AIDS vaccine research in Asia: needs and opportunities
Report from a UNAIDSWHONIID meeting Tokyo, 28-30 October 1998
*See Appendix for meeting participants.
Sponsors: Jointly organized by the Joint United Nations Programme on HIV/AIDS (UNAIDS), Geneva, Switzerland (José Esparza); the World Health Organization (WHO), Geneva, Switzerland (Teresa Aguado and Laurie Ingels); and the National Institute of Infectious Diseases (NIID), Tokyo, Japan (Tamami Umeda and Shudo Yamazaki). The meeting was funded by UNAIDS and WHO and by grants received from the Ministry of Health and Welfare of Japan and the Department of Health and Family Services of Australia.
Corresponding author and request for reprints: Dr José Esparza, Vaccine Team, Department of Policy, Strategy and Research, Joint United Nations Programme on HIV/AIDS (UNAIDS), 20 Avenue Appia, CH-1211 Geneva 27, Switzerland.
A meeting was organized by the Joint United Nations Programme on HIV/AIDS (UNAIDS), the World Health Organisation (WHO) and the Japanese National Institute of Infectious Diseases (NIID) with the following objectives: (i) to discuss public health and economic rationale to accelerate the development and evaluation of HIV vaccines suitable for use in Asia; (ii) to review ongoing preclinical HIV vaccine research in Asia; (iii) to review the Asian experience in conducting clinical trials of HIV candidate vaccines; (iv) to explore possibilities for international collaboration between countries in the region and with other countries and institutions; and (v) to discuss issues related to availability of future effective HIV vaccines. The meeting was attended by participants from Australia, China, France, Germany, India, Japan, Malaysia, Myanmar, South Korea, Thailand, United Kingdom, and the United States of America.
The HIV epidemic in Asia is rapidly spreading and has already resulted in a total of 7 million HIV infections in the region. The epidemic already has a significant public health and economic impact, which may be worse in the future, unless effective intervention programmes are successfully implemented. A safe, effective, and affordable vaccine should be considered as the best hope for a long-term solution to the HIV epidemic in Asia. Asian scientists and institutions have established a number of international collaborations to isolate and characterize prevalent HIV-1 strains (mostly belonging to subtypes C and E) and are developing candidate vaccines based on these subtypes. In the region, phase I/II clinical trials of preventative HIV candidate vaccines have been conducted in Australia, China and Thailand. Since 1993, a comprehensive National AIDS Vaccine Plan has allowed Thailand to conduct phase I/II trials of six different preventative or therapeutic candidate vaccines, and the first phase III preventative efficacy trial has been approved. The meeting identified both the needs and the opportunities to intensify international collaboration to accelerate the development of HIV vaccines in Asia.
According to estimates from the Joint United Nations Programme on HIV/AIDS (UNAIDS) and the World Health Organization (WHO), the number of people living with HIV by the end of 1998 has grown to 33.4 million, 10% more than just one year before .
More than 95% of all HIV-infected people now live in the developing world, which has also experienced 95% of all deaths from AIDS. Since the beginning of the epidemic, HIV/AIDS has cost the lives of nearly 14 million adults and children. An estimated 2.5 million of these deaths occurred during 1998, more than ever before in a single year, and more than the number of annual deaths caused by malaria (estimated by WHO to be over 1 million deaths per year). Tuberculosis, the second biggest infectious killer, is also on the increase, driven largely by the HIV epidemic. The multiple repercussions of these deaths are reaching crisis level in some parts of the world, posing a major threat to development.
Despite intense national and international efforts to contain the HIV/AIDS pandemic, every minute 11 men, women and children around the world were infected during 1998, close to 6 million people in all. AIDS is still an emerging epidemic, whose death toll rises every year, while the number of newly infected people swells by some 16000 a day. There is growing agreement that behavioural interventions alone will not be sufficient to control the HIV pandemic, especially in developing countries, and that a safe, effective, affordable and widely deployed preventative vaccine is our best hope for a long-term solution [2,3].
The development of an AIDS vaccine will probably require the conduct of multiple trials in human volunteers. These trials will be needed to assess the safety, immunogenicity, and efficacy of different vaccine approaches (or concepts) against different HIV-1 subtypes and in different populations, which may differ in relation to the route of virus transmission, genetic background, etc. The conduct of these multiple trials will require a well-coordinated international effort, involving scientists and communities in different parts of the world.
For these reasons, UNAIDS, WHO and the Japanese National Institute of Infectious Diseases (NIID) convened the meeting on ‚AIDS Vaccine Research in Asia: Needs and Opportunities‚ (Tokyo, 28-30 October 1998), with the participation of 59 scientists from countries belonging to the WHO Western Pacific and Southeast-East Asia Regions (Australia, China, India, Japan, Malaysia, Myanmar, South Korea, and Thailand), collaborators from France, Germany, the United Kingdom and the United States, and Secretariat from UNAIDS and WHO. The meeting had the following objectives:
1. To develop public health and economic rationale to accelerate the development of HIV/AIDS vaccines appropriate for evaluation and use in Asia;
2. To review ongoing activities in Asia in the area of preclinical development of HIV candidate vaccines, and identify possibilities for collaboration;
3. To review ongoing activities in Asia in the area of clinical evaluation of HIV candidate vaccines, and identify possibilities for collaboration; and
4. To initiate discussions related to the future availability of HIV vaccines, which may prove in the future to be safe and effective.
Overview of the HIV/AIDS epidemic in Asia
Epidemiological aspects (Sarkar, Wiput, Samuel, Shao)
The rapid spread of HIV through the Asian continent, especially in Southeast Asia and East Asia, is of major concern. Although rates remain low compared with some other regions, well over 7 millions Asians are already infected, and HIV is clearly beginning to spread through the vast populations of India and China. One out of every five HIV-infected people in the world live in the Asia/Pacific region. It is projected that by the year 2000, one in four infected persons in the world will be from the region.
The global distribution of HIV prevalence among adult populations shows that none of the developed countries in the world have prevalence of more than 1%. Available date have shown that out of 49 countries having such high prevalence only three are in Asia: Thailand, Cambodia and Myanmar. The other country almost approaching 1% prevalence is India, with 0.82%. It must be remembered, however, that India, with a population of approximately 500 million people in the age group 15-48 years, the absolute number of infected people is staggering, emphasizing the magnitude of HIV infection in that country. The low HIV prevalence rates in other countries in Asia indicate the later introduction of the virus in this region. However, the region is going through periods of rapid HIV transmission at present: each minute three persons become newly infected with HIV and one person dies of AIDS every 2 minutes.
The full demographic and economic impact of the HIV/AIDS epidemic has not been felt. The epidemic is still unfolding and the situation will be worse in the future, unless effective intervention programmes are implemented. The speed of the epidemic offers a small window of opportunity for behavioural intervention to prevent a large-scale epidemic in the general population, and the long-term need for a preventative HIV vaccine as a significant public health tool is apparent. At the same time, the relatively high HIV incidence in certain groups may provide appropriate study populations to assess the potential efficacy of HIV preventative candidate vaccines.
Thailand has reported approximately 60000 cases of AIDS since 1985, with an estimated 780000 people living with HIV/AIDS in 1997. HIV prevalence in different population groups has changed with time. The overall HIV prevalence among military conscripts reached a maximum of 3.6% in 1993, and dropped to less than 3% in 1997. Among military conscripts, HIV prevalence was very high in the upper north of the country, up to 14% in 1993, and decreased to less than 3% in 1998. Overall HIV prevalence among pregnant women reached a peak of almost 2.5% in 1995, decreasing to 1.5% in 1998, with maximum prevalence of more than 7% recorded in the north of the country in 1995. HIV prevalence among commercial sex workers is between 20 and 30%, from 8 to 11% among clients of sexually transmitted diseases (STD) clinics, and between 25 and 50% among intravenous drug users. From the epidemiological point of view, potential study populations for efficacy trials of HIV vaccines in Thailand could include intravenous drug users, commercial sex workers and community-based populations with well-developed primary healthcare facilities. Incidence data from a sex worker cohort in Thailand gave incidence rates of approximately 12/100 person-months (PM) in 1989, which had risen to approximately 17/100 PM for 1991, and subsequently declined to approximately 9.3/100 PM during 1992-1993 . Annual incidence rates estimated in villagers were approximately 1-2% during 1990-1992 . An approximately twofold higher incidence in opiate users was observed in the north . HIV-1 incidence among Bangkok injecting drug users (IDU) escalated from 20/100 person-years (PY) in 1987 to a peak of 57/100 PY in 1988, then gradually declined to a stable rate of approximately 11/100 PY during 1991 and 1992 .
The estimated number of people living with HIV/AIDS in India is over 4 million, although the country has only reported some 6000 cases of AIDS, the majority in Maharastra (2955), Tamil Nadu (1314) and Manipur (301). The main reported routes of transmission have been heterosexual (45.5%), unsafe blood transfusions (6%) and intravenous drug use (3.6%). HIV seroprevalence surveys conducted up to 1998, involving a total of more than 3 million people, revealed an overall seropositivity of 2.3%, with higher prevalence in selected populations of Manipur (17.7%), Maharastra (11%), Goa (2.6%), and Tamil Nadu (1.5%). The real overall HIV prevalence among adults in India may now be approaching 1%. India‚s response to AIDS has been prompt, and a debate on the rationale for conducting HIV vaccine trials is warranted.
The HIV epidemic reported in China appears to be at an early stage. The estimated number of people living with HIV/AIDS in China is between 200000 and 400000, but with a population of more than 1.2 billion people, the epidemic could rapidly progress to dramatic dimensions.
Economic impact (Alban)
Projections from UNAIDS estimate that 16-26 million people may be living with HIV/AIDS in India alone by the year 2010. These figures are overwhelming and they will have enormous economic implications .
Individual households will be badly affected by the epidemic. For example, a survey in rural Thailand showed dramatic decreases of 40-60% in income and consumption as a result of HIV/AIDS. The coping strategies for these rural households include selling off assets and livestock, taking children out of school, using savings, and generating debt. Households are not islands in the ocean of society but very much part of it: money spent on healthcare is not invested in production; there is no generation of wealth and the whole community suffers as a consequence.
Healthcare services will be put under pressure from the increased demand generated by the HIV/AIDS epidemic. For example, the Indian government currently subsidizes 21% of the total health expenditures. If overall HIV prevalence increases to 5% in the year 2010, the total health expenditures could increase from US$3.2 billion to US$10.5 billion, compared with US$8 billion if the prevalence of HIV does not increase.
The close association between HIV and tuberculosis (TB) in many populations will also increase health costs. WHO estimates that 30-50% of HIV-infected people will develop TB. In India, more than 2 million people may already be infected with both HIV and TB, making HIV an increasingly important factor in the spread of TB. It is estimated that approximately a quarter of TB deaths foreseen in 2020 among people not infected with HIV would not occur in the absence of the HIV epidemic.
Other government-subsidized programmes that will come under pressure are the welfare system catering for orphans, e.g. school education and health insurance. At the end of 1997 UNAIDS estimated that there are 8 million orphans as a result of AIDS globally.
Measured in growth of the gross national product (GNP), the economic impact of the HIV epidemic on society at large will be moderate unless the prevalence of HIV reaches the high levels found in Sub-Saharan Africa. However, some geographical areas will feel a heavy impact. The developmental impact of HIV consists of much more than the growth of GNP, and should not be underestimated. For example, increasing numbers of children will be deprived of an appropriate school education; income distribution may be severely restricted, which will slow social development; certain labour-intensive industries (such as transport and mining) will experience an increase of expenditure caused by the sickness of employees; the extra cost of recruitment, training and replacements will burden employers. Factors such as these will result in increased costs of goods that are ultimately borne by global consumers.
The economic crisis in Asia could accelerate the epidemic by creating increased unemployment, followed by decreased consumption, which could lead to increased prostitution and cases of STD, followed by HIV/AIDS and TB. For years, Thailand devoted a relatively significant proportion of its resources to HIV/AIDS prevention and, in more recent years, to care for persons living with HIV/AIDS. That level of expenditure may not be possible in the face of the current economic crisis and an increasing number of HIV-infected people. As a result of the economic crisis, the budget of the Thai Ministry of Public Health was cut by 14.6% between 1997 and 1998, thus affecting AIDS prevention and control activities. Whether the reduction in the HIV/AIDS budget will have any visible effect on mortality or the incidence of HIV remains to be seen .
From a public health and economic perspective, the possibility of making an eventual vaccine available depends on whether overall benefits outweigh costs, including discounting within a reasonable time horizon, e.g. a generation. Vaccination programmes often achieve an overall favourable benefit-cost ratio of 2-4 within 10-20 years (e.g. measles). It is crucial for the economic success of an immunization programme that the costs are restrained as much as possible and that the benefits fall early and are targeted to the most vulnerable populations. The costs involved in making a vaccine available include: education of experts, vaccine development including efficacy trials, production of the vaccine, and implementation of the vaccination programmes (including the costs of adverse reactions) . To ensure the highest possible efficiency of an HIV vaccine programme, it is paramount to develop a ‚master strategic plan‚. The plan should include: population access, expected effect on HIV incidence for target populations (and when), requirements for booster doses, etc. To ensure the efficiency of the vaccine development programme it is essential that lags are avoided between efficacy trials and large-scale production, and between availability and widespread use. A strategy should be developed to avoid lags and to establish financial mechanisms from the start to the end of the process.
Overview of international HIV vaccine research
Different national and international agencies are contributing to the global effort to develop safe, effective and affordable preventative HIV vaccines, including the National Institute of Allergy and Infectious Diseases (NIAID) of the National Institutes of Health of the United States of America; the United States Department of Defence (DOD); the National Agency on Research on AIDS (ANRS) of France; the Australian National Council on AIDS and Related Diseases; the National Institute of Infectious Diseases (NIID) of Japan; the International AIDS Vaccine Initiative (IAVI). UNAIDS and its co-sponsors, notably the WHO, also play an important role in providing global coordination, especially for the conduct of vaccine research in developing countries, and in exploring issues related to future vaccine availability .
Candidate vaccines in the pipeline (Johnston)
A global effort has resulted in a number of HIV candidate vaccines in the ‚pipeline‚, which are at different stages of development [13-15].
Despite the clinical evaluation of over 25 different candidate vaccines in phase I/II human trials, conducted since 1987, it was only in June 1998 that the first phase III efficacy trial of an HIV candidate vaccine was initiated. This trial is evaluating the efficacy of a bivalent (clade B/clade B) gp120 candidate vaccine (produced by VaxGen, South San Francisco, CA, USA) in high-risk volunteers in the United States. An efficacy trial with a similarly constructed but different bivalent (clade B/clade E) candidate vaccine (also produced by VaxGen) was approved for implementation in Thailand. Ancillary studies will hopefully provide information on whether humoral immune responses correlate with protection, and if the candidate vaccine has a measurable impact on HIV infection in those who do become infected .
The next vaccine concept to be evaluated in efficacy trials, under the sponsorship of the NIAID, is likely to be a recombinant canarypox vector (Pasteur Merieux Connaught, Lyon, France) expressing multiple HIV genes, which may be evaluated in combination with an envelope protein boost (e.g. ‚prime-boost‚). Unlike gp120 alone, which does not induce detectable cytotoxic T lymphocytes (CTL) in human volunteers, the canarypox plus envelope combination induces both antibodies and CTL in a majority of recipients [17,18]. Vector optimization studies and envelope combination studies are now underway so that an efficacy trial could begin in the next 2 years. In addition, a canarypox vector expressing clade E envelope boosted by various clade E envelope proteins is being considered for evaluation in Thailand, in collaboration with the United States DOD. Clade C canarypox vectors are earlier in development. A series of trials to determine if this prime-boost approach can help prevent maternal-infant transmission is also under discussion.
The first phase I trial of a candidate vaccine in Africa, also under the sponsorship of the NIAID is due to begin in Uganda early in 1999 This trial, which will evaluate canarypox expressing multiple clade B genes, will help answer several critical questions. In addition to safety, the trial will evaluate the level of CTL induced in Ugandan volunteers, and the breadth of cross-reactivity of those CTL, particularly against indigenous strains of HIV.
Other candidate vaccines are in earlier stages of clinical development and are unlikely to reach the stage of efficacy trial alone or in combination before the year 2002. In phase I trials are: HGP-30w, a peptide vaccine tested in the United States and Europe; DNA vaccines expressing Env/Rev or Gag/Pol tested in the United States; vaccinia vector expressing Gag/Pol/Env, tested in the United States; a salmonella vector expressing Env, tested in the United States; canarypox administered by mucosal routes in the United States.
Many interesting candidate vaccines are in preclinical development, including a recombinant bacillus Calmette-Guérin (BCG) expressing a portion of Env; DNA plus modified Ankara strain of vaccinia combination being designed for possible testing in the United Kingdom and Kenya; Venezuelan equine encephalitis replicons designed for possible testing in the United States and South Africa; pseudovirions to be tested in the United States; Gag particles to be tested in the United States.
International collaboration (Johnston, Birx, Fleury, Berkley, Esparza)
To give further support to many of the plans described in the previous section, the NIAID is launching several new specific programmes to expand all stages of the vaccine pipeline, and to help support all organizations with the talent and ideas to contribute to this worldwide priority.
The US DOD HIV Research Program, led by the Walter Reed Army Institute of Research, is concerned with all phases of preventative vaccine development as a primary mechanism of HIV/AIDS prevention. A cornerstone of the programme‚s strategic plan involves the development of vaccine approaches/strategies, which are designed to elicit a diverse array of effector mechanisms, characterized by strong and durable immune responses against multiple antigenic targets of HIV. It is the programme‚s strategic plan to advance ‚the best‚ candidate of each effector class (1. humoral; 2. cellular; 3. both) to proof-of-concept efficacy evaluation. Ideally, this entails a comparative multi-arm trial. Currently, this strategic approach incorporates development plans with milestones and advancement criteria, and agreement-in-principle from the Technical Subcommittee on AIDS Vaccine Development of the National Commission for the Prevention and Control of AIDS, Ministry of Public Health, Thailand, for the simultaneous development of bivalent B/E rgp120 (Chiron Vaccines, Emeryville, CA, USA), canarypox-HIV vCP1521 (Pasteur Merieux Connaught) with soluble recombinant gp120 or gp160 boost .
The ANRS of France coordinates studies on the characterization of neutralizing and enhancing antibodies, vaccination vectors, new antigen targets, animal models, and vaccine clinical trials. Different candidate vaccines are being developed, including trimeric gp120 (including field isolates), lipopeptides and pseudopeptides, DNA vaccines, and live viral and bacterial vectors (canarypox, adenoviruses, BCG). In humans, no protection trials have been carried out in France, but several phase I trials have been conducted, using recombinant canarypox-HIV recombinants, gp160 of HIV-1 MN/LAI plus V3 peptides and lipopeptides The main results are: neutralizing antibodies are effective only against laboratory isolates of HIV; prime-boost protocols induce good CTL responses and some protocols can also induce antibody responses, although of short duration; lipopeptides induce CD4 and CD8 cellular responses; immune memory can be established on a long time but restimulation is not systematically successful. The ANRS is also engaged in collaborative studies in Cambodia (Pasteur Institute of Phnom Penh) and Vietnam (with the Pasteur Institute and the Center for Preventive Medicine in Ho Chi Minh City), with the Pasteur Institute in Paris and the virus laboratory of Bordeaux University. This collaboration has involved epidemiological studies and virus isolation and characterization. For example, in Vietnam, subtype E strains were found to be the most prevalent subtype in the investigated groups (intravenous drug users, sex workers, STD patients), but subtypes B and C were also identified.
The IAVI was established as an international non-governmental agency in 1996 because of the perception that the HIV vaccine effort was lagging. Its mission is to ensure the development of safe, effective, accessible, preventative vaccines for use throughout the world. The three main strategies of the IAVI are: (i) communication, education and advocacy, to ensure that HIV vaccines are high priority; (ii) creating an enabling environment to provide adequate incentives for industry; and (iii) an aggressive scientific programme that focuses on the development of promising vaccines that are appropriate for testing and future use in developing countries.
One of the five global priorities of UNAIDS is to promote the development, evaluation and future availability of safe, effective and affordable HIV preventative vaccines for worldwide use, especially in developing countries. That goal is promoted through several activities: collection, exchange and analysis of information; creation of collaborative networks; assistance with capacity building in developing countries; provision of independent and authoritative advice; addressing ethical, regulatory and legal barriers; and advocating for HIV vaccines. Several of the UNAIDS partners (including NIAID, NIID, IAVI and the Australia-based MacFarlane Burnet Center for Medical Research) have been designated, or are in the process of being designated UNAIDS Collaborating Centres.
HIV vaccine research and development in Asia and the Pacific
Distribution of HIV genetic subtypes (Esparza, Shao, Gadkari)
HIV-1 strains are usually classified within genetic subtypes defined by phylogenetic analysis of the nucleotide or amino acid sequences of the env gene. Most HIV-1 strains are included within a main (M) group, in which multiple genetic subtypes (clades) have been defined and designated as envelope subtypes A to J, although it is increasingly recognized that many strains represent mosaic viruses generated by recombination of different subtypes . The geographical distribution of HIV-1 subtypes is not uniform. Overall, the most prevalent genetic subtype in the world is subtype C (48%), followed by A (25%), B (16%), E (4%), and D (4%). The epidemics in the Americas, Western Europe, Japan, and Australia/New Zealand are dominated by subtype B strains. Many subtypes are present in Africa, although the most important are C, mostly in southern Africa, and A in central and western Africa.
The epidemics in several developing countries in Asia were first started by subtype B viruses, especially among intravenous drug users, but later were supplanted by HIV-1 strains related to African strains: subtype E in Thailand and subtype C in India, both of which are primarily linked to heterosexual transmission [21-27]. Interestingly, in Thailand, the most prevalent strain is a recombinant virus with a subtype E env gene and a subtype A gag gene. Likewise, the virus that seems to be more rapidly spreading in China is also a recombinant C/B‚ virus, which probably originated in the Yunnan Province, where a subtype B‚ epidemic, mostly among intravenous drug users, encountered a mostly heterosexual subtype C epidemic probably introduced from South Asia .
The prevalence of non-B subtypes in developing countries in Asia, combined with specific vaccine development expertise and commitment of Thailand, has stimulated the development of candidate vaccines for subtype E strains. Work is also underway to develop candidate vaccines based on subtype C strains. These efforts are important, although the relevance of HIV-1 genetic variability in terms of potential vaccine-induced protection is unknown. Different laboratories have reported certain degrees of cross-neutralization among different subtypes, using sera from infected people, although the patterns of neutralization have been complex, not yet allowing for a clear identification of neutralization immunotypes. On the other hand, people infected with HIV, or immunized with certain candidate vaccines, have clearly been shown to develop CTL with cross-clade lytic capacity. It should be mentioned, however, that subtype E viruses seem to be more distantly related to the other subtypes, with respect to both humoral and cell-mediated responses .
If protective immune responses are based on CTL, then there is some rationale to believe that candidate vaccines may not have to be developed against each genetic subtype, with the possible exception of subtype E. On the other hand, if humoral immune responses are necessary for protection, then subtype-specific vaccines may be needed, unless new vaccine concepts are developed to induce neutralizing antibodies against highly conserved conformational epitopes in the HIV envelope protein. In any case, carefully designed efficacy trials will eventually be needed to address the question of cross-clade vaccine-induced protection.
Preclinical research (Mills, Yamazaki, Honda, Natth, Shao, Wolf, Gadkari)
Several countries in the Asia and Pacific region are engaged in research related to the preclinical development of potential candidate vaccines.
Australia‚s expertise in virology and immunology has fostered a vigorous HIV vaccine research and development effort, although the lack of resources and local success at containing the HIV epidemic has meant that none of these locally developed vaccine concepts has yet gone to clinical trials. Initial optimism that the ‚Sydney Blood Bank Cohort‚ strain of HIV-1, attenuated by virtue of nef-long-terminal repeat deletions, might be a candidate live attenuated vaccine has been markedly diminished by recent observations that some members of the cohort have been developing progressive declines in CD4 lymphocyte counts [30-32]. Another novel vaccine strategy pioneered in Australia is that of directing the vaccine immune response by the co-expression of cytokines with HIV-1 proteins. This strategy is being explored using an avipox expression vector, and changes in the qualitative and quantitative immune response have been achieved by the addition of IFN-g and IL-6 genes. An avipox-IFN-g vaccine construct is scheduled to go into therapeutic vaccine trials in 1999, and it is hoped that trials in uninfected volunteers can begin shortly after that. A third strategy that is well advanced is a ‚prime-boost‚ regimen, priming with a DNA expression system and boosting with an avipox vector. On the basis of promising data in mice, a study has recently been completed in the HIV-macaque system, which has shown protection from HIV infection by a relatively limited prime-boost strategy. This approach will be tested in the SIV-macaque model, and clinical trials are also planned. In addition to these main approaches, immunization (via a variety of methods) is being evaluated with synthetic class 2 epitopes (so called ‚polytopes‚), and efforts are being undertaken at a more basic level to understand how HIV vaccine immunogenicity can be enhanced. Two groups are using novel strategies to develop gp41/ gp120-based vaccines, and there is also preliminary work on the use of human papilloma virus as a vector to induce a mucosal immune response to HIV.
Currently, preclinical HIV vaccine research in Japan is focussed on five different areas: (i) recombinant BCG (rBCG)-HIV recombinant live-vectored candidate vaccines; (ii) HIV-1 gp120 peptides expressed by recombinant Sendai virus; (iii) chimeric virus-like particle (VLP) vaccines based on the core protein of the hepatitis B virus; (iv) live-attenuated SHIV (SIV/HIV) vaccines; and (v) DNA vaccines [33-38]. Considerable work has been done with BCG-vectored vaccines. The principal neutralizing domain of the V3 region of the gp120 envelope protein was included in the initial constructs, as a chimeric protein with the a antigen of BCG. Inoculation of the recombinant BCG-HIV(V3) was capable of inducing neutralizing antibodies against clinical isolates of HIV and delayed-type hypersensitivity to the synthetic peptide. The same construct induced a limited number of CTL in mice. Inoculation of cynomolgus monkeys with rBCG-HIV induced binding antibodies to the principal neutralizing domain and neutralizing antibodies against laboratory isolates of HIV-1 (although the neutralization of laboratory isolates remains to be confirmed). Initial protection experiments in macaques, using non-pathogenic SHIVs have shown some degree of protection with the rBCG-HIV-1(V3). New generations of the rBCG-HIV vector will include additional proteins/epitopes: gp41-2F5, Nef, and Gag, from different clades, including Japanese B consensus, Thai B‚, and Thai E.
The development of rBCG-vectored vaccine is now proceeding as a joint project between Japan and Thailand, based on a long history of collaboration between the scientists of both countries. For example, technology transfer from Japan led to the local production in Thailand of Japanese encephalitis vaccine using the Nakayama strain produced in suckling mouse brain; such technology was successfully transferred in 1988, resulting in the incorporation in 1992 of the Japanese encephalitis vaccine in the Expanded Program on Immunization. The objective of the present collaboration is to develop BCG-based HIV vaccines that incorporate genes from clade E viruses, prevalent in Thailand, into the rBCG cassette initially developed in Japan. After satisfactory animal studies and safety tests, the clade E candidate vaccines would be considered for phase I clinical trials in Thailand. This is an ambitious, long-term collaboration, with specific plans already discussed for the next 5 years. On the Japanese side, the project includes provisions for research and development of the rBCG candidate vaccines; evaluation of safety/immunogenicity and efficacy in animal models; establishment of laboratory reference services; and assistance in the development of cohorts in Thailand. To achieve the goal of technology transfer and capacity building, a network of Thai scientists has been established, including representatives from the Thai Minister of Public Health, National Institutes of Health, Department of Medical Sciences, and from the Chiang Mai, Chulalongkorn and Mahidol Universities. Four modules of cooperation have been established: development of rBCG candidate vaccines; molecular epidemiology of HIV in Thailand; immunology with emphasis on CTL; and animal facilities. In addition, discussions are underway to explore the possibilities of future pilot production of vaccines in good manufacturing practice facilities in Thailand. UNAIDS and WHO are also collaborating with Japanese scientists in the development of the rBCG-HIV vaccine concept.
Investigators from the University of Regensburg (Germany) and the Chinese Academy of Preventive Medicine are collaborating in the development of HIV-1 VLP candidate vaccines based on the Pr55Gag precursor that includes both T helper and CTL epitopes. An alternative p55Gag-Env construct is designed to present oligomeric HIV-1 envelope derivatives to the immune system. Some of the VLP formulations generated neutralizing antibodies and CTL in immunized rhesus monkeys and, although the candidate vaccines did not induce sterilizing immunity, they appeared to accelerate clearance of the primary viremia, although long-term outcomes remain to be determined. A representative clade B‚ strain from Yunnan Province has been molecularly cloned and characterized and is now available for the construction and evaluation of future candidate vaccines for testing in China [39,40].
India is experiencing an explosive epidemic of HIV, as revealed by studies in the western part of the country describing high incidence and high prevalence among STD patients [41,42]. The spread of HIV in low-risk populations has also reached a significant proportion. Although subtype C is the most prevalent in India, other subtypes and two genotypes of C have also been reported, suggesting the circulation of multiple subtypes in the same community. Fortunately, India has an excellent infrastructure, expertise and capability to undertake basic as well applied clinical research and eventually to develop its own indigenous candidate vaccines [43,44]. Combined efforts of the National AIDS Control Organization, the Department of Biotechnology and the Indian Council of Medical Research should expedite the research in this area. A Technical Resource Group on Research and Development in HIV/AIDS, based at the National AIDS Research Institute, in Pune, has identified HIV vaccine development as one of the priority areas for the next 5 years in India. The Department of Biotechnology is considering funding for several HIV vaccine development projects employing modern biotechnological approaches. The Indian Council of Medical Research, with its large network of institutes and regional medical research centres spread all over the country, can also participate in vaccine development and controlled clinical trials. Some of these activities may be undertaken in collaboration with experts from other countries, including the Indo-US Vaccine Action Program, IAVI, UNAIDS, and other agencies/institutions. Different areas have been preliminarily identified as priorities: HIV subtype and recombinant surveillance, including the establishment of an ‚HIV Virus Bank‚; characterization of HIV strains in India; vaccine development research (DNA vaccines, peptide vaccines, adjuvants, mucosal immune responses, etc); studies on the development of suitable animal models; immunological studies aimed at establishing correlates of protection in future vaccines, especially CTL studies; establishment of clinic and community-based cohorts of HIV-negative volunteers for future efficacy trials of preventative vaccines. Clinical studies related to HIV vaccines manufactured in India can be undertaken on priority, and an intense interaction and collaboration between researchers and vaccine manufacturers is envisaged.
Phase I/II(safety and immunogenicity) trials (Crowe, Shao, Dwip, Chirasac, Vina)
Phase I/II trials of both preventative or therapeutic HIV candidate vaccines have been conducted in different countries of the region, including Australia, China and Thailand.
Australia has developed an infrastructure for conducting HIV vaccine clinical trials based on activities of the three National Centers in HIV Research (HIV Epidemiology and Clinical Research, HIV Virology Research, and HIV Social Research). These centres and their collaborators have access to appropriate populations of relatively homogenous (economically and socially) volunteers for clinical trials, and there is an excellent track record for recruiting clinical trial participants. Laboratory support includes facilities to determine virus load, clade analysis and CTL and lymphoproliferative assays and a macaque facility for testing novel experimental vaccines. All this provides an excellent environment in which to conduct phase I/II trials of HIV candidate vaccines. The first phase I/II trial of an HIV candidate vaccine assessed the safety and immunogenicity of an HIV-1 MN octameric peptide (United Biomedical Inc., Haupauge, NY, USA) in 24 HIV-seronegative volunteers. A second trial analysed the safety and immunogenicity of p24-virus-like particles (Bristish Biotech, Cambridge, UK) in HIV-infected asymptomatic patients receiving zidovudine. Another trial is being planned, to study the safety and biological activity of avipox virus expressing Gag-Pol and IFN-g in asymptomatic HIV-infected volunteers.
The first HIV vaccine trial in Asia was conducted in 1993-1994, in Yunnan Province in China, where the United Biomedical Inc. HIV-1 MN octameric peptide candidate vaccine was tested in 23 HIV-negative volunteers .
The same octameric peptide vaccine from United Biomedical Inc. was the first HIV candidate vaccine tested in Thailand , a country which has already conducted a total of five phase I/II trials in HIV-negative volunteers and one in HIV-infected volunteers. HIV vaccine activities in Thailand are coordinated by the Scientific Subcommittee on AIDS Vaccine Development from the ‚National Commission for the Prevention and Control of AIDS‚. A National Plan for HIV/AIDS Vaccine Research, Development and Evaluation was prepared in 1992, with assistance from the former WHO Global Program on AIDS . Over the years, the Thai AIDS vaccine plan has evolved, from a ‚passive‚ plan, basically aimed at facilitating trials of existing candidate vaccines, to an ‚active‚ plan, which promotes the development of candidate vaccines that may be more appropriate for Thailand (such as those based on clade E), and the full participation of Thai scientists through the entire process of HIV vaccine development, evaluation and future availability.
The trial with the United Biochemical Inc. octameric V3 peptide candidate vaccine was initiated in June 1994, enrolling 30 low-risk HIV-negative volunteers, and it was conducted by investigators of Chulalongkorn University in collaboration with the Thai Red Cross Program on AIDS . This trial was followed, in February 1995, by a trial with a rgp120/ MN in alum (Genentech, Inc., South San Francisco, CA, USA) conducted in 33 HIV-negative recovering IDU in Bangkok, and conducted by the Bangkok Metropolitan Administration (BMA), the Vaccine Trial Center of Mahidol University, the Faculty of Medicine of Siriraj Hospital, the Ministry of Public Health, and the WHO Global Program on AIDS [48-50]. Shortly after, in August 1995, another rgp120 candidate vaccine derived from the clade B SF2 strain (Chiron Vaccines) was evaluated in 52 HIV-negative low-risk volunteers by the Bangkok-based Armed Forces Research Institute of Medical Sciences, the Research Institute for Health Sciences of Chiang Mai University, and the Walter Reed Army Institute of Research. All these trials were conducted with clade B candidate vaccines and showed that the products were safe and well tolerated and induced immune responses comparable to those induced by the same candidate vaccines in the United States.
The HIV epidemic in Thailand is mostly caused by clade E strains, and therefore because laboratory results suggested that clade E viruses were antigenically different from clade B strains, it was considered appropriate that vaccines for testing in Thailand include clade E antigens. Consequently, both Chiron Vaccines and VaxGen Inc. developed a bivalent approach, incorporating clade B and E strains. Although the initial clade B rgp120s were based on laboratory strains using CXCR4 as second receptor, the newly developed clade E rgp120s were based on CCR5-using clinical isolates (strains CM235 and A244). The first trial with the bivalent B/E rgp120 candidate vaccine (using the Chiron Vaccines product) was initiated in November 1997, enrolling a total of 380 HIV-negative volunteers . The second bivalent B/E rgp120 product (VaxGen) entered a phase II trial in Thailand in March 1988 in 90 HIV-negative volunteers. An initial evaluation of this second trial suggested that the bivalent vaccine was capable of inducing the same level of binding antibodies to both antigens when compared with the monovalent vaccine, which was the criteria selected to proceed to a phase III efficacy evaluation of this product early in 1999 .
Thailand has also been involved in therapeutic vaccine studies, using the gp120-depleted HIV-1 Immunogen or Remune (Immune Response Corporation, Carlsbad, CA, USA). An open-label study began in March 1996 with 30 HIV-infected volunteers from Ramathibodi Hospital, given four doses at 4 week intervals for 4 months. Immunization was well tolerated with no serious adverse events reported in the course of the 4 month study. Retrospective studies revealed that 29 out of the 30 subjects were infected with subtype E virus. One year follow-up of the same study showed decreased plasma HIV-RNA levels, and increases in subjects‚ body weight, CD4 cells, CD8 cells, and humoral immune responses detected by Western blot assay. On the basis of those studies, an additional 297 HIV-infected volunteers from various centres in Bangkok and in other regions of the country have been enrolled in a phase II, double-blind, randomized, adjuvant-controlled study. Three cohorts with 33 subjects each have already finished all four doses of HIV-1 Immunogen with no adverse events observed. The follow-up study of these cohorts has been expanded to include antiretroviral drugs (highly active antiretroviral therapy or the combination of two antiretroviral drugs) in combination with HIV-1 Immunogen given every 3 months for 2 years, to test the clinical benefit of this regime on subjects with subtype E infection prevalent in Thailand [53,54].
Preparation for phase III (efficacy) trials in Asia (Dwip, Brown, Gadkari, Esparza)
Before field efficacy trials of HIV candidate vaccines can be conducted in developing countries, several critical issues must be addressed, such as strengthening research infrastructures, monitoring HIV variability, and ethical and social-behavioural issues. Of critical importance is the identification of appropriate populations in which efficacy trials can be conducted, with sufficient HIV incidence after other preventative interventions have been implemented, accessible in sufficient numbers, and willing to participate in trials and be followed for several years.
HIV incidence in Thailand has been characterized as moderate and has stabilized in two high-risk groups: i.e. heterosexual and IDU [55-57]. Up to 1998, several prospective cohorts have shown that the heterosexual epidemic in Thailand is predominantly subtype E. However, the epidemiology of HIV-1 infection in the Bangkok IDU population is somewhat different and has been well described [57-59]. Between May 1995 and December 1996, a prospective cohort of 1208 IDU attending the BMA‚s 15 drug treatment clinics was established, with the co-sponsorship of UNAIDS and the HIV/AIDS Collaboration, a joint activity of the Thailand Ministry of Public Health and the US Centers for Disease Control and Prevention. HIV incidence in this cohort is 6.8% per person/year with 71% follow-up at 1 year, 80% of incident infections are caused by subtype E and 20% by B‚. The phase I/II trials of the Genentech/VaxGen rg120 B and B/E candidate vaccines were conducted in this cohort, Participants in the phase III trial with the VaxGen rgp120 B/E candidate vaccine will also be recruited from this cohort. To that effect, a consortium has been established called the Bangkok AIDS Vaccine Evaluation Group, comprising the BMA, Faculty of Tropical Medicine of Mahidol University, and the HIV/AIDS Collaboration. A total of 2500 IDU attending 17 BMA drug treatment clinics will be randomly allocated to receive either a VaxGen MN/A244 (300mg of each antigen) candidate vaccine or placebo at months 0, 1, 6, 12, and every 6 months until month 30. Vaccine endpoints will include the prevention of infection or modification of infection as defined by self-limiting viremia or reduced viral load.
Other potential study populations for future efficacy trials of HIV candidate vaccines are being explored in Thailand [60,61]. This is being done on the basis of 15 years of collaboration between the Armed Forces Research Institute of Medical Sciences, the Ministry of Public Health and Mahidol University, including large-scale efficacy trials of vaccines against Japanese encephalitis, hepatitis A and malaria. Previous studies of potential vaccine trial cohorts have evaluated women sex workers, STD and anonymous testing clinic attendees, rural villagers, factory workers, and military conscripts [62-67]. In general, incidence was inversely related to follow-up rates. Most studies have sought to identify population subgroups (based on risk behaviour or geographical clustering), and to develop systems to access them. An alternative approach is to identify the access system, then characterize the subgroup. Several collaborative teams are now utilizing both of these approaches to gather current incidence and follow-up rates in ‚community cohorts‚ and family planning clinic attendees. These efforts are on a timeline to generate data for analysis in 1999-2000. Planning for phase III trials of HIV vaccines in Thai heterosexuals includes a ‚go versus no-go‚ decision when the cohort data becomes available. These results will determine the sample size requirement and the feasibility of including multiple arms, but this situation should be viewed in a wider context. Candidate vaccines have been specifically constructed for the subtype E virus prevalent in Thailand by three major industrial partners, Chiron Vaccines, VaxGen and Pasteur Merieux Connaught; a fourth partner, Wyeth-Lederle Vaccines, has a clade E DNA vaccine in development. This same HIV-1 E clade predominates throughout the HIV epidemic of mainland Southeast Asia, where there is extensive human migration and trafficking of women. The leadership which Thailand has shown in HIV phase I/II/III trials will have to be followed by one of two courses. Additional efficacy trials in the ‚subtype E‚ region are likely to require a trial site of tens of thousands of volunteers if carried out within Thailand or, alternatively, a smaller number of volunteers if the trials were carried out as a regional collaboration.
India, where clade C predominates, is outside of the ‚subtype E‚ region. In this country, establishment of clinic and community-based cohorts for assessing the efficacy of candidate HIV vaccines is a high priority. One such cohort of HIV-negative, STD clinic attendees is being developed in Pune.
Efficacy trials of HIV candidate vaccines will be complex scientifically, logistically and ethically. To help ensure the ethical conduct of HIV vaccine trials, UNAIDS is developing a Guidance Document on Ethical Considerations on the Conduct of International Trials of HIV Preventive Vaccines. This document is being developed through an intense process of consultation, which has included community workshops in several countries (one was held in Bangkok in April 1998, with participants from several countries in the region). The final document will be released in 1999.
Working towards future availability of HIV vaccines (Bhamarapravati)
Developing countries can provide industry with unique incentives for the conduct of phase III HIV vaccine efficacy trials. In the case of Thailand, these incentives include: available cohorts and study populations with sufficiently high HIV incidence; relative genetic homogeneity of the prevalent HIV strains; reduced levels of therapeutic interventions; personal commitment of national scientists and authorities; and an urgent public health need for a vaccine. Trials in Thailand can offer a high likelihood of logistical success because of the existence of stable study populations, reasonable managerial structure, high compliance rate, cost-effectiveness, and adherence to ethical principles. These conditions could lead to a faster ‚proof of concepts‚ of candidate vaccines, providing good support for United States licensure and potentially resulting in earlier financial returns.
For ethical, humanitarian, public health and economic reasons, it is important, however, to ensure that those vaccines that are tested in developing countries and found to be safe and effective, be made reasonably available to these populations. To ensure that there are not delays in vaccine availability, it is important to approach the issue in a proactive way, rather than waiting until a successful efficacy trial is completed.
Early dialogue on accessibility, availability and affordability of the vaccine should be initiated with the manufacturers during the planning for phase I/II trials and more concretely before phase III trials commence. Previous experience indicates that manufacturers usually agree verbally to explore alternatives to make products available, but that they rarely do so in writing.
It should be appreciated that the first HIV vaccines found to be effective may be only moderately protective (perhaps in the range of 30-50%), and decisions should be made in advance if, or how, these vaccines could be used. That is a discussion that should involve specialists in infectious diseases, public health specialists, vaccine manufacturers and suppliers and regulatory authorities. The initial vaccines will also be subjected to free market competition, which may create supply problems, especially in developing countries.
As donations of future HIV vaccines to most developing countries is an unlikely initial possibility, different alternatives could be considered and discussed: special discounts or rebates, especially when trials are conducted in the country; bulk shipment and fill in appropriate dosage form in good manufacturing practice facilities in the developing country; joint-venture production; licensing for developing countries based on their own special requirements; and public-private sharing of costs. International agencies and developed countries could assist by: providing grants or loans for the purchase of vaccines; providing support for research and development and clinical trials under special conditions regarding the price for developing countries; providing grants or special loans for the construction of production facilities in developing countries; and assisting developing countries in strengthening their regulatory control authorities for HIV vaccines.
A highly controversial issue is the question of whether clinical trials contribute to new intellectual property rights (IPR). The main question is: Do trials in developing countries, which provide information for licensure, deserve especial consideration in relation to sharing IPR? Traditionally, only preclinical development leads to IPR, but results from clinical trials are the ones that lead to licensing. A possible innovation would be to consider that, if trials in developing countries are of definite advantage to the manufacturer in moving the products to licensing, then IPR could be shared.
The ultimate outcome will, however, depend on the creation of a situation in which the vaccine manufacturer could derive its commercial objective; the developing country could achieve its public health objective; and the international agencies and industrial countries could achieve the global objective of curtailing the spread of HIV/AIDS.
Final conclusions and recommendations
In Asia, the dual epidemic of HIV-TB will become a dominating disease burden within the next 5-10 years, leading to decreased economic growth and tremendous human suffering at all levels of society, although experience indicates that the poorest segments of the population will be the hardest hit. The best long-term solution to overcome the problems for future generations in Asia will be an effective, affordable, sustainable and equitably delivered HIV/AIDS immunization programme. It is in the self-interest of Asia to ensure the prosperity of the region, and it is in the self-interest of the industrialized countries outside of the region to assist in this process.
The future success of HIV vaccine development hinges on: (i) Establishing and maintaining a healthier pipeline of candidate vaccines; (ii) Developing international collaborations that cut across the sectors (private/public, developed/developing); (iii) Conducting parallel phase III efficacy trials of the most promising candidate vaccines in different populations, especially in those with the highest need of a vaccine; and (iv) Ensuring that, once a successful vaccine is identified, it is rapidly assessed, modified as necessary, and widely used to meet worldwide needs. Even an initial low efficacy HIV vaccine, in combination with other preventative interventions, could have a significant impact on the HIV/AIDS epidemic [68-70].
The meeting was chaired by Natth Bhamarapravati (Thailand) and co-chaired by Shudo Yamazaki (Japan) and Cathy Mead (Australia). The following participants were members of the drafting groups for the different sessions of the meeting: Anita Alban (UNAIDS), Isao Arita (Japan), Seth Berkley (USA), José Esparza (UNAIDS), Mitsuo Honda (Japan), Dwip Kitayaporn (Thailand), John McNeil (USA), Tikki Pang (Malaysia), Swarup Sarkar (UNAIDS), Yiming Shao (China), Masayoshi Tarui (Japan), and Takusei Umenai (Japan). Secretarial support was provided by Laurie Ingels and Jeanne Ryan. This report was prepared by José Esparza, based on working papers submitted by most participants and on the notes provided by the drafting groups. Substantive comments on the final draft were provided by Anita Alban, Arthur Brown, Deepak Gadkari, Margaret Johnston, Dwip Kitayaporn, John McNeil and John Mills.
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Australia: Suzanne Crowe (McFarlane Burnet Centre for Medical Research, Fairfield), Cathy Mead (National Centre for Disease Control, Canberra), John Mills (MacFarlane Burnet Center for Medical Research and Australia National Centre for HIV Virology Research, Fairfield); China: HeMing Li (Chinese Academy of Preventive Medicine, Beijing), Philip Ngai (Hong Kong Institute of Biotechnology, Hong Kong), Yiming Shao (Chinese Academy of Preventive Medicine, Beijing); France: Hervé Fleury (Groupe Hopitalier Pellegrin, Bordeaux); Germany: Hans Wolf (University of Regensburg, Regensburg); India: Deepak Gadkari (National AIDS Research Institute, Pune), N.M. Samuel (The Tamil Nadu Medical University, Madras), Pradeep Seth (All India Institute of Medical Sciences, New Delhi); Japan: Isao Arita (Agency for Cooperation in International Health, Kumamoto), Mitsuo Honda (National Institute of Infectious Diseases, Tokyo), Masaharu Ito (Ministry of Health and Welfare, Tokyo), Kenzo Kiikuni (International University of Health and Welfare, Tochigi), Hiroshi Kiyono (Research Institute for Microbial Disease, Osaka), Tomoyuki Miura (Kyoto University, Kyoto), Yoshiyuki Nagai (National Institute of Infectious Diseases and The Institute of Medical Sciences, Tokyo), Kikuo Nomoto (Kyusyu University, Fukuoka City), Kenji Okuda (Yokohama City University, Yokohama), Tadao Shimao (Japan Anti-Tuberculosis Association, Tokyo), Yutaka Takebe (National Institute of Infectious Diseases, Tokyo), Masayoshi Tarui (Keio University, Tokyo), Ichiro Toida (Japan BCG Laboratory, Tokyo), Sachio Tokiyoshi (The Chemo-Sero-Therapeutic Research Institute, Tokyo), Tamami Umeda (National Institute of Infectious Diseases, Tokyo), Takusei Umenai (The University of Tokyo, Tokyo), Shudo Yamazaki (National Institute of Infectious Diseases, Tokyo), Hiroshi Yoshikura (National Institute of Infectious Diseases, Tokyo); Malaysia: Tikki Pang (University of Malaya, Kuala Lumpur); Myanmar: Hla Htut Lwin (National AIDS Programme, Yangon), Khin Maung Tun (Sexually Transmitted Diseases Control Programme, Yangon); South Korea: Joo Shil Lee (National Institute of Health, Seoul); Thailand: Natth Bhamarapravati (Mahidol University, Bangkok), Arthur E. Brown (Armed Forces Research Institute of Medical Sciences, Bangkok), Vina Churdboonchart (Mahidol University, Bangkok), Chirasac Khamboonruang (Research Institute for Health Sciences, Chiang Mai University, Chiang Mai), Dwip Kitayaporn (Mahidol University, Bangkok), Sorachai Nitiyaphan (Armed Forces Research Institute of Medical Sciences, Bangkok), Wiput Poolcharoen (Ministry of Public Health, Bangkok), Paijit Warachit (National Institute of Health, Bangkok), Chantapong Wasi (Mahidol University, Bangkok); UK: Colin R. Howard (University of London, London); USA: Seth Berkley (International AIDS Vaccine Initiative, New York), Chris Beyrer (Johns Hopkins University, Baltimore), Deborah Birx (Walter Reed Army Institute of Research, Rockville), Arwind Diwan (University of Hawaii, Honolulu), Jean-Louis Excler (Henry M. Jackson Foundation, Rockville), Margaret Johnston (National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda), Yichen Lu (Virus Research Institute, Cambridge), John McNeil (Walter Reed Army Institute of Research, Rockville), Prem Sarin (Cel-Sci Corporation, Vienna, Virginia); UNAIDS: Anita Alban (Geneva), José Esparza (Geneva), Swarup Sarkar (New Delhi), Midori Shimizu (Bangkok); WHO: Gilles Poumerol (Manila), Jeanne Ryan (Geneva). Cited Here...
Asia; economic impact; epidemiology; vaccine evaluation; vaccine research
Copyright © 1999 Wolters Kluwer Health, Inc.
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