Most people armed to fight off COVID-19

Even in healthy, SARS-CoV-2-naïve repertoires of B cell receptors (BCR), precursors of neutralizing antibodies with potent activity against the virus can be detected, according to a recent study. This finding suggests that most uninfected people will be able to produce such antibodies against viral challenge.

Moreover, severe and mild infections elicit distinct B cell immune responses. The former triggers higher titres of antibodies against the receptor binding domain (RBD) of SARS-CoV-2, while the response tends to be highly variable in the latter, ranging from high to almost undetectable levels.

Eighteen convalescent donors were included in the study, of whom eight had experienced severe novel coronavirus disease (COVID-19). Compared to them, donors who were asymptomatic or only had mild symptoms mounted a significantly weaker antibody response, with fewer anti-RBD IgG (p=0.0008). There were no such differences in terms of anti-RBD IgM and IgA levels. [PLoS Pathog 2021;17:e1009165]

In addition, enzyme-linked immunosorbent assay showed that plasma samples from mild COVID-19 patients were significantly weaker at preventing the RBD from binding to a soluble angiotensin converting enzyme 2 (ACE2; p<0.0001). A significant link was found between the level of anti-RBD IgG and the inhibitory capacity of the plasma sample (p<0.0001).

The researchers then performed total BCR sequencing on samples from seven and six donors who had survived mild and severe disease, respectively. They found that B cell lineages had substantially lower overlap in mild vs severe donors; the latter had 96 shared B cell clones, while the former only had 55.

“[T]hese results indicate that severe SARS-CoV-2 infection is associated with unique B cell signatures … and a greater B cell clonal expansion,” the researchers explained, adding that the findings also suggest that severe disease could trigger higher B cell responses than mild infections.

To further characterize the antibody response in severe COVID-19, the researchers cloned 22 monoclonal antibodies (mAbs) from plasma samples of two donors. After neutralization assays, six of these mAbs demonstrated potent activity against SARS-CoV-2, seriously curtailing the ability of the virus to infect cells, and induced programmed death.

Notably, these neutralizing mAbs (nAbs) arose naturally following severe infection; such response was an optimal result for vaccination. Looking at unexposed BCR repertoires, the researchers found that precursors needed to produce these nAbs upon viral challenge were present in both mature and naïve unexposed BCR repertoires.

“Our data indicates that SARS-CoV-2 neutralization can be achieved in many ways and that the germline gene combinations that give rise to anti-SARS-CoV-2 nAbs are relatively frequent in the healthy BCR repertoire. Therefore, given enough antigenic stimulation (which is the case during severe COVID-19), these nAbs may be produced by the majority of individuals,” they said.

“Somewhat counterintuitively, many of the mild donors in our cohort did not develop anti-RBD IgGs that were able to inhibit RBD-ACE2 interaction,” they added. “This suggests that while most individuals have SARS-CoV-2 nAb precursors in their BCR repertoires, a single dose vaccine may not be sufficient to elicit protective anti-SARS-CoV-2 immunity.”