IL-12 Adjuvant Shows Promise in Boosting T-Cell Immunity

Scientists continue to look for new ways to improve vaccines and help the immune system defend against disease.

Vaccines that trigger strong antibody responses provide an important first line of defense. However, viruses can evolve to evade these antibodies as they spread through a population. “You always want to have a backup plan,” says Emily A. Aunins, a Ph.D. candidate in Biomedical Graduate Studies.

T-cells can serve as that backup. They vary widely between individuals but can still recognize and respond to viruses that have mutated or caused reinfection.

Researchers are now exploring ways to enhance T-cell responses to make vaccines more durable and long-lasting. One approach involves using adjuvants—substances that boost the effectiveness of a vaccine.

In a recent study, researchers from the School of Veterinary Medicine, the Perelman School of Medicine, and the Children’s Hospital of Philadelphia examined the effects of adding interleukin-12 (IL-12) to vaccines in mice. IL-12 is a cytokine—a type of protein released by various immune cells.

They found that IL-12 improved protection against both melanoma and listeria infection. It also enhanced CD8+ T-cell responses—white blood cells that help the immune system by targeting harmful cells—against SARS-CoV-2 and influenza. The study was published in Science Immunology.

Researchers have previously used IL-12 as a vaccine adjuvant to improve immune responses to bacterial, viral, and parasitic infections. The body naturally produces IL-12 when responding to certain infections.

Stimulating strong CD8+ T-cell responses through vaccination has historically been challenging. However, Christopher A. Hunter, a professor at Penn Vet and the study’s senior author, noted that mRNA vaccines have changed this.

Data from the past four years suggest that people who receive mRNA-based COVID-19 vaccines and develop strong T-cell responses are less likely to experience breakthrough infections. If they do, they are also less likely to require hospitalization.

A key advantage 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,” explained Anthony T. Phan, Research Associate in Hunter’s lab and Co-Lead Author alongside Aunins.

Phan added that the team’s findings about cytokine biology could help guide the development of targeted vaccines. These vaccines may protect specific organs, such as the lungs or the gut, and could also have applications in cancer treatment.

Cytokine mRNA is clearly a promising and clever approach to enhance immune stimulation against cancer and pre-cancer lesions. We are hopeful this technology can move as fast as possible into the clinic for patients and individuals at risk of cancer.

Susan M. Domchek, Director, Basser Cancer Interception Institute, Abramson Cancer Center

The study was funded by the Abramson Cancer Center’s Basser Cancer Interception Institute.

According to Hunter, the research was made possible by multiple areas of expertise. This included his lab’s ongoing interest in cytokine biology and Phan’s work on CD8+ T-cells. It also drew on vaccine development efforts led by Drew Weissman, a 2023 Nobel laureate and director of the Penn Institute for RNA Innovation. In addition, assistant professor Mohamad-Gabriel Alameh of Penn Medicine contributed expertise in designing and producing nanoparticles for bacterial vaccine delivery.

“This is why you are at a university, so you can meet people that you do not usually interact with, and you find common interests,” Hunter remarked.

Alameh, who met Hunter and Phan on campus, says he immediately saw the potential of combining cytokine-based immune regulation with material engineering. He believes this is the best approach to customizing vaccine responses.

The study also received support from the National Institutes of Health's Adjuvant Discovery Program.

The study, therefore, “paves the way to explore rationally designed mRNA vaccine adjuvants moving forward, capitalizing on decades of cytokine biology research,” according to Aunins.