Microbiota, a forgotten relic of vaccination

KEYWORDS:

• Vaccine
• microbiota
• immune response
• protection

1. Introduction

Human microbiota develops in the first couple of years after birth and is influenced significantly by environmental parameters such as delivery, diet, breast-feeding, geographical region, etc. The established microbiota influences the host physiology, pathophysiology, and both the innate and adaptive immune systems. Variability in microbiota that establishes and the different impact it has on the host’s evoked immune response may provide some explanation about the variation of vaccine efficacy in developed versus developing countries.

Several studies suggested that the microbiota may influence vaccine efficacy. However, the investigations into the role, mechanism, and optimal composition of microbiota on suitable induction of protective immune response by vaccines are still in the early stage. It is also not clear how the gut microbiota affects the response to vaccination and how vaccination may in turn influence gut microbiota. This is important when we consider that most commercialized vaccines are administered during childhood before the complete maturation of both the microbiome and the immune system. Various types of microbiota in each geographical population might be a reason for the variation of protective efficacy of vaccines; however, this important aspect has not been fully evaluated by vaccine manufacturers/organizations. A better understanding of the impact of microbiota on the host immune system prior to and after vaccination may lead to more optimally designed vaccines and vaccine scheduling in the future.

2. Microbiota and vaccines

The human body is the habitat for enormous numbers of microorganisms, communally called microbiota. Microbiota exists on both external and internal surfaces of body with the largest and greatest diversity of microbes in the gastrointestinal (GI) tract [1–4]. Recent findings have begun to shape our understanding of the critical role of gut microbiota in response to vaccines and susceptibility to infections. The microbiota plays an important role on the function of host immune system by contributing to the maintenance of mucosal homeostasis and defense against pathogens [5,6]. It has been shown that the establishment of different types of gut microbiota during the first 2 years of human life directly correlates with the development of mucosal IgA responses [7]. The role of gut microbiota in the development of the immune system has primarily been studied in several animal models. Mouse studies have shown that diversity of gut microbiota enhances the progenitor B cells in the lamina propria and assists in proliferation of B cells in the gut-associated lymphoid tissue [8,9]. B cells in the GI tract generate mucosal IgA and activate T-cell-dependent and T-cell independent pathways that target different commensal microorganisms. In a study performed by Seekatz et al. [10], macaques from different geographical regions were immunized with live attenuated Shigella dysenteriae vaccine and challenged afterwards with virulent Shigella dysenteriae. Mauritian macaques with the highest type II diversity community did not develop clinical shigellosis symptoms following challenge. The authors suggest that a more diverse intestinal microbiota enhances protective efficacy against enteric pathogens [11]. Several important parameters including the host genetic background, competitive exclusion, and the type of microbiota were not considered during this vaccine study. Although various animal studies showed that the microbiota limits colonization of bacterial pathogens, the effect of bacteria on enteric viruses is not still well understood. In a study by Kuss et al. [12], the effect of microbiota on poliovirus infection was studied in a mouse model. Animals were treated with antibiotics and the depletion of bacterial and viral loads were subsequently monitored. The intestinal bacteria in treated mice with antibiotics were reduced by a million-fold compared to the non-treated animals. Furthermore, the prevalence of poliovirus disease was increased in treated animals after exposure to fecal bacteria [12]. In an interesting study, it was shown that Drosophila is resistant to oral infection by variety of viruses [13,14]. This may be due to the fact that the microbiota in Drosophila limits infection through two signaling pathways. The first pathway is initiated by specific members of the microbiota by activation of NF-κB through the IMD pathway. In the second pathway, NF-κB is activated through Cdk9-dependent events following viral infection. The induction of NF-κB in these two pathways triggers the expression of Pvf2 which eventually activate ERK signaling and resulting in an antiviral state. These findings provide insight into how the gut microbiota limits not only bacteria but also viral infections.

Although the role of human inessential microbiota has been less studied, the importance of microbiota in inducing a protective response following vaccination has been shown in a few human clinical trials. It has been indicated that the immune response to oral polio and rotavirus vaccines in children of low-income countries is less than that of developed countries [15]. For instance, only 58% of Nicaraguan children and 46% of Bangladeshi children respond to oral rotavirus vaccine while the efficacy of the vaccine in Finland is over 98% [11,16,17]. In India, poliovirus transmission is currently under control; however, it was shown that over 77% of Indian children required several doses of oral polio vaccine for effective induction of a protective immune response against polio infection [18]. In two oral Salmonella vaccine studies performed in south-central and south-east Asia, the effectiveness of vaccines were varied, impacting population health in those regions [19,20]. The commercialized oral live-attenuated typhoid vaccine Ty21a was administered to 13 individuals and the composition of fecal microbiota were characterized using bacterial 16S rRNA pyrosequencing. The humoral and cell-mediated immune responses were also measured by evaluation of sera anti-LPS IgA and IgG titers and intracellular cytokine production, respectively. The results from these studies suggest that individuals with greater gut microflora diversity are able to generate stronger cell-mediated immune responses following vaccination. However, the predominant type of microbiota was not determined in this study.

In another study, the stool microbiota of 48 Bangladeshi infants was analyzed and demonstrated that the specific immune responses to oral polio, Bacille Calmette-Guérin (BCG), tetanus toxoid, and hepatitis B virus vaccines are positively correlated with Bifidobacterium abundance, a gram-positive bacteria which inhabits the healthy GI tract of infants [21]. Subjects whose intestinal microbiota is dominated by Bifidobacterium demonstrated a broader level of adaptive immune response to vaccinations. On the other hand, infants with higher ratios of Enterobacteriales, Pseudomonadales, and Clostridiales in their intestinal microbiota exhibited lower immune response to vaccination [21]. The predominance of Bifidobacterium may assist in thymic development, increasing immune responses to vaccines in infants. However, elimination of this bacterium and intestinal habitants by other diverse bacteria causes systemic inflammation (neutrophilia) which subsequently reduces vaccine responses. These results suggest that the type of microbiota diversity may be more crucial in enhancement of immune response following vaccination. Environmental parameters, maturity of the immunological immune system, interference of maternal antibodies, genetic parameters including HLA type, socioeconomic challenges, and last but not least the type, diversity, quantity, and quality of gut microbiota are plausible contributors to the variable efficacy of vaccines. In an interesting study by Dethlefsen et al. [22], three healthy volunteers that received ciprofloxacin demonstrated a significant loss of microbial diversity during treatment. The diversity of the microbiota in these individuals returned to normal in a few weeks; however, some bacterial taxa were eliminated for a period of 6 months. In attempting to boost the immune system after vaccination, there may be a way to ‘optimize’ the microbiota in order to elicit a stronger response to vaccination. Several studies have shown that probiotics affect the gut microbiota and alter the mucosal and systemic immune responses by enhancing both β-defensin and IgA [23–25]. However, adverse to these effects, the enhancement of the immune system might also modify metabolic pathways such as carbohydrate metabolism or in some cases cause certain diseases. We strongly encourage conducting further studies in order to fully understand how the microbiota composition shapes immune responses to vaccination. A better understanding of how different compositions of gut microbiota interact with various immune cells could open new insights into vaccine design.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Additional information

Funding

The manuscript was not funded.