[This article was published in 2009 and updated in May 2012. Read the update here.]
An HIV vaccine promises to be the magic bullet that ends the AIDS epidemic. Even a partially effective vaccine could gradually diminish HIV’s impact. According to the latest estimates by the International AIDS Vaccine Initiative (IAVI), new infections would decrease by a quarter if a 50-percent effective vaccine reached just 30 percent of the global at-risk population. But any level of vaccine protection has proved elusive despite 25 years of effort.
The long wait has only increased the sense of urgency. This decade has produced a number of vaccine candidates, and IAVI has emerged as a major player in the race for realizing an HIV vaccine accessible to all who need it. By 2000, IAVI was already cultivating connections with academic and corporate researchers to accelerate a pipeline of potential vaccines making their way to human trials. To ensure that such products work, vaccine candidates must undergo human testing in Africa and Asia, where the bulk of new infections occur. Regional factors may require adjustments in the vaccine’s composition. Different HIV subtypes are prevalent, and local differences in immune response may exist due to genetic and environmental factors.
IAVI, for this reason, has developed clinical research collaborations in eastern and southern Africa and in India. Working with local researchers, the organization has helped strengthen clinical research facilities’ physical and human resources so that when a promising vaccine candidate is ready, there will be a trial network prepared to test it.
At first, IAVI staff thought that a vaccine could be rapidly pushed to fruition. Pat Fast, M.D., Ph.D., IAVI’s chief medical officer recalls, “I started working with IAVI in 2001. We had one person in Kenya. I was told to prepare for efficacy trials in three years. We couldn’t just go to a CRO [contract research organization].” Efficacy trials involve thousands of trial participants distributed over a number of locales. IAVI decided to build on the existing resources to rapidly ramp up local trial capabilities. As it turned out, none of the available vaccine candidates performed well enough in early trials to justify moving them into the more advanced efficacy studies. The network IAVI established nonetheless has proved valuable in gathering the data needed to more efficiently develop and test future vaccine candidates. It has also enabled local investigators to study additional HIV prevention measures. Their research outlook has broadened to include other diseases, as well.
Upgrading Existing Capacity
When IAVI started considering bringing HIV vaccine trials to developing countries, capacity was limited for both conducting clinical trials and performing sophisticated laboratory testing. IAVI’s vision encompassed long-term capacity building; it wanted to create integrated trial centers able to do their own lab work and data collection. The goal was to establish a network prepared to do early, small clinical trials at first and then graduate to larger efficacy studies.
In 2001, IAVI sent a survey to about 50 facilities, asking about trial capabilities and local HIV epidemiology. Site visits followed. According to Fast, “The most important thing we were looking for was African leadership. Next was high HIV rate—you have to go where the risk is—and after that came the willingness of the researchers, community and government to work with us.” Infrastructure and staff training were lower on the list because these were “fixable.”
IAVI ultimately agreed to partner with researchers at 11 institutions, which became designated as Clinical Research Centers (CRCs). These centers involved partnerships with local research organizations in six countries: Uganda, Rwanda, Zambia, Kenya, South Africa and India. All the CRC facilities except some South African locations needed extensive renovations or new construction. A clinical trial unit has to collect a broad array of health data to check on safety as well as efficacy. It looks something like a modern doctor’s office, with a waiting room, exam and counseling rooms, HIV testing facility and bathrooms to collect urine samples. Labs to analyze biological specimens are required to diagnose HIV infection and evaluate vaccine safety. These labs need a standardized set of equipment and external quality assurance systems to assure that results from different trial units are comparable.
This huge organizational effort entailed shipping elaborate, high-tech equipment from distant manufacturers while at the same time working with local contractors. Regulations and construction practices were a little different in each country.
To successfully conduct multi-site trials, the CRCs have to adopt a uniform set of operating procedures. Leslie Nielsen, IAVI’s country director for Uganda, notes, “The Uganda CRC staff conduct research in Uganda according to the highest international standards. But the doctors and nurses here treat patients under very difficult conditions and have a heavy workload. In a clinical trial, you need rigorous recording of adverse events and the other data.” New medical personnel need education in internationally accepted good clinical practice. Lab staff requires training in good clinical laboratory practices. This training is coordinated by IAVI’s Human Immunology Laboratory in London and at the University of the Witwatersrand’s Contract Laboratory Services in Johannesburg. Quality assurance testing ensures continued consistency of lab assays across the network.
An intensive education effort also takes place within the communities that provide trial volunteers. Communities need to understand how a vaccine trial operates in addition to basic information on HIV transmission and disease. This information can be conveyed through community meetings and educational outreach materials. To provide informed consent, the actual trial volunteers require much more specific counseling on the details of the study and the risks and benefits they incur, if any. There are also a number of study benefits, as participants receive HIV prevention counseling and testing. When needed, they also receive care and/or referrals for HIV, sexually transmitted diseases, reproductive health issues and basic medical issues. All these efforts, of course, involve training staff in counseling and advocacy skills.
Local personnel directly manage community programs, and they have taken over the scientific activities, as well. IAVI maintains a trial monitor staff to ensure that proper trial procedures are followed. Megan McBride, IAVI’s senior director for clinical operations, says, “There’s still a lot of communications between IAVI headquarters and the CRCs, with frequent visits. But the centers are now performing at a high level, so they don’t need so much supervision or training anymore.”
Vaccine Preparatory Studies
With the vaccine pipeline constricted, the CRCs have moved into vaccine preparatory studies. The studies involve tracking HIV incidence in large cohorts so as to identify high-risk populations for future vaccine efficacy trials. Another study evaluates the immunologic and virologic responses in volunteers recently infected with HIV. There are also studies evaluating persons showing possible resistance to HIV: either because they are able to control virus levels over time without antiretroviral medication or appear to be high-risk “exposed but uninfected” persons. These immunologic/virologic studies are useful in determining protective immune responses that an HIV vaccine should trigger or mimic.
The study tracking HIV incidence has had to adapt to an evolving HIV epidemic. Observed HIV incidence has been lower than expected in certain groups, possibly related to extensive counseling and testing programs. The CRCs have enhanced their flexibility by broadening the high-risk populations they recruit. Aside from commercial sex workers, the centers follow discordant couples (in which one partner is HIV-infected and the other is not) and men who have sex with men.
Stigma remains strong against HIV infection and the risk activities associated with it. The CRCs have had to create a safe, nonjudgmental atmosphere in which study volunteers from each risk group can feel comfortable. Doing this involves staff with special sensitivity training and the creation of protected meeting places. “The objective is to conduct effective HIV prevention research in an environment of confidentiality and sensitivity to the needs and safety of the study volunteers,” says Pauli Amornkul, M.D., IAVI’s regional medical director, formerly based in Kenya.
A completed, published study measured standard clinical laboratory values in healthy Africans (see E. Karita et al. PLOS One 2009, 4(2):e4401). It analyzed the test results from 2,100 volunteers throughout the trial network to create local standard reference ranges for blood values and organ function. By United States and European standards, a third of these volunteers would have been ineligible for vaccine trials although their test results were within the normal range for Africans.
Individual Research Centers
Kenya: The first CRC collaboration was in Kenya. It expanded to centers in Uganda, Rwanda and Zambia before adding branches in South Africa and India.
The studies in Kenya take place at three locations. Two are in Nairobi and associated with the Kenya AIDS Vaccine Initiative based at the University of Nairobi. One installation is at the medical school, in Kenyatta National Hospital. The second is in the impoverished west Nairobi district Kangemi. It originally made use of converted shipping containers; these have been partially replaced by new construction. Another CRC, on the northern Kenyan coast, is run by the Kenya Medical Research Institute, which, like the University of Nairobi, is a government institution.
The principal investigator in Nairobi, Professor Omu Anzala, Ph.D., recalls the steps that led to his role in initiating the CRC network: “I was doing my postdoctoral work at the University of Oxford’s Institute of Molecular Medicine. My lab was already constructing an HIV vaccine, and IAVI was looking to sponsor trials. We made a proposal to IAVI, and I was given the responsibility to set up trials for the vaccine in Kenya.”
The vaccine in question involved “naked” HIV DNA plus a booster immunization with MVA, a weakened form of the small pox vaccine virus. Researchers genetically modified the MVA booster to produce HIV proteins. IAVI’s original plan was to move this candidate vaccine into advanced human trials after preliminary testing. However, the responses to the MVA and other early vaccines did not appear sufficiently protective, and scientists started working on alternate vaccine designs.
Aside from the stigma attached to groups with high HIV risk, Kangemi and other crowded, poverty-stricken Nairobi districts with high HIV rates have their own stigma arising from a history of violence and lawlessness. Anzala says that the challenging environment has not disrupted his studies. “We started slowly,” he says. “We worked with community groups and educated the community. The community respects us. We have been there eight years, and we don’t have any problems.” The Kangemi facility is also a neighborhood health care resource. It works with a nearby city clinic to ensure that study volunteers receive proper health care, including HIV treatment if they need it.
Rwanda-Zambia: The idea of studying discordant couples comes from Susan Allen, M.D., an Emory University (Atlanta) professor who directs the Rwanda Zambia HIV Research Group. This group’s three CRCs (Lusaka, Zambian copper belt, Kigali) joined the IAVI network in 2003 and 2004. Allen went to Rwanda in 1986. She ran an HIV prevention and research program there until the 1994 genocide. Allen’s group then moved to Zambia, returning later to Rwanda. She became interested in discordant couples during the first Rwanda period, when women in her HIV prevention projects asked her to involve their husbands in counseling.
Allen’s latest studies indicate that 80 percent of new HIV transmissions take place within such couples (see K. Dunkle et al. Lancet 2008, 371:2183-91). For that reason she has become a prime advocate of couples counseling, a practice that has become a normal procedure in IAVI trials. Allen says, “I would have a problem with any study that didn’t include partner counseling. We know the impact. It can increase condom use to 80 percent of sexual acts and reduce heterosexual transmission by at least two-thirds.”
The Rwanda-Zambia group identified more than 4,200 discordant couples between July 2003 and December 2005. This population forms a substantial base for the heterosexual transmission study cohort, which IAVI began funding in 2004. The study was following about 1,240 HIV-negative members of cohabiting discordant couples as of April 2009. Researchers check these volunteers’ HIV status monthly or quarterly. The cohort feeds into the CRC study of recent HIV infection. The Rwanda-Zambia group is also engaged in vaginal microbicide trials, which can also advance the study of HIV prevention within discordant couples.
Uganda: Uganda contains three CRCs: one established in partnership with the Uganda Virus Research Institute (UVRI) directly and two with UVRI and the U.K.’s Medical Research Council (MRC). UVRI is a long-established research organization dating back to 1936. In 2002, Pontiano Kaleebu, M.D., Ph.D., a highly trained scientist educated in Uganda and the United Kingdom, emerged as the point person for founding a CRC. He became its principal investigator and is now assistant director of research at UVRI as well as head of basic sciences at the MRC/ UVRI partnership.
Kaleebu had participated in an earlier Ugandan HIV vaccine trial funded by the U.S. National Institutes of Health (NIH) and was looking for ways to continue HIV vaccine research. Leslie Nielsen, who became the IAVI country director for Uganda, had also been part of the NIH trial’s Uganda investigative team. In addition, Jill Gilmour, Ph.D., the head of IAVI’s Human Immunology Laboratory in London, had worked in Uganda and was familiar with UVRI. She was able to coach the local lab team in meeting international standards. Nielsen comments, “The university here is excellent. The doctors and nurses are well educated and quite prepared to adopt new methods.”
Although the initial team was relatively easy to assemble, physical infrastructure was lacking. UVRI is a branch of the Uganda Ministry of Health, which has preferred to concentrate its scarce funding on treatment rather than research. The CRC started with a vacant piece of UVRI land that was previously a medical waste dump. IAVI had to build from the ground up. It constructed completely new offices, clinic and lab.
The center worked on an early trial of the same Oxford vaccine candidate studied in Kenya as well as a preliminary trial of another type of vaccine utilizing a bioengineered nonpathogenic virus. The CRC network meanwhile expanded to include two Uganda facilities operated by the MRC (one at nearby Entebbe Hospital and the other in Masaka on Lake Victoria). They conduct the CRC vaccine preparatory studies, such as the large HIV incidence cohort. Borrowing the idea from the Rwanda Zambia group, they are now recruiting discordant couples in an effort to find a population with high HIV incidence. Lake Victoria fishing communities are a new high-risk population being recruited.
Anatoli Kamali, M.D., principal investigator at the Masaka CRC facility, observes that the inability to move on to advanced vaccine trials has been frustrating, but “keeping up momentum has been easier than expected. We should not get distracted from our goal.” Kamali suggests broadening the CRC collaboration to include pharmaceutical companies that are developing HIV vaccines. “That way, we will be among the first to test them,” he says.
The UVRI laboratory has received funding from the Bill & Melinda Gates Foundation’s Collaboration for AIDS Vaccine Development and is now concentrating on basic science. One study that Kaleebu has organized tests a new gene expression assay (“microarray analysis”) as a way of predicting vaccine response.
The Benefits of International Collaboration
The UVRI CRC’s ability to conduct new basic science studies on its own is one example of the benefits emerging from the collaboration. IAVI helped the CRC researchers in the beginning, but now those researchers are the sources of ideas for new vaccine designs while keeping the trial organization ready for the time when efficacy trials are again opportune. As Anzala in Nairobi put it, “Even if there is no vaccine trial, we can study the mysteries of HIV, and that, in turn, will help in developing vaccines. We also want to put the infrastructure to good use by diversifying. We can test TB and malaria vaccines. Everyone has heard this is an excellent unit that can do more.”
The CRCs have also blazed the political and regulatory pathways needed to move future trials ahead quickly. It took Anzala’s group 18 months to get approval for its first vaccine trial. The Nairobi CRC then worked with the Ministry of Health to streamline the process. The two organizations sponsored a national stakeholders’ meeting in 2004 that established guidelines for vaccine research. The meeting also led to an accelerated system for approving new trials. Now a national vaccine protocol review committee submits recommendations to the two ministry of health regulatory boards that oversee pharmaceutical research.
The Ugandans, too, work to impart a sense of urgency to the country’s political structure. UVRI initially took advantage of its high standing in the Ministry of Health to secure government support for the CRC. IAVI CEO Seth Berkley ultimately met with Uganda President Yoweri Museveni, and the two wrote a letter to the Group of Eight (G8) appealing for more HIV vaccine funding.
UVRI continues to give health officials and members of parliament regular updates on HIV prevention technology. The meetings allow the officials to comment on the research agenda. Their comments can result in adjustments to the way research is conducted. These interchanges preserve the government’s commitment to Uganda’s leading role in vaccine research. In Kenya and elsewhere, this commitment smoothes over bureaucratic barriers. It also results in various kinds of material assistance, such as providing space for study centers or medical care to study participants.
Government support is not to be assumed, and its absence can prove disastrous. When Allen started in Rwanda in the 1980s, the government forbade her from publishing results. It feared that publicizing the nation’s HIV problem would drive away investors and tourists. Then the government-promulgated 1994 genocide resulted in the deaths of half the Rwanda project’s research staff plus the disappearance of hundreds of the cohort members. The new government in Rwanda, however, has been very supportive of HIV vaccine and other prevention research. Despite that support the CRCs in several countries face challenges recruiting men who have sex with men into cohorts due to stigma against homosexuality.
Work on the community level helps to protect against the capriciousness of national politics. As described, considerable time is spent on public education so that residents understand and cooperate with the studies taking place in their locales. Also, each Clinical Research Center has a community advisory board, established with IAVI’s guidance. Some have gender advisory boards or work with peer leader networks.
These types of local organization have broader effects: They combat HIV stigma and homophobia by providing a sense of empowerment. As the community boards and networks gain experience, they seek to advise government officials on policy matters. In this way, there emerges a grassroots constituency for scientifically sound, ethical HIV vaccine research. This constituency’s existence ultimately will engender greater appreciation of medical research and health care in general.
By David Gilden