Structural and Host Factors Influencing Vaccine Responses
CitationSun, Ximei. 2019. Structural and Host Factors Influencing Vaccine Responses. Doctoral dissertation, Harvard University, Graduate School of Arts & Sciences.
AbstractVaccines represent a promising strategy not only against bacterial infections, but also against other diseases, including viral infections and cancer. The immunogenicity of vaccines can be influenced by various factors, from vaccine composition (antigen and adjuvant selection) to host factors (genetics, age, microbiota).
There are two parts to this study. In the first part, we have explored the immunological mechanism underlying the response to different glycoconjugate vaccines. Particularly, we found that antibody response to glycoconjugate of group C polysaccharide of Neisseria meningitidis (MenC) is not regulated by carbohydrate-specific T cells (Tcarbs), a newly identified subset of helper T cells, that are essential to elicit effective antibody responses to several glycoconjugate vaccines. In addition, we showed that in the endolysosome, MenC is markedly reduced in size to monomers by oxidation and acidic hydrolysis. As a result, the processed sugar cannot be recognized by T-cell receptors as an antigen independent of the peptide. Overall, this part of the study emphasizes the diversity of bacterial polysaccharides in terms of their interaction with the immune system and the coexistence of at least two mechanisms governing adaptive immune responses to glycoconjugates.
In the second part of the study, we elucidated the positive effects of a healthy microbiota on responses to systemic immunization with adjuvanted vaccines. We observed a marked reduction of IgG responses to several adjuvanted vaccines in Swiss Webster (SW) germ-free (GF) mice and antibiotic-treated SW mice. Interestingly, we also found different level of antibody responses in SW mice from different facilities. The differences can be vertically transferred to GF mice when given the respective fecal samples. The results indicate that microbiota composition is critical in regulating vaccine responses in SW mice. In addition, we uncovered another layer of complexity, where genetic background determines whether the microbiota is involved in the regulation of responses to adjuvanted vaccines. We observed no significant differences in specific IgG responses between GF and SPF inbred (C57BL/6J, BALB/c) mice. In summary, we propose that, in future mouse studies and vaccine trials, it will be critical to stratify individuals according to their microbiota profiles as well as host genetic influences.
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