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

Bivalent coronavirus disease 2019 (COVID) mRNA vaccines encoding Wuhan-1 and Omicron BA.4/BA.5 spike proteins (S) can prevent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, but the quality of adaptive immune responses and the importance of hybrid immunity are not well documented.

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

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

The COVID⁺ group had higher anti-S IgG levels before and after boost and higher neutralization activity against BA.4/BA.5 than the COVID^- group. Spike antibody levels positively correlated with neutralizing activity against Omicron variants of concern in all participants. For variants of concern, lowest neutralization capacity was against XBB.1.5. At baseline, the proportion of S1⁺RBD⁺ B cells was higher in COVID⁺ than in COVID^- subjects, but an increase of these cells after 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-cell responses and breath of class II epitope SARS-CoV-2-specific clonotypes were increased after boost only in COVID^- participants.

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.