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), 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 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 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 ancestral vaccine strains. We establish correlation of anti-S IgG4 responses to reduced nAbs and 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.

The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: R.K., M.Z., S.C.C., A.P., D.G., Z.C., M.R.C., S.M., G.C., A.M.M., and J.S.P. are current or former employees of Novavax, Inc. and as such receive a salary and may hold Novavax, Inc. stock. L.F. and L.M.D. are consultants to Novavax, Inc. A.W.C. has received grant funding from NHMRC, MRFF, and NIH. A.W, received research funding from NIH, GSK, Assembly Biomedical and Moderna, and is a consultant for GSK, Aicuris, Innovative Molecules and Bayer. T.M.B. has served on an advisory board for Sanofi. P.R., L.C.A., and K.J.S. have no competing interests to declare.

NCT04611802; NCT05463068; NCT05372588; NCT05975060;

This study was funded by Novavax, Inc. Samples from 2019nCoV-301 (ClinicalTrials.gov: NCT04611802) were included in the present study. 2019nCoV-301 was funded by the Office of the Assistant Secretary for Preparedness and Response, Biomedical Advanced Research and Development Authority (BARDA; contract Operation Warp Speed: Novavax Project Agreement number 1 under Medical CBRN [Chemical, Biological, Radiological, and Nuclear] Defense Consortium base agreement no. 2020-530; Department of Defense no. W911QY20C0077); and the National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health. The NIAID provides grant funding to the HIV Vaccine Trials Network (HVTN) Leadership and Operations Center (UM1 AI68614), the HVTN Statistics and Data Management Center (UM1 AI68635), the HVTN Laboratory Center (UM1 AI68618), the HIV Prevention Trials Network Leadership and Operations Center (UM1 AI68619), the AIDS Clinical Trials Group Leadership and Operations Center (UM1 AI68636), and the Infectious Diseases Clinical Research Consortium leadership group (UM1AI148684). Samples from 2019nCoV-307 (ClinicalTrials.gov: NCT05463068) were included in the present study. 2019nCoV-307 was funded by Novavax, Inc. with support from the US BARDA (Contract W15QKN-16-9-1002, Project Number MCDC2011-001).

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

The details of the IRB/oversight body that provided approval or exemption for the research described are given below: for 2019nCoV-307: The study was reviewed, approved and overseen by the Advarra Institutional Review Board, Columbia, MD. for 2019nCoV-301: The following Institutional Review Boards / Independent Ethics committees reviewed and gave ethical approval for the PREVENT-19 study: Western Copernicus Group IRB, US; Great Plains IRB, US; Comite de etica en investigacion del Instituto Nacional de Ciencias Medicas y Nutricion, Salvador Zubiran, Mexico; Comite de etica en investigacion de la Unidad de Atencion Medica e Investigacion en Salud S.C., Mexico; Comite de etica en investigacion del Instituto Nacional de Salud Publica, Mexico; Comite de etica en investigacion de Medica Rio Mayo S.C., Mexico; Comite de etica en investigacion del Hospital La Mision S.A. de C.V., Mexico. All necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived.

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.

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All data produced in the present work are contained in the manuscript.