With every new variant of SARS-CoV-2 that emerges to cause a surge in cases, a worrisome question also arises: Could the virus eventually arrive at a set of mutations that would enable it to fully evade our immune response?

Anew study, published inNature, suggests that it will be hard for the virus to get there. Studying dozens of naturally occurring and laboratory-selected mutations, including those found in Deltaand other concerning variants, researchers found that a future SARS-CoV-2 variant will need to pack about 20 of the right mutations to become fully resistant to the antibodies that an average person generates in response to a coronavirus infection or vaccination.

But even if the virus pulls off this genetic feat, it still remains vulnerable to an improved set of antibodies: those arising after natural infection and further boosted through mRNA vaccines.

The findings suggest that our immune system, if properlystimulated, is capable of dealing with the worst that the coronavirus may have to offerfor theforeseeablefuture. "Immunity in people who fought off COVID last year and later received mRNA vaccines is impressively broad," saysPaul Bieniasz, head of the Laboratory of Retrovirologyat Rockefeller. "This tells us that although natural infection or the vaccines lead to immunity, they have in no way come close to exhausting the capacity of the human immune system to mount defense against this virus."

Polymutantviruses

Just as the coronavirus comes in many variants, so do our antibodies. That's why even theDeltavariant, the most contagious version of SARS-CoV-2 so far, doesn't entirely escape our immune response. It may be dodging some of the antibodies we produce, but not all of them. ButDeltais not the last version of SARS-CoV-2 that we are going to see. The virus is still replicating at a high rate in large populationsnew mutations are popping up, and new variants are continuously arising.

Postdocs Fabian Schmidt and Yiska Weisblum set out to identify which kinds of mutations give SARS-CoV-2 the edge over antibodies. For the study, they first createda safe stand-in for the coronavirusby tweaking a different, harmless virus to express SARS-CoV-2 spike protein on its surface.As the faux coronaviruses replicated, some picked up mutations as they made mistakes copying themselves. The team then bathed the faux coronaviruses in plasma samples from people who had recovered from COVID, and selected the mutants that escaped neutralization by antibodies. A few rounds of this and the team found many mutations that were in the same locations as those occurring naturally in SARS-CoV-2 variants, including those found in Delta or other variants of concern.

The researchers then created a "polymutant" virus: a faux coronavirus sporting a spike protein featuring 20 of the worst of those mutations all at once. Thispolymutantshowed near-complete resistance to antibodies generated by individuals who have been infected by or vaccinatedagainst SARS-CoV-2. "Soit is possible for the virus to evolve and evade the majority of our antibodies, but the genetic barrier to thatoccurringis quite high," Bieniasz says.

Extra immunity

Findings from one group of people suggest that in the long run, our immune system will win the race against the mutating coronavirus. People who have experienced both natural infection and vaccination produce remarkably effective antibodies. Previously, the Rockefeller team that includes Michel Nussenzweig,Paul Bieniasz,andTheodora Hatziioannou, a research associate professor at Rockefeller,found that after the infection subsides,antibodies continue to evolveover several months, becoming better at binding tighter to the spike protein. Receiving mRNA vaccinesstrongly booststhose antibodies even more, increasing them in numbers and improving their ability to cope with many of the variants simply by binding tighter and tighter to the original sequence.

In thecurrentstudy, plasma fromthose who had been both infected and vaccinatedneutralized thepolymutantspike.It also neutralized the sixSARS-CoV-2variants tested,as well asthe original SARS coronavirus and SARS-like viruses found in bats and pangolins. "Antibodies from this group of peopleareincredibly potent and flexible,"saysHatziioannou, who co-directed the study. "It's likely that they offer protection against any SARS-CoV-2 variants in the future and possibly against future coronavirus pandemics."

More studies would show whether booster shots could lead to a similar improvement of antibodies in vaccinated people who have never been infected with the coronavirus.