An HIV vaccine: how and when?

An HIV vaccine: how and when? Jose´ Esparza1 Abstract The best long-term hope for controlling the human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS) pandemic is a safe, effective and affordable preventive vaccine, but its development has encountered unprecedented scientific challenges. The first phase I trial of an HIV vaccine was conducted in 1987. Subsequently, more than 30 candidate vaccines have been tested in over 60 phase I/II trials, involving approximately 10 000 healthy volunteers. Most of these trials have been conducted in the USA and Europe, but several have also been conducted in developing countries. The first phase III trials began in the USA in 1998 and in Thailand in 1999 to assess the efficacy of the first generation of HIV vaccines (based on the HIV envelope protein, gp120); the results will be available within the next 1–2 years. To accelerate the development of an HIV vaccine, additional candidate vaccines must be evaluated in parallel in both industrialized and developing countries. This will require international collaboration and coordination and critical ethical issues will need to be addressed. To ensure that future HIV vaccines contribute to the overall HIV/AIDS prevention effort, we should begin planning now on how best to use them. Keywords HIV infections/prevention and control; Acquired immunodeficiency syndrome/prevention and control; AIDS vaccines/immunology; HIV/genetics; Clinical trials; Models, Animal (source: MeSH ). Mots cle´s HIV, Infection/pre´vention et controˆle; SIDA/pre´vention et controˆle; Vaccin anti-SIDA/immunologie; HIV/ ge´ne´tique; Essai clinique; Mode`le animal (source: INSERM ). Palabras clave Infecciones por VIH/prevencio´n y control; Sı´ndrome de inmunodeficiencia adquirida/prevencio´n y control; Vacunas contra SIDA/inmunologı´a; VIH/gene´tica; Ensayos clı´nicos; Modelos animales (fuente: BIREME ). Bulletin of the World Health Organization, 2001, 79: 1133–1137. Voir page 1136 le re´sume´ en franc¸ais. En la pa´gina 1136 figura un resumen en espan˜ol. Introduction Although acquired immunodeficiency syndrome (AIDS) was described only in June 1981, it has subsequently become the most important infectious disease, being the leading cause of death in Africa and the fourth leading cause of death worldwide (1). Despite international efforts to control the HIV/ AIDS pandemic, through behavioural modification and other interventions, more than 15 000 people become infected with human immunodeficiency virus (HIV) every day, 95% of whom live in developing countries, particularly in sub-Saharan Africa. The best long-term hope for controlling the pandemic would be a preventive vaccine that is safe, highly effective, and affordable (2, 3). In 1983–84, the discovery that HIV was the etiological agent of AIDS raised hopes that a preventive vaccine would soon be developed and, in fact, the first human trial of a candidate HIV vaccine was carried out in 1987 in the USA. At that time, however, the magnitude of the scientific challenge presented by the development of a vaccine was not appreciated. Since then, several candidate vaccines have been tested in human trials and efforts to develop an HIV vaccine are increasing (2–4). Depending on the results from ongoing and planned large-scale phase III trials, the first HIV- preventive vaccine could be available within the next 2–6 years. If these first-generation HIV vaccines work, they may not be highly effective, and we must decide how they could be used in public health programmes. An HIV vaccine with moderate efficacy (ca 50%) could still play a significant role in preventing new infections, especially in populations with high incidences of HIV infection and where other preventive interventions are not readily avail- able. In any case, we should not expect that a future HIV vaccine, especially one with only moderate efficacy, will be a ‘‘magic bullet’’ that replaces other preventive interventions. Instead, vaccines will be part of comprehensiveHIV prevention packages that also include health promotion and behavioural interventions (2). The scientific challenges There are three major scientific challenges for HIV vaccine development, as discussed below (2–4). 1 Coordinator, WHO/UNAIDS HIV Vaccine Initiative, World Health Organization, 1211 Geneva 27, Switzerland (email: esparzaj@who.int). Ref. No. 01-1504 1133Bulletin of the World Health Organization, 2001, 79 (12) # World Health Organization 2001 The immunological correlates of HIV/AIDS protection are not known A major stumbling block for the rational develop- ment of HIV vaccines has been the lack of information on the immunological correlates of protection against HIV/AIDS. With most vaccine- preventable diseases, naturally occurring (or vaccine- induced) immune responses correlate with protec- tion against infection or disease. In contrast, even though most people infected with HIV develop a broad range of immune responses against the virus, these responses neither eliminate the infection nor prevent progression to AIDS. Ongoing HIV vaccine development strategies are targeted at the two major types of immune responses, humoral and cell- mediated immunity, and include strategies to induce both of them. The genetic variability of HIV Genetic analysis of HIV strains isolated from different parts of the world has revealed that several HIV genes exhibit extensive sequence heterogeneity, particularly in the gene coding for the viral envelope proteins, gp120 and gp41.a This heterogeneity has been used to classify HIV type 1 (HIV-1) strains into groups and subtypes; most HIV infections are caused by viruses belonging to HIV-1 group M (or ‘‘major’’) which, in turn, is divided into at least nine genetic subtypes (A–J).b Viruses from different subtypes can also recombine among themselves, generating unique and circulating recombinant forms (CRFs). HIV subtypes and CRFs have unequal geo- graphical distributions. For example, in the Americas most infections are caused by subtype B, whereas subtype E causes the major HIV/AIDS epidemic in Thailand. In Africa, several subtypes cause the epidemic, but most are of subtype C. Although much is known about the genetic variability ofHIV, it is unclear how the genetic variability relates to potential vaccine-induced protection. For example, it is not known whether the genetic subtypes define immu- nological types, or whether specific vaccines will need to be designed for each subtype. The results of human trials with candidate vaccines that are based on different genetic subtypes may provide the answer to this (5). The lack of good animal models Several experimental HIV vaccines have induced different degrees of protection in primate models, including chimpanzees challenged with HIV or monkeys challenged with the analogous simian immunodeficiency virus. The problem is that different experimental vaccines produce different results in these two animal models. It is also unclear whether the animal results will be predictive of vaccine-induced protection in humans — such information will only result from human trials. Candidate vaccines Despite the uncertainties, a number of experimental vaccines have been developed in the laboratory and are being tested in animal models (and some in human volunteers). For safety and ethical reasons, the two classic approaches for developing viral vaccines — using whole inactivated or live-attenu- ated viruses — have not been seriously considered for HIV. Instead, the effort has concentrated on developing subunit vaccines, which contain only part of the virus obtained using genetic engineering techniques. The first-generation HIV candidate vaccines were based on the envelope proteins of HIV, especially gp120. These vaccines, which are designed to induce the production of neutralizing antibodies, may have the limitation that the gp120 protein is the most variable component of the virus. Second- generation candidate vaccines are being designed to induce cell-mediated immunity, using either live vectors (such as vaccinia, canarypox, and others) or ‘‘naked’’ DNA that codes for different HIV genes. Third-generation vaccines, based on regulatory nonstructural proteins of HIV, such as Tat (a trans- activator of HIV gene expression) and Nef (a multifunctional myristylated protein), are also emerging. Some immunization protocols use a combination of two different vaccines to induce broader and/or stronger anti-HIV immune re- sponses. Many of these experimental vaccines and their combinations are being tested in primate models, with different degrees of success, and it is expected that several will eventually move to clinical trials in humans. Clinical trials in humans Once a promising candidate vaccine is identified and tested in the laboratory and in animal models, it can be moved to clinical evaluation in humans (6), a long process with several phases. Phase I trials are conducted with a small number of volunteers, usually 20–50, to obtain initial information on the immuno- genicity and safety of the candidate vaccine. Phase II trials usually involve several hundred volunteers and are conducted to obtain additional safety and immunogenicity data, as well as information about different populations, vaccine doses, etc. Phase III trials are large-scale field trials to assess the efficacy of the candidate vaccine for preventing infection or disease. Phase III trials usually involve several thousand healthy volunteers at a relatively high risk of HIV infection. For statistical reasons, the number of volunteers participating in a phase III trial depends largely on the frequency of HIV infections in the a Note: Both these envelope proteins are expressed at a gp160 precursor that is subsequently cleaved into gp120 and gp41. b Note: The original subtype I was subsequently found to be a recombinant. 1134 Bulletin of the World Health Organization, 2001, 79 (12) Special Theme – HIV/AIDS study population: the higher the HIV incidence, the lower the number of volunteers required in the trial. In a typical phase III trial, a total of approximately 5000 volunteers would be required if the incidence of HIV infection in the population is 1.5% per year. Half of the volunteers would receive the experi- mental vaccine and the other half, a control injection (a placebo or an unrelated vaccine). For ethical reasons, all trial participants should receive counsel- ling and other risk-reduction interventions. Hope- fully, these actions will decrease the baseline incidence of HIV infections in the study population, an effect that should be considered when estimating the trial sample size. To avoid experimental bias, neither the volunteers nor the investigators should knowwho is receiving the candidate vaccine andwho is receiving the control injection (i.e. it should be a ‘‘double-blind, placebo-controlled’’ trial). The study population is usually followed for three years, after which the code is broken and the number of HIV infections in the control group is compared with that in volunteers receiving the vaccine, from which the vaccine efficacy can be estimated. For example, if the number of infections in the vaccine group is ten times less than in the control population, vaccine efficacy would be 90%. Phase III trials are long and complex and in the most optimistic scenario it takes 6–9 years between phase I trials and the results of a phase III efficacy trial. The first phase I trial of an HIV candidate vaccine was conducted in the USA in 1987, using a gp160 candidate vaccine. Subsequently, more than 30 HIV candidate vaccines have been tested in 60 phase I or phase II trials, involving more than 10 000 healthy volunteers. Most of the trials have been conducted in the USA and Europe, although some have also been conducted (or are being conducted) in developing countries, including Brazil, China, Cuba, Haiti, Kenya, Thailand, Trinidad and Tobago, and Uganda. Trials in developing countries are important for several reasons. First, most infections occur in such countries, where an effective vaccine would eventually be used and be most beneficial. Second, to produce valid and timely results, phase III efficacy trials need to be conducted in populations with high incidences of HIV infec- tions. Third, the genetic and antigenic variability of HIV may necessitate testing candidate vaccines in different areas of the world. Finally, it may be necessary to evaluate how different routes and/or cofactors for HIV transmission influence vaccine protection (7). Human trials of HIV candidate vaccines have provided important information that has permitted new generations of improved candidate vaccines to be designed. Phase I/II trials have shown that candidate vaccines are safe, with the only significant side-effect being pain at the site of the injection. Candidate vaccines based on gp120 induce anti- bodies in essentially 100% of volunteers, although the antibodies are basically directed against homo- logous laboratory-adapted strains of the virus. Novel HIV envelope constructs are being designed, with the ultimate purpose of inducing broadly neutraliz- ing antibodies against clinical isolates of the virus. The leading HIV candidate vaccine designed to induce cell-mediated immunity uses a canarypox vector to express several HIV genes, but has induced cytotoxic T-lymphocytes in only a fraction of the vaccinees and stronger immunogens may have to be designed. Phase I/II trials do not provide information on the protective efficacy of the candidate vaccine; for this, phase III trials are required. The first phase III trial of an HIV candidate vaccine began in June 1998 in the USA (with ‘‘sites’’ in Canada and the Nether- lands), using a bivalent BB (i.e based on two different subtype B strains) gp120 candidate vaccine (VaxGen, Brisbane, CA, USA). This candidate vaccine is being tested in 5400 human volunteers, the majority of whom are homosexually active men. The second phase III trial, started in March 1999 in Thailand, is designed to assess a bivalent BE gp120 candidate vaccine (also from VaxGen) in 2500 volunteers recruited among recovering injecting-drug users in Bangkok. Results from these trials will be available within the next 1–2 years and offer the first opportunity of having an HIV vaccine. A phase III trial is being planned by the US National Institutes of Health, to be initiated in several countries in the Americas early in 2003. This will assess the efficacy of a prime-boost regime, combining a canarypox–HIV vector (Aventis Pasteur, Lyon, France) and gp120 (VaxGen, Brisbane, CA, USA). Both vaccines are based on HIV subtype B, the most prevalent in the region. A similar prime-boost phase III trial using candidate vaccines based on the subtype E of the virus is also being planned in Thailand. Efficacy results from these trials will be available around 2006 at the earliest, and would represent a second chance of identifying an effective vaccine. Conclusions During the United Nations General Assembly Special Session on HIV/AIDS, held in New York on 27 June 2001, it was recommended to ‘‘increase investment in and accelerate research on the development of HIV vaccines’’ (8). Numerous institutions are contributing to this global effort, especially the US National Institutes of Health, the US Military HIV Research Programme, the US Centers for Disease Control and Prevention, the French National Agency for Research on AIDS, the European Community, the International AIDS Vaccine Initiative, WHO, UNAIDS and others, including the vaccine industry. In addition, several developing countries are establishing their own national AIDS vaccine plans and initiatives. The participation of multiple partners is a welcome development, but will require international coordina- tion and collaboration. 1135Bulletin of the World Health Organization, 2001, 79 (12) An HIV vaccine: how and when? The most rational way to accelerate HIV vaccine development is to proceed with multiple clinical trials simultaneously, thereby permitting assessment of the protective efficacy of different candidate vaccines against different HIV subtypes in different countries and populations. More basic research is also needed to improve understanding of the human immune response to HIV and vaccination, and to design better immunogens for future clinical trials (9). A major effort must be made to develop and evaluate candidate vaccines in Africa, themost affected continent.WHO andUNAIDS are promoting an ‘‘African AIDS Vaccine Programme’’ — a network of African scientists working to promote HIV vaccine research and evaluation in Africa through capacity-building and regional and international collaboration. Critical ethical issues will need to be tackled during these trials, including the level of care and treatment that should be offered to volunteers who become infected during the course of the trial, and how to make vaccines available to the population once their efficacy has been demonstrated (10, 11). To ensure that the policies contribute to the overall HIV/AIDS prevention effort, we should begin planning now on how to introduce and use future HIV vaccines (12). n Conflicts of interest: none declared. Re´sume´ Un vaccin contre le VIH : quand et comment ? Le meilleur espoir a` long terme pour la lutte contre la pande´mie de virus de l’immunode´ficience humaine/ syndrome d’immunode´ficience acquise (VIH/SIDA) serait de disposer d’un vaccin pre´ventif sans danger, efficace et abordable, mais le de´veloppement d’un tel vaccin s’est heurte´ a` des difficulte´s techniques sans pre´ce´dent. Le premier essai de phase I d’un vaccin anti-VIH a e´te´ re´alise´ en 1987. Par la suite, plus de 30 vaccins candidats ont e´te´ teste´s au cours de plus de 60 essais de phase I/II sur environ 10 000 volontaires sains. La plupart des essais ont e´te´ re´alise´s aux Etats-Unis d’Ame´rique et en Europe, mais plusieurs ont e´galement eu lieu dans des pays en de´veloppement. Les premiers essais de phase III ont de´bute´ aux Etats-Unis d’Ame´rique en 1998 et en Thaı¨lande en 1999 afin d’e´valuer l’efficacite´ de la premie`re ge´ne´ration de vaccins anti-VIH (dirige´s contre la prote´ine d’enveloppe gp120) ; les re´sultats seront connus d’ici un a` deux ans. Pour acce´le´rer la mise au point d’un vaccin contre le VIH, d’autres vaccins candidats devront eˆtre e´value´s en paralle`le dans les pays industrialise´s et dans les pays en de´veloppement, ce qui ne´cessitera une collaboration et une coordination internationales ainsi que l’examen de questions e´thiques fondamentales. Pour assurer que les futurs vaccins anti-VIH contribueront a` l’effort global de pre´vention du VIH/SIDA, nous devons de`s maintenant commencer a` re´fle´chir a` la manie`re dont ils seront le mieux utilise´s. Resumen Una vacuna contra el VIH: ¿co´mo y cua´ndo? Aunque la mejor esperanza a largo plazo para controlar la pandemia de VIH/SIDA es una vacuna preventiva que sea segura, efectiva y accesible, su desarrollo ha obligado a afrontar varios retos cientı´ficos sin prece- dentes. La primera prueba clı´nica de fase I de una vacuna contra el VIH se llevo´ a cabo en 1987. Desde entonces se han probado ma´s de 30 vacunas experimentales en ma´s de 60 pruebas de fase I/II, con la participacio´n de unos 10 000 voluntarios sanos. La mayorı´a de esas pruebas clı´nicas se han hecho en los Estados Unidos y Europa, pero tambie´n se han hecho varias en paı´ses en desarrollo. Las primeras pruebas de fase III, disen˜adas para determinar la eficacia de la primera generacio´n de vacunas contra el VIH (dirigidas contra la proteı´na gp120 de la cubierta del virus) comenzaron en 1998 en los Estados Unidos y en 1999 en Tailandia. Dentro de 1-2 an˜os tendremos los resultados de esas pruebas. Para acelerar el desarrollo de vacunas contra el VIH, debera´n emprenderse simulta´neamente pruebas clı´nicas adicio- nales tanto en paı´ses industrializados como en paı´ses en desarrollo. Ello exigira´ colaboracio´n y coordinacio´n a nivel internacional, y obligara´ a resolver varios aspectos e´ticos de crucial importancia. Tambie´n es esencial comenzar a planificar la manera de usar las futuras vacunas contra el VIH, para asegurar que contribuyan al esfuerzo integral de prevencio´n del VIH/SIDA. 1136 Bulletin of the World Health Organization, 2001, 79 (12) Special Theme – HIV/AIDS References 1. Piot P et al. The global impact of HIV/AIDS. Nature, 2001, 410: 968–973. 2. Esparza J, Bhamarapravti N. Accelerating the development and future availability of HIV-1 vaccines: why, when, where, and how? Lancet, 2000, 355: 2061–2066. 3. Esparza J, Osmanov S. Current issues in HIV vaccine devel- opment. Journal of Health Management, 2000, 2: 245–255. 4. Esparza J, Heyward WL, Osmanov S. HIV vaccine research: from basic science to human trials. AIDS, 1996, 10: S123–S132. 5. Approaches to the development of broadly protective HIV vaccines: challenges posed by the genetic, biological and antigenic variability of HIV-1. Report from a meeting of the WHO-UNAIDS Vaccine Advisory Committee, Geneva, 21–23 February 2000. AIDS, 2001, 15: W1–W25. 6. Esparza J, Burke D. Epidemiological considerations in planning HIV preventive vaccine trials. AIDS (in press). 7. Heyward WL, Osmanov S, Esparza J. Preparing for HIV vaccine efficacy trials in developing countries. In: Mann J, Tarantola D, eds. AIDS in the world, II. New York, Oxford University Press, 1996: 193–195. 8. Declaration of commitment on HIV/AIDS. United Nations General Assembly Special Session on HIV/AIDS, 27 June 2001. New York, United Nations, 2 August 2001 (document A/RES/S26/2). 9. Nabel GJ. Challenges and opportunities for development of an AIDS vaccine. Nature, 2001, 410: 1002–1007. 10. Ethical considerations in HIV preventive vaccine research. Geneva, UNAIDS, May 2000 (unpublished document UNAIDS/00.07E, available at: http://www.unaids.org/publications/documents/ vaccines/vaccines/JC072-EthicalCons-E.pdf). 11. Guenter D, Esparza J, Macklin R. Ethical considerations in international HIV vaccine trials: summary of a consultative process conducted by the Joint United Nations Programme on HIV/AIDS (UNAIDS). Journal of Medical Ethics, 2000, 26: 37–43. 12. Future access to HIV vaccines. Report from a WHO-UNAIDS consultation, Geneva, 2–3 October 2000. AIDS, 2001, 15: W27–W44. 1137Bulletin of the World Health Organization, 2001, 79 (12) An HIV vaccine: how and when?