New Preventive Technology: Providing New Options to Stop the Spread of HIV/AIDS Dublin, Ireland June 24, 2004 AIDS Vaccines - An R&D Briefing
This paper has been prepared by the International AIDS Vaccine Initiative (IAVI) as part of the background for the meeting "New Preventive Technologies - Providing new options to stop the spread of HIV/AIDS" to be held on 24 June in Dublin, Ireland. IAVI is privileged to have been asked to undertake this task and would like to acknowledge the efforts of the many other groups and individuals working towards a safe, effective, affordable, preventive HIV/AIDS for use throughout the world. For additional information, please contact: International AIDS Vaccine Initiative -European Office Postbox 15788 1001 NG Amsterdam The Netherlands Tel. +31 20 521 0030 Fax +31 20 521 0039 www.iavi.org 1
The World Needs an AIDS Vaccine The need for a safe, effective, accessible, preventive HIV vaccine for use throughout the world is critical. More than 60 million persons have now been infected with HIV since 1983, when the virus was determined to be the cause of AIDS. More than 20 million people have already died of AIDS, and approximately 14,000 new HIV infections occur each day, with over 95% of these infections occurring in the developing world. The pandemic has dramatically decreased life expectancy in several sub- Saharan countries, created a new generation of orphans in the developing world, and threatens the very fabric of society in resource poor settings. Moreover, recent projections suggest that rapidly growing HIV epidemics in Asia, Russia and Central Europe will continue to fuel an expanding pandemic, with 70 million deaths expected by 2020 in the absence of effective worldwide AIDS prevention and control measures. Prevention programs, including education, condom and clean needle distribution and peer counselling, have had some limited success when concentrated in targeted and focused campaigns to slow the spread of HIV, but on a global scale have not been successful at blunting the epidemic. Similarly, advances in antiretroviral chemotherapy have yielded important new AIDS therapies, but the cost and complexity of their use puts them out of reach for most people in the countries and regions of the world where they are needed the most. Furthermore, even when current treatment regimens are available, in the absence of an effective vaccine, HIV infection most likely will remain an incurable, ultimately fatal disease. The best hope for preventing the spread of HIV is the development, distribution and use of safe, accessible, affordable and effective new prevention technologies such as microbicides and vaccines. A Preventive HIV/AIDS Vaccine Is Feasible A vaccine is a substance that trains the immune system to recognize and protect against a disease caused by an infectious organism or virus. In the current HIV/AIDS vaccine field, two strategies are being explored - therapeutic vaccines and preventive vaccines. This paper will focus on the status of efforts to develop a preventive vaccine for use throughout the world. A preventive vaccine is intended to prevent a disease from occurring by priming the immune system to respond to a pathogenic organism. An effective preventive HIV vaccine given before exposure will protect the vaccine recipient from HIV disease, namely by preventing the establishment of infection, with no signs of disease in the vaccine recipient and no transmission to others. Due to several observations in human natural history studies and pre-clinical vaccine studies, scientists today agree that an effective HIV vaccine capable of successfully achieving criteria for efficacy, licensure, and use in the developing world is feasible. First, a small number of individuals appear to have been repeatedly exposed to HIV, yet remain uninfected. Although the mechanisms for their resistance to infection remains undefined, they generate anti-hiv immune responses which are likely responsible for the observed resistance. Human studies have shown that anti-hiv cellular immune responses can suppress viral load to undetectable levels, slowing the progression of disease and inhibiting HIV transmission. Studies in monkeys have shown that neutralizing antibodies against HIV can completely prevent infection in monkeys challenged with simian HIV, and that monkeys immunized with live attenuated vaccines are completely protected against pathogenic simian immunodeficiency virus (SIV) challenge. More simply put, an HIV vaccine design capable of eliciting antibodies which neutralize a broad spectrum of HIV circulating strains, generating cell-mediated immune responses able to blunt viral load to undetectable levels, and capable of providing the same level of protection conferred by live attenuated vaccines, should be an achievable goal. 2
Current Global Efforts in AIDS Vaccine Research and Development I. Clinical Pipeline The list below summarises the different types of vaccine concepts that are currently in clinical trials. Attachment I provides an overview of the current clinical trial pipeline. Recombinant subunit vaccines. Recombinant subunits are vaccines that are produced by genetically engineering cells to produce one or more foreign genes, such as HIV genes. The gp120 developed by VaxGen was the first vaccine candidate to have undergone Phase III trial ( in 2003). More recently, Glaxo-SmithKline has evaluated a mixture of subunit proteins (Env, nef-tat) in Phase I trials, aiming to elicit cellular immune responses to multiple HIV antigens. Similarly, Chiron has recently begun Phase I trials of a V2 deleted gp140, to be used as a booster for DNA immunization, with the goal of stimulating more effective neutralizing antibodies than previously seen with gp120. Live recombinant viral vector vaccines. In this approach, HIV genetic material is placed into harmless viruses that then present pieces (e.g. proteins) of HIV to the immune system, which leads to the development of HIV-specific immune responses elicited by the vaccine. The potential advantage of the viral vector strategy is to mimic as closely as possible the efficacy of live-attenuated vaccines, while at the same time offering much greater safety. Several viral vector systems are currently being tested in clinical trials including: Alphavirus vectors (Venezuelan Equine Encephalitis replicon particles, AlphaVax, Inc); Adenovirus (Recombinant Adeno Type 5 [rad-5]; Merck) Adeno-Associated virus (AAV, Targeted Genetics-Children s Research Institute-IAVI); and Pox Viruses (e.g. Canarypox- Aventis; Fowlpox-Australian Consortium; Modified Vaccinia Ankara [MVA]- Oxford University- University Nairobi-IAVI; Vaccinia-St. Jude s Hospital; and NYVAC- EuroVac). DNA vaccines. This represents one of the newest technologies for vaccine design. Pieces of HIV DNA are incorporated into harmless plasmid DNA from bacteria and used to cause the body's cells to produce HIV proteins for the immune system that will recognize and mount responses against the virus. Preclinical studies with non-hiv vaccines have demonstrated the significant potential of this vaccine strategy as a prime for either protein or viral vector boosting. However, data thus far from clinical trials have yet to realize this potential, as DNA vaccines from Merck, Oxford University, and the NIH-Vaccine Research Centre have not reproduced the level of CD8 responses observed in small animals and non-human primates. Other groups are currently testing innovative strategies to enhance DNA immunization, including Epimmune (minigenes), Aaron Diamond-IAVI (novel promoters), Chiron (PLG microparticles), Emory-GeoVax (early and late genes), Wyeth (IL-12), NIH-VRC (IL-2), FIT Biotech (nuclear anchoring), and the University of Massachusetts-ABL (multiple clades). Data from these Phase I clinical trials will likely become available in late 2004. Synthetic peptide vaccines: Synthetic peptides are small portions of HIV proteins. Extensive basic research on potential cytotoxic T cell (CTL) and antibody epitopes of HIV have shown that the immune system will mount a response to very short peptide sections of a protein antigen when presented appropriately to the immune system. Synthetic peptides can be linked to lipid molecules (e.g. lipopeptides) to facilitate induction of cellular immune responses such as cytotoxic T cells. In addition, random libraries of peptides can be engineered to bind to antibody molecules, as a strategy to mimic (e.g. mimetope) the structure necessary to stimulate the desired antibody response. Finally, peptides can be combined as multi-peptide vaccines as a strategy for increasing the breadth of the vaccine induced response. France s ANRS is spearheading the development of lipopeptides, aimed at eliciting cell mediated immune responses against HIV. Data from Phase I trials has shown that lipopeptides can be engineered to elicit CD8 + cell mediated immune responses, and this strategy is now being explored as a booster for DNA or viral vector priming. Combination vaccines: Recognizing that protection from HIV may require a broad spectrum of immune responses including humoral (e.g. neutralizing antibodies); cellular (e.g. cytotoxic T cells, cytokines and chemokines) and mucosal immunity, scientists have designed combination regimens in attempts to elicit such broad spectrum immunity. Several combinations are now being tested in clinical trials, including among others: Canarypox + gp120 (Phase III); DNA + MVA (Phase I-II); Recombinant Adeno + Canarypox (Phase I); Canarypox + lipopeptides (Phase I); DNA + recombinant Adeno (Phase I) ; DNA + protein (Phase I) ; DNA + lipopeptides (Phase I). 3
Due to safety concerns, whole inactivated and live attenuated vaccine approaches are not currently being actively pursued. However, live attenuated vaccines have shown to provide complete protection in monkeys challenged with SIV and efforts to understand and identify ways of mimicking this mechanism would represent an important contribution to the field. HIV vaccines approaches recombinant protein (gp120) synthetic peptides naked DNA live-recombinant vectors (viral, bacterial) whole-inactivated virus live-attenuated virus Graph source: WHO-UNAIDS II. Efficacy Trials To date three approaches in the clinical pipeline have either completed Phase III efficacy trials, are undergoing or are being prepared to enter Phase III trials. VaxGen gp120. Recently the first two Phase III efficacy trials have been completed in North America/Europe and Thailand.The trials involved vaccines developed by VaxGen composed of recombinantly produced HIV gp120 of either clade B or clade B/E composition. Although the vaccine failed to demonstrate efficacy, the global AIDS vaccine effort gained important knowledge from the trials, including the proof that AIDS vaccine efficacy trials are indeed feasible. They also answered the important scientific question that although a monomeric gp120 vaccine induces neutralizing antibodies to T cell laboratory adapted isolates in >90% of subjects, this is not necessarily sufficient to elicit neutralizing antibodies against primary isolates of HIV, eg. those HIV isolates circulating in the population responsible for transmission. This enables the scientific community to focus future efforts on generating more effective humoral immunity and/or to stimulating cell-mediated immunity. Canarypox (Aventis) + gp120 (VaxGen). An efficacy trial is now underway in Thailand to assess the immunogenicity and protective efficacy of an avipox vectored vaccine that expresses various HIV-1 proteins as a prime, followed by the gp120 (B/E) developed by VaxGen as a boost. Data from this trial is expected to be available by 2008. Recombinant replication-defective adenovirus type 5 (Merck). An efficacy trial for the replicationdefective adenovirus type 5 vaccine vector engineered to express HIV-1 consensus clade B gag, pol and nef protein is being planned by Merck in conjunction with the HVTN, and will likely start before the end of 2004. In Phase I/II clinical trials the vaccine has elicited the most robust and durable CD8+ cellular immune response of any HIV vaccines currently in clinical trials. However data also show that prior exposure to adenovirus type 5, which occurs in approximately 40-50% of people in developed countries and over 80% in the developing world, significantly blunts the percentage of subjects who respond to the rad-5 vector. Nevertheless, this vaccine is an excellent candidate for a proof-ofconcept efficacy trial to test the hypothesis that cell medicated immune responses against HIV in the context of immunization can provide benefit upon exposure to HIV. 4
Major Challenges in AIDS Vaccine R&D Despite the increasing global effort and commitment to AIDS vaccine development over the past few years, to accomplish the goal of an effective, affordable and accessible preventive AIDS vaccine remains a daunting task. The following is a summary of the major challenges currently facing the field, as well as recommendations of how to address the challenges. Product development: Despite the over thirty candidates in clinical development, the global product development pipeline is narrow and duplicative and is focused primarily on testing a single scientific hypothesis (cell-mediated-immunity-based vaccines). The only CMI candidate tested for efficacy (gp120, Vaxgen), failed to prevent HIV infection, and no data from ongoing or planned efficacy trials of other candidates is expected before 2008. Therefore, the field will only learn whether vaccines aimed at eliciting cell-mediated immune responses against HIV provide any protective efficacy in 2008. Recommendation: 1) Conduct efficacy trials of the CMI-based vaccine concept; 2) Evaluate multiple immunologic parameters in these trials to gain as much information as possible on correlates of protective immunity; and 3) Develop promising candidates to address other scientific hypotheses for future efficacy testing. In this regard, greater attention should be given to developing CMI-based viral vectors not likely to face anti-vector immunity problems, strategies to elicit effective neutralizing antibodies, strategies to generate effective mucosal immunity, particularly in gut-associated lymphoid tissues where initial amplification of HIV appears to occur post-infection, and strategies utilizing novel adjuvants and vaccine delivery modalities to broaden the immune response against HIV conferred by vaccines. Scientific challenges: Limited progress has been made to date in answering certain fundamental scientific challenges such as how to elicit effective neutralizing antibodies against globally diverse and circulating strains of HIV, and how to achieve the level of protection against pathogenic SIV conferred by live attenuated vaccines. There is virtually universal agreement that neither current public sectorsupported basic research initiatives nor current private sector funded product development programs will adequately address these scientific challenges. Recommendation: The creation of adequately resourced scientific consortia, involving the collaboration of leading laboratories and scientists, represents an effective mechanism to bridge the gap between basic research and product development and has the potential for success to tackle these challenges. Process development and manufacturing: Many candidates in the current pipeline are not developable due to limited attention to process development and manufacturing issues. Recommendation: Process development resources need to be provided for the most promising candidates, with key milestones clearly delineated that are similar to those used to advance candidates through clinical development. In addition, close linkages need to be established between the applied research/translational studies aimed at optimising, combining and comparing candidate vaccines with those process development studies aimed at ensuring that the leading candidates can in fact be developed. Clinical trials infrastructure: Clinical trials capacity in preparation for efficacy trials is limited, particularly in regions of the world where HIV incidence is greatest. Several stakeholders have carried out important epidemiology, HIV prevention and Phase I vaccine trials. However, they have not focused investment comprehensively on preparation for efficacy trials. Furthermore regulatory capacity in the developing world needs to be significantly strengthened. Recommendation: Establish HIV vaccine trials regional centres in the developing world, which contain the core clinical, laboratory, cohort, logistics, public health and political elements required for successful conduct of efficacy trials. A long-term commitment to these sites, including the provision of significant resources for training and infrastructure, are essential for the creation and maintenance of such centres. 5
The Way Forward It is estimated that approximately US$ 600 million is currently spent annually on global AIDS vaccine R&D. This is clearly inadequate given the urgency of the pandemic. A significant increase in current resources dedicated to this effort is required to ensure real progress in the next decade, and that these resources should be focused on addressing the scientific challenges, prioritising the most promising candidates, establishing facilities to produce clinical-grade materials and preparing for large-scale manufacturing, ensuring that effective regulatory processes are established, and ensuring that access to successfully licensed AIDS vaccines will be accelerated for those that need them most in the developing world. 6
Attachment I: Global Clinical Trial Pipeline (updated May 2004) Candidates Principal Developer Subtype Phase Subunits gp120 VaxGen B No significant efficacy gp120 VaxGen B/E No significant efficacy gp120+nef-tat GSK B Phase I gp140 V2 deleted Chiron B Phase I gp160 MN/LAI-2 Aventis B Phase I EnvPro St Jude's Hospital D Phase I tat ISS B Phase I Viral Vectors radeno 5 - gag, pol, nef Merck B Phase III initiates Q4 04, data 2008 radeno 5 - gag Merck B Phase I/II ALVAC vcp1521 - env (E), Aventis B/E Phase III gag/pol (B) ALVAC vcp205 - env, gag, Aventis B Phase II pol MVA - gag + CTL epitopes IAVI-Oxford-Kenya A Phase I/II FPV - gag, RT, rev, tat, vpu, Australian Thai Consortium B Phase I/II env NYVAC - gag, pol, nef, env EuroVac C Phase I VEE - gag AlphaVax C Phase I AAV - gag, pro, rt IAVI-CRI-TGC C Phase I Vaccinia - multi, env St. Jude's Hospital B, D Phase I DNA gag+ CTL epitopes IAVI - Oxford - Kenya A Phase I/II env-gag, pol, nef-tat IAVI - ADARC C Phase I gag Merck B Phase I/II 21 CTL epitopes fm gag, pol, Epimmune B Phase I env, nef, rev, vpr nef (nuclear anchoring) FIT Biotech B Phase I env, gag, pro, RT, tat, vpu, rev Emory B Phase I gag, env gp140 + Chiron B Phase I/II microparticles gag, pol, nef, env + IL-2 NIH-VRC A, B, C Phase I gag, rt, env, tat, rev, vpu Vical B Phase I gag + IL-12 Wyeth B Phase I gag, RT, rev, tat, vpu, env Australian Thai Consortium B Phase I/II gag + 5 env U. Mass - ABL A, B, C, E Phase I Peptides Lipopeptides 5, CTL epitopes ANRS - Aventis B Phase I fm gag, nef, pol Lipopeptides 6T, CTL epitopes ANRS - Aventis B Phase I fm gag, nef and env Lipopeptides 4T, CTL epitopes ANRS - Aventis B Phase I fm gag, pol, RT, nef poly-epitopic - env, gag, nef Wyeth B Phase I Prime-Boost Combination ALVAC vcp1521 + gp120 Aventis-VaxGen B, E Phase III, data 2008 DNA + MVA IAIV-Oxford-Kenya A Phase I/II DNA + Fowlpox Australian Thai Consortium B Phase I/II DNA + Adeno VRC B Phase I/II Adeno + ALVAC vcp205 Merck-Aventis B Phase I ALVAC + Lipo-peptides Aventis + ANRS B Phase I DNA + Lipo-peptides ANRS B Phase I DNA+V2 deleted gp140 Chiron B Phase I DNA + gp120 U. Mass - ABL A, B, C, E Phase I 7
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