BACKGROUND: Despite advances in respiratory syncytial virus (RSV) immunoprophylaxis, RSV remains a leading cause of severe respiratory illness in infants. Immunity at the site of infection is potentially important yet airway mucosal immunity against RSV infection remains poorly defined.

METHODS: We collected nasal and blood samples across three pediatric cohorts: 1) children presenting to the emergency department with respiratory symptoms; 2) infants and mothers presenting to an urban hospital system across the RSV season; 3) infants born to mothers vaccinated with maternal pre-Fusion (F) vaccine. We analyzed mucosal and serologic anti-RSV antibodies and assessed for factors impacting titer magnitude and durability.

RESULTS: Specimens from 285 infants/young children and 39 mothers were analyzed. Mucosal anti-RSV antibody levels were lower in infants presenting with RSV infection compared to age-matched controls both in infants experiencing their first viral season (p = 0.0011) and older children (p < 0.0001). Higher levels of mucosal antibodies were seen in infants whose mothers received maternal pre-F vaccination, with IgG against RSV fusion protein tightly correlating between infant's serum and nasal compartments (p < 0.0001). However, mucosal anti-RSV IgG waned significantly by 6 months of age (p < 0.0001).

CONCLUSIONS: Higher mucosal anti-RSV antibody levels are associated with protection against RSV-related illness. Current immunoprophylactic strategies drive robust anti-RSV IgG responses in the infant mucosal and serological compartments; however, passive immunity wanes over 6 months. These results suggest that RSV immunization strategies optimizing durable mucosal immunity may protect infants from RSV-related respiratory illness.

The innate immune system is rapidly activated following antigen exposure and plays a critical role in shaping the ensuing adaptive immune responses. In this study, we performed bulk RNA sequencing and proteomic profiling in a cohort of 25 rhesus macaques following Ad26.COV2.S immunization to characterize early innate correlates of vaccine immunogenicity and protection. Our results show that innate immune activation occurred as early as day 1 post-vaccination and demonstrated a systemic enrichment of antiviral interferon pathways, cytokine signaling, and activation of innate immune cell signatures. These early transcriptomic signatures correlated positively with humoral and cellular immune responses at 6 weeks following vaccination and correlated inversely with viral loads following SARS-CoV-2 challenge. Similar correlates of immunogenicity were observed in a cohort of 25 adult healthy participants vaccinated with Ad26.COV2.S. Taken together, these findings highlight the importance of early activation of the innate immune responses following Ad26.COV2.S vaccination in shaping the protective adaptive immune response.IMPORTANCEEarly innate immune responses may shape vaccine immunogenicity and protection. We evaluated responses to Ad26.COV2.S vaccination in rhesus macaques and humans and found that day 1 innate immune signatures correlated with subsequent adaptive responses. These findings suggest that early post-vaccination immune programming influences immunogenicity and protective efficacy months later.