Prior SARS-Cov-2 infection affects adaptive immune responses to Omicron BA.4/BA.5 mRNA booster.

Abstract

Background: Bivalent COVID-19 mRNA vaccines encoding Wuhan-1 and Omicron BA.4/5 spike proteins can prevent SARS-CoV-2 infection, but the quality of adaptive immune responses and the importance of hybrid immunity are not well-documented.

Objectives: Adaptive immune responses to the bivalent vaccine were studied in 40 healthy participants with (COVID+) or without (COVID-) prior history of SARS-CoV-2 infection.

Methods: We analyzed anti-N and anti-S IgG titers and surrogate virus neutralization capacity against variants of concern (VOCs) and assessed SARS-CoV-2 specific B and T cell responses by high-dimensional spectral flow cytometry, intracellular cytokine staining assay upon stimulation with SARS-CoV-2 peptides and TRB and IGH repertoire analysis.

Results: The COVID+ group had higher anti-S IgG levels pre- and post-booster and higher neutralization activity against BA.4/5 than the COVID- group. Spike antibody levels positively correlated with neutralizing activity against Omicron VOCs in all participants. For VOCs, lowest neutralization capacity was against XBB1.5. At baseline, the proportion of S1+ RBD+ B cells was higher in COVID+ than in COVID- subjects, but an increase of these cells post-boost was detected only in the COVID- group. Consistent with natural infection, COVID+ subjects had a higher frequency of IgA+ CXCR3+S1+RBD+ B cells at baseline than COVID- subjects. CD4+ memory T cells responses and breath of class II epitope SARS-CoV-2 specific clonotypes were increased post-boost only in COVID- participants.

Conclusions: The bivalent vaccine induces robust adaptive immune responses against the Omicron variant. Prior SARS-CoV-2 infection provides increased protection, but optimal timing of booster administration after natural infection should be defined to maximize benefits.