Microbial drivers of oral vaccine failure

Environmental Enteric Dysfunction (EED) is a pervasive subclinical syndrome of intestinal malabsorption that has been strongly linked with undernutrition and linear growth stunting. Intestinal pathogens are common in undernourished populations and likely contribute to both growth stunting and EED. Rotavirus (RV) is the number one cause of childhood deaths from diarrhea. Unfortunately, Oral Rotavirus Vaccination (ORV) is significantly less effective in undernourished populations with the greatest need for protection. Nutrient-poor diet alone does not reduce the efficacy of ORV in mice; however, human studies have linked the composition of the gut microbiome to ORV responses. Gut microbes play a pivotal role in shaping the development of intestinal immunity, particularly in early life. Recent work has shown that children with EED have altered gut microbial communities and mucosal immune composition, including increased microbiota- directed Immunoglobulin A (IgA), small intestinal antibody-producing plasma cells (PC) and CD25+ regulatory T cells (Treg). In a murine model of enteropathy, microbiota-dependent Rorγt+ Treg suppressed responses to oral vaccination. In order to identify mechanisms by which human microbes influence mucosal immune function, our lab has developed a murine model of intergenerational undernutrition in which germ-free (GF) breeding mice are colonized with microbiota obtained from stunted (SD) or healthy (HD) human infants. Offspring born to these mice (SD or HD pups) are colonized with distinct microbial communities from birth and weaned onto a nutrient-deficient diet, capturing a critical window of immune development. We find that SD pups show increased microbiota-directed IgA, elevated small intestinal IgA+ PC and increased Rorγt+ Treg relative to HD pups, mirroring immune alterations observed in EED. Based on these results, we propose to test the hypothesis that specific members of the SD gut microbiota drive dysregulated intestinal immunity and poor oral vaccine responses. We will use our intergenerational mouse model to investigate cellular and humoral responses to oral vaccination against RV and evaluate protection from subsequent challenge. We will then identify critical microbial taxa implicated in immune dysregulation by sorting and sequencing IgA-bound microbes from these animals. This work will pave the way for future investigation of microbial functions that could be harnessed or disrupted to improve vaccine efficacy, leading to more effective oral vaccination and reduced mortality due to diarrhea in children. Project Number: 1R21AI196611-01 | Fiscal Year: 2026 | NIH Institute/Center: National Institute of Allergy and Infectious Diseases (NIAID) | Principal Investigator: Carrie Cowardin | Institution: UNIVERSITY OF VIRGINIA, CHARLOTTESVILLE, VA | Award Amount: $242,250 | Activity Code: R21 | Study Section: Vaccines Against Infectious Diseases Study Section[VID] View on NIH RePORTER: https://reporter.nih.gov/project-details/1R21AI19661101