A Sound Rationale Needed for Phase III HIV-1 Vaccine Trials

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Science  16 Jan 2004:
Vol. 303, Issue 5656, pp. 316
DOI: 10.1126/science.1094620

The need for a human immunodeficiency virus-1 (HIV-1) vaccine [HN1] is unquestioned, and we strongly support its development as the highest AIDS research priority. We have a concern about the wisdom of the U.S. government's sponsoring a recently initiated phase III trial [HN2] in Thailand of a vaccine made from the live-replicating canarypox vector ALVAC (from Aventis Pasteur) [HN3] with a boost of monomeric gp120 (from VaxGen) [HN4] (1). The original aim of this trial was to determine whether a combination of immunogens designed to induce cellular immunity (ALVAC) and humoral immunity [HN5] (gp120) could prevent infection and/or lead to the immune control of HIV-1 replication postinfection. These remain questions fundamentally worth addressing, but we doubt whether these immunogens have any prospect of stimulating immune responses anywhere near adequate for these purposes.

A phase III trial of similar design was scheduled to be conducted in the U.S.A. by the HIV Vaccine Trials Network (HVTN) [HN6], the world's largest consortium of AIDS vaccine scientists and clinicians. However, the trial was canceled last year. [HN7] Multiple phase I and II clinical trials have revealed that the ALVAC vector is poorly immunogenic (2). The gp120 component has now been proven in phase III trials in the United States and Thailand to be completely incapable of preventing or ameliorating HIV-1 infection (1, 3). [HN8] There are no persuasive data to suggest that the combination of ALVAC and gp120 could induce better cellular [CD8+ cytotoxic T lymphocyte (CTL)] [HN9] or humoral (neutralizing antibody [HN10]) responses than either component can alone. Instead, the rationale for the Thai trial is reported to have now shifted toward an exploration of the hypothesis that the combination ALVAC + gp120 vaccine might induce an improved CD4+ T helper (TH) cell response [HN11] that would enhance host defenses (1). The evidence underlying this hypothesis is derived from phase I/II trials of the same or very similar vaccines and is, in our opinion, extremely weak (46). Moreover, the same data were available to the HVTN. We concur with the HVTN's decision not to proceed with a phase III trial of the ALVAC + gp120 vaccine (2). What scientific reasons mandate a different decision for the Thai trial? We also take issue with the scientific rationale for the revised hypothesis underlying the trial (1). Merely trying to answer a question about the protective role of the TH response does not seem to justify an experiment on this scale. Whether induction of TH responses by the gp120 component could enhance the breadth or magnitude of CTL responses to the ALVAC vector sufficiently could be answered rapidly by a small trial using methodology that was not available at the time of the earlier studies (46).

The cost of the phase III trial in Thailand is reported to be $119m, with at least $3m for the purchase of the gp120 component from its commercial manufacturer, itself a controversial point based on past precedent (7). The trial will involve 16,000 volunteers. [HN12] Approval was obtained from several committees, including one from the World Health Organization. But the latter committee's recommendation to proceed was made over a year before the results of the gp120 efficacy trial in Thailand were available, and it was made irrespective of the outcome of that trial (1). Our opinion is that the overall approval process lacked input from independent immunologists and virologists who could have judged whether the trial was scientifically meritorious. The U.S. National Institutes of Health (NIH) investment in basic and applied immunology research has been massive and appropriate over the past 15 years; the cumulative expertise gained should be used when important strategic decisions are made.

Society expects the scientific community to develop a vaccine to counter the AIDS pandemic, but there are adverse consequences to conducting large-scale trials of inadequate HIV-1 vaccines. We have recently seen two large phase III trials of immunogens that, all too predictably, failed to generate protective immunity (1, 2). We seriously question whether it is sensible now to conduct a third trial that, in our opinion, is no more likely to generate a meaningful level of protection against infection or disease. One price for repetitive failure could be crucial erosion of confidence by the public and politicians in our capability of developing an effective AIDS vaccine collectively. This seems to us to be another readily predictable scenario that is best prevented.

Phase III trials are, ultimately, the only way to judge HIV-1 vaccine efficacy, but sometimes a formal end point is not needed. Applying judgment about the value of existing data is an essential part of the scientific process when determining whether or not to move ahead with any experiment. The failure of the gp120-only vaccine was, for example, fully predicted by phase II trial data (8). For a phase III trial to be justifiable, there should be a reasonable prospect that the vaccine will benefit the study population, i.e., that it will protect at least some of the participants from HIV-1 infection or its consequences. The decision about whether or not to proceed with mounting a phase III HIV-1 vaccine trial needs to take into account the likelihood of success and the consequences of failure, the value of what can realistically be learned, and the human and financial costs involved. As a whole, the scientific community must do a better job of bringing truly promising vaccine candidates to this stage of development and beyond. More highly immunogenic HIV-1 vaccines that offer a greater hope of success than the ALVAC-gp120 combination are, in fact, now in early-phase clinical trials.

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 HIV Vaccine Glossary is provided by the National Institute of Allergy and Infectious Diseases (NIAID). The Body also makes this glossary available.

A Glossary of Clinical Trials Terms is provided by ClinicalTrails.gov.

Web Collections, References, and Resource Lists

The Yahoo Directory provides AIDS/HIV 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.

MEDLINEplus from the National Library of Medicine (NLM) provides links to Internet resources on AIDS, vaccines, and clinical trials. The NLM's Specialized Information Services Division offers a portal to HIV/AIDS information.

AIDSinfo is a service of the U.S. Department of Health and Human Services.

The HIV Vaccine Trials Network provides a collection of links to HIV vaccine-related Internet resources.

Online Texts and Lecture Notes

J. Kimball maintains Kimball's Biology Pages, an online biology textbook and glossary. Presentations on AIDS and vaccines are included.

The immunology section of the University of Arizona's Biology Project offers an HIV and AIDS tutorial.

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

The Department of Microbiology and Immunology, University of Rochester Medical Center, offers (in PDF format) lecture notes in virology. Included are lecture notes titled “HIV/AIDS: Pathogenesis, virology and vaccines.”

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.

HIV InSite, an information resource on HIV/AIDS treatment, prevention, and policy, is provided by the UCSF Center for HIV Information. Included is an online textbook with sections on the natural science of HIV, HIV vaccine development, and policy issues of AIDS vaccine development.

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

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 4th edition of Medical Microbiology, edited by S. Baron, is also provided.

The 27 June 2003 issue of Science had an Enhanced Policy Forum by R. D. Klausner et al. titled “The need for a global HIV vaccine enterprise.”

The 28 June 2002 issue of Science had a special report titled “HIV/AIDS: Therapies, Vaccines, Challenges.” A News Focus article about vaccines by J. Cohen titled “Monkey puzzles” was included.

The 19 September 2003 issue of Science had a special News Focus report on AIDS/HIV in Asia. Included was an article by J. Cohen titled “Thailand beats the odds in completing vaccine test.”

The 29 November 2002 issue of Science had four essays on HIV/AIDS, including an Enhanced Viewpoint by R. C. Gallo and L. Montagnier titled “Prospects for the future.”

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.

The January 2003 issue of the Hopkins HIV Report had an article by C. Beyrer titled “The HIV/AIDS vaccine research effort: An update.”

Numbered Hypernotes

1. HIV vaccines. Search for a vaccine is a presentation on NOVA Online's Surviving AIDS Web site. AIDSinfo offers a resource page and overview of vaccines. The World Health Organization's HIV/AIDS Web site offers an introduction to HIV vaccines. NIAID makes available a May 2003 fact sheet titled “Challenges in designing HIV vaccines” and a August 2003 fact sheet titled “Clinical research on HIV vaccines,” as well as the online brochures Understanding Vaccines and HIV Vaccines Explained (in PDF format). The NIAID Division of AIDS offers a resource page on HIV vaccines. IAVI provides an overview titled “Preventive AIDS vaccine approaches currently in human testing” and the IAVI Database of Preventive AIDS Vaccines in Human Trials. The Pipeline Project, a collaboration of the UCSF Center for HIV Information and the HIV Vaccine Trials Network, provides information about vaccines in development; links to Internet resources on vaccine development are included. HIVandHepatitis.com offers news reports about HIV vaccines. The Body, an AIDS and HIV information resource, provides links to articles about HIV vaccines. The AIDScience archive from Science Online makes available a March 2002 article by H. Köhler, S. Müller, and V. Veljkovic titled “No hope for an AIDS vaccine soon.”

2. Phases of clinical trails. Definitions of the phases of clinical trials are provided by the CenterWatch glossary. IAVI provides an introduction to the phases of clinical trials. ClinicalTrials.gov provides an introduction to clinical trials. D. Stevens, Department of Pediatrics, University of South Dakota School of Medicine, provides lecture notes on clinical trials.

3. Canarypox vector ALVAC from Aventis Pasteur. Canarypox, vector, and ALVAC-HIV are defined in the HIV Vaccine Glossary. Aventis Pasteur provides an introduction to its R&D program. Aventis makes available a 8 July 2002 press release titled “Aventis Pasteur and AIDS vaccine research: An overview”; the fact sheets on ALVAC and Prime Boost are also available in PDF format. The IAVI Database of Preventive AIDS Vaccines has an entry for ALVAC vCP1521 (the vector to be used in the phase III trial in Thailand).

4. VaxGen's gp120 vaccine. The NIAID HIV Vaccine Glossary defines gp120. VaxGen provides information about its AIDSVAX HIV vaccine candidates and the associated clinical trials. Information about gp120 vaccines is provided by aidsmap.com.

5. Cellular and humoral immunity. Humoral immunity and cell-mediated immunity are defined by the AIDSinfo glossary. Understanding the Immune System is a presentation of the News Center of the National Cancer Institute. S. Baron's Medical Microbiology includes an immunology overview. Kimball's Biology Pages offers an introduction to cell-mediated immunity. J. Decker offers tutorials on humoral immunity and cell-mediated immunity for an immunology course. P. Bugl provides introductions to cell-mediated immunity and humoral immunity in lecture notes for a course on epidemics and AIDS. HIV InSite provides information on humoral and cellular immune responses in the presentation on the science of HIV vaccine development.

6. The HIV Vaccine Trials Network, formed in 1999 by the NIAID Division of AIDS, conducts all phases of clinical trials, from evaluating candidate vaccines for safety and the ability to stimulate immune responses to testing vaccine efficacy.

7. Cancellation of the U.S. phase III trial. NIAID issued a 25 February 2002 press release titled “NIAID phase III HIV vaccine trial to determine correlates of protection will not proceed.” The January-February 2002 issue of the IVAI Report had an article by P. Kahn titled “NIH drops plans for phase III trial.” The 1 March 2002 issue of Science had a News of the Week article by J. Cohen titled “Disappointing data scuttle plans for large-scale AIDS vaccine trial.”

8. Previous trials. The IAVI Database of Preventive AIDS Vaccines provides information on ALVAC vCP1452 and ALVAC vCP205 trials, as well as information on AIDSVAX B/E and AIDSVAX B/B trials. Information about ALVAC trials is provided by aidsmap.com. VaxGen issued a 24 February 2003 press release titled “VaxGen announces initial results of its phase III AIDS vaccine trial” and a 12 November 2003 press release titled “VaxGen announces results of its phase III HIV vaccine trial in Thailand: Vaccine fails to meet endpoints.” 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.” 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.” BioMed Central makes available a 7 November 2003 daily news story (provided by The Scientist) by R. Walgate titled “AIDS answers and questions: Failed vaccine trial in Thailand teaches many lessons, says the UN's José Esparza.”

9. CD8+ cytotoxic T lymphocyte. CD8+ T lymphocyte and cytotoxic T lymphocyte (CTL) are defined by the HIV Vaccine Glossary. Dalhousie University School of Medicine's Immunology Book Case provides introductions to cytotoxic T cells and cytotoxic T lymphocyte activity. Kimball's Biology Pages offers an introduction to cytotoxic T lymphocytes.

10. Neutralizing antibody is defined in the HIV vaccine glossary. IAVI issued a 9 July 2002 press release titled “IAVI launches Neutralizing Antibody Consortium to accelerate search for preventive AIDS vaccine.”

11. CD4+ T helper cells. CD4+ T lymphocyte is defined by the HIV Vaccine glossary. CD4+ cells are defined in the AIDSinfo glossary. An entry for helper T cell is included in the Wikipedia online encyclopedia. Kimball's Biology Pages offers an introduction to CD4+ T cells and T helper cells.

12. The phase III trial in Thailand. UNAIDS provides a brief on Thailand's response to AIDS. The HIV/AIDS Surveillance Web site of the U.S. Census Bureau makes available in PDF format an HIV/AIDS profile of Thailand. The Thai Prime-Boost HIV Vaccine Phase III Trial Web site provides a FAQ and information about the researchers. The AIDS Vaccine Clearinghouse provides information about the Thailand trial. The IAVI Database of Preventive AIDS Vaccines provides information on the Thailand phase III trial. IVAI provides a 28 February 2002 news report titled “U.S. government announces plans for final stage human trial of ALVAC-AIDSVAX in Thailand.” The October-December 2001 issue of the IAVI Report (a special issue on Thailand & AIDS Vaccines) had an article by P. Kahn titled “Thailand prepares for a new phase III trial” and an article titled “Thailand, AIDS and vaccines: An interview with Supachai Rerks Ngarm.” The 21 November 2003 issue of Science had a News of the Week article by J. Cohen titled “AIDS vaccine still alive as booster after second failure in Thailand.”

13. Dennis R. Burton is at the Scripps Research Institute. Ronald C. Desrosiers and Judy Lieberman are at Harvard Medical School. Robert W. Doms, James A. Hoxie, and Neal Nathanson are at the University of Pennsylvania. Mark B. Feinberg is at Emory University; Robert C. Gallo is at the Institute of Human Virology. Beatrice Hahn and Eric Hunter are at the University of Alabama at Birmingham. Bette Korber is at the Santa Fe Institute. Alan Landay is at the Rush Medical College. Michael M. Lederman is at Case Western Reserve University. Joseph M. McCune is at the Gladstone Institute for Virology and Immunology. John P. Moore is at the Weill Medical College of Cornell University. Louis Picker is at the Oregon Health and Science University. Douglas Richman is at the University of California, San Diego, and San Diego Veterans Affairs Healthcare System. Charles Rinaldo is at the University of Pittsburgh. Mario Stevenson is at the University of Massachusetts Medical School. David I. Watkins is at the University of Wisconsin. Steven M. Wolinsky is at Northwestern University. Jerome A. Zack is at the University of California, Los Angeles.


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