Evolution of antibody immunity following Omicron BA.1 breakthrough infection

Abstract

Understanding the longitudinal dynamics of antibody immunity following heterologous SAR-CoV-2 breakthrough infection will inform the development of next-generation vaccines. Here, we track SARS-CoV-2 receptor binding domain (RBD)-specific antibody responses up to six months following Omicron BA.1 breakthrough infection in six mRNA-vaccinated individuals. Cross-reactive serum neutralizing antibody and memory B cell (MBC) responses decline by two- to four-fold through the study period. Breakthrough infection elicits minimal de novo Omicron BA.1-specific B cell responses but drives affinity maturation of pre-existing cross-reactive MBCs toward BA.1, which translates into enhanced breadth of activity across other variants. Public clones dominate the neutralizing antibody response at both early and late time points following breakthough infection, and their escape mutation profiles predict newly emergent Omicron sublineages, suggesting that convergent antibody responses continue to shape SARS-CoV-2 evolution. While the study is limited by our relatively small cohort size, these results suggest that heterologous SARS-CoV-2 variant exposure drives the evolution of B cell memory, supporting the continued development of next-generation variant-based vaccines.

Have Diagnostics, Therapies, and Vaccines Made the Difference in the Pandemic Evolution of COVID-19 in Comparison with “Spanish Flu”?

“…Thus, although the immune response to the other partially cross-reacting viral strains was modest, it was able to powerfully boost the immune response to the priming viral strain, so maintaining a high level of immune response to the priming antigen for life, without a robust and lasting protective response against the new antigenic variants. This phenomenon has been repeatedly observed by different authors with influenza [100,101], other viruses [102], and more recently, even in the neutralizing antibody response to SARS-CoV-2 Omicron variant bivalent vaccine, which was not significantly higher than the one induced by the monovalent vaccine composed by the original Wuhan strain, associated with a lack of increase of T-cell response [98,[103][104][105][106][107][108]. A phenomenon similar to the "original antigenic sin" has even been described for cytotoxic T lymphocytes [109].…”

SARS-CoV-2 Omicron infection augments the magnitude and durability of systemic and mucosal immunity in triple-dose CoronaVac recipients

“…We speculate this discrepancy might be largely due to the relatively longer interval (12 months) between breakthrough infection and the third CoronaVac ( 9 , 23 , 24 ). The long interval before Omicron breakthrough infection might preferentially recall cross-reactive antibodies that exhibit increased affinity and neutralization potency against Omicron, which could then drive a greater response given a subsequent antigen exposure ( 25 ). In addition, our finding aligns with recent evidence showing that either Omicron vaccination boosting or breakthrough infection not only triggers rapid memory cellular responses but also induces de novo B ( 26 ) and T cell ( 27 ) responses.…”

Synthetic coevolution reveals adaptive mutational trajectories of neutralizing antibodies and SARS-CoV-2

“…2A, Table S1). Also, several of the antibodies possessed features associated with convergent germlines or public clones (2,9), suggesting they may be representative of antibodies that can shape viral evolution. The selected antibodies possessed high reactivity to the RBD of the ancestral Wu-Hu-1 and varying degrees of cross-reactivity to other variants, with most having substantially reduced reactivity to Omicron BA.1 (BA.1) (4).…”

“…S2). While it has been observed that affinity maturation generally increases antibody breadth and binding affinity to variants (2,15,16), it is conceivable that certain adaptations may produce local maxima that prevent further breadth.…”

“…This leads to a coevolutionary arms race between antibodies and SARS-CoV-2, where each side tries to gain an advantage over the other through mutational adaptation. For example, after encountering a new variant such as Omicron BA.1, pre-existing memory B cells that are specific to an earlier variant (e.g., ancestral Wu-Hu-1) can undergo somatic hypermutation to generate antibodies with enhanced binding and neutralization to Omicron BA.1 (2,3). Conversely, SARS-CoV-2 can evolve variants with RBD mutations that reduce or escape binding and neutralization to existing antibodies (4)(5)(6).…”