Targeted Delivery of Mucosal HIV Vaccines to Human M Cells
University of California, Los Angeles
Basic Biomedical Sciences
The mucous membrane (mucosa) of the intestine is a major site of HIV-1 infection. Therefore, in order to be effective, HIV vaccines must provide a critical first line of defense at this key virus entry site and elicit a strong immune response at the intestinal mucosa. Such a response can be induced most effectively in humans and mice when a vaccine is given through the oral route.
Orally administered vaccines make their way to the small intestine and, once taken up by the specialized immune cells existing there, activate a variety of immune responses. Therefore, to activate strong mucosal immune responses, it is important to efficiently target oral vaccines to these intestinal immune cells. Most of the oral HIV vaccines currently being developed are not targeted to the immune cells, resulting in the induction of weak immune responses and incomplete protection from HIV infection. Thus, in the proposed study, we will develop a novel vaccine delivery technology that can target HIV vaccines to the intestinal immune cells.
The majority of pathogens resemble HIV and invade the body through the mucosal surface. Thus, to combat mucosal infections, humans and mice produce a specialized antibody, called secretory immunoglobulin A (SIgA), which is present on the intestinal surface. An important function of SIgA is to capture pathogens at the mucous membrane of the intestine and deliver them to the intestinal immune cells so that these cells can produce protective immune responses against these pathogens. Our goal is to imitate this natural pathogen delivery mechanism and use SIgA as a vaccine delivery vehicle to target HIV vaccines to the intestinal immune cells.
We will produce an HIV vaccine in a special way so that, when mixed in a test tube with the recombinant human SIgA we produce, it can be captured by this antibody. Once the HIV vaccine is bound by SIgA, it will be administered orally to mice. We will then determine if SIgA can efficiently target the HIV vaccine to the intestinal immune cells and induce potent anti-HIV immune responses. A major advantage of this vaccine delivery system is that, because SIgA is a human protein naturally exiting in the human intestine, it is expected to be safe when used in humans.
Every year, millions of people are newly infected with HIV worldwide. Even here in California, where AIDS education is prevalent, there are thousands of new infections annually. Thus new approaches to preventing infection are urgently needed. In addition to being effective in inducing mucosal immune responses, a significant advantage of oral vaccines over traditional vaccines is that they do not require sterile injection equipment or highly skilled medical personnel. Thus, oral vaccination provides a very cost-effective approach for immunizing a large number of people.
Our research will provide the fundamental knowledge necessary for the development of a safe and effective oral vaccine that prevents HIV infection. Preventing new HIV infections will not only save many lives, but will also result in a decrease in the health care costs associated with treating those infected with HIV.