“Polymutant” Spike Points Way Toward More Durable COVID-19 Vaccine

Researchers at The Rockefeller University previously found that people who recover from COVID-19 and subsequently are vaccinated appear to have protection for at least a year, including against variants of concern. In the team’s latest study, participants with a prior SARS-CoV-2 infection who received 2 mRNA vaccine doses produced polyclonal antibodies capable of neutralizing a spike protein engineered with a suite of antibody-resistant mutations. The findings suggest that plasma antibodies from “infected-then-vaccinated” individuals may be even more potent and broad than previously known. The researchers combined 20 SARS-CoV-2 spike mutations into a “polymutant” spike, which they named PMS20. The naturally occurring mutations included receptor binding domain and N-terminal domain changes that either arose under pressure in laboratory experiments or have been identified in neutralization-resistant variants of concern. Nonreplicating HIV-1 viruses engineered with PMS20 were about as infectious as those with the original SARS-CoV-2 spike protein but were far less susceptible to antibodies. In fact, neutralization was undetectable with plasma from 17 of 21 previously infected individuals and 8 of 14 infection-naive participants who were fully vaccinated. But the infected-then-vaccinated participants had more potent antibodies. A panel of plasmas from 14 such individuals neutralized the HIV pseudotypes with the polymutant spike. Their plasma was also broadly neutralizing against related viruses, including SARS-CoV—the original SARS virus—and bCoV-WIV16, a bat coronavirus. One takeaway is that lasting protection may require inducing antibodies against sites beyond the spike’s receptor binding domain, the approved vaccines’ target. “Overall, the diversity, maturity and high concentration of neutralizing antibodies likely explains why polyclonal plasma from individuals who have been both infected and subsequently vaccinated could effectively neutralize the otherwise highly neutralization resistant PMS20 polymutant, as well as sarbecoviruses that are divergent from SARS-CoV-2,” the authors wrote in Nature. Eliciting similar antibodies—with appropriately timed boosters or updated vaccines—should provide resistance to future SARS-CoV-2 variation, the researchers noted.