Rapid hypermutation B cell trajectory recruits previously primed B cells upon third SARS-CoV-2 mRNA vaccination

Abstract

High antibody affinity against the ancestral SARS-CoV-2 strain seems to be necessary (but not always sufficient) for the control of emerging immune-escape variants. Therefore, aiming at strong B cell somatic hypermutation - not only at high antibody titers - is a priority when utilizing vaccines that are not targeted at individual variants. Here, we developed a next-generation sequencing based SARS-CoV-2 B cell tracking protocol to rapidly determine the level of immunoglobulin somatic hypermutation at distinct points during the immunization period. The percentage of somatically hypermutated B cells in the SARS-CoV-2 specific repertoire was low after the primary vaccination series, evolved further over months and increased steeply after boosting. The third vaccination mobilized not only naive, but also antigen-experienced B cell clones into further rapid somatic hypermutation trajectories indicating increased affinity. Together, the strongly mutated post-booster repertoires and antibodies deriving from this may explain why the booster, but not the primary vaccination series, offers some protection against immune-escape variants such as Omicron B.1.1.529.

Immunogenicity and durability against Omicron BA.1, BA.2 and BA.4/5 variants at 3 to 4 months after a heterologous COVID-19 booster vaccine in healthy adults with a two-doses CoronaVac vaccination

“…The results showed that the NAbs induced by heterologous mRNA and viral vector as a third dose vaccination had broad neutralizing activity against several subvariants of SARS-CoV-2. Consistent with a previous study, after the homologous mRNA booster, the percentage of somatic hypermutated memory B cells increased and indicated B cell affinity maturation (Paschold et al, 2022). In comparison, the median %inhibition of neutralizing activity against Omicron BA.2 and BA.4/5 showed a significantly lower susceptibility than against wild type.…”

A long interval between priming and boosting SARS-CoV-2 mRNA vaccine doses enhances B cell responses with limited impact on T cell immunity

“…This difference persisted as a strong trend at the memory time point. These results are consistent with the fact that germinal centers remain active for several weeks after vaccination (Turner et al, 2021), with continuous evolution of the B cell compartment for several months (Cho et al, 2021) and accumulation of somatic hypermutations (Kim et al, 2022;Paschold et al, 2022;Turner et al, 2021). Hence, an early second dose likely corresponds to a suboptimal timing in terms of re-exposure to the cognate antigen, while a longer interval allows for a better evolution of the B cell repertoire.…”

Persistence of immunity against Omicron BA.1 and BA.2 variants following homologous and heterologous COVID-19 booster vaccines in healthy adults after a two-dose AZD1222 vaccination

“…Herein, we observed that the heterologous mRNA-based booster, but not the AZD1222-boosted, effectively produced a high level of cross-neutralization against SARS-CoV-2 variants 28 days after the booster dose. The breadth and cross-reactivity of NAbs after the third dose may be related to increasing memory B cell affinity maturation through extensive somatic hypermutation like those observed in a previous mRNA-boosted study (Paschold et al, 2022). However, reductions in neutralizing activity against Omicron variants were found compared with those against Delta variants in both BNT162b2-primed and CoronaVac-primed individuals (Assawakosri et al, 2022, Pérez-Then et al, 2022, Planas et al, 2022.…”