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. 2025 Aug;91(2):106543.
doi: 10.1016/j.jinf.2025.106543. Epub 2025 Jun 26.

Anti-spike IgG4 and Fc effector responses: The impact of SARS-CoV-2 vaccine platform-specific priming and immune imprinting

Raj Kalkeri  1 , Mingzhu Zhu  2 , Shane Cloney-Clark  2 , Anand Parekh  2 , Drew Gorinson  2 , Zhaohui Cai  2 , Miranda R Cai  2 , Soham Mahato  2 , Gordon Chau  2 , Tara M Babu  3 , Anna Wald  4 , Pradhipa Ramanathan  5 , L Carissa Aurelia  5 , Kevin John Selva  5 , Anthony M Marchese  2 , Louis Fries  2 , Lisa M Dunkle  2 , Amy W Chung  5 , Joyce S Plested  2
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Free article

Anti-spike IgG4 and Fc effector responses: The impact of SARS-CoV-2 vaccine platform-specific priming and immune imprinting

Raj Kalkeri et al. J Infect. 2025 Aug.
Free article

Abstract

Proportional increases in anti-Spike (S) IgG4 associated with decreased Fc effector functions have been reported following repeated mRNA, but not recombinant protein-based (rS) (NVX-CoV2373, Novavax, Inc.), SARS-CoV-2 vaccination. We demonstrate the first evidence of a negative correlation between anti-S IgG4 and neutralizing antibody (nAb), as well as antibody-dependent surrogate Fc effector functions. Priming with two NVX-CoV2373 vaccines followed by a third dose was associated with higher IgG1 and IgG3, lower IgG4, higher nAb titers and surrogate Fc effector functions versus mRNA. Immune imprinting of anti-S IgG4 and nAbs, and Fc effector function imprinting after mRNA priming was observed. This effect was partially overcome by updated XBB.1.5 protein subunit vaccination, but not by ancestral vaccine strains. We establish correlation of anti-S IgG4 responses to reduced nAbs and surrogate Fc effector functions and demonstrate the impact of additional booster vaccination on subsequent immune response and Fc effector functions in the context of ancestral and XBB.1.5 strains.

Keywords: COVID-19; IgG3; IgG4; Immune imprinting; SARS-CoV-2; Vaccination.

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Conflict of interest statement

Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Raj Kalkeri, Mingzhu Zhu, Shane Cloney-Clark, Anand Parekh, Drew Gorinson, Zhaohui Cai, Miranda R. Cai, Soham Mahato, Gordon Chau, Anthony M. Marchese, and Joyce S. Plested are current or former employees of Novavax, Inc. and as such receive a salary and may hold Novavax, Inc. stock. Louis Fries and Lisa M. Dunkle are consultants to Novavax, Inc. Amy W. Chung has received grant funding from NHMRC, MRFF, and NIH. Anna Wald received research funding from NIH, GSK, Assembly Biomedical and Moderna, and is a consultant for GSK, Aicuris, Innovative Molecules and Bayer. Tara M. Babu has served on an advisory board for Sanofi. Pradhipa Ramanathan, L. Carissa Aurelia, and Kevin John Selva have no competing interests to declare.

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