Do our own bugs determine our response to vaccines? – Likely yes!

From the Kublin lab, Vaccine and Infectious Disease Division

What determines whether a vaccine is going to be effective at protecting us against disease? In a recent paper in the Journal of Immunology, Dr. Jim Kublin and his research team identified an unexpected role of the microbiome in regulating immune responses elicited by nucleic acid vaccines.

Whether it’s your annual flu shot or the jabs you got as a kid, vaccines are among the most effective tools for protecting us against disease. Vaccines work by introducing a small part of a pathogen, such as a protein, or a weakened version of a pathogen into our bodies. Our immune system then detects this as foreign and produces antibodies which bind to the pathogen and prevent it from causing an infection. Recently, nucleic acid vaccines, made with DNA or mRNA, have emerged as a new technology that offer significant benefits over traditional protein-adjuvant approaches. These include rapid adaptability to new pathogens, such as SARS-CoV-2 (COVID-19) and triggering an antibody response as well as a cellular immune response involving T cells, a type of immune cell that kills infected cells. The importance of nucleic acid vaccines was  highlighted by this year’s Nobel Prize in Physiology or Medicine, awarded in part to Drew Weissman, co-author on this paper, for discoveries which unlocked their potential. Nucleic acid vaccines are therefore promising tools in the fight against existing pathogens for which effective vaccines don’t exist, emerging pathogens in the future, and possibly even cancer.

Despite numerous vaccine success stories, there are plenty of failed vaccines since vaccine effectiveness is frustratingly hard to predict. DNA vaccines have shown considerable promise in preclinical studies but have so far not translated to sufficiently strong immune responses in humans. The determinants of vaccine response remain poorly understood, especially for nucleic acid vaccines but likely involve a variety of independent factors such as age, genetics, nutrition, and previous infections.

Immune responses from DNA and mRNA vaccines are differentially regulated by gut microbes in mice.
Immune responses from DNA and mRNA vaccines are differentially regulated by gut microbes in mice. Figure provided by Dr. Kublin.

The Kublin lab is particularly interested in how the microbiome (the variety of bacteria, viruses and fungi that live on and inside our body) regulates vaccine responses. “There has been much effort to understand how the microbiome impacts the immune system and susceptibility to disease,” said Dr. Kublin. Previously, there was not any evidence supporting that “microbial exposure contributed in any way to nucleic acid vaccine responses.” Making use of the UW Gnotobiotic Facility accessed via the Cancer Consortium, the Kublin research team found that the presence or absence of specific gut microbes in mice influences nucleic acid vaccine responses and that microbes affect DNA vaccines and mRNA vaccines in distinct ways. For example, microbiota suppressed both antibody and cellular immune responses to a DNA vaccine against HIV whereas they enhanced the cellular response to a SARS-CoV-2 mRNA vaccine.

Looking to the future, these findings raise important questions of how nucleic acid vaccines are processed once inside the body and how signals coming from the microbiome affect immune responses to vaccines. “Investigating how microbial exposure impacts these responses may shed light on how better to improve the immune response and reduce adverse reactions” says Dr. Kublin. One key difference between DNA and mRNA vaccines is where in the cell the vaccines are processed. DNA vaccines must travel to the nucleus where transcription occurs whereas mRNA vaccines are processed directly in the cytoplasm. Understanding how our immune system recognizes and processes nucleic acid vaccines formed the basis of this year’s Nobel Prize to co-author Drew Weismann, and furthering our understanding of the impact of microbes on these processes will be critical for improving vaccine responses. So far, these studies have only been performed in mice, although associations between vaccine response and microbiota composition have been observed in humans. But perhaps in the future we will be downing a probiotic shot before getting our annual flu shot!

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

Fred Hutch/University of Washington/Seattle Children's Cancer Consortium members James G. 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. The Regulation of Nucleic Acid Vaccine Responses by the Microbiome. J Immunol. 2023