Early-life gut microbiome is associated with immune response to the oral rotavirus vaccine in healthy infants in the US.

Background: Rotavirus remains a leading cause of childhood mortality worldwide, despite the widespread introduction of oral rotavirus vaccines (ORVs). While emerging evidence supports a link between microbiome and vaccine response, findings have been inconsistent, especially across geographic and socioeconomic contexts, and none have been conducted in a US-based cohort. This study investigates the development of the infant gut microbiome and its association with immunogenicity following RotaTeq administration in U.S. infants. Methods: We conducted a longitudinal analysis of infants in Rochester, New York, using 16S rRNA sequencing data to assess microbiome composition. We used rotavirus-specific immunoglobulin A (Rotavirus-IgA) titers at the sixth-month study visit (M6) in plasma to determine the seroresponse to vaccination. Clinical metadata were used to evaluate the influence of different factors on microbial diversity over the first year of life and Rotavirus-IgA titers at the M6 visit. Microbiome data from the M1 visit and Rotavirus-IgA at the M6 visit were used to assess the relationship between the infant gut microbiome and ORV immune responses. Findings: The infant gut microbiome followed characteristic developmental patterns during the first year (N=264). At the M6 visit, 65 infants had a Rotavirus-IgA geometric mean titer of 455, 95% CI:[272-761]. In a sub-cohort that included the complete dataset of immunogenicity and microbiome (N=47), higher alpha diversity at the month 1 (M1) visit was significantly associated with higher Rotavirus-IgA titers at the M6 visit (β= 2.151, 95% CI:[0.31- 3.99], p=0.023). Specific taxa present at the M1 visit, including Collinsella (β: 0.243, 95% CI:[0.076, 0.392], q= 0.037), Atopobium (β: 0.262, 95% CI:[0.066, 0.458], q= 0.062), and Schaalia radingae (β: 0.28, 95% CI:[0.116, 0.458], q=0.018), were positively associated with Rotavirus-IgA titers. In contrast, Bifidobacterium (β: -0.204,95% CI:[-0.323, -0.085], q=0.012), Lactobacillus (β: -0.17, 95% CI:[-0.314, -0.035], q= 0.087), Klebsiella (β: -0.195, 95% CI:[-0.331, -0.058], q= 0.042), Escherichia-Shigella (β: -0.128, 95% CI:[-0.245, -0.012], q= 0.162), Streptococcus salivarius (β: -0.229, 95% CI:[-0.359, -0.098], q= 0.012), and Peptostreptococcus anaerobius (β: -0.176, 95% CI:[-0.338, -0.014], q= 0.162) were negatively associated. Interpretation: In a healthy U.S.-infant cohort, we report a significant association between the early-life infant gut microbiome and RotaTeq-vaccinated infants' Rotavirus-IgA titers. This study contributes to a clearer understanding of microbiome-vaccine interactions, particularly in high-income settings where existing evidence has been limited. Funding: Office of the Director of the National Institutes of Health, National Institute of Mental Health of the National Institutes of Health, and the National Center for Advancing Translational Sciences of the National Institutes of Health