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MEDICINE:
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.

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

1. J. Stover et al., Lancet 360, 73 (2002) [Medline].
2. D. P. Francis, personal communication.
3. See www.hvtn.org
4. See www.iavi.org

HyperNotes
Related Resources on the World Wide Web

General Hypernotes

Dictionaries and Glossaries

The On-line Medical Dictionary is provided by CancerWeb.

A glossary of HIV/AIDS-related terms is provided by AIDSinfo.

An AIDS vaccine glossary is provided by the International AIDS Vaccine Initiative.

Web Collections, References, and Resource Lists

The Yahoo Directory provides HIV/AIDS Internet links, as well as news coverage related to AIDS.

D. Sander's All the Virology on the WWW includes a section on AIDS information and research. A virology glossary is also provided.

MEDWEB, provided by the Health Sciences Center Library of Emory University, includes links to Internet resources on HIV and AIDS.

MedlinePLUS from the National Library of Medicine (NLM) offers links to AIDS Internet resources. NLM's Specialized Information Services Web page provides a collection of HIV/AIDS information resources.

HIV Databases are provided by the Theoretical Biology and Biophysics Group at the Los Alamos National Laboratory. A review article collection and links to Internet resources are provided.

NIH's AIDSinfo is an information resource for the latest federally approved information on research, clinical trials, and treatment for patients and health care providers.

Other U.S. government AIDS resources include those offered by the Division of Acquired Immunodeficiency Syndrome of the NIH's National Institute of Allergy and Infectious Diseases (NIAID), the National Center for HIV, STD and TB Prevention of the Centers for Disease Control and Prevention (CDC), and the U.S. Military HIV Research Program at the Walter Reed Army Institute of Research.

International Internet resources relating to HIV and AIDS include those provided by the CDC's Global AIDS Program, UNAIDS (the United Nations Programme on HIV/AIDS), the World Health Organization (WHO), the WHO Department of HIV/AIDS, the United Nations Development Programme, the World Bank, and the Pan American Health Organization.

Other Internet resources focusing on AIDS research, prevention and treatment, and news include the American Foundation for AIDS Research, the Johns Hopkins AIDS Service, the Harvard AIDS Institute, the AIDS Education Global Information System (AEGiS), The Body, and the Kaiser Family Foundation.

Online Texts and Lecture Notes

J. Kimball provides Kimball's Biology Pages, a Web textbook and glossary.

Microbiology and Immunology On-line is a Web textbook provided by the Department of Pathology and Microbiology, University of South Carolina School of Medicine. A section on virology is included.

J. Decker, Department of Veterinary Science and Microbiology, University of Arizona, offers tutorials for an immunology course.

G. Lindquester, Department of Biology, Rhodes College, Memphis, TN, provides lecture notes for an immunology course.

P. Bugl, Department of Mathematics, University of Hartford, offers lecture notes and related readings for a course on epidemics and AIDS.

AIDScience is a Web resource on prevention and vaccine research provided by Science Online.

HIV InSite, provided by the UCSF Center for HIV Information, includes an online textbook with sections on the natural science of HIV, HIV vaccine development, and policy issues of AIDS vaccine development.

The International AIDS Vaccine Initiative (IAVI) offers presentations on the need for a vaccine and vaccine science. The IAVI Report is a newsletter available online that covers international HIV vaccine research.

General Reports and Articles

The Bookshelf provided by the National Center for Biotechnology Information makes available the searchable full text of Immunobiology by C. Janeway et al. and Retroviruses by J. Coffin et al.

The June 2002 issue of Scientific American had an article By C. Ezzell titled "Hope in a vial: Will there be an AIDS vaccine anytime soon?"

The 28 June 2002 issue of Science had a special report titled "HIV/AIDS: Therapies, Vaccines, Challenges." Included were a News Focus article about therapies titled "Confronting the limits of success" and a News Focus article about vaccines titled "Monkey puzzles," both by J. Cohen.

The 29 November 2002 issue of Science had four essays on HIV/AIDS: an Enhanced Viewpoint by R. C. Gallo and L. Montagnier titled "Prospects for the future" and three historical essays. A collection of Science historical news articles is provided as a Science Online feature.

The December 2001 issue (a special issue on HIV/AIDS) of the Bulletin of the World Health Organization had an article (available in PDF format) by J. Esparza titled "An HIV vaccine: How and when?"

How Do You Fight a Disease of Mass Destruction? is the May 2003 report (available in PDF format) on the status of AIDS vaccine research by the AIDS Vaccine Advocacy Coalition (AVAC).

Numbered Hypernotes

1. HIV/AIDS. Cells Alive offers an animated presentation on HIV infection. AEGiS provides an illustrated presentation on the life cycle of HIV. Kimball's Biology Pages includes an introduction to AIDS. The immunology section of the University of Arizona's Biology Project offers an HIV and AIDS tutorial. An HIV tutorial is provided by E. Klatt's Internet Pathology Laboratory for Medical Education. A. Cann, Department of Microbiology and Immunology, University of Leicester, UK, provides lecture notes on the pathogenesis of AIDS for a virology course. The Department of Microbiology and Immunology, University of Rochester, makes available (in PDF format) lecture notes on HIV/AIDS for a virology course. Microbiology and Immunology On-line includes a presentation on HIV by R. Hunt. In Their Own Words...NIH Researchers Recall the Early Years of AIDS is presented by NIH. The July 2001 issue of the Hopkins HIV Report had article by J. Bartlett titled "HIV: Twenty years in review."

2. Developing a vaccine against HIV. Kimball's Biology Pages includes a presentation on vaccines. Understanding Vaccines and HIV Vaccines Explained (in PDF format) are online brochures from NIAID; also provided are a May 2003 fact sheet titled "Challenges in designing HIV vaccines" and a May 2002 fact sheet titled "Clinical research on HIV vaccines." The NIAID Division of AIDS offers a presentation on HIV vaccines. The WHO HIV/AIDS Web site offers a presentation about HIV vaccines. The WHO-UNAIDS HIV Vaccine Initiative makes available a collection of publications and documents about AIDS vaccines. The January 2003 issue of Current HIV Research (published by Bentham Science Publishers) had an article by P. Spearman titled "HIV vaccine development: Lessons from the past and promise for the future." The Jordan Report 20th Anniversary: Accelerated Development of Vaccines 2002, made available by NIAID in PDF format, includes a section on HIV vaccines. HIV Vaccine Handbook: Community Perspectives on Participating in Research, Advocacy, and Progress is a 1999 book made available in PDF format by AVAC. The Body, an AIDS and HIV information resource, provides links to articles about HIV vaccines. HIV InSite provides a collection of Internet resources about HIV vaccines.

3. The AIDS pandemic. IAVI offers a presentation about the HIV/AIDS epidemic. The 1 June 2001 issue of MMWR (Morbidity and Mortality Weekly Report) had an article titled "The global HIV and AIDS epidemic, 2001." UNAIDS provides the July 2002 Report on the Global HIV/AIDS Epidemic and the December 2002 AIDS epidemic update. The January 2003 issue of the Hopkins HIV Report had an article by T. Quinn titled "World AIDS Day: Reflections on the pandemic" and the January 2001 issue had an article by T. Quinn titled "The global HIV pandemic: Lessons from the past and glimpses into the future." The September 2002 issue of the Population Bulletin, published by the Population Reference Bureau, had an article (available in PDF format) by P. Lamptey, M. Wigley, D. Carr, and Y. Collymore titled "Facing the HIV/AIDS pandemic." The Guardian offers a special AIDS report. UNAIDS makes available (in PDF format) an article (from the 6 July 2002 issue of Lancet) by J. Stover et al. titled "Can we reverse the HIV/AIDS pandemic with an expanded response?" (1).

4. HIV vaccine candidates. The January 2003 issue of the Hopkins HIV Report had an article by C. Beyrer titled "The HIV/AIDS vaccine research effort: An update." IAVI provides a presentation titled "Preventive AIDS vaccine approaches currently in human testing" and a database of preventive AIDS vaccines in human trials; an HIV clinical trials watch poster is also available. The European Vaccine Effort against HIV/AIDS (EuroVac), funded by the European Union, provides information about component HIV vaccine projects. AIDSinfo provides information about HIV vaccine trials. The Global Projects feature of AIDScience provides information about AIDS vaccine projects.

5. Clinical trials. Definitions of the phases of clinical trials are provided by the CenterWatch glossary. IAVI offers an introduction to the phases of vaccine clinical trials. NIH's ClinicalTrials.gov offers an introduction to clinical trials. D. Stevens, Department of Pediatrics, University of South Dakota School of Medicine, provides lecture notes on clinical trials. The HIV Sequence Database makes available a 2000 review article by B. Graham titled "Clinical trials of HIV vaccines."

6. Negative results of a phase III efficacy trial. IAVI provides a resource page on the AIDSVAX candidate vaccine. VaxGen provides information about the AIDSVAX candidate vaccine and clinical trials and makes available a 24 February 2003 press release about the phase III trial results. HIV InSite offers a 24 February 2003 commentary by Laurence Peiperl about the VaxGen announcement. AVAC offers a 24 February 2002 press release and a consensus statement about the AIDSVAX trial results. The 28 February 2003 issue of Science had a News of the Week article by J. Cohen titled "AIDS vaccine trial produces disappointment and confusion"; the 7 March 2003 issue had a News of the Week article by J. Cohen titled "Vaccine results lose significance under scrutiny"; and the 4 April 2003 issue had a News of the Week article by J. Cohen titled "A setback and an advance on the AIDS vaccine front."

7. Neutralizing antibody is defined in the IAVI vaccine glossary. AIDScience offers an 14 March 2003 article by R. Fernandez-Larsson titled "Neutralizing antibody response to HIV and virus escape."

8. HIV-1 variability. The NIAID Division of AIDS offers a presentation on HIV variation. P. Bugl offers lecture notes on types of HIV-1 for a course on epidemics and AIDS. The HIV Sequence Database offers a tutorial on HIV and SIV nomenclature with a section on subtypes, as well as a 2000 review by M. Peeters titled "Recombinant HIV sequences: Their role in the global epidemic" with information about HIV-1 strains and a 1999 review by E. Fenyo et al. titled "The history of HIV-1 biological phenotypes past, present, and future." UNAIDS makes available a FAQ on HIV variability and a paper by S. Osmanov, W. Heyward, and J. Esparza titled "HIV-1 genetic variability: Implications for the development of HIV vaccines." The WHO-UNAIDS HIV Vaccine Initiative provides in PDF format a report titled "Approaches to the development of broadly protective HIV vaccines: Challenges posed by the genetic, biological and antigenic variability of HIV-1." The 28 June 2002 issue of Science had a review article by B. Gaschen et al. titled "Diversity considerations in HIV-1 vaccine selection."

9. Childhood acute lymphocytic leukemia. Acute lymphocytic leukemia (ALL) is defined in the Cancer.gov dictionary. Cancer.gov provides an overview of ALL as well as ALL treatment information written for patients and health professionals. The eMedicine Web site offers a review article by J. Rubnitz on the diagnosis and treatment of childhood ALL. The NCI's Cancer Research Awareness Web site offers a presentation on childhood cancer with a section on treatment progress.

10. The Pipeline Project, a collaboration of the UCSF Center for HIV Information and the HIV Vaccine Trials Network, provides information about vaccines in development.

11. The NIH Vaccine Research Center provides a statement of its mission and goals and a resource page on clinical studies with a section on HIV candidate vaccines.

12. Novel adjuvants, cytokines and chemokines. Adjuvant is defined in the IAVI vaccine glossary. The AIDSinfo HIV Glossary defines adjuvant, cytokines, and chemokines. H. Ibelgaufts' Cytokines Online Pathfinder Encyclopaedia includes articles on chemokines and cytokines. J. Decker provides notes on cytokines for an immunology course. 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.

13. Parenteral is defined in the IAVI glossary and in the AIDSinfo glossary.

14. The Agence Nationale de Recherches sur le Side is constructing a Web site.

15. Humoral and cell-mediated immunity; measuring immune response. Humoral immunity and cell-mediated immunity are defined in the AIDSinfo glossary. J. Decker offers presentations on humoral immunity and cell-mediated immunity for an immunology course. G. Lindquester provides lecture notes on humoral immunity and cell-mediated immunity for an immunology course. HIV InSite's presentation on the science of HIV vaccine development includes sections on humoral and cellular immune responses. The October-November 2002 issue of the IAVI Report had an article by E. Bass titled "Immunogenicity assay standardization efforts underway." The NIAID Division of AIDS provides a resource page on assay development.

16. Clinical research in developing countries. The Nuffield Council on Bioethics makes available an April 2002 report titled The Ethics of Research Related to Healthcare in Developing Countries. The HIV/AIDS Developing World Bioethics Web site is provided by the Bioethics Division, Faculty of Health Sciences, Witwatersrand University, Johannesburg, South Africa. The 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."

17. The Human Genome Project. The National Human Genome Research Institute offers a presentation on the Human Genome Project and its history. An interactive timeline of the human genome sequencing is provided by Science's Functional Genomics Web site. The 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."

18. R. D. Klausner is at the Bill and Melinda Gates Foundation.