Vaccine imprinting drives increased SARS-CoV-2 variant infection in children

Timothy S. Johnston; Rahul Subramanian; Wakinyan Benhamou; Emily Howerton; Robin Schlesinger; Stephen D. Schmidt; Rachel Kazmierski; Mike Castro; Bob C. Lin; Amy R. Henry; Sarah C. Smith; Jesmine Roberts-Torres; Farida Laboune; I‐Ting Teng; Shuishu Wang; Dabeluchi Isiofia; Levi Dong; Mark M. Painter; Alicen Burns Spaulding; Chaim A. Schramm; David Winston Kimberlin; Samuel R. Dominguez; Hai D Nguyen-Tran; Perdita Permaul; E. John Wherry; Matthew R. Vogt; Kevin Messacar; Tongqing Zhou; Leonid Serebryannyy; Bryan Thomas Grenfell

doi:10.64898/2026.08.12.739589

ImmunologybioRxivAug 17, 2026

Preprint

Vaccine imprinting drives increased SARS-CoV-2 variant infection in children

Timothy S. Johnston iD, Rahul Subramanian iD, Wakinyan Benhamou iD, Emily Howerton iD, Robin Schlesinger, Stephen D. Schmidt iD, Rachel Kazmierski iD, Mike Castro iD, Bob C. Lin iD, Amy R. Henry, Sarah C. Smith iD, Jesmine Roberts-Torres iD, Farida Laboune, I‐Ting Teng iD, Shuishu Wang iD, Dabeluchi Isiofia, Levi Dong, Mark M. Painter iD, Alicen Burns Spaulding iD, Chaim A. Schramm iD, David Winston Kimberlin iD, Samuel R. Dominguez iD, Hai D Nguyen-Tran iD, Perdita Permaul iD, E. John Wherry iD, , Daniel C. Douek iD

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.

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