High genetic barrier to escape from human polyclonal SARS-CoV-2 neutralizing antibodies

Abstract

The number and variability of the neutralizing epitopes targeted by polyclonal antibodies in SARS-CoV-2 convalescent and vaccinated individuals are key determinants of neutralization breadth and, consequently, the genetic barrier to viral escape. Using chimeric viruses and antibody-selected viral mutants, we show that multiple neutralizing epitopes, within and outside the viral receptor binding domain (RBD), are variably targeted by polyclonal plasma antibodies and coincide with sequences that are enriched for diversity in natural SARS-CoV-2 populations. By combining plasma-selected spike substitutions, we generated synthetic polymutant spike proteins that resisted polyclonal antibody neutralization to a similar degree as currently circulating variants of concern (VOC). Importantly, by aggregating VOC-associated and plasma-selected spike substitutions into a single polymutant spike protein, we show that 20 naturally occurring mutations in SARS-CoV-2 spike are sufficient to confer near-complete resistance to the polyclonal neutralizing antibodies generated by convalescents and mRNA vaccine recipients. Strikingly however, plasma from individuals who had been infected and subsequently received mRNA vaccination, neutralized this highly resistant SARS-CoV-2 polymutant, and also neutralized diverse sarbecoviruses. Thus, optimally elicited human polyclonal antibodies against SARS-CoV-2 should be resilient to substantial future SARS-CoV-2 variation and may confer protection against future sarbecovirus pandemics.

The BNT162b2 mRNA SARS-CoV-2 vaccine induces transient afucosylated IgG1 in naive but not antigen-experienced vaccinees

“…In antigen-experienced individuals, matters are reversed, as these individuals start off with lower afucosylated anti-S IgG levels prior to vaccination, which significantly increased after vaccination. This suggests an enhanced corresponding memory B cell response, which would be in line with stronger protection in this group (46)(47)(48). Similarly, a gradual increase in afucosylation has been observed with repeated natural immunizations to antigens displayed on the membrane of P. falciparum-infected red blood cells (23).…”

Preclinical evaluation of a SARS-CoV-2 mRNA vaccine PTX-COVID19-B

“…For example, the marked reduction of neutralization potency of the immune sera against VOC Beta (B.1.351) suggests that the main epitopes comprise K417, E484, and/or N501 in RBD, which are mutated to N/K/Y in this VOC. Schmidt et al ( 75 ) recently reported that an mRNA vaccine elicited much broader polyclonal nAb in subjects who were previously infected by SARS-CoV-2 than subjects who were not, suggesting that, in convalescent subjects, the mRNA vaccine induced nAb targeting more conserved epitopes. Fine epitope mapping of the nAb from vaccinees, including convalescent subjects receiving vaccination, may help design next-generation broad-spectrum SARS-CoV-2 mRNA vaccines.…”

Statistics of antibody binding to the spike protein explain the dependence of COVID 19 infection risk on antibody concentration and affinity

“…First, there is a distribution of binding site number. Second, it is known that an antibody population with a range of affinity is induced either by vaccination or by infection 3,19,23 . The induced affinity distribution may depend on the specific vaccine.…”