— An Interview with Zackie Achmat
The Joint United Nations Programme on HIV/AIDS (UNAIDS) and the World Health Organization (WHO) recently released their annual report on the global AIDS epidemic. It highlights the progress made by some countries in lowering HIV infection rates despite a continued increase in the total number of people infected with HIV throughout the world. The report, AIDS Epidemic Update 2005, was released in advance of World AIDS Day on December 1st and focuses on the importance of HIV prevention efforts and the need to increase and improve these efforts throughout the world.
Kenya and Zimbabwe are two countries where an increase in the uptake of voluntary counseling and testing (VCT) and a delay in the initiation of sexual contact are linked with a decline in HIV prevalence over the past few years. Burkina Faso also had an overall decline in infection rates among adults.
But there were still 4.9 million new infections in 2005, taking the total number of HIV-infected individuals worldwide to over 40 million. Sub-Saharan Africa was the hardest hit region globally, accounting for 64% of all new infections or more than 3 million newly HIV-infected people. The sharpest rise in infection rates was seen in Eastern Europe and Central Asia where the epidemic is now being fueled by both injection drug users (IDUs) and heterosexual transmission. Pakistan and Indonesia are two countries facing explosive epidemics among both IDUs and sex workers.
"We really are failing to prevent this epidemic in most parts of the world," says Jim Kim, director of WHO's HIV/AIDS program. "And we have real opportunities to scale up prevention." He said one of those opportunities is ensuring that some of the momentum created around starting HIV treatment programs in developing countries is extended to HIV prevention efforts, such as massively scaling up VCT programs and focusing on preventing mother-to-child transmission. Kim also suggested that the increase in available funding for HIV treatment could be used to help countries start comprehensive prevention programs.
IAVI is partnering with Transgene, a French biopharmaceutical company, on the development and production of an AIDS vaccine candidate that uses an adenovirus serotype 35 (Ad35) vector to deliver HIV antigens into the body. The naturally-circulating form of adenovirus causes the common cold in humans and two ongoing AIDS vaccine trials are evaluating adenovirus serotype 5 (Ad5) as a vector, including a Phase IIb "test of concept" trial with a candidate developed by Merck.
The development of a novel candidate based on the Ad35 vector may have advantages over the Ad5 vector because fewer people worldwide have been previously infected by this serotype and therefore are less likely to have pre-existing immunity to the viral vector, which could limit the vaccine's efficacy (see February 2005 Primer onUnderstanding Pre-Existing Immunity).
IAVI has worked with Transgene on past studies and on the production processes for other AIDS vaccine candidates that the organization has tested in clinical trials.
At a meeting of the G7 countries in London earlier this month, finance ministers approved a pilot project to spend approximately US$1 billion that will ultimately aid the development of vaccines for the world's biggest killers: AIDS, malaria, and tuberculosis. The vaccine proposal was developed by the Italian minister, Giulio Tremonti, and will ultimately emphasize the use of Advance Market Commitments (AMCs) to give pharmaceutical companies more incentive to invest in vaccines that they can then sell for a guaranteed price (see September 2005 Spotlight, An industrial incentive).
Several organizations involved in vaccine development and advocacy, including Aeras Global TB Vaccine Foundation, PATH Malaria Vaccine Initiative, and IAVI, expressed their support for AMCs as a way to combine the expertise of private industry with the urgent need to develop vaccines for the world's most neglected diseases.
All articles written by Kristen Jill Kresge
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.