Effect of gut microbiota composition on malaria vaccine-induced immune responses

ABSTRACT Understanding heterogeneity in vaccine-induced immune responses and its impact on efficacy outcomes is important for developing effective vaccines. Diverse host and environmental factors, such as the gut microbiome, can impact vaccine responses. Important roles of gut microbiota in the development and function of the local gut and gut-distal immune system are only beginning to be appreciated. Importantly, how gut microbiota composition may shape vaccine-induced immune responses is not fully understood. Interestingly, malaria vaccines are initially tested in US or European individuals, who have distinctly different gut microbiota communities than individuals living throughout Africa. The effect of differential gut microbiota between US and African individuals on immune responses to malaria vaccines may greatly impact vaccine efficacy in the target population. The objective of this proposal is to evaluate how differential gut microbiota populations may influence malaria vaccine-induced immune responses using a controlled, genetically tractable microbiome- repopulated mouse model. Observations in animal models demonstrate that gut microbiota can function as adjuvants via activation of pattern recognition receptor signaling pathways for non-adjuvanted vaccines. Limited human observation and intervention studies (i.e., antibiotic treatment) also support the idea that gut microbiota affect vaccine-induced immune responses. These studies highlight an urgent need to understand better the effect of differential gut microbiota on vaccine-induced immunity. Many malaria vaccines rely on the induction of antibody responses via germinal center (GC) reactions, including the two recently approved by WHO (RTS,S and R21) and pre-clinical malaria vaccine candidates under investigation in the laboratory of Dr. Srinivasan. These studies underscore the importance of robust antibody titer in mediating parasite neutralization of sporozoites (infecting hepatocytes) and merozoites (infecting erythrocytes). Dr. Schmidt's laboratory has shown in mice that differences in gut microbiota determine the magnitude and quality of GC reactions and efficient control of parasites following Plasmodium yoelii (Py) infection. These observations support the central hypothesis that gut microbiota composition, through its effects on GC reaction, will impact the quantity and quality of malaria vaccine-induced immune responses, thereby influencing vaccine efficacy. We will test this hypothesis through the following aims: Specific Aim 1. How do differential murine gut microbiota populations impact malaria vaccine-induced antibody responses? Specific Aim 2. How do African and US human gut microbiota communities shape malaria vaccine-induced antibody responses?