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. 2025 Jun;155(6):2038-2051.
doi: 10.1016/j.jaci.2025.02.026. Epub 2025 Mar 3.

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

Brianna T Wachter  1 , Qin Xu  2 , Lihong Shi  2 , Peter D Burbelo  3 , Kathy Myint-Hpu  1 , Pamela L Schwartzberg  2 , Muhammad Tauseef Rehman  4 , Robin L Dewar  4 , Kristin L Boswell  5 , Richard A Koup  5 , Cihan Oguz  6 , Luisa Imberti  7 , Lorenza Bellusci  8 , Sara Pourhashemi  8 , Surender Khurana  8 , Kalpana Manthiram  2 , Luigi D Notarangelo  9 , Ottavia M Delmonte  10
Affiliations

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

Brianna T Wachter et al. J Allergy Clin Immunol. 2025 Jun.

Abstract

Background: 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.

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

Methods: 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.

Results: 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.

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.

Keywords: B-cell receptor repertoire; COVID-19; Omicron BA.4/BA.5 bivalent mRNA booster vaccination; SARS-CoV-2; T-cell receptor repertoire; hybrid immunity; variants of concern (VOC).

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Conflict of interest statement

Disclosure statement Supported by the Division of Intramural Research Programs of NIAID (grant AI001270) and of the National Institute of Dental and Craniofacial Research, National Institutes of Health. The PsV neturalization assays and ORF8 work was supported by the US Food and Drug Administration, Office of Counterterrorism and Emerging Threats (OCET)–Medical Countermeasures initiative (OCET 2023-0235 to S.K.); the funders had no role in study design, data collection and analysis, decision to publish, or preparation of the report. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services or the Centers for Disease Control and Prevention, nor does mention of trade names, commercial products, or organizations imply endorsement by the US government. Opinions, interpretations, conclusions, and recommendations are those of the authors and are not necessarily endorsed by the US government. Disclosure of potential conflict of interest: The authors declare that they have no relevant conflicts of interest.

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