Safe Haven for Vaccine Antigens

Three images of antigen localized to cells, the leftmost in cyan and magenta circles against a black background, the center a field of green spheres punctuated with magenta dots, and the rightmost a field of grey spheres lined in blue.

Left and middle: HIV antigens (magenta) localized to dendritic cells (cyan) that reside among cells in the follicle (green) three days after immunization. Right: Intact antigen (blue) localized to follicular dendritic cells. 

The Irvine Lab found that in order to mount a successful immune response, vaccines must deliver antigens to specific sites inside the lymph node called follicles.

Vaccines teach the body to produce a protective response to viruses and other microbes by introducing the immune system to antigens, protein fragments that mimic structures on foreign pathogens. But for a vaccine to work, the antigens need to reach the lymph nodes, where B cells can produce antibodies to initiate an immune response.

Between the injection site and the lymph nodes, the vaccine antigens may run into protein-cleaving proteases that break down the antigens. In turn, B cells that interact with these damaged antigens make antibodies that produce less effective, or even irrelevant, responses to the pathogen. If researchers can build protease-resistant vaccines, they may give the body better odds of producing a protective immune response.

In a study appearing in Science and featured in The Scientist, the researchers first assessed vaccine stability in lymph nodes by vaccinating a mouse model with a fluorescent antigen that stops emitting light when the antigen degrades. After 48 hours, only the follicles remained bright, showing that the follicle might protect antigens from degradation. With the help of a probe designed to track protease activity, the team confirmed that there was much less protease activity inside the follicles than elsewhere in the lymph node. Taken together, their results showed that antigens not rapidly directed to the follicles were destroyed by proteases.

The researchers then tested whether they could improve vaccine response by going directly to the follicles. They created a nanoparticle-based vaccine designed to carry HIV antigens to the surface of follicular dendritic cells—a class of immune cells that keep B cells in a steady supply of antigens. Compared to a traditional vaccine, they found that the nanoparticle-based vaccine produced far more B cells targeting the intact antigen. Their findings suggest that vaccine strategies that deliver undamaged antigens to the follicles may elicit stronger immune responses, and may be especially useful against more difficult pathogens such as HIV.