Beyond circulating immunoglobulins, memory B cells represent a second line of immune defense against SARS-CoV-2, the virus responsible for COVID-19. These cells can be rapidly mobilized upon re-exposure to the virus and give rise to antibody-secreting cells. However, the quality of this B-cell memory following messenger RNA vaccination remained poorly characterized, particularly the distinction between individuals who had never encountered the virus and those who had recovered from a prior infection. This question is all the more important given that the emergence of variants of concern threatens the efficacy of the antibodies initially induced.
To address this, the authors followed longitudinal cohorts of naïve and convalescent subjects for a period of up to two months after vaccination. The quality of the memory response was assessed through analysis of antibody repertoires, measurement of their affinity, and their neutralizing capacity against variants of concern. These analyses relied on the unbiased culture of 2,452 memory B cells, complemented by immunoglobulin heavy-chain sequencing, affinity measurement by biolayer interferometry, and viral neutralization assays by focus reduction against several variants, including the B.1.1.7, B.1.351, P.1, B.1.617.1, and B.1.617.2 lineages.
In convalescent subjects, the vaccine dose led to a selective expansion of the memory B-cell compartment, further maturation of these cells, and the emergence of potent neutralizers directed against the variants, all while preserving repertoire diversity. In naïve subjects, the serum neutralizing response against the variants proved weaker. Nevertheless, half of the memory B cells specific for the receptor-binding domain displayed high affinity for several variants, including the delta variant (B.1.617.2), and one-third retained neutralizing activity against the beta variant (B.1.351). Mapping of the residues involved in binding, inferred from the variants' mutation-sensitivity profiles, made it possible to link these clones to key positions in the receptor-binding domain, such as K417, N501, E484, and L452.
This work thus shows that, even in the absence of robust serum neutralization against the variants, vaccination of naïve individuals generates a reservoir of high-affinity memory B cells recognizing all the variants of concern studied. The authors suggest that additional stimulation in these naïve vaccinees could recall these matured memory cells and enable them to respond effectively to the variants.