Important note: Information in this article was accurate in April 2001. The state of the art may have changed since the publication date. IAVI Report - April / June 2001
José Esparza is Coordinator of the WHO-UNAIDS HIV Vaccine Initiative (HVI) in Geneva. A Venezuelan-born physician and Ph.D. biologist, he spent over a decade doing basic research in human virology at the Venezuelan Institute of Scientific Research in Caracas before joining the World Health Organization (WHO) in Geneva in 1986. For the past ten years Esparza has worked to promote HIV vaccine development, with an emphasis on preparing for clinical trials in developing countries. Three weeks before UNGASS, he spoke with the IAVI Report on a wide range of topics concerning global activities in AIDS vaccine development.
For UNAIDS, this is a very important event. What is important are the voices of the United Nations member states. They are the ones who have to tell the UN to do more. It is not for the UN to say this to countries. It is actually the other way around.
From my position, our role is to support the member states.
It is a continuation of an effort started in 1989 with the vaccine team at WHO, called the GPA (Global Program on AIDS). That year we held our first meeting, which developed the general scientific, ethical and logistical guidelines for the conduct of HIV vaccine trials in developing countries. It was a very large meeting, with all the big players from industrialized and developing countries. Looking back, I see that already then we identified the key issues.
In 1996 our vaccine team moved to UNAIDS. We were there for four years. Then Drs. Gro Bruntland (Director-General of WHO) and Peter Piot (Executive Director of UNAIDS) decided to join WHO and UNAIDS to create this new initiative. They did this to take better advantage of WHO's long experience in vaccinology, and because they thought that approaches to industry would be more convincing if we came with a package of vaccines, not only HIV vaccines.
But making an HIV vaccine is not only about immunology and vaccinology. It's also about community involvement, ethics, and creating a vaccine development program within an overall prevention effort. Our joint initiative takes advantage of the expertise of both organizations.
That goes back ten years, to the time when scientists first began seeing signs of protection in monkeys given experimental HIV vaccines. A number of people approached us asking for help in developing sites where these vaccines could move into efficacy trials. It was evident for epidemiological reasons that some trials would have to be done in developing countries.
So in 1990 and 1991, we assessed 15 countries on different continents, to identify those where vaccine trials could best be conducted. We presented this information to our vaccine advisory committee, and they recommended that we initiate activities in four countries: Brazil, Thailand, Uganda, and Rwanda. In 1992 and 1993, these four countries developed national AIDS vaccine plans.
The development of the plans was actually more important than the plans themselves. That's because they were created through a series of workshops and meetings that raised awareness in the community and among politicians, media and scientists. And they required a process of consensus building.
A national plan states the country's policy on HIV vaccines at the highest possible level and spells out the mechanisms for review, approval and monitoring of clinical trials. That's very important, because a big problem with initiating these trials in many countries is that nobody knows how to do them—who should give authorization, how protocols should be reviewed, and so on.
These plans also make recommendations for the conduct of preparatory research needed before launching a trial, including virology, epidemiology, cohort development and social and behavioral research. And they cover supportive activities like data management, public information, and communication.
Through these first national plans we also developed a number of cohorts in those countries. One of them, in Bangkok, is in use in the ongoing Phase III trials in Thailand.
So we actually created the beginnings of a vaccine culture in these countries. It was a long and painful process. But it brought results: a majority of the trials that have been done in developing countries so far were conducted in those countries, except for Rwanda, which was lost in the terrible war.
We are now going through this process in several countries. Last January, Nigeria held a workshop to begin creating a national plan. They now have a draft, which has to be discussed and digested. We did the same in the Ivory Coast in April, together with the US CDC (Centers for Disease Control, US), Ministry of Health and the French ANRS (l'Agence National de Recherches sur le SIDA). Tanzania will hold a workshop at the end of July, and Zambia is also interested in a plan.
Coordination is something that everybody wants. But nobody likes to be coordinated. That's a problem.
We don't see coordination as somebody telling everyone else what to do. National plans are essentially mechanisms for the different agencies to share information on what they are doing, so that they don't step on each other's toes.
For example, Tanzanian scientists have been working with scientists from Germany, Sweden, the US, the European Community. Through the years, they have built a very substantial infrastructure. But next month's meeting is the first time that the different international donors come together to present what they are doing and see how they can work together.
It began with a meeting we convened together with SADC (Southern African Development Community). The seven SADC countries, instigated by the regional director of WHO in Africa, Dr. Samba, wanted to discuss ways of coordinating their efforts on HIV vaccines. We were planning a similar meeting. So we joined up.
The meeting in Nairobi, in June 2000, brought together 40 African scientists from different disciplines—virologists, ethicists, epidemiologists, and public health people—to discuss what could be done to accelerate vaccine development for Africa. The participants signed a document called The Nairobi Declaration. It is a political document, and the scientists began pushing it in different regional forums, saying that these ideas should be implemented.
Afterwards the potential leaders came to Geneva and spent several days discussing it and brainstorming how to turn the intentions of the Nairobi Declaration into something tangible. We discussed many possibilities, from the creation of an African vaccine institute to simply a network of people that would exchange information. William Makgoba (president of South Africa's Medical Research Council) came up with the idea of an African AIDS vaccine program.
A steering committee was formed. Then they established five working groups: clinical and laboratory science; population studies, which includes epidemiology and social and behavioral research; ethics, law and human rights; advocacy and resource mobilization; and national and strategic planning. WHO and UNAIDS furnished US$ 1 million in seed money for the first year, to jumpstart the program.
Since then, several important political bodies in Africa have endorsed the program. And something very interesting: the 15 countries of the West African Health Organization each pledged $50,000 from their own funds, to create a vaccine development fund for West Africa. For me, it is a very, very important gesture that they put in their own resources. It says that research on AIDS vaccines is a high priority for the countries. I would like to see the African Development Bank and other African countries contribute, too.
They have what I would say is a very credible plan for the first year. It's not extremely ambitious, but it's a good start. They developed a set of activities and are now ready to invite international collaboration. They didn't want to do that until they had something concrete. That's because last year, when some African colleagues presented the idea for the first time to our international group in Geneva, the reception was very poor. People said, you don't have a specific plan; what are you proposing to do? So they learned that to have credibility, they needed a well-developed plan.
Their proposals will be presented to the international community at a meeting called the Forum of the African AIDS Vaccine Programme, planned for late this November in Capetown.
A high priority for the first year is that each of the five working groups will do an inventory of resources and needs in key countries. There are also training activities in the different areas, and funding for some preparatory social and behavioral research along the lines of what's included in the national vaccine plans. They decided not to get involved in cohort development—they don't have the resources for that.
The basic idea of the program is really a network of scientists. Eventually, they will move to developing local reference centers in different areas, for ethics, epidemiology, data management, laboratory issues, etc.
The plan for year one does not specifically mention clinical trials. The focus is on activities that will support any organization or country doing vaccine trials in Africa—what I'd call pre-trial infrastructure: advocacy, including education of the media, and strengthening laboratories for trials.
Of course, there are some. One thing is worrying me a lot these days. I am very concerned about the danger that countries are developing their own "national vaccines"-the South African vaccine; the Chinese vaccine; the Indian vaccine.
I perfectly understand the political drive for this. I mean, South Africa would not embark on all they are doing on HIV vaccines—which is an enormous amount, and a big investment from their government—if they didn't feel that they must develop a vaccine for themselves; that if they don't do it, nobody else will.
But it will be a very sad outcome if we have, for example, a subtype C vaccine from India but don't know if it can be used in other parts of the world, which also have subtype C strains. It is very important not to isolate and compartmentalize those national efforts. We need to bring them together, share reagents, and compare immunogenicity of candidate vaccines that have been developed in India against subtype C, with those being developed in South Africa with subtype C, or in China with subtype C.
So networks can be very important, not only from the scientific point of view, but from the strategic point of view.
I recently returned from South Africa. They are using the document there as a basis to develop their own ethical guidelines for vaccine trials. This is precisely what we wanted, and what the guidelines recommend. What we provided was a procedural document that people could use to conduct their own discussion, not a recipe for all countries.
Another interesting development is that in June a UNAIDS team, with two Thai counterparts, will travel to Bangkok to do an ethics assessment of the VaxGen Phase III trial. The principal investigator there requested this assistance, asking us to look at what they are doing, tell them what we think and make suggestions for improvements. This was also recommended in our guidelines—that clinical trials be monitored to ensure that ethical aspects of the trial are being respected.
I think the guidelines are helping to dispel the idea some people still have, that ethics is an obstacle to vaccine development. I always say that, just as immunology is not an obstacle for HIV vaccine development, ethics is not an obstacle, either. You just have to identify the issues, solve them as well as you can, and move on.
When the guidelines came out, some people said it was enough to provide the currently available level of care. We defended the position of providing the highest attainable level of care in the country, and that is how the guidelines read.
This issue is very controversial, because the Helsinki Declaration talks of the best proven therapy But 'best' where? In the country where the trial is taking place, or anywhere in the world? This lack of precision is what has led to so many fights and letters to journals.
We aimed for the highest attainable level of care, and for helping countries identify what that level is. And that is a moving target. Two or three years ago, people proposed giving therapy right after seroconversion—hit early, hit hard. Today, the recommendation is to wait. And the cost of antiretroviral therapy is decreasing. So the attainable level may be different.
A few years ago, French President Jacques Chirac proposed a therapeutic solidarity fund. I just saw him on TV, saying that everyone called him crazy for that. They said it was completely unrealistic. Now it's what the whole world is after.
This was the only ethical proposal, I mean, we cannot accept the status quo, that people in developing countries have no access to even a basic level of treatment.
The study is intended to help to plan for access to future HIV vaccines, and is a collaboration with IAVI.
One goal is to identify policy issues that will guide the introduction and use of future HIV vaccines in countries. When I say policy issues, I mean questions like what a country's position will be if a vaccine is only 40% or 50% effective. Would they introduce it into their national strategy for AIDS prevention and control? Then there are questions about how countries would introduce it. Would they target specific populations? How will they make sure that use of an HIV vaccine doesn't interfere with other preventive interventions?
We also want to make estimates on the size of the target population for a given vaccine, based on these potential policy decisions, and figure out how much vaccine would actually be needed.
We are holding a series of regional workshops to discuss these issues, focusing on three hypothetical scenarios: one with a vaccine showing 30-40% efficacy; one with 90% efficacy, and an intermediate scenario, around 60%. We recently met in Brazil, and I'm on my way to Korea to meet with people from Asia and the Pacific. Later in June we'll have workshops for Africa and for Europe, the US and other industrialized countries.
The Brazil workshop had 25 people, including policy makers, health ministry people, community representatives, people with experience funding public health programs, or in immunization programs. These workshops are not quantitative. They are qualitative workshops.
Participants had a very clear opinion that even a relatively low efficacy vaccine should be introduced in national programs—as a complement to other types of prevention, not a replacement. And they were clear that it should be targeted to high-risk groups.
But there was some concern. People saw a danger. Their message was, if we were to use this vaccine, we would have to increase our prevention efforts. So the overall prevention effort may not be cheaper, although hopefully it would be more effective.
We also learned that people were relatively comfortable making a recommendation for both low- and high-efficacy vaccines. But for intermediate vaccines, they couldn't decide. They said we need more data. We would need to have mathematical models to be able to decide.
One difference will probably concern the low efficacy vaccines, which would most likely be targeted to specific populations. People have already modeled the potential use of low-efficacy vaccines. For example, Roy Anderson has concluded that a vaccine with an efficacy around 40% may have a positive effect in populations that meet two conditions: HIV incidence is more than 1-1.5%, and that preventive interventions are not readily available.
Other modelers, like Sally Blower (University of California) have proposed that if you use a low-efficacy vaccine in San Francisco, where she modeled, it could have a deleterious effect; it could in fact lead to increased incidence, because of the potential for interfering with other types of preventives. We are working in collaboration with people from Emory University and with CDC, modeling vaccine use for public health purposes.
The different economic realities and levels of the epidemic will also play a role. For instance, in Europe and the US, we may find a situation that doesn't exist elsewhere: competition between the public and private demand. There could be individuals willing to pay a thousand dollars for a vaccine. For public health purposes, the vaccine cannot cost that much. How will you deal with this?
We will have a very rich list of policy issues to help us plan vaccination strategies and identify gaps we need to fill by going back and doing targeted research.
Using feedback from the workshops on how different countries are likely to use vaccines of low, medium and high efficacy, we will also try to estimate the size of the target population for these vaccines. This is not so easy, but fortunately we have use of a UNAIDS database on potential risk populations in different countries. This provides a good starting point to estimate the size of the population that would benefit from an HIV vaccine.
Then we need to estimate how many of these people would actually receive a vaccine. This depends on the accessibility of the target population and, of those who are accessible, how many will be willing to receive, say, three vaccine doses. We went through an intensive exercise on this, although we had to make some guesses.
But now we are getting numbers.
Based on the preliminary information we have so far, the numbers look manageable.
Sometimes I feel like I did early in the epidemic, when we used to talk with Jonathan Mann about not knowing how many people in the world were infected. Was it 100 million, or five million, or one million? We had no idea.
Today, when we talk about the use of a vaccine in the future, we really don't have a handle on how many doses we are talking about. I have seen calculations that go up to three billion, which is absolutely impossible; there is no production capacity in the world for that. With reasonable estimates in hand, countries can plan public health programs, industry can plan manufacturing facilities and financing institutions like the World Bank can calculate the financial need.
We will also have some basis to start discussing serious business with industry and with the financial institutions, so that when a vaccine is developed, we can move as quickly as possible to delivery. That's why I'm so excited to work with IAVI on this. And we can tell Kofi Annan and others: from this war chest of several billion dollars, we will need this much for HIV vaccines.
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©2001. The IAVI Report.
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