Will the next coronavirus variant escape our best immune defenses?

It is now well known that SARS-CoV-2, the virus that causes COVID-19, can mutate to evade vaccine protection against infection. The Omicron variants — BA.1, B1.1 and BA.2 — can infect those who were previously infected by other variants, even when vaccinated. A third booster shot offers some protection from an Omicron infection, but it wanes after three or four months, leaving most people susceptible to reinfection. That said, the immunity conveyed by prior infection or vaccination still dramatically reduces the incidence of hospitalization and death.

We have also come to realize that our main saviors against COVID-19 turn out not to be antibodies, but rather another part of the immune system: T cells. Studies show that the strength of our long-lived T-cell response to the virus’ proteins — especially by T cells that recognize the spike protein — strongly correlates with the degree of protection.

There are two types of T cells, CD4+ and CD8+, which are distinguished by proteins on their surface. Because CD4+ T cells mostly assist in the production of antibodies, the CD8+ T cells are the real heroes of the story. Once they identify an invader they remember from a previous encounter, they act quickly to move in for the kill, demolishing infected cells and cutting short the life cycle of the virus.

Until Omicron, the differences in neutralization by vaccine-induced antibodies and by monoclonal antibodies were relatively minor. But the process by which T cells recognize viral proteins is very different from that of antibodies, which recognize structures on the intact viral protein. We know that these critical structures, particularly those of the exterior spike protein, differ from variant to variant. It is precisely such structural diversity that allows the virus to evade most antibodies made in response to infection and vaccination.

By contrast, T cells do not recognize intact proteins. Rather, Tcell recognition occurs when a viral protein within a cell is chopped into short segments and cradled in the grip of a cellular protein called MHC type 1. MHC type 1 presents the viral fragment to the T cell at the cell surface, where the T cell can recognize the combination of the viral fragment presented by the MHC type 1 protein.

T cells recognize and react to a very broad array of viral protein fragments. For SARS-CoV-2, these fragments overlap very little with the regions of the virus that are sensitive to neutralization by antibodies. That is why T-cell responses to viral infection are generally preserved across variants.

Until Omicron, vaccines that use one viral protein raised almost the same T-cell response to all variants. But now the situation has changed. Our MHC type 1 proteins are diverse, and each recognizes a unique set of viral protein fragments. Our reaction to viral proteins thus depends on their sequence and that of our own particular MHC type 1 set of proteins.

Consider a recent study by Gaurav D. Gaiha and his colleagues, examining T-cell responses to the Wuhan, Delta and Omicron strains in people who have been either infected, vaccinated and boosted, or infected and vaccinated but not boosted. They found that most people who are infected after vaccination have strong and durable CD4+ and CD8+ responses to all three variants.

But there was one worrying discovery. Approximately 20% of those vaccinated showed a decline of greater than 50% in T-cell response to Omicron, compared to the Wuhan and Delta variants. These poor T-cell responses were not correlated with sex or age, and follow-up experiments revealed that the difference was due to lower CD8+ reactivity, rather than to the CD4+ T-cell response.

The authors speculate that CD8+ T cells’ inability to respond to Omicron may reflect lack of recognition of the mutated peptides. Indeed, their theoretical calculations are consistent with the hypothesis that changes in the amino acid sequence of the Omicron spike protein underlie the blind spots in T-cell recognition. Inherited differences in the ability to recognize specific protein fragments likely account for some people’s failure to mount anti-Omicron defenses. The authors offer the conjecture that “it is possible that these individuals will have reduced protection against severe disease.”

One sobering conclusion is that Omicron has drifted so far from the original strain that 20% of people in the study may not be fully protected either from infection or from hospitalization and death. However, the study found that a third vaccine dose increases T-cell responses by 20 times or more.

“While the Omicron spike protein was able to escape T cells in a subset of individuals,” Gaiha told me, “what we learned is that this deficiency in T-cell recognition can be overcome by booster vaccination. In addition, we found that non-spike proteins could be attractive targets for second-generation vaccines to protect against future SARS-CoV-2 evolution.”

Gaiha espouses an optimistic interpretation. But Omicron is a warning that future variants may escape both antibodies and T-cell immunity. We cannot predict whether a variant will arise that evades the vaccines’ ability to protect against infection and serious illness, but we must be prepared for such a threat, lest we remain unguarded against it.