Vaccines are the most effective means available for preventing infectious diseases. However, vaccine-induced immune responses are highly variable between individuals and between populations in different regions of the world. Understanding the basis of this variation is, thus, of fundamental importance to human health. Although the factors that are associated with intra- and inter-population variation in vaccine responses are manifold, emerging evidence points to a key role for the gut microbiome in controlling immune responses to vaccination. Much of this evidence comes from studies in mice, and causal evidence for the impact of the microbiome on human immunity is sparse. However, recent studies on vaccination in subjects treated with broad-spectrum antibiotics have provided causal evidence and mechanistic insights into how the microbiota controls immune responses in humans.
Humans are inhabited by trillions of diverse microorganisms, known collectively as the microbiome. The terms microbiome and microbiota are often used interchangeably, with the former referring to the aggregate of genomes from all the microorganisms in the body and the latter referring to the specific microorganisms contained in the body. In addition to bacteria, the microbiota also consists of viruses, fungi, protozoa, and archaea (Pfeiffer and Virgin, 2016; Robinson and Pfeiffer, 2014). The microbiota performs a wide range of essential and beneficial functions, including controlling mucosal immunity, breaking down nutrients, and preventing pathogen colonization (Kundu et al., 2017). The colonization of microbes starts at birth and continues through the first years of life, establishing a symbiotic relationship with the host that lasts a lifetime. The impact of the microbiota on the immune system is well established and has been reviewed elsewhere (Belkaid and Hand, 2014; Belkaid and Harrison, 2017; Levy et al., 2017).Research during the past decade using animal models has revealed a major impact of the microbiota on diverse physiological processes such as metabolism (Nicholson et al., 2012; San-Cristobal et al., 2020; Sonnenburg and Bäckhed, 2016), cardiovascular function (Zhao and Wang, 2020), central nervous system function (Carabotti et al., 2015) as well as on susceptibilities to inflammatory disorders, such as allergic (Mitre et al., 2018; Patrick et al., 2020) and autoimmune diseases (Kostic et al., 2014; Scher et al., 2013). The microbiota has also been linked to the efficacy of anti-programed cell death protein 1 (anti-PD-1)-based cancer immunotherapy (Gopalakrishnan et al., 2018; Routy et al., 2018).Despite growing evidence of a connection between the microbiota and the immune system, its impact on immunity to vaccination remains poorly understood. Recent studies have demonstrated a profound impairment in vaccine-induced antibody responses during microbiota perturbation. Yet, much of this evidence comes from studies in animal models, such as germ-free mice or mice treated with antibiotics. Even though vaccines and antibiotics represent the most widely used and important public health interventions, surprisingly little is known about the interaction between them. In this review, we discuss the impact of the microbiota on vaccine immunogenicity and efficacy. This review will primarily focus on gut bacteria, as this is by far the most studied aspect of the microbiota.First, we summarize the known knowns and known unknowns about how the microbiota, which is widely distributed in diverse tissues, can act locally or at distal sites in the body. Then, we discuss how vaccine efficacies vary in populations throughout the world and between individuals and consider the ways in which the microbiota could contribute toward this variation. Much of the experimental evidence for this comes from studies in mice and correlative studies in humans but establishing causality in humans has been challenging. However, emerging studies using systems vaccinology approaches to study vaccine responses in healthy humans that were given antibiotics are providing causal evidence for the role of the microbiota on human immunity (Hagan et al., 2019). We discuss these studies and the mechanistic insights into how the microbiota controls the immune system. We conclude by considering the major challenges that need to be addressed to understand the complex and dynamic interplay between the human microbiota and the host response to vaccines, especially in the very young and the very old, and how this knowledge can be exploited to advance novel vaccines.
Games Microbiota Play
Microbial communities are widely distributed in the gut, lung, skin, and other epithelial surfaces. The microbiota can influence host responses locally at the site, or act at a distance, and exercise profound systemic influence (Figure 1A). This, in turn, could potentially impact immune responses to vaccination. The mechanisms by which the microbiota exerts local or systemic effects are considered below.
Figure 1The Microbiota Exerts Local and Global Immune Influence Through a Variety of Mechanisms
Concept 1: Acting Locally
Gut Microbiota
The alimentary canal presents a very diverse set of niches for colonization by the microbiota. Local interaction with the immune system primarily occurs in the small and large intestines, which harbor large numbers of B and T cells as well as antigen-presenting cells. These cells can detect many of the biomolecules produced by the microbiota, including short-chain fatty acids (SCFAs) (Macia et al., 2015), tryptophan metabolites (Li et al., 2011), bacterial DNA (Hall et al., 2008), vitamin A (Al Nabhani et al., 2019), sphingolipids (An et al., 2014), polysaccharide A (Mazmanian et al., 2005), and muramyl dipeptide (Jiang et al., 2013). Some of these compounds are passively or actively transported across the epithelial lining of the gut and can be detected and acted upon by immune cells in the lamina propria. Antigen-specific immunity is generated by dendritic cells that continuously sample the intestinal lumen (Macpherson and Uhr, 2004), and even simple bacterial cell adhesion to the gut epithelium has the potential to modulate the immune system (Atarashi et al., 2015). Naturally, the responses to such stimuli are context dependent and have the potential to elicit complex changes in the gut immune system.Imprinting of the gut immune system by the microbiota might also affect its capabilities to respond to pathogens. The most commonly administered oral vaccines are live-attenuated versions of microorganisms that replicate in the gastrointestinal tract, such as polio, cholera, typhoid fever, and rotavirus. Understanding the local interplay between gut microbiota and the immune system is vital to improve the efficacy of oral vaccines. Oral and systemic antibiotics can also have a profound effect on the gut microbiome and therefore potentially on responsiveness to (oral) vaccines. Consistent with this idea, low microbiota diversity early in life has been associated with differences in immune phenotype (Olin et al., 2018) and differences in gut microbiota composition have been correlated to vaccine response (discussed below).
Skin Microbiota
Compared with the gut, the community of skin microbes is less diverse and are fewer in number. However, there is still communication with the skin immune system. Bacterial cues from the skin can trigger interleukin-1 (IL-1) signaling (Naik et al., 2012) and steer the recruitment of innate lymphoid cells (Kobayashi et al., 2019). Identifying specific signals has been difficult, but the secretomes of Staphylococcus epidermidis and Staphylococcus aureus provoked opposing effects on immune activation, indicating phylum-specific effects (Laborel-Preneron et al., 2015). Lipopeptides binding the Toll-like receptor-2/6 (TLR-2/6) heterodimer have also shown to be immunosuppressive in this context (Skabytska et al., 2014). Microbiota-host interaction at the skin has the potential to modify immune function, as illustrated by the connection between the microbiota and various immune-related skin disorders (Stacy and Belkaid, 2019) and could potentially impact immunity to vaccination.
Airway Microbiota
While the lungs were long believed to be sterile, sequencing-based methods and new techniques of bacterial cell culture have revealed that the luminal surface harbors a microbiota, albeit a less diverse one than that of the gut (Dickson et al., 2016). So far, the live-attenuated influenza vaccine is the only vaccine administered through the intranasal route. However, several vaccines for respiratory pathogens, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are being developed (World Health Organization, 2020), and will require the appropriate quality and quantity of mucosal antibody response, and T cell response in the lung, to be effective. These mucosal responses could conceivably be influenced by the lung microbiota. For example, plasma cells and tissue-resident memory T cells (TRMs) in the lung may derive signals from lung bacterial products that enhance their survival and/or function. In this context, our recent study demonstrates that TRMs in the vaginal tissues provide signals to neighboring cells, including myeloid cells, to enhance antiviral responses in such cells (Arunachalam et al., 2020). The extent to which the local microbiota could impinge on such TRM-innate interactions and whether such interactions are pervasive in other tissues remain to be seen.
Concept 2: Acting Globally
In addition to affecting their local milieu, microbes can also influence immune reactions in anatomical locations distal from the site of colonization. This can conceivably happen through several mechanisms (Figure 1B): (1) translocation of bacterial products, such as lipopolysaccharides (LPSs) from mucosal sites to the systemic circulation (Sandler and Douek, 2012), (2) a “domino effect” mechanism, where signals from the microbiota are delivered to cells in the vicinity, which then circulate throughout the body and relay this information (perhaps through cytokines, metabolites, or other molecules), and (3) via dissemination of microbiota-derived metabolites (metabolite second messenger model). Consistent with this idea, microbiota-derived metabolites can be identified in various tissues and, thus, have the potential to be detected by the immune system at those sites (Uchimura et al., 2018).
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