Breakthrough infections with COVID-19 Delta variant linked to lower memory B cell response

The memory B cell response appears to be weaker in vaccinated individuals who develop breakthrough infections with the Delta variant of the coronavirus disease 2019 (COVID-19), according to a new Singapore study.

“The current study provides additional impetus for future prospective studies to closely examine memory B cell and T cell responses,” the researchers said.

Using plasma and peripheral blood mononuclear cell samples, researchers compared 55 patients with vaccine breakthrough infections with 86 vaccinated, uninfected close contacts. They found that memory B cells specific to the receptor binding domain (RBD) of SARS-CoV-2 were present at much lower frequencies in patients who contracted COVID-19 despite being vaccinated. [EMBO Mol Med 2022;doi:10.15252/emmm.202115227]

In contrast, there was no significant between-group difference in the frequency of anti-Spike protein antibodies. In both breakthrough and uninfected groups, 100 percent of participants tested positive for such antibodies, suggesting that cases of reinfection were true vaccine breakthroughs rather than vaccine failures.

Breakthrough infections were defined as testing positive for SARS-CoV-2 through polymerase chain reaction tests at least 2 weeks after the second vaccine dose. Most cases of vaccine breakthrough were of the Delta variant.

In a subsequent experiment, the researchers assessed the neutralization efficiencies of antibodies secreted by the memory B cells. They found that breakthrough infection patients had stronger RBD-targeted neutralizing responses than their uninfected counterparts, showing higher levels of neutralizing antibodies against both the wildtype and Delta strains.

“This increase may be due to memory B cell priming by ongoing infection in the vaccine breakthrough cases, which would indicate that vaccine-elicited memory B cells can be efficiently reactivated by Delta variant infection,” the researchers explained.

Aside from B cell responses, T cells also constitute an important part of the body’s antiviral response. Comparing CD4+ and CD8+ T cell profiles between participants with vs without breakthrough infections, the researchers found that both groups had broadly similar T cell responses, except for a slightly higher T central memory cells among those with breakthrough infections.

Breakthrough patients also had a similar systemic cytokine profile as the uninfected close contacts, suggesting an overall noninflammatory state. Moreover, levels of cytokines associated with severe disease, such as interleukin-1β and interferon gamma, were significantly lower in cases of vaccine breakthrough infection as opposed to a prior cohort of unvaccinated individuals with primary SARS-CoV-2 infection.

“This provides further evidence for immune-mediated protection against virus-induced inflammation and disease despite vaccine breakthrough infection,” the researchers said.

“Protective effects of memory B cells may become more apparent with increased time since vaccination, as plasma antibody levels wane,” they added.

“Should vaccine-elicited memory B cell responses prove to be long-lived, and also a mechanistic correlate of protection, vaccines may provide a longer duration of protection compared to what might be expected based on plasma antibody levels alone,” according to the researchers.