Improving T-cell responses to vaccines

In the quest to design vaccines that better help the body’s immune system fight disease, scientists are always looking for more tools for their arsenal. The strong antibody responses generated by vaccines provide an important first round of defense, but “you always want to have a backup plan,” says Biomedical Graduate Studies Ph.D. student Emily A. Aunins, considering viruses mutate to evade antibody responses that become widespread in a population. T-cells, however, vary more between people and can still respond to reinfection and mutated viruses.

But scientists also continue to seek ways to improve T-cell responses so the benefits of vaccines last longer. One avenue is adjuvants, substances that increase the efficacy of treatments. In a new study, researchers from the School of Veterinary Medicine, Perelman School of Medicine, and Children’s Hospital of Philadelphia tested the effects of adding interleukin-12 (IL-12)—a cytokine, or type of protein, that is produced by various immune cells—to vaccines in mice.

They found that this enhanced responses from CD8+ T-cells—white blood cells that aid in the body’s immune response by killing harmful cells—against SARS-CoV-2 and influenza, and that it improved protection against melanoma and listeria infection. Their findings are published in Science Immunology.

IL-12 is naturally produced by the body in response to many infections, and researchers have utilized IL-12 as a vaccine adjuvant to promote immunity against parasitic, viral, and bacterial infections.

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Designing vaccines that induce strong responses from CD8+ T-cells has historically been a challenge. But mRNA vaccines changed the game, says Penn Vet professor Christopher A. Hunter, senior author on the paper. Data from the last four years show that people who generate strong T-cell responses from the mRNA-based COVID vaccines are less likely to get breakthrough infections or become hospitalized if they do.

One practical aspect of an IL-12 mRNA vaccine “is being able to reduce the frequency and amount of vaccine. Anything that can be used to reduce injection frequency and dose-related adverse events is a good thing, and so this allows us to think about that as a strategy,” says Anthony T. Phan, a research associate in Hunter’s laboratory and co-lead author with Aunins. Phan adds that the team’s findings about cytokine biology could inform therapeutics for tumors as well as targeted vaccines that provide protection of the gut or lungs.

“Cytokine mRNA is clearly a promising and clever approach to enhance immune stimulation against cancer and pre-cancer lesions,” says Susan M. Domchek, director of the Abramson Cancer Center’s Basser Cancer Interception Institute, which provided funding for the study. “We are hopeful this technology can move as fast as possible into the clinic for patients and individuals at risk of cancer.”

Hunter says the study came together through his lab’s interest in cytokine biology and Phan’s particular interest in CD8+ T-cells; the work of Drew Weissman, 2023 Nobel laureate and director of the Penn Institute for RNA Innovation, on vaccine development; and the expertise of Penn Medicine assistant professor Mohamad-Gabriel Alameh in nanoparticle design, production, and development of vaccines against bacterial pathogens.

“This is why you’re at a university, so you can meet people that you don’t usually interact with, and you find common interests,” Hunter says. Alameh, who met Hunter and Phan on campus, says he quickly realized that combining cytokine-based immune modulation and material engineering is the best route to tailor vaccine responses.

The support from the National Institutes of Health’s Adjuvant Discovery Program also made this work possible.

The paper also “paves the way to explore rationally designed mRNA vaccine adjuvants moving forward, capitalizing on decades of cytokine biology research,” Aunins says. For example, this team continues to work on the impact of other cytokine mRNAs that might can be used to modulate the immune response. Additionally, Phan says Weissman is interested in understanding whether IL-12 could improve vaccine candidates for HIV, while ongoing research with Scott Hensley from Penn Medicine is focused on the ability to deploy this approach across species for avian influenza.

Emily Aunins is a fourth-year Ph.D. student in cell and molecular biology: microbiology, virology, and parasitology.

Christopher A. Hunter is the Mindy Halikman Heyer Distinguished Professor of Pathobiology at the University of Pennsylvania School of Veterinary Medicine.

Anthony Phan is a research associate in Hunter’s lab.

Drew Weissman is the Roberts Family Professor in Vaccine Research, director of vaccine research in the Division of Infectious Diseases, and director of the Penn Institute for RNA Innovation in the Perelman School of Medicine. 

Mohamad-Gabriel Alameh is an assistant professor of pathology and laboratory medicine in the Perelman School of Medicine and Children’s Hospital, and co-director of the mRNA Core at the Penn Institute for RNA Innovation.

Other co-authors include Molly E. Bunkofske, David A. Christian, Elisa Cruz-Morales, Maria Merolle, Phillip Scott, Keenan M. O’Dea, and Anabel Zabal Peñafiel of Penn Vet; Garima Dwivdedi, Colleen Furey, Scott E. Hensley, and Robert H. Vonderheide of Penn Medicine; Ying Tam of Acuitas Therapeutics; and Ross M. Kedl of the University of Colorado Anschutz School of Medicine.

This research was supported by the National Institute of Allergy and Infectious Diseases at the National Institutes of Health (UO1 AI160664, UO1 AI157247, RO1 AI 189513, U19-AI142596, U19-AI142596, UM1-AI144371, 75N93019C000550, P01AI158571, 75N93021C00015, and R01AI08686, T32 AI007632, and T32 CA009140), the Basser Cancer Interception Institute at the University of Pennsylvania, the Commonwealth of Pennsylvania, and the Abramson Cancer Center NCI Grant (P30 016520).