The most recent studies suggest that hybrid immunity is, at least partly, due to immune players called memory B cells. The bulk of antibodies made after infection or vaccination come from short-lived cells called plasmablasts, and antibody levels fall when these cells inevitably die off. Once plasmablasts are gone, the main source of antibodies becomes much rarer memory B cells that are triggered by either infection or vaccination.
Some of these long-lived cells make higher-quality antibodies than plasmablasts, says Michel Nussenzweig, an immunologist at the Rockefeller. That’s because they evolve in organs called lymph nodes, gaining mutations that help them to bind more tightly to the spike protein over time. When people who recovered from COVID-19 are re-exposed to SARS-CoV-2’s spike, these cells multiply and churn out more of these highly potent antibodies.
“You get a sniff of antigen, in this case of mRNA vaccine, and those cells just explode,” says Goel. In this way, a first vaccine dose in someone who has previously been infected is doing the same job as a second dose in someone who has never had COVID-19.
Differences between the memory B cells triggered by infection and those triggered by vaccination — as well as the antibodies they make — might also underlie the heightened responses of hybrid immunity. Infection and vaccination expose the spike protein to the immune system in vastly different ways, Nussenzweig says.
In a series of studies
3,
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5, Nussenzweig’s team, which includes Hatziioannou and Bieniasz, compared the antibody responses of infected and vaccinated people. Both lead to the establishment of memory B cells that make antibodies that have evolved to become more potent, but the researchers suggest this occurs to a greater extent after infection.
The team isolated hundreds of memory B cells — each making a unique antibody — from people at various time points after infection and vaccination.
Natural infection triggered antibodies that continued to grow in potency and their breadth against variants for a year after infection, whereas most of those elicited by vaccination seemed to stop changing in the weeks after a second dose. Memory B cells that evolved after infection were also more likely than those from vaccination to make antibodies that block immune-evading variants such as Beta and Delta.
