Understanding Mucosal Immunity

How could the need to assess mucosal immunity affect AIDS vaccine trials?

The most common way that HIV can be transmitted from person to person is through sexual contact with an HIV-infected partner. Researchers estimate that about 85% of HIV infections are caused by sexual transmission of the virus. HIV can enter the body during vaginal or anal sex, and also very rarely during oral sex, through the surface tissues (mucosae) of the genitals.

The human immune system can be divided into several parts. One of these, referred to as the mucosal immune system, relies on immune cells and a specific class of antibody to prevent pathogens such as viruses or bacteria from penetrating and then replicating at mucosal surfaces-including those of the genital, intestinal, and respiratory tracts.

For sexually-transmitted viruses like HIV that enter the body through the genital mucosae, the mucosal immune responses are the first line of defense and play an important role in fending off a possible infection. Since an effective preventive AIDS vaccine will primarily have to protect an individual from sexual transmission of HIV, researchers think it will probably be important for a vaccine candidate to induce strong mucosal immune responses.

So in recent years there has been an increased interest among researchers in developing vaccines that stimulate mucosal immunity. But there is still relatively little known about the events leading up to the sexual transmission of HIV or the immune responses necessary to prevent infection. Researchers are now beginning to study the mucosal immune responses induced by AIDS vaccine candidates in animal models and are also looking at ways to improve and optimize these responses.

Vaccines to induce mucosal immunity

One factor that affects the level of immune responses at the mucosal tissues is the route of vaccine administration. Most of the AIDS vaccine candidates that are currently in clinical trials around the world are delivered by intramuscular or intradermal injection. This route of administration can produce antibodies and cell-based immune responses in the blood (systemic immunity), but does not guarantee a robust immune response at the mucosal surfaces. Scientists think that mucosally-administered vaccines, including those by oral or nasal administration, will be more effective at producing responses in these tissues.

But the immune responses generated by mucosally-administered vaccines may vary greatly between the different mucosal surfaces in the body. Vaccines that are taken orally tend to produce the greatest immune responses at the mucosae of the intestinal tract, but are not very efficient at producing a specific class of antibody known as immunoglobulin A (IgA) at the vaginal mucosae, which could be necessary for protection against infections that can be sexually transmitted. Oral vaccines however are effective at preventing infections that primarily target intestinal tissues. There are a few licensed vaccines that are administered orally, including one for polio and two for cholera, which is a diarrheal disease caused by bacteria that mainly infect the intestine.

Recent research suggests that vaccines that are administered to humans as sprays into the nasal passages can give rise to substantial IgA production in the mucosal tissues of the vagina, making this type of immunization appealing to AIDS vaccine researchers. However there are also possible safety issues with nasal immunization that will need to be fully explored before they are evaluated in human clinical trials.

Another way that mucosal immune responses can be optimized is by the choice of delivery system for the vaccine components. Several bacterial and viral vaccine vectors are currently being developed as AIDS vaccine candidates and some of these are known to generate strong mucosal immune responses, depending on how they are administered. Researchers are also studying how some factors, such as cholera toxin, which are known to be potent inducers of mucosal immunity, can be altered to make them safe for human administration.

Scientists are also looking at how substances called adjuvants delivered along with the vaccine candidate can be used to improve the mucosal immune responses induced. Adjuvants are already used with several licensed vaccines for other diseases to boost the level of immune responses and their duration. Now several research groups are looking at novel substances that can specifically increase the production of antibodies and immune cells at mucosal surfaces.

Measuring mucosal immune responses

Researchers are studying how AIDS vaccine candidates induce mucosal immunity in animals, but they are not sure how these responses will differ in humans who receive the vaccine candidate in clinical trials. In the future they may need to actually measure in people the level of antibody or cellular immune responses at the mucosae during an AIDS vaccine trial. While systemic immunity can be measured by a simple blood test, measuring mucosal immunity will involve more invasive procedures that would need to be done repeatedly throughout the course of the trial.

This could make AIDS vaccine trials more complex because it will involve fully and clearly explaining these procedures to all potential trial volunteers as part of the informed consent process. It would also require training the site staff on how to take mucosal samples and providing the trial sites with the equipment required to assess the level of mucosal immunity from the small quantity of cells obtained through such sampling.

It will be important that mucosal immune responses are measured in diverse populations of people during clinical trials because differences in nutrition, intestinal environment, and previous infections have been shown to affect the efficacy of mucosal vaccines.