotland; 14+ d||60.00%|
|AstraZeneca AZD1222||Dose 2||Symptomatic||n=2085; England; Test negative case control design||59.80%|
|AstraZeneca AZD1222||Dose 2||Death||n=14019; United Kingdom||100.00%|
|AstraZeneca AZD1222||Dose 2||Hospitalization||n=14019; United Kingdom||92.00%|
|AstraZeneca AZD1222||Dose 2||Symptomatic||n=14019; United Kingdom||67%|
|Bharat Biotech (BBV152/Covaxin)||Dose 2||Symptomatic||n=16973; India; Phase 3 final analysis||65.20%|
|Pfizer/BioNTech BNT162b2||Dose 1||Symptomatic||n=14214; Scotland; 28+ d||30.00%|
|Pfizer/BioNTech BNT162b2||Dose 1||Symptomatic||n=7085; England; Test negative case control design||33.20%|
|Pfizer/BioNTech BNT162b2||Dose 1||Hospitalization||n=14019; United Kingdom||94.00%|
|Pfizer/BioNTech BNT162b2||Dose 1||Symptomatic||n=14019; United Kingdom||36%|
|Pfizer/BioNTech BNT162b2||Dose 2||Symptomatic||n=53679; Scotland; 14+ d||79.00%|
|Pfizer/BioNTech BNT162b2||Dose 2||Symptomatic||n=6425; England; Test negative case control design||87.90%|
|Pfizer/BioNTech BNT162b2||Dose 2||Hospitalization||n=14019; United Kingdom||96.00%|
|Pfizer/BioNTech BNT162b2||Dose 2||Symptomatic||n=14019; United Kingdom||88%|
As the Delta variant continues its rapid emergence and spread around the world, it is evidently very important for all to get vaccinated, and completely as per dosing recommendations of health officials. It also paves way for therapies that are either host-targeted or can contain antibody escape by variants. These include therapies directed at host viral entry factors, management of the cytokine storm or new-age designs of multimeric vaccines that are equipped to handle variant epitopes as well. A detailed report on vaccine effectiveness among various developers for COVID-19 VOCs can be accessed in the Vaccines topic of the Diagnosis and Mitigation in the dashboard (Go to Vaccines).
Updated: 04 July, 2021.
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