Important note: Information in this article was accurate in July / August 2000. The state of the art may have changed since the publication date. IAVI Report - July / August 2000
Patricia Kahn and Donald Burke
On 30-31 May 2000, IAVI held a workshop in New York to discuss prospects for establishing large-scale HIV vaccine trial sites in developing countries. Participants were drawn from various government agencies and from African nations not already committed to specific vaccine projects or partnerships but potentially interested in becoming involved.
A working assumption of the meeting was that at least several Phase III sites will be needed, so that a variety of vaccine designs can be tested against the real-life challenges they will have to meet: HIV strains that vary around the world; different routes of transmission, and populations with different genetic, nutritional and health status.
The past year has already brought more international activity into HIV vaccine trials. Thailand and the U.S. became the first (and so far only) countries to launch Phase III trials, while Uganda hosted Africa's first HIV vaccine trial, a Phase I study of a canarypox-based vaccine. Kenya and South Africa are expected to follow suit, beginning soon with Phase I tests of the first vaccines specifically targeted to African strains of HIV. And this month, three Latin American countries will start a multi-site Phase II canarypox study. Other developing nations, including India and China, are establishing national AIDS vaccine programs that include building capacity for conducting efficacy trials.
Yet even moving from small Phase I and II trials into Phase III - let alone starting from scratch - is an enormous undertaking, as shown by Thailand's experience building its infrastructure over ten years, eight Phase I and II HIV vaccine trials and tens of millions of dollars. That's because the scale-up usually means moving from hospital or clinic-based work with small numbers of low-risk volunteers to community-based studies involving thousands of high-risk participants. And it means establishing everything from laboratories for handling and testing tens of thousands of blood samples to building trust between trial sponsors and host country governments, media, clinical scientists and communities.
In considering the future of Phase III trials, the workshop focused on several questions: Where is the epidemic going? What is needed to establish a Phase III trial site? What capacity exists, or can be built upon existing projects? This report will briefly summarize the first two and describe in more detail the discussions on capacity and on the participating African sites. [Upcoming issues of the IAVI Report will focus on other cohorts in different parts of the world.] [For a full report of the meeting, click here.]
Since vaccine cohorts should ideally reflect the population to be protected, it is crucial to follow the epidemic's geographic and demographic trends - information that also provides key baseline data for vaccine trial sites. Karen Stanecki of the U.S. Census Bureau presented selected data from the agency's latest compilation, which show that sub-Saharan Africa is still the most severely affected region in the world, with high prevalence rates especially among teenage women and males in their early 20's. Uninfected spouses of HIV-positive people are also at high risk. She also pointed out that there are few overall incidence studies in most parts of the world, so that estimates of infection rates are usually based on seroprevalence in pregnant women who visit antenatal clinics, or extrapolated from very limited data sets; studies in rural populations are especially rare.
Another important trend for vaccine scientists to follow is the genotypic movement of the epidemic: which HIV subtypes predominate where, and how this is changing. Here, the key trend appears to be the continued generation and/or spread of recombinants wherever two widely different strains overlap in geographic space. Prominent recent examples are the A/B recombinant strains in Russia, the B/C recombinants in China and the A/C recombinant in Tanzania. Given this rapidly shifting picture, it is all the more important to resolve whether vaccines can work across the full range of HIV-1 subtypes.
Participants agreed that strong political commitment to AIDS control is key to the success of HIV vaccine trials. So is local commitment to the trial's goals; as Merlin Robb of the Walter Reed Army Institute of Research said, "Are there local people who identify with getting the trial done?" Another absolute requirement is access to sufficiently large cohorts (at-risk or with a high baseline prevalence) that are interested and willing to participate.
Other factors were identified as being important, but could be built up during the trial preparedness phase. These include having clear procedures for approval of clinical trials and reviews of ethics; a core of trained personnel for HIV testing and other laboratory work, informed consent and prevention counseling; and an infrastructure that provides basic transportation, communication and utilities. Laboratories must be able to handle, store and ship blood samples, and ideally also carry out other HIV diagnostic and research assays, and to work under the standards of good clinical practices (GCP). Experience with other vaccine trials or international collaborations was also seen as a major advantage.
Only two developing countries (Thailand and Uganda) have carried out HIV vaccine trials within the framework of a national plan that commits the country to combating HIV. (Three others conducted trials without this framework - China and Brazil, both participants in a Phase I trial in 1994, and Cuba, which has an ongoing Phase I trial.)
Several other developing countries are now beginning to build Phase III cohorts. Preparations are underway for Phase I/II trials in Haiti, Trinidad and Brazil sponsored by the U.S. National Institutes of Health (NIH), and cohorts in these countries are being evaluated for possible inclusion in Phase III studies within two years. Salim Abdool Karim's unit of the Medical Research Council in Durban, South Africa has been building capacity as a U.S. HIVNET site since 1997, with the community of Hlabisa (300 km north of Durban) as a potential Phase III cohort. Numerous other high HIV-incidence countries throughout the Americas, Asia, and Africa have the potential to establish cohorts for HIV vaccine efficacy trials, based on building up their ongoing work.
Several presentations were devoted to the activities of four sub-Saharan countries with the potential to become future Phase III trial sites: Botswana, Ethiopia, Côte d'Ivoire and Tanzania.
Moketsi "Joseph" Makema of the Princess Marina Hospital in Gaborone discussed the explosive HIV epidemic in Botswana, a nation of only 1.6 million people but now one of the most severely affected countries in the world. HIV prevalences at antenatal clinics in Francistown rose from less than 10% in 1991 to 45% in 1997 and are stabilized near 50% (virtually all subtype C). These statistics have now brought about a strong commitment to HIV control from the highest levels of government, which has seen its formerly stable economy devastated by the epidemic.
Botswana has already built some of the infrastructure needed for HIV vaccine trials. The government funds surveillance work and a health system providing "reasonably good" access to care, according to Makema, and several international collaborations have added capacity on HIV. Most important is a strong working relationship with the Harvard AIDS Institute, which has helped build up a laboratory and train personnel to carry out many HIV research and diagnostic assays. Botswana is also about to launch a UNICEF-sponsored pilot study on reducing breastmilk transmission from mother to child, a three-arm trial that will compare formula-fed babies of HIV-positive mothers to breastfed infants treated with either AZT alone or AZT plus nevirapine. The country also has experience in tracking and treating people, gained through a TB control program with the U.S. Centers for Disease Control and Prevention (CDC).
Makema says that there is substantial interest in HIV vaccine trials in Botswana. There are no established cohorts for this purpose yet, but several prospects: A cohort of diamond miners is now being set up, both to study incidence and provide triple-drug therapy for infected people, and the possibility of a military-based cohort is also under discussion.
Ethiopia is similarly hard hit by the epidemic, and as a highly populous country is home to more HIV-infected people (3 million) than any nation in the world except India and South Africa. HIV prevalences are now a staggering 50-75% in commercial sex workers and 10-20% at urban antenatal clinics, according to Arnaud Fontanet of the Ethiopia-Netherlands AIDS Research Project (ENARP), the focal point of the country's HIV/AIDS research efforts.
Fontanet described the beginnings of ENARP in 1994 as a bilateral collaboration between Ethiopia and The Netherlands. Since then it has built a substantial scientific program that carries out HIV surveillance, cohort studies on the progression of HIV infection, and studies on the interaction of HIV and TB, the most common opportunistic infection. It also runs a training program for graduate students, who rotate through collaborating labs at the University of Amsterdam and then return to set up new techniques, as well as for technical and computing staff. The laboratory at the Ethiopian Health and Nutrition Institute, built up with US$10 million over the past 5 years, can now carry out procedures ranging from standard viral load, T-cell subset determination and antibody testing to more sophisticated analyses, such as HIV gene sequencing and T-cell proliferation assays. Funding at this level of US$2 million annually is committed from the Dutch government through at least 2002.
In 1997, ENARP established two cohorts of factory workers, a population chosen because the high desirability of secure factory employment makes it a highly stable group. These two cohorts of approximately 1,200 people each have been followed closely, and HIV incidences measured at 1 and 0.5 per 100 person-years. Follow-up rate was over 90%, after an initial drop of 15% shortly after enrollment. The project has generated a solid infrastructure for informed consent, HIV testing and counseling, collection and storage of blood samples, and providing medical treatment. A workshop on HIV vaccines in Ethiopia was held in Addis Ababa this past March, as a first step to building a national consensus around vaccine development and evaluation in the country.
Madeleine Sassan-Morokro, head of the surveillance, vaccine and clinical section at Projet Retro-CI at the Côte d'Ivoire/CDC site in Abidjan, presented the research program at her unit. Côte d'Ivoire is now the most severely affected country in West Africa and among the 15 most severely affected countries in the world, according to the latest UNAIDS statistics. Surveillance among pregnant women shows that 8-14% are HIV-infected, with higher prevalences in the southeastern regions of the country. Among TB patients, 50% are also HIV-infected, most with HIV-1 but 2-3% with HIV-2. Among the HIV-1 strains prevalent in Côte d'Ivoire, 75% are circulating recombinant forms A/G (CRF-02A/G), commonly called the IbNg strain. This subtype appears to predominate throughout West Africa.
To date the project has not conducted vaccine studies, but Sassan-Morokro reported that follow-up rates in clinical studies are very high, around 90% for one year. The laboratory in Abidjan is well-supported financially and technically by the CDC and can carry out basic HIV tests as well as more sophisticated T-cell assays (including ELISPOT, flow cytometry and cytokine intracellular stain assays). It is also a UNAIDS drug access pilot study site. No cohorts have been established yet, but Sassan-Morokro said that there would probably be a very positive response to suggestions of HIV vaccine trials in Côte d'Ivoire.
Alan Greenberg, chief of the CDC's AIDS epidemiology branch, also indicated his agency's interest in pursuing cohort development and further buildup of this site. They are collaborating on development of a subtype A/G DNA vaccine made by Harriet Robinson (Emory University and Yerkes Primate Research Center, Atlanta).
Michael Hoelscher of the University of Munich reviewed the HIV epidemic in Tanzania, focusing on the Mbeya AIDS control program, a joint cooperation of regional and national health authorities, Germany's Gesellschaft für Technische Zusammenarbeit (GTZ), and the University of Munich. The project began 12 years ago and is now one of the largest intervention programs in Africa, conducting surveillance, molecular epidemiology, and behavioral intervention studies. During this period HIV prevalences at antenatal clinics throughout the region have increased from less than 10% to 15-30%.
Because Tanzania is at the interface of the east African A and D subtypes and the southern African C subtypes, all three types are present in appreciable proportions. Detailed studies in collaboration with the Henry M. Jackson Foundation (including 9 full-length sequences) have detected an extraordinary number of A/C and C/D recombinants: around 50%, says Hoelscher. And most of them are different from one another, suggesting that they have independently developed and implying that an unexpectedly high proportion of people in this region have dual infections. To look closer at this question, the project (a partnership called the HIV Superinfection Study, or HISIS) is now putting together a cohort study of 600 female bar workers, who will be followed over 3 years to establish the prevalence of dual infections, determine when they happened and look for immune correlates. In a pilot study with 104 women, the HIV prevalence was 56% and 10% of the women had dual infections. The study, which is funded by the European Commission's International Cooperations, Developing Countries division (INCO), plans to start recruiting in about two months. Other cohorts have also been well characterized in Kagera, Mwanza, Ifakara, and Dar-es Salaam, and Hoelscher said that acceptance of the studies among the local communities is high when they are done in the context of an intervention program such as the Mbeya AIDS control project. There is also a good laboratory for handling cells and blood samples in Mbeya, and the Muhimbili Medical Center in Dar-es-Salaam is establishing facilities for carrying out various cellular immunity assays.
This talk led to a discussion of the need for more full-length sequencing of HIV from regions like Tanzania and Uganda that have several circulating subtypes. Hoelscher said that little full-length data has been available (since it is arduous to generate), but the more it is, the more frequent recombinants are turning out to be. Merlin Robb said that the Henry M. Jackson Foundation and Walter Reed Army Institute of Research (WRAIR) are working on techniques to detect recombinants more easily by taking a quick sampling across the whole HIV genome.
Increasing capacity for large-scale HIV trials in developing countries is happening largely through the targeted efforts of national and multi-lateral agencies, some of which presented their current programs and future plans at the workshop. Peter Wright of Vanderbilt University reported on NIH's new HIV Vaccine Trial Network (HVTN), a restructured program based on the former AVEG and HIVNET projects (see article), with the goal of conducting Phase I, II and III trials at nine domestic sites and some international ones. (The number, locations and funding levels of the international sites had not yet been announced as the IAVI Report went to press.) The revamped NIH program also includes an HIV Prevention Trials Network that will conduct trials of non-vaccine preventions such as microbicides, nevirapine, STD control and behavioral measures. Sten Vermund of the University of Alabama at Birmingham, a member of the PTN leadership group, said that the cohorts at some sites are also highly suitable for vaccine studies and could offer additional capacity.
WRAIR's Merlin Robb summarized the Army's small but tightly-focused HIV vaccine development program, which has already developed and tested subtype E vaccines in Thailand. WRAIR is building up cohorts and doing baseline studies of HIV and subtype prevalences in the Rakai region of Uganda where further clinical trials are planned. Cohort development and molecular epidemiological studies are also being conducted in Keya and Tanzania.
Several agencies are contributing to vaccine trial preparedness in other ways. UNAIDS, which recently merged its HIV vaccine program with WHO, now supports a range of capacity-building activities that includes help in preparing national AIDS control plans, monitoring epidemiological trends and fostering consensus on ethical issues, according to Saladin Osmanov. David Stanton of the U.S. Agency for International Development (USAID) reported that the agency has already spent US$1.2 billion in AIDS prevention worldwide over the past 13 years. The result is a well-established infrastructure for STD control and condom distribution along with trained, community-based HIV counselors, in many nations of Africa and elsewhere, that might assist in providing prevention services to HIV vaccine cohorts. The CDC is now carrying out research on selected behavioral, social and virological aspects of the ongoing Phase III trial in the U.S. and is working in supoort of the Thai government in the Phase III trial in Thailand. They are also supporting the Abidjan site, as described above. Alan Greenberg (CDC AIDS epidemiology branch) also reported that Tim Mastro, who has directed CDC's research station in Thailand, will return to head the agency's HIV vaccine unit formerly run by Bill Heyward, and could expand CDC's involvement in AIDS vaccine trials.
Lastly, Michael Sweat of Johns Hopkins University and the CDC described efforts to track and analyze cohort data through the Prevention Research Synthesis Project, which has established a database of international behavioral research projects worldwide, both published and unpublished.
Overall, participants concluded that several cohorts with relatively high HIV incidence and good follow-up rates do exist, but none has a large enough study population to support HIV efficacy studies. To conduct Phase III trials in developing country settings therefore means either expanding existing cohorts, studying new ones, or merging multiple cohorts from one region into a single trial population (as in VaxGen's Phase III North American study, which involves over 60 separate trial sites).
The workshop finished with a recommendation that IAVI continue to explore potential Phase III trial sites, with the goal of identifying several that collectively encompass diversity in populations, HIV strains and routes of transmission.
Donald Burke, who organized and chaired this workshop, is Director of the Johns Hopkins Center for Immunization Research, Scientific Advisor to IAVI, and principal investigator of an HVTN site at Hopkins.
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©2000. The IAVI Report.
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