Comments on prof. Paul Bieniasz’s presentation on 'SARS-CoV-2 Vaccines and variants’

Updated: May 13

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In his presentation, prof. Paul Bieniasz emphasizes the importance of antibody (Ab)-mediated selective immune pressure. He explains how immune escape variants can emerge in the presence of anti-Sars-CoV-2 neutralizing (monoclonal) antibodies and how VSV (vesicular stomatitis virus) decorated with S protein from an Ab-escaping mutant may resist neutralization by one or more anti-Sars-CoV-2 Abs directed against the receptor-binding domain (RBD). Prof. P. Bieniasz acknowledges that monoclonal Ab therapies, as well as convalescent sera and also vaccines could impart selection pressure on the circulating virus, especially if the latter encounters suboptimal levels of neutralizing Abs or if those don’t match well with the antigenic features of the viral spike (S) protein (e.g., in case of viral variants).

P. Bieniasz points out that resistance to those therapies or vaccines is likely to depend on the number of viral escape mutations that confer resistance to individual S-specific Abs. He also explains how affinity maturation as well as the presence of multiple Abs in vaccine recipients could make up for Ab-resistant mutations. He recognizes that the capacity of the vaccines to remain effective in preventing disease will also largely depend on the potential emergence of new, more infectious variants and that an ‘update’ of the current vaccines may be required to counter that evolution.

Based upon the findings of prof. Bieniasz’s team and those made by several other scientists, it can no longer be denied that suboptimal quality or quantity of anti-S Abs exerts selective immune pressure and will, therefore, selectively drive emergence of viral variants. It is also clear that these immune escape variants can be transmitted from one person to another. This being said, it would be critically important to investigate what happens to this selective immune escape variants when repeatedly passaged (in vitro) or transmitted (in vivo) under the very conditions of suboptimal immune pressure prof. Bieniasz has been alluding to. This particularly applies to the current situation where world-wide mass vaccination campaigns are conducted to a background of high infection rates. Under these circumstances, large parts of the population are in the process of seroconversion and hence, endowed with suboptimal Ab titers. In addition, large cohorts exhibit suboptimal levels of Abs due to partial immunization (e.g., in those who only received the first dose of 2-shot vaccine) or as a result of asymptomatic infection. Because Ab levels are suboptimal in large parts of the population, the likelihood that viral escape mutants are transmitted between individuals with suboptimal Abs becomes increasingly likely. This, combined with the growing amount of more infectious variants only adds to the enhanced occurrence of selective immune pressure imparted on the virus. As none of the current vaccines is capable of preventing viral transmission, I strongly believe that repeated transmission of immune escape variants under Ab selective pressure will drive accumulation of selective Ab escape mutations and, therefore, lead to the emergence of new, even more potent, variants. It doesn’t make any scientific sense to me that increasing adaptation to Ab-mediated immune pressure would at the same time provide for sufficient compensation of diminished seroneutralizing capacity provided by Abs that are directed at other, unmutated domains of the spike protein.

As prof. Bieniasz shows in his presentation, polyclonal plasma obtained from naturally infected patients or vaccine recipients is much less potent at neutralizing more infectious variants (e.g., S-African or Brazilian variant) than wild virus in subjects with low levels of neutralizing potency. The combination, therefore, of repeated exposure to both suboptimal Ab levels and more infectious variants is likely to enhance selective immune ‘adaptation’ in the population. This combination increasingly occurs when mass vaccinations are conducted in the heat of a pandemic.

As much as I respect and honor prof. Bieniasz’s work, I do not agree that similar vaccines adapted to the new variants will solve the problem of selective immune escape and adaptation. As mentioned in my previous documents and interviews, the question rises as to which variants one is going to include and how well those would possibly match the steadily evolving series of new variants. More importantly, vaccination with such new vaccines will first and foremost recall Abs from previous immunization(s) (e.g., due to natural infection or vaccination with first generation vaccines). This phenomenon is known as ‘antigenic sin’ and will result in rapid exposure of variants to mismatched Abs, which, again, will promote selective immune pressure and hence, enhanced propagation and transmission of Ab-resistant variants.

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