Modulation of immune responses to vaccination by the microbiota: implications and potential mechanisms

Abstract

The need for highly effective vaccines that induce robust and long-lasting immunity has never been more apparent. However, for reasons that are still poorly understood, immune responses to vaccination are highly variable between different individuals and different populations. Furthermore, vaccine immunogenicity is frequently suboptimal in the very populations who are at most risk from infectious disease, including infants, the elderly, and those living in low-income and middle-income countries. Although many factors have the potential to influence vaccine immunogenicity and therefore vaccine effectiveness, increasing evidence from clinical studies and animal models now suggests that the composition and function of the gut microbiota are crucial factors modulating immune responses to vaccination. In this Review, we synthesize this evidence, discuss the immunological mechanisms that potentially mediate these effects and consider the potential of microbiota-targeted interventions to optimize vaccine effectiveness.

The intestinal microbiota and improving the efficacy of COVID-19 vaccinations

“…The composition of the intestinal microbiome and its physiological functions have close links to host health, metabolic diseases as well as aging ( Turroni et al, 2009 ). The intestinal microbiota is well-known to be associated with the development of immune cells and maintenance of adequate immune responses ( Lynn et al, 2021 , Vitetta et al, 2017 ). An important distinghuishing feature of the aging intestines is the over-expression of pro-inflammatory activity such as cytokine IL-6 which has an adverse effect on the function of the intestinal barrier and the mucosal immune system ( Man et al, 2015 ).…”

“…Gut dysbiosis has been associated with the severity of COVID-19 caused by many risk factors ( Chen, J. et al, 2021 ). Indeed, the roles of the gut microbiota in immune responses to vaccination against viruses other than SARS-CoV-2 have been well demonstrated in both animal experiments and clinical studies ( Lynn et al, 2021 , Vitetta et al, 2017 ). In animal models, germ-free (GF) mice or antibiotics-treated mice had decreased immune responses in various aspects.…”

“…In humans, the roles of the gut microbiota in vaccine efficacy have been evidenced by various approaches. The same vaccines elicited different responses in lower middle income countries (LMICs) and high income countries (HICs) and the low efficacy in LMICs was accounted for by gut dysbiosis in the populations ( Lynn et al, 2021 ). Gut dysbiosis in infants with short-term breast-feeding, malnutrition and diarrhea was linked with the lower efficacy of oral polio vaccines ( Haque et al, 2014 ).…”

“…The mechanisms for the roles of gut microbiota in vaccine efficacy have been attributed to pattern recognition receptors (PRRs) of antigen presenting cells activated by gut bacterial molecules such as flagellin and peptidoglycan ( Lynn et al, 2021 ). PRRs are abundant in innate immune cells, which will respond to stimuli rapidly once activated by gut bacterial molecules (i.e., termedimmune training) ( Smith et al, 1988 , Yakabe et al, 2021 ).…”

“…Based on the effects that the gut microbiota has on the efficacy of vaccines against various microbes and the role of dysbiosis in the severity of COVID-19, it is not surprising that the gut microbiota may be critical for the efficacy of COVID-19 vaccinations ( Ferreira et al, 2020a , Stefan et al, 2021 ) and that gut dysbiosis could reduce COVID-19 vaccine efficacy ( Lynn et al, 2021 ). It has been proposed that the vulnerable population that presents with severe COVID-19 and high mortality should be vaccinated with priority ( Leong et al, 2021 , Russo et al, 2021 , Wingert et al, 2021 ).…”