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.

Conflict of interest statement

D.J.L. receives funding from GlaxoSmithKline as part of a collaborative research agreement in this area. B.P. serves on the External Immunology Network of GlaxoSmithKline and is on the scientific advisory board of Medicago. S.C.B. and M.A.L. declare no competing interests.

© 2021. Springer Nature Limited.

Figures

Fig. 1. Differences in the composition and functional capacity of the gut microbiota between low-income and high-income countries correlate with differences in vaccine immunogenicity.

Highlighted are example studies that have compared vaccine immunogenicity in individuals from low-income and middle-income countries (LMICs; red, orange and yellow) to those living in high-income countries (HICs; purple); see Table 1 for further details. The data for oral vaccines having reduced immunogenicity in LMICs are particularly convincing but further work is required to confirm whether responses to parenteral vaccines are impaired in LMICs as many of the reports so far are based on post hoc analyses of independent cohorts. Intriguingly, reported differences in vaccine immunogenicity correlate with differences in the composition and functional capacity of the gut microbiota between these populations. Classifications of income status are based on data from the World Bank, which within the broad category of LMICs, classifies countries as low income (red), lower-middle income (orange) and upper-middle income (yellow). BCG, Bacillus Calmette-Guérin; DTP–HepB–Hib, diphtheria, tetanus, pertussis–hepatitis B virus–Haemophilus influenzae type B; IFNγ, interferon-γ.

Fig. 2. Factors with the potential to influence vaccine immunogenicity and/or efficacy.

A range of intrinsic host factors (such as age, sex, genetics and comorbidities) and extrinsic factors (such as perinatal, nutritional, environmental and behavioural factors) have been suggested to influence vaccine immunogenicity and/or efficacy (reviewed in detail in ref.). The influence of these factors on vaccine immunogenicity is likely mediated indirectly via the effects of these factors on baseline immunity and/or the composition of the microbiota. Vaccine immunogenicity is also, of course, dependent on vaccine-intrinsic factors such as the adjuvant used, and vaccine efficacy may be influenced by factors other than vaccine immunogenicity such as the degree of match between the vaccine and the strains circulating at the time.

Fig. 3. Differences in the gut microbiota of infants and the elderly compared with that of young adults correlate with altered immune status and suboptimal vaccine immunogenicity.

a | The composition of the gut microbiota in early life is unstable and has low levels of diversity, with a small number of bacterial families tending to dominate. Over time, the diversity of the gut microbiota increases until an adult-like composition is reached between 2 and 3 years of age. The adult gut microbiota is more complex than in infancy (higher levels of diversity) but is also more homogeneous between individuals and, in the absence of external perturbations (such as antibiotics), is generally quite stable. b | As people age, the diversity and stability of the gut microbiota decline. There is also an increased relative abundance of the inflammation-associated Proteobacteria and a decrease in Actinobacteria. c | The composition of the gut microbiota can strongly influence immune function and the baseline status of the immune system at the time of vaccination. Baseline immune status has been shown to be predictive of responses to vaccination in several studies. An in-depth discussion of other factors that influence changes in immune status with ageing is outside the scope of this Review. d | Compared with healthy adults, vaccine immunogenicity is poorer in infants and in the elderly. Increasing data suggest causal links between these phenomena.

Fig. 4. Potential mechanisms by which the microbiota could modulate vaccine immunogenicity and efficacy.

a | Immunomodulatory molecules produced by the microbiota, such as flagellin and peptidoglycan, have been shown in animal models to modulate vaccine responses by providing natural adjuvants that are sensed by pattern recognition receptors (PRRs), such as Toll-like receptors (TLRs) and NOD2, expressed by antigen-presenting cells. Other immunomodulatory molecules, such as lipopolysaccharide, may also similarly modulate responses. PRRs expressed by T cells and B cells may also sense these molecules directly. b | Dendritic cells (DCs) have a crucial role in immune responses to vaccination by presenting vaccine antigens to T cells and secreting immunomodulatory cytokines. The microbiota regulates the production of type I interferons by plasmacytoid DCs (pDCs), which in turn instruct a specific metabolic and epigenomic state in conventional DCs (cDCs) that enhances T cell priming. c | Immunomodulatory metabolites produced by the microbiota, such as short-chain fatty acids (SCFAs), can enhance B cell metabolism to support the energy demands of antibody production and can increase the expression of genes involved in plasma cell differentiation and class switching, potentially altering responses to vaccination. d | Increasing data suggest that the microbiota can encode epitopes that are cross-reactive with pathogen-encoded or vaccine-encoded epitopes. The presence of cross-reactive B cells or T cells could potentially alter the responses to vaccination.