Exposure to two antigenically distinct SARS-CoV-2 variants broadens neutralization patterns
Melanie Schmitt, Annika Rössler, Antonia Netzl, Ludwig Knabl, Albert Falch, Patrick Neckermann, Marta Bermejo‐Jambrina, Wegene Borena, Gagandeep Singh, Florian Krammer, Dorotheé von Laer, Ralf Wagner, Derek J. Smith, Janine Kimpel
Abstract
Previous exposure to one severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variant influences neutralizing antibody responses induced by subsequent exposures. Consecutive exposures predominantly back-boost pre-existing immunity and expand cross-neutralizing antibodies while de novo variant-specific responses are poorly induced. In this study, we analyzed neutralizing antibodies against a panel of variants in plasma samples from individuals after exactly two exposures: twice pre-Omicron variant (either two dose vaccinated or infected and one dose vaccinated), pre-Omicron followed by early Omicron variant, or twice early Omicron variant. We found that exposure to two antigenically distinct variants, either pre-Omicron followed by Omicron or two different Omicron variants, increased the neutralization breadth. However, no significant cross-neutralization against the genetically closely related human coronavirus SARS-CoV was induced. Using depletion experiments, we showed that the first exposed variant strongly influences the specificity of antibodies. The second exposure primarily expanded cross-reactive antibodies rather than inducing a variant-specific response against the later variant, highlighting the phenomenon of immune imprinting in the context of SARS-CoV-2. Overall, our results indicate that multiple exposures to SARS-CoV-2 improve cross-neutralization against a variety of variants, but also underscore the lack of de novo antibody production against the more recently encountered variant.