Clinical correlates of maternal antibody interference with oral rotavirus vaccine immunogenicity 2255869

Abstract Introduction Maternal antibodies (MatAbs) are critical for providing immune protection to neonates whilst their own immune responses are developing. Paradoxically, MatAbs can also interfere with the ability of neonates to respond to vaccination. This a major concern for rotavirus, a leading cause of gastroenteritis in infants for which vaccines are routinely administered at 6-8 weeks of age. We have recently demonstrated how MatAb interference with rotavirus vaccination is mediated by rapid vaccine clearance in a mouse model. Our current goal is to understand how MatAbs interfere with vaccine responses in human cohorts. Methods We analyzed infant serum samples from two vaccine clinical trials. We used the first cohort to evaluate how MatAbs are associated with vaccine immunogenicity, comparing pre-vaccination rotavirus-specific IgG titres between seroconverters and non-seroconverters. In the second cohort, protection from severe gastroenteritis following vaccination was documented. This allowed us to investigate the functional capacity of MatAbs to mediate vaccine clearance in the context of clinical outcome. Results Pre-vaccination rotavirus-specific IgG titres were significantly elevated in non-seroconverters compared to seroconverters, implicating MatAbs in vaccine failure. In the clinical outcome cohort, MatAb neutralization capacity against both extracellular and intracellular virus was significantly correlated with the risk of disease. Infants whose MatAbs pre-vaccination could robustly block virus replication before and after cell entry had increased risk of severe gastroenteritis when MatAbs had waned. Conclusion MatAb interference operates through multiple clearance mechanisms in human infants. MatAb characteristics predict both vaccine response and clinical outcomes. These findings provide mechanistic insights into vaccine underperformance in high-burden settings. This is valuable for developing strategies to overcome MatAb interference and optimizing vaccination schedules to maximize protection. Funding Source PATH, Affinito Stewart, Baker Institute for Animal Health Topic Categories Vaccines and Immunotherapy (VAC)