VIDI member Dr. Ann Duerr is pursuing a novel approach to HIV vaccination using an unlikely assistant – the tonsils.
Most vaccines are given as intramuscular shots, a vaccination method that can often elicit a systemic immune response because the vaccine and the immune cells which recognize it can circulate throughout the body. The HIV vaccine candidates examined to date, nearly all given intramuscularly, have not produced robust protective responses. This may be because the responses they produce are not strong enough, broad enough, or are not directed against the right targets in the virus.
“We usually measure vaccine responses in the blood, but responses in other places could be as, or more, important,” Duerr said. Duerr is focusing on responses at mucosal surfaces, which consists of the tissue lining internal organs such as the gastrointestinal tract, as well as the nose, mouth, lungs, vagina and rectum.
“If you think about it, our mucosa is where we contact most pathogens,” Duerr said. “Respiratory viruses, viruses and bacteria that transmit gastrointestinal diseases, organisms that cause sexually transmitted diseases – these are all pathogens that you contact at your mucosal surfaces.” This could be an important avenue to explore in HIV vaccine research, Duerr said, because the most common places for HIV to be acquired through sexual activity are the mucosal surfaces of the genitals and rectum.
While direct vaccination at these sites is probably not feasible, vaccination at other mucosal sites may produce a robust and systemic immune response. Evidence has suggested that parts of the mucosal system share a common immune response, as past studies have indicated that immune cells traffic throughout different mucosal tissues and that exposure to an immune stimulus at one site can induce responses at mucosal sites in other parts of the body. For example, studies showed that a swallowed vaccine induced antibody responses in the gastrointestinal tract, tear ducts, and mammary glands. Inhaled vaccines have been shown to induce responses in the nose, lung, and genital mucosa.
Duerr came to the Center in 2004 after spending 13 years at the Centers for Disease Control (CDC) in Atlanta working on HIV transmission and infection in women. During her time at the CDC, Duerr conducted a variety of research studies relating to HIV infection in at-risk women around the world, including prevention of mother-to-child HIV transmission through breast feeding in resource-poor countries, reproductive options for couples where one partner is HIV positive and one is HIV negative, and the effectiveness of female condoms.
“For me and for other scientists of my generation, HIV/AIDS has been the public health emergency of our lifetime,” Duerr said.
Over the years, as knowledge about HIV grew, Duerr became convinced that a vaccine was the only way to stop the AIDS epidemic. Dr. Larry Corey, co-director of VIDI and principal investigator of the HVTN, recruited Duerr to join the HVTN as a faculty member. Since joining the Center, Duerr has been actively involved in the Step trial, a large clinical trial of a promising HIV vaccine made by Merck, and its follow-up. Vaccinations in the Step trial were halted in 2007 after initial results showed that the vaccine didn’t offer any protection against HIV transmission or ameliorate the course of disease progression. Additionally, uncircumcised men who received the vaccine had a slightly higher risk of acquiring HIV. Like many other HVTN researchers, Duerr wants to know why the vaccine in the Step trial failed to protect and is following HIV-infected trial participants to see how their disease progresses over time.
Duerr wants to explore alternates to the “shot in the arm” HIV vaccine. She is now exploring ways to induce genital and rectal immunity against HIV in research that is supported by an R01 grant from the National Institutes of Health.
The mucosae of the genital and gastrointestinal tracts are part of the type 1 mucosal system, which includes the nose and tonsils. Nasal vaccination, such as the flu vaccine FluMist, can effectively induce immune responses in the blood and mucosal surfaces, including the genital tract. However, nasal vaccines require rigorous safety checks and balances because the olfactory nerves can traffic substances from the nose into the brain, Duerr said. For this reason, she is concentrating on the tonsils, which are part of the same mucosal system as the nose, but vaccination in this area doesn’t pose the same safety risk to the brain.
Duerr and her group are currently conducting studies to test vaccines against the HIV-like simian immunodeficiency virus (SIV) in macaques by comparing vaccines given as shots in the muscles to those injected into the tonsils. The scientists will then examine immune cells in the lung, small bowel, rectum and blood for their response to the vaccination, which will tell them the strength and specificity of the reaction, how the immune response to the SIV vaccine spreads throughout the body, and how the route of vaccination effects the distribution of that response. Duerr and her colleagues will then expose the monkeys to repeated low doses of SIV applied to the rectal mucosa to test their vaccine-induced immunity as compared to unvaccinated animals. This will be a proof of concept study, Duerr said, and if it works they will look to developing a tonsil spray or patch for an easier delivery of the vaccine. This work that tests vaccines to an HIV-like disease in monkeys is an important first step toward discovering whether mucosal HIV vaccines are likely to work in humans.
In a second branch of her work, Duerr plans to look at flu vaccines in humans and test the immune responses in various parts of the body. Her group will compare responses to flu vaccines given nasally or as a shot in the skin, the tonsils, or the cheek (which is part of a different mucosal system than the tonsils). They will look at immune responses in the blood, the nose, the rectum and the genital tract to see whether tonsil vaccination in humans can elicit immunity in other mucosal tissues. Pending FDA approval, this project will begin in 2010.
While the urgent need for a working HIV vaccine is the main motivator behind these studies, Duerr thinks her studies may have broader implications for other diseases contracted through mucosal contact, such as other sexually transmitted infections. “We don’t have very good vaccines against many STDs,” she said. “So being able to elicit better mucosal responses would be extremely useful. If this approach is successful, we could use it as a model for lots of other vaccines.”