High genetic barrier to SARS-CoV-2 polyclonal neutralizing antibody escape.

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 the genetic barrier to viral escape1-4. Using HIV-1 pseudotypes and plasma-selection experiments with vesicular stomatitis virus/SARS-CoV-2 chimeras5, we show that multiple neutralizing epitopes, within and outside the receptor binding domain (RBD), are variably targeted by human polyclonal antibodies. Antibody targets coincide with spike sequences that are enriched for diversity in natural SARS-CoV-2 populations. By combining plasma-selected spike substitutions, we generated synthetic 'polymutant' spike protein pseudotypes that resisted polyclonal antibody neutralization to a similar degree as circulating variants of concern (VOC). By aggregating VOC-associated and antibody-selected spike substitutions into a single polymutant spike protein, we show that 20 naturally occurring mutations in SARS-CoV-2 spike are sufficient to generate pseudotypes with near-complete resistance to the polyclonal neutralizing antibodies generated by convalescents or mRNA vaccine recipients. Strikingly, however, plasma from individuals who had been infected and subsequently received mRNA vaccination, neutralized pseudotypes bearing this highly resistant SARS-CoV-2 polymutant spike, or diverse sarbecovirus spike proteins. 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 potential future sarbecovirus pandemics.