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Vaccine Development
Policy Issues in AIDS Vaccine Development
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Introduction
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The Status of Research
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Incentives for Private Sector Involvement
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Issues for Trial Participants
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Ensuring Access to an HIV Vaccine
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Introduction
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Public health officials have placed enormous hope on the potential of an HIV vaccine to bring the global HIV/AIDS epidemic under control. Yet numerous scientific, ethical, and public policy challenges remain before a vaccine can reach all those who need protection from HIV. For decades, vaccines have proven to be among the most powerful and cost-effective disease prevention tools available. Vaccines also have potential advantages over existing HIV prevention interventions: they can reach populations that otherwise have limited access to health care and prevention services, and they do not depend on consistent and sustained behavior change by millions of individuals.

An HIV vaccine capable of controlling the international epidemic would need to satisfy several criteria. It would need to be effective against multiple strains (or clades) of HIV, especially those predominant in developing countries. It would have to be made accessible to at-risk populations throughout the world, including populations with minimal ability to purchase the vaccine. And it would have to be deliverable in developing countries with rudimentary health care infrastructures. Each of these priorities presents special challenges to scientists and policymakers.

In 1997, President Bill Clinton set a national goal of achieving an AIDS vaccine within 10 years. Though many scientists are skeptical about the chances of meeting that deadline, most are increasingly positive about the likelihood of eventually developing an HIV vaccine. Even so, it is still unknown how an AIDS vaccine might actually work. An HIV vaccine might not be able to actually prevent infection, but would instead stop or delay progression to HIV disease, or simply reduce the infectiousness of people who do become infected with HIV. Another question is whether vaccines developed based on one clade of HIV will be effective against other clades of the virus.

Still another conundrum is the effect deployment of a partially effective vaccine will have on self-protective behavior in the population. If a vaccine that provides only 60 percent protection were widely distributed, there is the concern that vaccinees would assume they are totally protected from HIV and cease to practice safer sex, ultimately leading to an increased number of infections.

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The Status of Research
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As of May 2000, there had been over 60 phase I/II clinical trials of at least 30 candidate HIV vaccines. These initial trials were designed to test the safety and immunogenicity (ability to elicit an immune response) of the candidate vaccines. But, to date, AIDSVAX (produced by VaxGen) is the only HIV/AIDS vaccine that has reached phase III clinical trials designed to determine actual preventive efficacy in human beings. The trial in North America and Europe includes 5,400 participants and the one in Thailand 2,500. An interim analysis of the phase III trial in North America and Europe is scheduled for November 2001. (Some results drawn from the final report on the phase I/II trial of AIDSVAX in the U.S. were released at the 8th Conference on Retroviruses and Opportunistic Infections in Chicago in February 2001 [VaxGen news release, 2/9/01].)

HIV vaccine research is being conducted at numerous institutions around the world. The (U.S.) National Institutes of Health is the lead U.S. agency developing the basic science needed to drive HIV research. In recent years, the NIH HIV vaccine research budget has increased significantly, from $100 million in 1995 to $240 million in 2000. Several private organizations are also engaged in efforts to develop an HIV vaccine. The International AIDS Vaccine Initiative (IAVI) and the South African AIDS Vaccine Initiative (SAAVI) fund development of HIV candidate vaccines that are particularly appropriate for use in developing countries. IAVI has launched four research partnerships with researchers at universities and biotech companies. Each project seeks to develop a candidate HIV vaccine that can be used in the developing world. One project being supported by IAVI is the Oxford AIDS Vaccine Initiative, a collaboration of the universities of Nairobi and Oxford. This project involves the first AIDS vaccine candidate designed specifically for Africa, which will enter clinical trials in Nairobi in early 2001 (IAVI press release, 1/27/01).

The American Foundation for AIDS Research (amfAR) and the Elizabeth Glaser Pediatric AIDS Foundation also fund HIV vaccine research. The Global Alliance for Vaccines and Immunization (GAVI) is a worldwide partnership dedicated to improving access to immunization services in developing countries and accelerating the development and introduction of new vaccines and technologies, including an AIDS vaccine.

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Incentives for Private Sector Involvement
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Despite the urgent public health need, HIV vaccine research is at best a questionable financial investment; private sector pharmaceutical and biotech companies, which play a critical role in vaccine design and manufacture, have not raced to develop a vaccine for HIV. The scientific challenges are daunting, and the development timeline is long, expensive, and unsure. In addition, the vast majority of people who need an HIV vaccine live in developing countries where there are few resources to pay for health care or vaccines. This concern about the lack of a paying market in developing countries discourages private companies that fund HIV vaccine research from investing in research on products particularly suitable for lower-income countries. (This problem is not unique to AIDS. Research efforts regarding vaccines for other diseases endemic to the developing world have received only nominal private investments.)

The lack of private sector enthusiasm for HIV vaccine research is troubling for public health advocates because much of the expertise to develop and manufacture vaccines rests in private sector companies. A range of incentives has been proposed to encourage private sector investment in HIV and other priority vaccines. In his 2000 State of the Union Address, President Bill Clinton proposed a tax credit on sales of vaccines for malaria, tuberculosis, and HIV, and a significant increase in vaccine research at the NIH. The Vaccines for the New Millennium Act, introduced by Rep. Nancy Pelosi (D-CA) and Senator John Kerry (D-MA), would provide a tax credit on research and development costs for vaccines against the same three diseases. The act would also create a purchase fund to buy these vaccines for developing countries and includes a tax credit on sales. (The 106th Congress failed to pass any of these proposed incentives by the time it adjourned in late 2000.)

The European Union is now considering an incentive package for private sector investment in research on HIV, TB, and malaria vaccines. The proposed incentives include low-cost loans for small biotechnology companies, purchase funds, and limited patent extension on lucrative products in exchange for transfer of some patent rights to international public health organizations.

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Issues for Trial Participants
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It is likely that multiple large-scale trials of several HIV vaccines will be necessary before a highly effective product is identified. These trials will involve thousands of volunteers around the world over several years. Clinical trials of HIV vaccines raise important concerns about participant protections and research ethics.

Some HIV vaccine candidates may engender an antibody response in vaccinees, causing trial volunteers to test "positive" on standard HIV antibody tests even though they are not truly infected with HIV. In the U.S. and other countries, a positive HIV test result could lead to discrimination in health insurance and to social stigma. The simple fact of participating in an HIV vaccine trial may cause someone to be labeled a "high-risk" individual, a gay person, or a drug user. It is incumbent upon researchers to ensure they have the protections in place to warn trial participants about these risks and assist them if they should encounter problems. Confirmatory testing technology that can distinguish between vaccine-induced infection and actual infection should be accessible to all those enrolled in vaccine trials.

With the advent of postexposure prophylaxis and early treatment for HIV infection, access to therapy has become a critical ethical issue in international HIV vaccine trials. Should all people participating in these trials receive "state-of-the-art" antiretroviral treatment for HIV if they become infected during a trial, even if this treatment is not otherwise available in their country? In May 2000, UNAIDS released a guidance document that was not conclusive on this issue. The UNAIDS report called for medical treatment for HIV vaccine trial participants, "with the ideal being to provide the best proven therapy, and the minimum to provide the highest level of care attainable in the host country." Some ethicists have criticized the document as not providing adequate protection for trial participants in poorer countries.

There are several other important documents useful in considering the myriad ethical issues in HIV vaccine trials, including the Declaration of Helsinki and the (U.S.) National Bioethics Advisory Commission (draft) report "Ethical and Policy Issues in International Research".

Community education is an essential component of HIV vaccine trials. For example, in KwaHlabisa in KwaZulu-Natal, South Africa's Medical Research Council and the National AIDS Convention of South Africa (NACOSA) launched a four-year project entitled South African HIV Vaccine Action Campaign (SA HIVAC), funded by the European Commission. The project aims to help South Africans make informed decisions about participation in vaccine trials.

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Ensuring Access to an HIV Vaccine
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Developing an AIDS vaccine does not guarantee its use. For example, the highly effective vaccine for hepatitis B has been available in the industrialized nations for over 17 years, yet this vaccine has only recently become accessible in much of the developing world. Health advocates and public health officials agree that it is unacceptable for an HIV vaccine to follow the standard decade or longer delay between licensing in rich countries and availability in developing countries. But ensuring simultaneous access to an HIV vaccine in rich and poor countries alike involves many challenges.

Because HIV vaccines employing advanced technology may be expensive compared with current vaccines, a major issue is the severely limited health care resources in poorer countries for purchase of HIV vaccines. In addition, marginal health care infrastructures in many developing countries will render it difficult to distribute a vaccine. And vaccination programs will have to be adapted to reach the risk groups that need an HIV vaccine most urgently. Current immunization programs in developing countries focus on reaching children, but it is sexually active adolescents and adults that will most immediately need a vaccine for HIV. Part of the challenge will involve many countries' reluctance to acknowledge that young people are sexually active; reaching highly mobile or displaced populations with a vaccine will also have to be examined.

There are several proposals for accelerating access to HIV vaccines in the developing world. International organizations including the World Bank are considering establishing purchase funds to buy HIV and other vaccines. These funds could be financed with donations from industrialized governments and major foundations. Governments could also encourage tiered-pricing structures, in which vaccine purchasers in industrialized countries pay a significantly higher price for the vaccine than poor countries and aid organizations. IAVI has developed innovative intellectual property agreements with its research partners that will facilitate more rapid access to HIV vaccines in developing countries. Elected officials, other policymakers, and public health leaders in these countries will also need to make acquisition and distribution of HIV vaccines a priority.

Despite all the challenges inherent in HIV vaccine development and delivery, a preventive vaccine for AIDS remains the best hope to end the global epidemic. Researchers, public health leaders, governments, private organizations and companies, and affected communities must work together closely to accelerate research and delivery of HIV vaccines that can stem the tide of new infections throughout the world.

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