Abstract
The resident microbial consortia of the human gastrointestinal tract play an integral role in modulating immune responses both locally and systemically. However, detailed information regarding the effector immune responses after vaccine administration in relation to the gastrointestinal microbiota is absent. In this study, the licensed oral live-attenuated typhoid vaccine Ty21a was administered in a clinical study to investigate whether oral immunization resulted in alterations of the microbiota and to identify whether a given microbiota composition, or subsets of the community, are associated with defined S. Typhi-specific immunological responses. The fecal microbiota composition and temporal dynamics were characterized using bacterial 16S rRNA pyrosequencing from individuals who were either immunized with the Ty21a typhoid vaccine (n = 13) or served as unvaccinated controls (n = 4). The analysis revealed considerable inter- and intra-individual variability, yet no discernible perturbations of the bacterial assemblage related to vaccine administration were observed. S. Typhi-specific cell mediated immune (CMI) responses were evaluated by measurement of intracellular cytokine production using multiparametric flow cytometry, and humoral responses were evaluated by measurement of serum anti-LPS IgA and IgG titers. Volunteers were categorized according to the kinetics and magnitude of their responses. While differences in microbial composition, diversity, or temporal stability were not observed among individuals able to mount a positive humoral response, individuals displaying multiphasic CMI responses harbored more diverse, complex communities. In line with this preliminary observation, over two hundred operational taxonomic units (OTUs) were found to differentiate multiphasic and late CMI responders, the vast majority of which classified within the order Clostridiales. These results provide an unprecedented view into the dramatic temporal heterogeneity of both the gut microbiota and host immune responses.
Highlights
Using the naıve Bayesian classifier with the Greengenes database implemented within mothur [17,18], a total of 164 genera were identified from 13 separate phyla, with 15 of these genera appearing at $2% abundance in at least two samples (Fig. 1)
With the caveat of small sample size, we identified that multiphasic cell-mediated immunological (CMI) responders harbored significantly greater diversity in all three measures of community diversity compared to the late CMI responders (Fig. 5)
Summary There is growing support from clinical trials in developing countries that the gastrointestinal microbiota can impact the efficacy of a given vaccine [12], as well as evidence in animal models that modulation of the gastrointestinal microbiota can enhance vaccine efficacy [15,16]
Summary
Typhi), the causative agent of typhoid fever, is responsible for over 20 million illnesses and .200,000 deaths worldwide, and continues to be a major health concern in developing countries, because of the emergence of antibiotic-resistant strains [1,2]. Typhi antigens (e.g., lipopolysaccharide O, H antigen), as well as a wide array of specific cell-mediated immunological (CMI) responses [5,6,7,8,9,10]. CMI responses are believed to play a key role in the host’s defense against this intracellular bacterium by several mechanisms (e.g., cytokine production, killing of infected cells) and detailed kinetic studies have shown that multiphasic CMI responses are characteristic in responders following Ty21a vaccination [4,7,11]. The overall protective efficacy of Ty21a has been demonstrated to range substantially from 35–96% in field studies depending on the formulation, dosing schedule (three to four doses are necessary for vaccination with Ty21a), and duration of follow-up post-vaccination [4,11]
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