Is the microbiome a springboard or barrier to effective vaccination?

From the Kublin Lab, Vaccine and Infectious Disease Division

During the recent SARS-CoV-2 pandemic, DNA, mRNA, and protein subunit-based vaccines were rapidly developed to combat COVID-19 disease. But how might responses between these vaccine types differ and which (if any) are optimal to consistently prevent disease? These questions represent critical steppingstones for vaccine design and distribution to best address each disease, now and in the future. It has been shown that the microbiome, or one’s viral and bacterial community, can affect the response to vaccination. The Kublin Lab sought to assess immune responses elicited by various vaccine platforms (protein, DNA, and RNA) and elucidate their regulation by the microbiome. While the microbiome had little effect on immune responses to protein adjuvant subunit vaccines, the researchers observed that the endogenous microbiome suppressed immune responses to vaccination with a DNA plus protein-boost vaccine regimen while a contrasting effect was observed, microbe-dependent immune enhancement, in mice vaccinated with an mRNA platform vaccine. Thus, the role of the microbiome in nucleic acid vaccine-induced immune responses represents a two-sided coin. These findings are available on bioRxiv.

Vaccines are routinely used to elicit an immune response to a pathogen (virus, bacteria, or bacterial toxin) to give your body a “leg up” when encountering these biological assailants at a later time. Vaccines come in several different flavors that include proteins, DNA and/or RNA alone or in various combinations. Nucleic acid (DNA or RNA) based vaccines have several potential advantages that include enhanced activation of certain anti-viral immune responses, quicker and more flexible vaccine design and cost-effective production compared to protein only platforms. While many vaccines prevent major disease to numerous pathogens, variability in immune activation between individuals exists. This confounding factor limits our ability to predict vaccine efficacy. Several determinants of immune response regulation include the age and genetics of an individual as well as nutrition, past microbial infections and one’s microbiome, or bacteria and viruses that colonize our bodies, predominantly the skin and mucosal surfaces. The Kublin lab was particularly interested in determining if different vaccine platforms vary in their susceptibility to microbiome regulation of immune activation.

“We explored a spectrum of microbiomes, from germ free [GF] to microbial communities found among the wild-like mice,” commented Dr. James Kublin. This spectrum included GF mice raised in the absence of bacteria, specific-pathogen-free (SPF) raised in the presence of bacteria, but with murine pathogens excluded, and lastly GF mice deliberately colonized with the microbiome from “wild-like” mice or with a microbial consortia designed for immune-stimulation. “In these gnotobiotic mice, we characterized immune responses from various nucleic acid and protein vaccine platforms including multiple adjuvants [or factors that activate the immune response] and have found some illuminating trends,” stated Dr. Kublin. “The vaccines used include an mRNA vaccine that is very similar to the Moderna COVID-19 vaccine, a DNA vaccine against HIV that has been tested in clinical trials, as well as several protein-adjuvant vaccines that include either HIV gp120 or a model Ovalbumin protein,” added Dr. Andrew Johnson, a staff scientist in the Kublin lab. SPF mice had an enhanced T cell response to the mRNA vaccine compared to GF mice, which was especially apparent by increased antigen-responsive IFN-γ-, TNF-α- and IL-2-producing CD8 T cells. These observations indicate that the immune response to this mRNA vaccine platform is enhanced by the microbiome. In contrast, SPF mice had reduced CD4+ T cell and antibody responses to a combined DNA-protein HIV vaccine regimen compared to GF mice, indicating suppression of this vaccine platform by the microbiome. Differing from these microbiome-influenced responses to nucleic acid vaccines, the responses of SPF and GF mice to protein-adjuvant vaccines (in the absence of DNA or mRNA) were not significantly different. These findings uncover different effects of the microbiome on each of these vaccination platforms.

“In mRNA vaccinated mice, the SPF microbiome promoted pathways associated with myeloid cell activation and Type-I IFN responses, which is an important regulator of antiviral immunity, and may underlie the different effects of the microbiome on T cell responses induced by RNA and DNA vaccine platforms,” commented Dr. Johnson. These findings have potential “implications for the intranuclear and cytosolic processing of these platforms”, mainly a possible block in immunogen transcription for DNA-based vaccines that is bypassed in the case of mRNA-based vaccines, “and the induction of effective immunity,” added Dr. Kublin.

Spleen cells harvested from vaccinated mice, germ free (GF) or specific-pathogen-free (SPF), were re-stimulated with spike peptides. Mice with established microbiomes had enhanced CD8+ T cells producing IFN as compared to germ free mice.
Spleen cells harvested from vaccinated mice, germ free (GF) or specific-pathogen-free (SPF), were re-stimulated with spike peptides. Mice with established microbiomes had enhanced CD8+ T cells producing IFN as compared to germ free mice. Image modified from primary article

“We are very excited about these data which are the result of some real arduous work under various gnotobiotic conditions,” stated Dr. Kublin. “Some of these findings may lead to a deeper understanding of the foundational mechanisms of these platforms and how to improve on critical parameters such as durability and breadth of response. We’re continuing to explore these trends with other mRNA platforms such as self-amplifying mRNA and other modified DNA strategies” and “investigating the associations in clinical trials between the microbiome and nucleic acid vaccine responses. Ultimately, we would like to see these platforms improved and further simplified, for example to remove cold-chain requirements,” which would increase the accessibility to vaccines.

The spotlighted research was funded by the National Institute of Allergy and Infectious Diseases.

Fred Hutch/University of Washington/Seattle Children's Cancer Consortium member Jim Kublin contributed to this work.

Johnson AMF, Hager K, Alameh MG, Van P, Potchen N, Mayer-Blackwell K, Fiore-Gartland A, Minot S, Lin PJC, Tam YK, Weissman D, Kublin JG. 2023. The Regulation of Nucleic Acid Vaccine Responses by the Microbiome. bioRxiv. 2023.02.18.529093.