Longitudinal SARS-CoV-2 mRNA vaccine-induced mucosal, serological, and cellular immunity in children and human milk

PROJECT SUMMARY COVID-19 cases and hospitalizations in children have increased dramatically worldwide. Although most COVID- 19 is mild in children, severe illness and post-infectious complications can occur. We and others have found that children are an important source of household and community transmission. Vaccination is the most effective way to prevent severe infection and decrease transmission. Infants under 6 months of age are at high risk for life-threatening complications, but a vaccine for this age group is not yet in clinical trials; thus, maternal vaccination and breastfeeding may be an important strategy to protect infects. SARS-CoV-2 infection and vaccine immunity studies have focused predominantly on adults, but children have developing immune systems and may respond to the new mRNA vaccination platform differently from adults. This proposal addresses the critical need to study the short- and long-term immune responses to COVID-19 mRNA vaccination in children, human milk, and breastfeeding infants. We have a successful ongoing longitudinal COVID-19 vaccination cohort that began in December 2020, in which we have collected biologic specimens from 368 individuals including adults, children, and lactating mother-infant pairs. We will enroll a total of 560 individuals down to 6 months of age after the mRNA vaccine receives Emergency Use Authorization (EUA) for the younger age group. Participants are followed every 3 months for nasal, saliva, milk (if lactating), and blood samples. We will test all COVID-19 symptomatic or exposed participants for breakthrough infection throughout the study period. Our central hypothesis is that the repertoire, magnitude, and longevity of COVID-19 vaccine- induced immune responses will be dependent on age and previous experience with SARS-CoV-2 infection. Importantly, our study will also move beyond the systemic immune responses to examine mucosal immunity in the respiratory tract and in human milk. To test the hypothesis, we will characterize vaccine induced serum, nasal, and saliva SARS-CoV-2-specific antibody response (Aim 1) and cellular (CD4+/CD8+) response (Aim 2) in children compared with adults and identify key immunologic correlates of protection against breakthrough infection. We will also determine humoral and cellular responses in human milk and secretory IgA in the breastfed infants' upper respiratory tract and evaluate vaccine-induced differential gene expression in milk that direct the immune response (Aim 3). Our collaborative team with expertise in vaccinology, immunology, virology, epidemiology, and bioinformatics will ensure successful integrative analyses and interpretation of these immunologic and transcriptomic data. Completion of the study will provide a comprehensive characterization of longitudinal COVID-19 mRNA vaccination-induced immunity across age groups and in human milk to inform vaccination strategies to optimize the protection of children and infants.