Understanding the mechanisms of maternal antibody interference with oral vaccination

Maternal antibodies (MatAbs) pose a significant challenge to neonatal immune responses, leading to reduced vaccine efficacy and heightened susceptibility to preventable viral infections. This interference phenomenon is particularly critical in the context of rotavirus (RV) vaccination, which causes a substantial global burden of infant gastroenteritis, particularly in low-middle income countries (LMIC). While various factors have been proposed as contributors to reduced RV vaccine efficacy, the elevated levels of MatAbs in LMIC mothers have been negatively correlated with vaccine efficacy in multiple studies. Currently, the molecular mechanisms responsible for MatAb interference with RV vaccination are unknown. This project aims to bridge this knowledge gap using a valuable human clinical samples and studies in mice. Firstly, this project will take advantage of a new mouse model of MatAb interference, whereby pups vaccinated with live attenuated RV display significantly reduced seroconversion if MatAbs are present. A significant challenge in MatAb research till now has been the absence of a suitable system to study interference at the molecular level. The new mouse model provides a valuable opportunity for a mechanistic evaluation of interference hypotheses, and our preliminary data has identified vaccine clearance as a key mechanism of interference. We now aim to advance our understanding of this using transgenic mouse models and recombinant monoclonal antibody technology to identify the cell types and biophysical antibody features responsible. We will perform comprehensive analysis of RV-specific MatAbs in bio-banked human samples to validate and expand data generated from our mouse model. We will study samples from mothers that have been naturally infected with RV and their infants that have been vaccinated for RV. A panel of RV-specific biophysical and functional antibody assays will be used to determine if there is a subset of RV-MatAbs that are more closely associated with MatAb transfer or vaccine interference. We aim to identify the relative contributions of placental MatAbs and breast milk MatAbs in mediating interference. Successful completion of this project will provide critical insights into which MatAbs are associated with vaccine interference in humans and elucidate the mechanisms by which these are mediating interference. This knowledge will inform the development of new vaccination strategies, potentially identifying promising vaccine approaches that are capable of eliciting protective immune responses in the presence of MatAbs. Ultimately this research will therefore contribute to global efforts to combat RV-induced infant morbidity and mortality. Project Number: 1R01AI189774-01A1 | Fiscal Year: 2026 | NIH Institute/Center: National Institute of Allergy and Infectious Diseases (NIAID) | Principal Investigator: Sarah Caddy | Institution: CORNELL UNIVERSITY, ITHACA, NY | Award Amount: $653,742 | Activity Code: R01 | Study Section: Immunity and Host Defense Study Section[IHD] View on NIH RePORTER: https://reporter.nih.gov/project-details/1R01AI18977401A1