Impact of vaccination and preterm delivery on maternal RSV-specific peripheral and mucosal immunity

About This Grant

In the United States and globally, respiratory syncytial virus (RSV) is a leading cause of morbidity and mortality in infants under 6 months, leading to ~50,000 deaths per year. Preterm infants are at particularly high risk of severe disease. To boost protection, a bivalent RSV vaccine formulated as recombinant pre-Fusion glycoprotein (preF) was recently licensed for use in pregnancy and provides ~70% protection from severe RSV disease in infants under 6 months of age. To date, the efficacy of this vaccine has been attributed solely to the transplacental transfer of maternal IgG to the fetus. However, maternal vaccination may also impact breastmilk immunity, where breastmilk exposure and breastmilk RSV-specific IgG are both associated with protection from RSV infection and reduced disease severity. We and others have also demonstrated that breastmilk also contains RSV-specific IgA and mucosal memory T cells, which increase during RSV-infection in the maternal-infant dyad. Breastmilk IgG and IgA may be systemically absorbed in the first few days of life and could contribute to viral neutralization. In addition, animal data demonstrate that breastmilk T cells can integrate into offspring organs including the lung, where they may facilitate viral clearance. Together, these observations suggest that adaptive immunity derived from breastmilk is functionally distinct from transplacental IgG and, importantly, can provide mucosally active IgA, IgG, and durable T cell protection to the infant. However, the impact of RSV-VX on breastmilk immunity is currently unknown. To address this knowledge gap, we have recently demonstrated that there is increased preF- specific IgA and IgG in the breastmilk of women who received RSV-VX compared to those who did not. Thus, our central premise is that breastmilk provides a distinct form of mucosal immunity to the infant which can be boosted with vaccination. Further, prior data demonstrate that transplacental transfer of IgG is reduced in preterm dyads, but early breastmilk IgA and T cell concentrations are increased. Thus, we hypothesize that the relative importance of RSV-VX on breastmilk immunity is greater in preterm versus term infants, where preterm infants receive less transplacental IgG but more breastmilk IgA and cellular immunity. To test our hypothesis, we will enroll a cohort of pregnant women at delivery who did or did not receive RSV-VX, including preterm and term deliveries. We will collect maternal and cord blood at delivery, maternal breastmilk and blood at 2-, 6-, and 12- weeks postpartum, and infant blood at 12-weeks. In Aim 1, we will determine the impact of RSV-VX and preterm delivery on breastmilk and peripheral RSV-specific antibody levels and function. In Aim 2, we will determine the impact of RSV-VX and preterm delivery on frequency and function of peripheral blood and breastmilk RSV- specific CD4 and CD8 T cells. The proposed studies will address a critical knowledge gap regarding the ability of RSV-VX to boost mucosal breastmilk and peripheral immune responses in term and preterm dyads. These data will provide rationale for the development of next generation maternal vaccines designed to induce mucosal immunity as a targeted strategy to improve infant protection.