Prior SARS-CoV-2 infection affects adaptive immune responses to Omicron BA.4/BA.5 mRNA booster - 04/06/25

Doi : 10.1016/j.jaci.2025.02.026

Brianna T. Wachter, BS ^a, Qin Xu, MD, PhD ^b, Lihong Shi, MD ^b, Peter D. Burbelo, PhD ^c, Kathy Myint-Hpu, PNP ^a, Pamela L. Schwartzberg, MD, PhD ^b, Muhammad Tauseef Rehman, PhD ^d, Robin L. Dewar, PhD ^d, Kristin L. Boswell, PhD ^e, Richard A. Koup, MD ^e, Cihan Oguz, PhD ^f, Luisa Imberti, MD ^g, Lorenza Bellusci, PhD ^h, Sara Pourhashemi, PhD ^h, Surender Khurana, PhD ^h, Kalpana Manthiram, MD ^b, Luigi D. Notarangelo, MD ^a,^⁎ , Ottavia M. Delmonte, MD, PhD ^a,^⁎
^a Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, Md
^b Laboratory of Immune System Biology, NIAID, NIH, Bethesda, Md
^c Adeno-Associated Virus Biology Section, National Institute of Dental and Craniofacial Research, NIH, Bethesda, Md
^d Virus Isolation and Serology Laboratory, Frederick National Laboratory, Frederick, Md
^e Immunology Laboratory, Vaccine Research Center, NIAID, NIH, Bethesda, Md
^f Integrated Data Sciences Section, Research Technologies Branch, NIAID, NIH, Bethesda, Md
^g Spedali Civili di Brescia, Universita’ Degli Studi di Brescia, Brescia, Italy
^h Division of Viral Products, Center for Biologics Evaluation and Research, Food and Drug Administration, Silver Spring, Md

^∗Corresponding authors: Ottavia M. Delmonte, MD, PhD, Immune Deficiency Genetics Section, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Building 10, Room 6-4750, 10 Center Drive–MSC, Bethesda, MD 20892.Immune Deficiency Genetics SectionLaboratory of Clinical Immunology and MicrobiologyNational Institute of Allergy and Infectious DiseasesNational Institutes of HealthBuilding 10Room 6-475010 Center Drive–MSCBethesdaMD20892^∗Luigi D. Notarangelo, MD, Immune Deficiency Genetics Section, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Building 10, Room 5-3750, 10 Center Drive–MSC, Bethesda, MD 20892.Immune Deficiency Genetics Section, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Building 10Room 5-375010 Center Drive–MSCBethesdaMD20892

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Graphical abstract

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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.

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

Abbreviations used : CDR3, COVID, HLA, IGH, MIRA, N, PBMC, PsVNA, RBD, S, SARS-CoV-2, smB, TCR, TRB, VOC, WT

Plan

Methods

Participant recruitment

Measurement of SARS-CoV-2–specific anti-S and anti-N antibodies

Seroreactivity of samples to SARS-CoV-2 ORF8 by ELISA

SARS-CoV-2 neutralization assays

SARS-CoV-2–specific B-cell characterization with flow cytometry

Unsupervised analysis of high-dimensional flow cytometry data

Intracellular cytokine staining of activated T cells

T- and B-cell receptor repertoire analysis

Results

Cohort description

Antibody responses to Omicron BA.4/BA.5 bivalent mRNA vaccine

Memory B-cell responses to Omicron BA.4/BA.5 bivalent mRNA vaccine

Memory T-cell responses to Omicron BA.4/BA.5 bivalent mRNA vaccine

Discussion

The last 2 authors contributed equally to this article, and both should be considered senior author.

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Vol 155 - N° 6

P. 2038-2051 - juin 2025 Retour au numéro

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Prior SARS-CoV-2 infection affects adaptive immune responses to Omicron BA.4/BA.5 mRNA booster - 04/06/25

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Results

Conclusions

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