Richard D. Klausner [HN18], Anthony S. Fauci, Lawrence Corey, Gary J. Nabel, Helene Gayle, Seth Berkley, Barton F. Haynes, David Baltimore, Chris Collins, R. Gordon Douglas, Jose Esparza, Donald P. Francis, N. K. Ganguly, Julie Louise Gerberding, Margaret I. Johnston, Michel D. Kazatchkine, Andrew J. McMichael, Malegapuru W. Makgoba, Giuseppe Pantaleo, Peter Piot, Yiming Shao, Edmund Tramont, Harold Varmus, Judith N. Wasserheit*
Enhanced: The Need for a Global HIV Vaccine Enterprise
Since the discovery of HIV 20 years ago and the demonstration that HIV is the cause of AIDS [HN1], the world has awaited the development of an effective preventive vaccine [HN2]. Recent projections from the World Health Organization (WHO) and the Joint United Nations Programme on HIV/AIDS (UNAIDS) indicate that if the pandemic proceeds at its current rate, there will be 45 million new infections by 2010 and nearly 70 million deaths by 2020 (1) [HN3]. Although the scientific establishment has made extensive progress on extending survival of people with HIV and reducing maternal-fetal HIV transmission by antiretroviral therapy, transferring concepts for HIV-1 vaccines into clinical application has lagged.
Almost everyone involved in HIV vaccine development agrees that there is an urgent need to create and to evaluate systematically more candidate vaccines. Despite the wide variety of conceptual approaches to HIV vaccine design, the pace of development of new HIV vaccine candidates needs [HN4] to be accelerated. In 2001 and 2002, only seven immunogens entered clinical trials [HN5]. Only one candidate vaccine, aimed at eliciting neutralizing antibodies to a soluble HIV envelope protein, entered human phase III testing. Unfortunately, the recently released results from this trial did not demonstrate vaccine efficacy in the overall trial cohort (6) [HN6]. Although many approaches to producing immunogens have been discussed and initiated, systematic evaluation and optimization have proceeded slowly, in part because of factors such as the expense and complexities in advancing new candidate vaccines into phase I trials and scientific challenges.
These challenges include (i) the inability of current vaccine designs to elicit effective neutralizing antibodies [HN7] against the circulating strains of HIV, (ii) the inability of current designs to prevent HIV from establishing persistent infection, (iii) the extensive global variability of HIV, (iv) the lack of understanding regarding the mechanisms of protection in the most effective HIV vaccine animal model system--the live attenuated approach, and (v) the lack of understanding of which HIV antigens induce protective immunity and which immune effector mechanisms are responsible for protection. The best engine for solving these major scientific challenges is the creativity of individual scientists working together in multidisciplinary problem-solving consortia, adequately resourced and linked to vaccine development capabilities. Two decades after the discovery of HIV, even with a variety of advanced cell and molecular technologies, the need remains for improved vaccine designs that will deal with the genetic and phenotypic variation of HIV-1 [HN8] and effectively prevent the establishment of lifelong infection. The "enterprise" of HIV vaccine development must be designed as a high-quality collaborative research system that goes well beyond the high-quality but separate research projects that we have today.
We propose a model that could achieve the goals of a more efficient and integrated HIV vaccine research enterprise. We hope this Policy Forum helps open an international dialogue about options to achieve the goal of developing a safe and effective HIV vaccine in the shortest time possible.
Basic Principles for the Enterprise
Vaccine development has historically been empiric and iterative, building on sequential successes to define correlates of immune protection that guide product development. Preclinical and clinical experiments and evaluation systems with objective measurements and analysis have been critical. Perhaps one of the most successful examples of such a concerted, empiric approach in medicine generally is the improvement in the treatment of childhood acute lymphocytic leukemia (ALL) [HN9]. Cure rates for children with ALL have improved from ~10% in the 1950s to more than 80% (and for some subtypes, 100%) in 2002. This increase has been produced almost entirely by a coordinated and iterative series of preclinical drug evaluations and subsequent clinical trials, in which partially effective drug regimens have been systematically altered (through studies of the effects of combination and sequence), to produce steady and significant improvement in survival as well as reduced toxicity.
HIV vaccine development has several similarities with developing treatment for ALL: (i) Although animal model data provide major conceptual insights, human clinical trials are ultimately required to define vaccine or drug effectiveness; (ii) the number of possible variables in reagent design and clinical outcome are large but definable; (iii) combinations of reagents (vaccines for HIV, drugs for ALL) are likely needed to maximize benefit; (iv) no single regimen is likely, at least initially, to provide the optimal balance of efficacy, safety, and cost for all regions of the world; (v) a centralized, coordinated clinical trial and laboratory evaluation system facilitates progress in the field; and (vi) the program has substantial support from medical and political communities.
There are also features that are unique to developing an HIV vaccine. The pace of progression of the HIV epidemic, as well as the international, political, and economic toll, require a more rapid iterative process than the multidecade process described above. A well-coordinated global enterprise necessary to drive this scientific effort does not exist and must be created. The cost and process of developing new vaccine candidates, especially protein-based immunogens or noninfectious particles is typically substantially higher than those of new or modified drugs. Also, as the scientific risk of failure and the cost of vaccine development are high, reliance on industry to carry the major load for discovery and development for HIV vaccines is unrealistic. Thus, creative new public and public-private partnerships are necessary to drive the vaccine discovery effort, with industry's development expertise a key element that must be marshaled effectively.
HIV Vaccine Development Centers
Even with the current paucity of prototype antigens in clinical trials, the portfolio of vaccine candidates contains significant overlap in approach [see "the pipeline project" [HN10] (3) and (4)]. Increasing the diversity of approaches and coordinating the types of vaccines entering clinical trials are fundamental to speeding global HIV vaccine development. We believe that this requires the creation of a series of coordinated global HIV vaccine centers, each of which has the critical mass, focus, and scientific expertise, especially in vaccine development, to advance the rational development of a particular HIV vaccine approach rapidly and systematically. Features we believe vital to the success of such centers are as follows: (i) a critical mass of researchers with experience in basic and clinical research and an appreciation for the empiric aspects of vaccine development, (ii) concentrated dedication to the single goal of a global preventive vaccine, (iii) long-term commitment free of the strict requirements of the classical short-term measures of success used by academic institutions, (iv) sufficient resources to conduct costly preclinical development activities, and (v) collaborative arrangements with the private sector.
Each of these centers would have the funding, structure, and resources to devote itself to a specific vaccine development need and product. The sole focus would be to test systematically and to improve incrementally the immunogenicity and safety of the immunogens that they develop. The core of an integrated enterprise approach to HIV vaccine development would begin by conceiving of the world of potential vaccine concepts as a grid, with each cell representing a particular approach to immunogen construction, composition and delivery. We propose the development of as many HIV vaccine development centers (VDCs) as are needed to fully cover the agreed-on "cells" of the vaccine product pipeline grid; they would be supported by a variety of international funding agencies. The structure, scope, and scale of each VDC would be organized to explore fully design, development, and testing in preclinical and early-phase human trials of a particular approach with the capacity to examine an adequate range of variables of dose, delivery, adjuvants, and combinations. The goal would be to learn whether their approach is immunogenic, with what characteristics (nature of the immune response, breadth of response, intensity and persistence of the response) and whether any of the variables modify the response in a way that indicates whether and how to produce second- and third-generation candidates.
The structure of the VDCs could vary. These centers may be self-contained, as in the National Institutes of Health (NIH) Vaccine Research Center [HN11], or may be virtual centers such as those funded by the public-private partnerships of the International AIDS Vaccine Initiative (IAVI) and NIH. These VDCs may be developed within commercial or academic and/or research institutes, or through novel collaborations between different types of institutions, but would be unified by a central concept or theme. For example, multiple investigators and laboratories interested in the evaluation of a particular approach (e.g., specific viral vectors or protein antigens) would work together to systematically "cover the grid" of vaccine immunogenicity and toxicity for this specific vaccine vector or concept. Each center would be expected to work in collaboration with the larger global enterprise.
Areas of potential emphasis might be the development of novel adjuvants including recently discovered cytokines and chemokines [HN12], systematic modification of the envelope protein to maximize immunogenicity, bacterial vector design and delivery, optimized DNA and viral vector delivery, construction of immunogenic particles or structures, practical nonparenteral [HN13] delivery systems and systematic approaches to define enhanced antigen presentation. Each center would systematically create reagents and conduct preclinical experiments that would provide vaccine prototypes for human clinical trials. We estimate that between 6 and 10 new VDCs are needed to comprehensively cover the approaches outlined in the figure. As the most significant problem relates to developing vaccines that achieve rapid and broad viral neutralization, priority should be given to developing VDCs with this focus.
Schematic of global enterprise for HIV vaccine development.
This system of collaborating vaccine developers would allow centers that work on cross-cutting technologies, such as novel adjuvant development or mucosal delivery, to work with the most promising antigens so that each component of a candidate vaccine would be optimized. This is currently lacking in HIV vaccine development. The purpose of this approach is to create a systematic and coordinated pipeline of vaccine constructs that can be tested, evaluated, and redesigned. It is especially important that combination vaccine regimens are developed and tested early and that there is a systematic evaluation of the strains and antigens used. Ways must be found to address how proprietary issues, such as exclusive licensing deals, can be reconciled with open communication and vaccine development paths that combine materials and technology platforms owned by different entities. Creative solutions to this problem will be required if the critically important role of industry in this enterprise is to be realized.
Organizations like NIH, IAVI, Agence Nationale de Recherches sur le Side (ANRS) [HN14], and the European Union (EU) as well as pharmaceutical companies have funded vaccine development programs that are directed at many of these issues. Their work could form the foundation for this collaborative enterprise. Our concept could facilitate increased scale as well as greater communication and cooperation. This is particularly important among groups working on similar vaccine concepts. We expect that the infusion of funds, intellectual focus, and collaborations brought by such centers will result in increased participation of industry in HIV vaccine development. As product development and process engineering have largely resided in the biotechnology and/or pharmaceutical industry, incorporation of these skills should be an integral part of each VDC.
Vaccine Science Consortia
Many of the fundamental scientific questions impeding AIDS vaccine development have remained unchanged and unsolved since the identification of HIV as the etiologic agent responsible for AIDS. Answering these questions would provide crucial support to the VDCs and would be aided by the creation of a series of coordinated HIV vaccine scientific consortia. As with the vaccine research centers, we do not propose a specific structure for a given consortium, but the goal is to focus a range of researchers from many disciplines on a specific applied vaccine problem. The ultimate goal is to create effective, novel antigens for the pipeline. Commercial, academic, and research institutes must work together to solve the scientific challenge. Features we believe critical to the success of such consortia are (i) clearly defined goals and effective project management, (ii) dynamic scientific leadership and commitment of consortium members to the mission, (iii) a critical mass of researchers and the resources and infrastructure to rapidly translate preclinical leads toward clinical development, (iv) creative intellectual property agreements to provide incentives for data sharing and cooperative research, (v) long-term commitment free of the strict requirements of the classical short-term measures of success used by academic institutions, (vi) sufficient resources for each element of the consortium and flexibility to move resources between elements of the consortium, and (vii) collaborative arrangements with the private sector and/or the VDCs. Some of the possible scientific challenges are noted above, although these will undoubtedly change over time.
Development of Dedicated HIV-1 Vaccine Manufacturing Capacity
At present, there is inadequate capacity to produce vaccines to the standards needed for human clinical testing and insufficient resources devoted to the process of taking a research construct through the rigors of vaccine production. Therefore, the resources and facilities involved in manufacturing candidate HIV vaccines must be increased markedly. This entails the development of dedicated personnel and manufacturing facilities devoted to the process development, scale-up, formulation, stability, safety, toxicology, and production (in accord with "good manufacturing practice" or GMP) of experimental HIV vaccines, disciplines that are largely found in the private sector. A critical feature of this is the need for assay development to control the manufacturing process, something that is required for each technology and is often responsible for slowing product development. The importance of building manufacturing infrastructure has become even more acute as the major focus of HIV vaccine development has shifted from large pharmaceutical corporations to small biotechnology companies, or nonprofit or academic organizations, all of which have little or no vaccine manufacturing capabilities and experience. This lack of manufacturing capacity and expertise for vaccines and uniformity in production facilities has accounted for repeated delays in the HIV vaccine clinical trials programs. A system must be devised in which experienced industrial colleagues and facilities are devoted to the development and manufacturing of candidate HIV vaccines for human clinical trials. Expansion of this program must be coordinated with expansion of the product pipeline from the HIV VDCs.
Establishment of Standardized Preclinical and Clinical Laboratory Assessment
Although regulators and clinical trial specialists have recognized the need to standardize laboratory measurement in human clinical trials, preclinical assessments of candidate immunogens are still based largely on experiments in single research laboratories. As such, access to the primary data, standardization of the laboratory assays utilized, and interpretations of such data within the context of the field are generally not available. A more transparent and standardized preclinical evaluation system for candidate immunogens is essential for defining and developing successful vaccine regimens. For example, despite a wide variety of prototype vectors, only one standardized preclinical evaluation of their comparative immunogenicity has been initiated, and comparative human trials have not been performed. This issue has been recognized and begun to be addressed by NIH and IAVI, but should be considerably expanded.
Standardized protocols and immunogenicity measurements need to be broadly implemented at the preclinical and clinical stages of vaccine development to measure humoral and cell-mediated immunity [HN15] and to provide a test bed for reproducibly assessing the immune response to HIV antigens and adjuvants. The preclinical discovery system provides a foundation on which choices for manufacturing and testing of formulations for human clinical trials can be made. Laboratories should be established to develop and deploy robust, reproducible, and interpretable assays of immune response; to standardize reagents for such assays; and to incorporate quality-control measures for consistency. This paradigm might prove challenging to academic- based laboratories; therefore, linking these laboratories with clinical trials requires wider use of novel confidentiality agreements, working relationships, and information-sharing technologies. Such a preclinical laboratory program will also improve the pace of developing immunologic assessments in human clinical trials and will increase the likelihood of defining important correlates of immune protection.
Expansion of an Integrated, International Clinical Trials System
Large, comprehensive, coordinated, international clinical trials programs to conduct phase I, II, and III trials of candidate HIV vaccines have been established by the National Institute of Allergy and Infectious Diseases (NIAID), ANRS, IAVI, and the European Union. A rapid, iterative HIV vaccine trials enterprise will require expanded clinical trials capacity with emphasis on speed of accrual and retention of participants, high ethical standards, and enrollment of participating populations appropriate to the antigens being tested. Phase I/II clinical trials to define safety and immunogenicity are an integral part of vaccine development because, to date, animal models have been used with limited success in predicting human immune responses to HIV vaccines, especially to vector-based immunogens. The expanded global clinical trials system must therefore be considered part of vaccine product development and design. The clinical trials themselves must use standardized protocols and immunogenicity measurements. After an initial and rapid safety assessment in phase I trials, phase II trials must be adequately powered to define immunogenicity of new constructs as preclinical discovery and phase I/II clinical trials systems provide the foundation for choosing sets of large-scale phase IIb/III efficacy trials. Initial phase IIb/III clinical trials must assess laboratory and clinical efficacy and also attempt to define correlates of protection with validated assays.
Phase I safety and immunogenicity assessment of candidate HIV vaccine trials average 100 persons per protocol and phase II evaluations to define optimal dose and schedules, between 300 and 600 persons. The number of enrollees into phase III vaccine trials varies, depending on their goals, the nature of the population, and the transmission rate--but in general have averaged from 2500 to 10,000 persons per trial. To keep pace with the expanded pipeline, eventually the vaccine development enterprise would need to support a clinical trials program that enrolls about 5000 individuals in phase I/II and 30,000 persons into the phase III efficacy trials yearly. Multiple phase III trials will be needed to assess the protective efficacy of different vaccine concepts against different HIV-1 clades and in populations that may differ on the route of HIV-1 transmission or genetic background. In addition, gender, diversity in viral strains, duration, and magnitude of the ongoing epidemic are likely to influence vaccine efficacy. Most of these phase III trials will need to be conducted in developing countries, where most infections are occurring, and where a vaccine will have the most benefit. Assuring that true partnerships are developed with the research, medical, public health policy, and civic communities in those countries is essential and must begin early in the design of this enterprise. The international clinical trials system must engage local investigators, communities, ethical review committees, and regulatory bodies and must be coordinated with other national efforts to control the HIV/AIDS epidemic [HN16].
Optimizing Interactions Among Regulatory Authorities
Cooperation, communication, and sharing of information among regulatory authorities in various countries involved in licensing HIV vaccines are essential. We are not implying reduced standards in safety or manufacturing. In fact, the proposed system, with its more centralized manufacturing and immunogenicity programs, may be viewed as advantageous by regulatory bodies. This iterative process requires that regulatory bodies in a large number of regions or countries share access to preclinical and clinical information. Risk-benefit analyses for regulatory decisions should recognize regional variations in the social, economic, and health burdens of HIV and decisions by local regulatory authorities. Participation in the enterprise requires transparency and equality for all countries and regions involved. Vaccines that are partially effective should be made available for regions of the world that might benefit from their use at their explicit request while new trials and improved vaccines are being developed and evaluated.
Coordinating International HIV Vaccine Development
The Human Genome Project [HN17] provides an interesting model for international coordination as many funders agreed on a scientific road map, voluntarily divided the work, and agreed to an evolving set of production standards. The frequent sharing of progress and problems allowed coordination, cooperation, and internal competition. The "governance" was driven by an open agreement of the scientists and the funders about the blueprint of the project, which allowed coordination without unnecessary duplication. No one entity actually ran the international genome project, although the leadership was assumed by the major funders and implementers. We believe that the time is right for the major scientific and product-development leaders and the stakeholders involved in the global HIV vaccine development enterprise to come together in an analogous way.
We propose the development of a road map for the Global Vaccine Enterprise that (i) would prioritize the scientific challenges to be addressed as well as product development efforts, (ii) would rapidly develop an implementation plan for all the components of the system, and (iii) would develop a plan that identifies the resources needed. The enterprise, however, should have multiple models for structures to accomplish these goals and must find solutions that engage the public and private sectors.
For this system to work, it must address several challenges. Funders and major stakeholders of HIV vaccine development must agree to a common vision so that they can coordinate their activities with other components of the enterprise. There must be considerable sharing of information among vaccine developers regarding preclinical investigation and trial results, with the ultimate goal of advancing to clinical trials. Solving problems of access to reagents, platforms, and technologies of potential commercial interest will be required. Finally, this must be a global effort. The research and development enterprise described here must build and include full participation of the developing world where this pandemic is raging. Tens of millions of lives are dependent on the development of a safe and effective HIV vaccine. It is essential that we aggressively explore all mechanisms that might expedite this process. While comparable vaccine access initiatives will also be required to ensure that HIV vaccines are made available to populations in need throughout the world, the expanded global AIDS vaccine effort proposed here hopefully would be a major step towards accelerating successful HIV vaccine development.
References and Notes
- J. Stover et al., Lancet 360, 73 (2002) [Medline].
- D. P. Francis, personal communication.
- See www.hvtn.org
- See www.iavi.org
R. D. Klausner and H. Gayle are at the Bill and Melinda Gates Foundation, Seattle, WA 98102, USA. A. S. Fauci is director of the National Institute of Allergy and Infectious Diseases (NIAID), NIH, Bethesda, MD 20892, USA; E. C. Tramont is director of the Division of AIDS (DAIDS), NIAID, NIH; G. Nabel is director of the Vaccine Research Center, NIAID, and M. I. Johnston is associate director of the Vaccine and Prevention Research Program, DAIDS. L. Corey and J. N. Wasserheit are with the HIV Vaccine Trials Network, Program in Infectious Diseases, Fred Hutchinson Cancer Research Center, and the University of Washington, Seattle, WA 98109, USA; L. Corey is also in the Department of Laboratory Medicine, University of Washington. S. Berkley is with the International AIDS Vaccine Initiative, New York, NY 10038, USA. B. F. Haynes is at the Duke University School of Medicine, Durham, NC 27710, USA. D. Baltimore is at the California Institute of Technology, Pasadena, CA 91125, USA. C. Collins is at the AIDS Vaccine Advocacy Coalition, New York, NY 10011, USA. R. G. Douglas Jr. is at the Sequella Global Tuberculosis Foundation, Rockville, MD 20850, USA. J. Esparza is coordinator of the HIV Vaccine Initiative of the World Health Organization-Joint United Nations Programme on HIV/AIDS (WHO-UNAIDS), Geneva 27, Switzerland. D. P. Francis is at the VaxGen, Inc., Brisbane, CA 94005, USA. N. K. Ganguly is in the Indian Council of Medical Research, New Delhi 110029, India. J. L. Gerberding is at the Centers for Disease Control and Prevention, Atlanta, GA 30333, USA. M. D. Kazatchkine is at the Agence Nationale de Recherches sur le Side (ANRS), Paris 75013, France. A. J. McMichael is at the MRC Human Immunology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS, UK. M. W. Makgoba is at the University of Natal, Durban 4041, South Africa. G. Pantaleo is in the Division of Immunology and Allergy, Centre Hospitalier Universitaire Vaudois, University of Lausanne, Lausanne CH-1011, Switzerland. P. Piot is with UNAIDS, Geneva 27, Switzerland. Y. Shao is at the National Center for AIDS/STD Control and Prevention, Beijing 100050, China. H. Varmus is at the Memorial Sloan Kettering Cancer Center, New York, NY 10021, USA.
Related Resources on the World Wide Web
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On-line Medical Dictionary is provided by
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Adjuvant is defined in the
IAVI vaccine glossary.
AIDSinfo HIV Glossary defines
chemokines. H. Ibelgaufts'
Cytokines Online Pathfinder Encyclopaedia includes articles on
J. Decker provides notes on
cytokines for an
N. Holmes, Department of Pathology, University of Cambridge, makes available
lecture notes on cytokines prepared for a pathology course.
The February-April 2003
IAVI Report had a
meeting report by M. Boaz and R. Jefferys titled "Can DNA vaccines get a boost from cytokines?"
The 20 November 2000 issue of Science had an
Enhanced Perspective by X. Shen and R. Siliciano titled "Preventing AIDS but not HIV-1 infection with a DNA vaccine" about a
report in that issue by D. Barouch et al. titled "Control of viremia and prevention of clinical AIDS in rhesus monkeys by cytokine-augmented DNA vaccination."
AEGiS provides a
collection of resources about chemokines.
Parenteral is defined in the
IAVI glossary and in the
Agence Nationale de Recherches sur le Side is constructing a
Humoral and cell-mediated immunity; measuring immune response.
Humoral immunity and
cell-mediated immunity are defined in the
J. Decker offers presentations on
humoral immunity and
cell-mediated immunity for an
G. Lindquester provides lecture notes on
humoral immunity and
cell-mediated immunity for an
HIV InSite's presentation on the
science of HIV vaccine development includes sections on
cellular immune responses.
The October-November 2002 issue of the
IAVI Report had an
article by E. Bass titled "Immunogenicity assay standardization efforts underway."
NIAID Division of AIDS provides a resource page on
Clinical research in developing countries.
Nuffield Council on Bioethics makes available an
April 2002 report titled The Ethics of Research Related to Healthcare in Developing Countries.
HIV/AIDS Developing World Bioethics Web site is provided by the
Bioethics Division, Faculty of Health Sciences, Witwatersrand University, Johannesburg, South Africa.
WHO-UNAIDS HIV Vaccine Initiative makes available in PDF format a
symposium paper by J. Esparza et al. titled "Past, present and future of HIV vaccine trials in developing countries."
The 13 December 2002 issue of Science had an
Enhanced Policy Forum titled "Fair benefits for research in developing countries."
The Human Genome Project.
National Human Genome Research Institute offers a
presentation on the Human Genome Project and its history.
interactive timeline of the human genome sequencing is provided by
Science's Functional Genomics Web site.
Human Genome Project Information Web site provides
links to institutions of the International Human Genome Sequencing Consortium.
The 11 April 2003 issue of Science had a
Viewpoint article by F. S. Collins, M. Morgan, and A. Patrinos titled "The Human Genome Project: Lessons from large-scale biology."
R. D. Klausner is at the
Bill and Melinda Gates Foundation.