Abstract
Virus exposure history, particularly first exposure, is believed to shape vaccine efficacy and infection susceptibility; however, evidence for mechanistic links between immune responses in individuals and epidemiological outcome in populations is scarce. Recent co-circulation of SARS-CoV-2 variants XFG and BA.3.2 has revealed a striking enrichment in BA.3.2 cases among children. By combining epidemiological modeling, serology and monoclonal antibody analysis in children and adults, we show the dependence of effective variant-specific antibodies on vaccination history which may explain birth-year influence on differential susceptibility to these co-circulating variants. Ancestral cross-reactive site I antibodies frequently neutralize BA.3.2, but not XFG. By contrast, Omicron type-specific site I/III and III antibodies frequently neutralize XFG but not BA.3.2, revealing a tradeoff in the ability to neutralize these two co-circulating strains. These findings mechanistically link immune history, variant neutralization, antibody repertoire and variant infection risk, and suggest that vaccination regimens in children should prioritize neutralization breadth.
Competing Interest Statement
E.J.W. advises Arpelos Bioscience, Arsenal Biosciences, Coherus, Danger Bio, IpiNovyx, New Limit, Marengo, Pluto Immunotherapeutics Related Sciences, Santa Ana Bio, and Synthekine. E.J.W. is a founder of and holds shares of Coherus, Danger Bio, and Arsenal Biosciences. All other authors declare no competing interests.
Funder Information Declared
National Institute of Allergy and Infectious Diseases, https://ror.org/043z4tv69, 75N93021C00015, U19AI082630, AI105343, AI108545, AI155577, AI149680
National Cancer Institute, 75N91019D00024, 75N91022F00005, 75N91023F00016
Source:
Link: https://www.biorxiv.org/content/10.64898/2026.08.12.739589v1
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