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The number and variability of neutralizing epitopes targeted by polyclonal antibodies in convalescent persons vaccinated with SARS-CoV-2 are key determinants of the extent of neutralization and of the genetic barrier to viral escape1–4. Use of HIV-1 Pseudotypes and Plasma Selection Experiments with Vesicular Stomatitis Virus / SARS-CoV-2 Chimeras5, we show that several neutralizing epitopes, inside and outside the receptor binding domain (RBD), are variably targeted by human polyclonal antibodies. The antibody targets coincide with spike sequences that are enriched for diversity in natural populations of SARS-CoV-2. By combining selected spike substitutions in plasma, we generated pseudotypes of synthetic “polymuting” spike proteins that resisted neutralization of polyclonal antibodies to a degree similar to that of circulating variants of concern (VOC). By aggregating the antibody-selected VOC-associated spike substitutions into a single polymuting spike protein, we show that 20 natural mutations in the SARS-CoV-2 spike are sufficient to generate pseudotypes with almost complete antibody resistance. Polyclonal neutralizers generated by convalescents or mRNA vaccine recipients. Strikingly, however, the plasma of individuals who had been infected and subsequently received mRNA vaccination, neutralized pseudotypes carrying this highly resistant SARS-CoV-2 polymuting peak, or various sarbecovirus peak proteins . Thus, optimally obtained human polyclonal antibodies against SARS-CoV-2 should be resistant to substantial future variations in SARS-CoV-2 and could confer protection against potential future pandemics of sarbecovirus.
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