IAVI Report - October - November 2001
Jean-Louis Excler

Jean-Louis Excler is a pediatrician and epidemiologist who became involved in immunization programs while working in Africa, where his six years included a stint as chief of UNICEF's Expanded Program of Immunizations and Primary Health Care in the Central African Republic. He became involved with HIV vaccines upon his return to France in 1991 as chief of HIV vaccine clinical development at Pasteur Mérieux Connaught (now Aventis Pasteur). In 1998, he moved to the Henry M. Jackson Foundation in Rockville, Maryland, where he worked on the US Army's HIV vaccine program, then moving to Bangkok to help prepare for the Army's Phase III efficacy trial. He now consults for UNICEF on issues surrounding HIV and safe motherhood in the East Asia/Pacific region.

Over the past few years, effort and commitment to develop an AIDS vaccine have gained a great deal of momentum in many countries and international agencies. Much of the activity is happening in American, European, Australian and Japanese institutions, but a growing number of less developed countries-including Thailand, South Africa, Uganda, Kenya, China, Brazil, India, Trinidad & Tobago, Haiti and Cuba—are also participating, despite their poverty and often difficult political and logistical conditions.

Yet twenty years into the epidemic, we must ask why we aren't farther along in this endeavor. Are the different worldwide efforts always well-focused on the challenge, which is to make available an effective, affordable HIV/AIDS vaccine? Are we putting enough effort into reasonable vaccine approaches that already exist and could be tested in the field, and into building trial site infrastructures in highly affected countries, or are our efforts too scattered?

My answers to these questions are based on the premise that vaccine research is distinct from vaccine development, and that most activity over the past two decades has focused on vaccine research. While some of this research is critical to feeding the development pipeline upstream, at other times it seems detached from the emergency of the epidemic and the public health task at hand. My sense, after ten years working on this problem in academic, industry and government settings, is that the task requires much more attention to product development and to collaborating more effectively on driving a limited number of vaccine approaches more forcefully through the pipeline.

What are some specific areas where greater focus and collaboration could accelerate vaccine development? One is manufacturing. This is a serious bottleneck even at early stages of vaccine clinical testing (when only small pilot lots of vaccines are required), since most candidate vaccine manufacture is subcontracted to biotechnology companies with very limited production capacity. The longer-term picture may be even worse for all but the few vaccines being developed by big pharmaceutical companies, since small production units cannot support the large-scale manufacturing needed for Phase III trials.

There are certainly no easy fixes to this problem. But there is little effective concentration of production efforts, know-how or funding to develop sorely needed capacity in GMP (Good Manufacturing Practices) and QC (Quality Control). For example, there are institutions in at least six countries working on prime-boost strategies that combine HIV-DNA vaccines with MVA (or similar attenuated vaccinia vectors). These projects could benefit from a concerted focus on a limited number of manufacturing and QC units, concentrating and strengthening their capacities to meet the production needs of different products. I am afraid this is not at all the case.

The strength of a water current must reach a certain threshold to move a mill wheel. The same applies to vaccine production and development. Massive funding support to a few GMP manufacturing plants that can produce pilot lots would consequently benefit the overall vaccine effort by increasing the availability of products for testing. Another mid- and long-term approach to this problem is to involve vaccine manufacturers from developing countries. For example, India, Brazil, China, Cuba and South Africa already have capacity, while others could be upgraded to GMP and QC international standards.

Another area in need of more focused effort is preparation of vaccine trial sites. The AIDS epidemic is a moving target and therefore difficult to hit. Still, HIV vaccines need to be developed for and tested in countries where the epidemic is raging and where efficacy trials are feasible. We are facing the classical dilemma of developing cohorts without a vaccine and developing vaccines without populations for testing them.

One exception is Thailand, a country that has attracted and supported HIV vaccine developers for over a decade. This stems from the country's outstanding intellectual and technical capacities for clinical research, its political stability and strong economy, and of course the explosion of the epidemic there in the mid-1990s. Continuing its pioneering role in HIV vaccine development, Thailand is now hosting the first efficacy trial in a population of injecting drug users (IDUs), in this case, with a non-clade B vaccine. A second Phase III trial—a prime-boost study of canarypox plus gp120 in community-based cohorts—is likely to start in 2002 (see article), while a few other vaccine candidates are on the pathway to Phase I/II trials in Thailand.

However, the rate of new infections in Thailand has now dropped below 1% in the general population (i.e., outside high-risk groups such as IDUs and commercial sex workers). At this low rate, trials must become much larger and therefore more expensive, and it could become very difficult to conduct any other community-based efficacy tests—yet these are essential for testing vaccine efficacy against heterosexual transmission and for ensuring that large numbers of women are included in cohorts.

Soon Vietnam may face the same situation. Yet, with the exception of India and to a lesser extent China, which both recently became active in vaccine development, other eastern Asian countries have few or no vaccine efforts underway. Why not?

Several explanations can be given. One is that some of these countries were slow to acknowledge the extent of their AIDS problem. Another is that research sponsors and foreign investigators often have an insufficient, superficial knowledge of these countries, leading to concerns—legitimate or not—about whether obstacles such as local political turbulence, difficulties in building technical and/or national consensus, and slower approval processes, will prove insurmountable. In addition, local power agendas may take root, especially in the absence of effective collaboration between foreign or domestic institutions and/or individuals within the country.

But such explanations for not investing in these countries are not justifications. HIV vaccine development should be a high priority in Southeast Asia, alongside HIV/AIDS prevention and care. Research and funding institutions must have the courage to commit to regions with growing epidemics, whatever the local difficulties are. None of these difficulties are insurmountable and we must accept some risk that vaccine trials may not always go smoothly.

Ten years ago, WHO (then the Global Programme on AIDS) assessed a group of developing countries regarding their willingness and capacity to participate in vaccine testing, an exercise which led to a focus on Uganda, Rwanda, Brazil and Thailand. A similar in-depth, objective assessment of countries heavily affected by HIV today should be urgently renewed by WHO, since many more countries now wish to participate and are willing to undertake the steps needed to reach international standards of clinical development.

Political will on the part of foreign sponsors, institutions and investigators and an open-minded approach towards the difficulties of local conditions are essential ingredients of working successfully in developing regions. So is recognition that vaccine trials will require a long-term commitment from foreign scientists, rather than the much more common short-term, limited collaborations involving little cost or commitment (along the lines of "Let's set up a small lab and see how things turn out").

I favor a regionally-focused, integrated approach to HIV vaccine development. Countries in a given geographical area (for example, South East Asia or East Africa) should establish a task force that includes all national and international partners. This trans-agency taskforce should formulate a clear, specific vaccine development plan appropriate to the region, including a list of ways to establish effective interactions among the different players and to avoid situations in which different groups work in parallel without effective communication. It should also define the HIV subtype(s) to be used, vaccine concept, design and manufacturing and the appropriate and available populations for testing, along with any epidemiological studies needed to assess the feasibility of efficacy trials. The task force would prioritize the vaccine concepts to be moved forward and recommend the most appropriate countries for testing these vaccines. (One country may be more appropriate for Phase I trials, and another to test vaccine efficacy in specific types of populations).

But effective coordination can only happen under strong leadership—the definitive gap in HIV vaccine development. How many battles against disease would have been lost without the leadership of Louis Pasteur, the World Health Organization, Médecins Sans Frontières, and many others?

Where should this leadership come from? I have no magical formula to offer, but I would say to developing country leaders: "Don't wait for a solution from outside—be bold!" The United Nations and NGOs can also help embolden highly affected countries to be effective, pro-active partners in the process, and perhaps thereby to help mold new leadership.

Regions coming together in this way would have several advantages. It would allow for much bigger investments in infrastructure, technical and managerial capacity-building and cohort development. It would also help ensure that in-country people are fully involved with international partners in setting the overall vaccine agenda, not only in the late stage of designing and implementing specific trials, as is too often the case.

While these collaborations are not without their difficulties, and can be time-consuming to establish and maintain, proceeding without them could ultimately become an even bigger obstacle to the common goal of getting an effective vaccine as quickly as possible.

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©2001. The IAVI Report.

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