Mechanisms of maternal antibody interference to rotavirus vaccination

Maternal antibodies (MatAbs) are transferred transplacentally during pregnancy and through breast milk after birth to provide protection whilst the neonatal immune response is immature. However, MatAbs also suppress the development of neonatal B cell responses via mechanisms that are not well defined. MatAbs can therefore result in poor vaccine performance in the infant, placing them at risk against potentially life-threatening pathogens such as rotavirus. It is essential we understand the mechanisms by which MatAbs interact with neonatal immunity, so that strategies can be developed to overcome this major vaccine issue. To investigate mechanisms of interference we developed a mouse model of neonatal oral rotavirus vaccination in the presence and absence of MatAbs. Oral vaccination with attenuated murine rotavirus induced robust neonatal antibody responses, whereas vaccination failed to induce seroconversion in the presence of MatAbs. Vaccination with heterologous strains, reduced MatAb titers and vaccination in Fc{gamma}RIIB knockout mice did not overcome interference. However, live vaccine replication was blocked in the presence of MatAbs and more rapid waning of MatAbs was observed following vaccination. This is indicative of premature vaccine clearance and likely reduced antigen encounter by B cells. Single-cell RNA sequencing of mesenteric lymph nodes revealed diminished plasma and germinal center B cell subpopulations as well as global reduction of interferon-stimulated genes in the presence of MatAbs. Our model has also enabled identification of strategies to reduce the effects of interference. In summary, we have tested multiple hypotheses for MatAb-mediated interference to rotavirus vaccination in a mouse model, and demonstrated that premature Fc{gamma}RIIB signaling and epitope masking are not the primary mechanisms of vaccine failure. Rather our data supports the conclusion that MatAb-mediated vaccine clearance is a key mechanism of interference to oral rotavirus vaccine.