Building better therapeutic vaccines for chronic infections

Study finds that poor T cell responsiveness limits current approaches

In recent years, researchers have become increasingly interested in developing therapeutic vaccines. Most Americans are familiar with prophylactic, or preventive vaccines, which protect an individual from infections; examples include the common pediatric vaccines as well as the flu shot. But therapeutic vaccines are designed instead to be administered to patients who have already acquired chronic infections, such as HIV or hepatitis. These therapeutic vaccines aim to enhance the immune system’s ability to combat an infectious agent, such as a virus. Researchers are also developing therapeutic vaccines to treat a variety of cancers.

But many experimental therapeutic vaccines have thus far fallen short of expectations. Now, scientists at The Wistar Institute and Emory University offer details about what may prevent the immune system from responding effectively to a therapeutic vaccine during a state of chronic infection. Their findings suggest how scientists might alter therapeutic vaccination approaches to make the immune system respond better. Their work is published today in the Journal of Virology.

“In this study, we wanted to look at why therapeutic vaccines are generally less effective than prophylactic vaccines,” says E. John Wherry, Ph.D., assistant professor in Wistar’s Immunology Program and lead author of the study. Wherry conducted the research as a postdoctoral fellow in the Emory University laboratory of Rafi Ahmed, Ph.D., before joining Wistar earlier this year. “What we found was that the T cells in the chronically infected mice responded poorly to the vaccine.”

Specifically, Wherry says, the T cells failed to proliferate, or expand in number. This failure to proliferate seemed to correlate with a high viral load, which suggests several directions researchers might pursue in improving response to therapeutic vaccines.

“The ongoing stimulus to the immune system that occurs in chronic infection seems to prevent the immune cells from responding optimally to a therapeutic vaccine,” Wherry says. “If we could lower viral load before therapeutic vaccination, we might be able to improve efficacy.”

The next step for the research, Wherry says, will be to combine therapeutic vaccines with other modalities that either lower viral load or enhance T cell function, particularly the proliferative capacity of T cells. Possible examples include anti-virals that could be given prior to therapeutic vaccination, or a cytokine that might boost the proliferation or survival of responding cells.

Wherry’s group at Wistar is continuing to work on understanding at a fundamental level why the T cell proliferation is poor when a therapeutic vaccine is administered during a state of chronic infection. He is also planning to compare the immune response using different therapeutic vaccine platforms. While Wherry’s primary interest is in chronic infection, he notes that research in this area should inform the design of better therapeutic cancer vaccines as well because many of the deficiencies in immune response are similar whether the antigen confronting the immune system is a virus or a tumor.

In addition to Wherry and senior author Ahmed, the other co-author of the paper is Joseph N. Blattman, Ph.D., of Fred Hutchinson Cancer Research Center. Funding for the work was provided by the National Institutes of Health and the Cancer Research Institute.