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Review 2: "Qualitatively distinct modes of Sputnik V vaccine-neutralization escape by SARS-CoV-2 Spike variants"

This study reports antibodies generated from Sputnik V vaccination exhibit less neutralizing activity against B.1.351 and E484K variants than wildtype and B.1.1.7. Reviewers deem these findings informative, but caution more standard assays and clinical studies are necessary.

Published onMay 29, 2021
Review 2: "Qualitatively distinct modes of Sputnik V vaccine-neutralization escape by SARS-CoV-2 Spike variants"
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Qualitatively distinct modes of Sputnik V vaccine-neutralization escape by SARS-CoV-2 Spike variants
Description

ABSTRACTThe novel pandemic betacoronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has infected at least 120 million people since its identification as the cause of a December 2019 viral pneumonia outbreak in Wuhan, China. Despite the unprecedented pace of vaccine development, with six vaccines already in use worldwide, the emergence of SARS-CoV-2 ‘variants of concern’ (VOC) across diverse geographic locales suggests herd immunity may fail to eliminate the virus. All three officially designated VOC carry Spike (S) polymorphisms thought to enable escape from neutralizing antibodies elicited during initial waves of the pandemic. Here, we characterize the biological consequences of the ensemble of S mutations present in VOC lineages B.1.1.7 (501Y.V1) and B.1.351 (501Y.V2). Using a replication-competent EGFP-reporter vesicular stomatitis virus (VSV) system, rcVSV-CoV2-S, which encodes S from SARS coronavirus 2 in place of VSV-G, and coupled with a clonal HEK-293T ACE2 TMPRSS2 cell line optimized for highly efficient S-mediated infection, we determined that 8 out of 12 (67%) serum samples from a cohort of recipients of the Gamaleya Sputnik V Ad26 / Ad5 vaccine showed dose response curve slopes indicative of failure to neutralize rcVSV-CoV2-S: B.1.351. The same set of sera efficiently neutralized S from B.1.1.7 and showed only moderately reduced activity against S carrying the E484K substitution alone. Taken together, our data suggest that control of emergent SARS-CoV-2 variants may benefit from updated vaccines.

RR:C19 Evidence Scale rating by reviewer:

  • Reliable. The main study claims are generally justified by its methods and data. The results and conclusions are likely to be similar to the hypothetical ideal study. There are some minor caveats or limitations, but they would/do not change the major claims of the study. The study provides sufficient strength of evidence on its own that its main claims should be considered actionable, with some room for future revision.

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Review:

The Sputnik V COVID-19 vaccine or Gam-COVID-Vac is a recombinant adenovirus type 26 (rAd26) and recombinant adenovirus type 5 (rAd5) vector-based heterologous prime-boost COVID-19 vaccine. Both vectors delivered separately in a first and second dose, 21 days apart, carry the gene for SARS-CoV-2 spike glycoprotein which the virus uses to bind to and infect host cells, enter cells, express the spike protein, and then stop. The choice of using two different vectors is based on the concept that it is necessary to reduce the risk that, after the first dose, the body produces antibodies against the vector and destroys it when the second dose is administered, with a consequent reduction in the effectiveness of the vaccination.

An interim analysis of a phase 3 trial published in The Lancet showed 91·6% efficacy against COVID-19 and reported that the Sputnik V COVID-19 vaccine was well tolerated in almost 20,000 subjects. In a second interim analysis, data obtained 42 days after the first dose (corresponds with 21 days after the second dose) indicated an efficacy of the vaccine above 95%.

These findings are certainly important and rightly place Sputnik V among the vaccines to be held in high regard in the fight against the virus. Additionally, the vaccine has a 100% efficacy against severe disease or death, does not have the ultracold storage temperature requirements of the mRNA vaccines making it easier to deliver, and has a low cost. This is extremely important bearing in mind the need to provide fair access to COVID-19 vaccines for people living in low- and middle-income countries. This consideration supersedes any concerns on the clinical development of this vaccine and also the interpretation of some data produced in the various clinical trials.

Nevertheless, we cannot fail to highlight an important limitation of this vaccine, precisely in view of its global use.

The data relating to the phase 3 study with Sputnik V, which is based on the SARS-CoV-2 spike protein of the original Wuhan-hu-1, refer to patients treated by November 2020, whereas in December 2020, an unexpected rise in reported COVID-19 cases was attributed to the emergence of the new SARS-CoV-2 variants B.1.1.7 (501Y.V1) in the UK and B.1.351 (501Y.V2) in South Africa. Both variants had a mutation (N501Y) in the receptor-binding domain of the spike protein. N501Y is the major spike determinant driving increased transmission of these variants. In addition to the N501Y mutation, the South African variant also contains the K417N and E484K mutations in the spike protein. The E484K mutation can help virus variants to escape neutralization by serum antibodies from recovered COVID-19 patients.

These two variants and also P.1, a new variant circulating in December in Manaus (Brazil) rapidly gained prevalence and spread across borders from late 2020 onwards. The P.1 variant contains a unique constellation of lineage-defining mutations (17 unique amino acid changes and 3 deletions), including the N501Y, K417N, and E484K. Another variant, classified P.2, with the E484K mutation has now been detected in several locations in Brazil.

The impact of SARS-CoV-2 variants can be a pivotal modifying factor that can alter the real clinical impact of the Sputnik V vaccine against COVID-19.

It is believed that the higher the efficacy and level of neutralizing antibodies a vaccine has against the original virus, the more likely it is that it will work against new variants. Sputnik V induces a very large effect on the peak level of neutralizing antibodies against SARS-CoV-2. However, the phase 3 study does not report data regarding the impact of SARS-CoV-2 variants on the efficacy Sputnik V vaccine.

The study by Ikegame and colleagues is therefore absolutely welcome because it sheds light on a fundamental aspect to establish what is the real potential of the Sputnik V vaccine. The fundamental information generated is that 8 out of 12 (67%) serum samples from a cohort of recipients of Sputnik V vaccine in Argentina showed dose-response curve slopes indicative of a failure to neutralize B.1.351, but data also showed that Sputnik V efficiently neutralized spike from B.1.1.7 and showed only moderately reduced activity against spike carrying the E484K substitution alone. Ultimately, sera from Sputnik vaccine recipients had a median 6.1-fold and 2.8-fold reduction in neutralizing potency against B.1.351 and the E484K mutant spike, respectively.

These data must be considered important because they demonstrate that Sputnik V has a reduced neutralizing capacity against the B.1.351 and E484K mutant spike, respectively. Furthermore, they suggest that the B.1.351 variant is resistant to Sputnik V with a different mechanism from that of the E484K mutant. However, resistance of the E484K mutant is competitive and is absent at higher serum concentrations.

The B.1.1.7 variant is rapidly spreading around the world, replacing the original strain of the virus in many cases and it is currently the most widespread in the USA, just as it happens in Western Europe. Fortunately, the Sputnik V vaccine is effective in countering this variant and is, consequently, suitable for mass vaccination, which is what we must do to bring the pandemic to a quicker end.

We are aware that the genetic variability of SARS-CoV-2 questions the putative efficacy of commercialized vaccines based on the Spike protein. However, we must be pointed out that adenovirus vaccines are more suitable for mass vaccination because they are not bound to the cold chain, they must not be transported in cold rooms at -80° C and, therefore, are better suited to reach the most remote places and weaker and marginalized populations.

Obviously, we fully agree with the opinion of the authors of the paper that, as with all other vaccines, continuous surveillance of the neutralizing activity induced by the Sputnik V vaccine sera will be required.

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