A Timeline for the Initiation of the RV144 Prime-Boost Trial
U.S. Military HIV Research Program/Thai Ministry of Public Health collaboration tests various combinations of ALVAC prime/Env protein boost vaccines, eventually choosing to move ahead with the ALVAC vCP1521 vector boosted with AIDSVAX B/E. Cohort studies are conducted in Chon Buri, showing an annual incidence of 0.68 new infections per 100-person years (95% confidence interval: 0.34-1.02). The lower bound of the CI is used to design RV144, which will only enroll low-risk heterosexual participants due to the U.S. Military’s policy precluding the enrollment of injection drug users or gay men. These preparatory studies are reviewed in Military Medicine 169;8:588-593, 2004.
Science magazine’s Jon Cohen breaks the story of the planned shift of the U.S. Military HIV Research program from the Department of Defense to the National Institutes of Health (“Pentagon Proposes to Cut AIDS Research From Defense Budget,” Science, July 20, 2001).
IAVI Report article by Patricia Kahn cites phase III prime-boost milestones: “The final decision on launching Phase III testing will be based on whether results from an ongoing Phase II study (RV135) in Bangkok meet immunogenicity milestones. These are: a CTL response to selected antigens of HIV subtype E, the predominant clade in Thailand, in at least 30% of vaccinated volunteers at one or more time points (called a “cumulative” CTL response); LPR in 60% of vaccinees; and neutralizing antibodies to a standardized laboratory-grown HIV strain in 70%.”
HVTN 501, a primarily U.S.-based trial that would have compared the protective efficacy of ALVAC to ALVAC+AIDSVAX B/B and evaluated CD8 T-cell responses as a correlate of immunity, is cancelled due to the fact that ALVAC did not induce detectable CD8 T-cell responses in a large enough percentage of participants in a preparatory phase II trial.
National Institute of Allergy and Infectious Diseases (NIAID) issues a release stating in part that: “NIAID, part of the National Institutes of Health (NIH), and the U.S. Army Medical Research and Materiel Command (USAMRMC) of the Department of Defense (DoD) recently signed an Interagency Agreement to transfer oversight and management of the U.S. Military HIV Research Program (USMHRP) to NIAID. According to the terms of the agreement, funds to support the DoD program will be provided to USAMRMC from the NIH HIV/AIDS research budget. As identified last February by the FY 2003 President’s Budget, NIH will assume responsibility for managing and funding the program through NIAID effective October 1, 2002. … The agreement establishes a formal relationship between NIAID and USAMRMC for planning and implementing various facets of HIV vaccine research. NIAID will continue to support HIV research and development that is relevant to and supportive of the military mission. These include ongoing and proposed projects such as the following: A Phase 3 trial in Thailand of an HIV vaccine, ALVAC vCP1521 prime plus AIDSVAX B/E gp120 boost.” (“Interagency Agreement Transfers DoD HIV Research to NIAID“). In other words, NIAID makes a seemingly irreversible commitment to fund RV144 to completion.
The majority of members of the World Health Organization (WHO) and Joint United Nations Programme on HIV/AIDS (UNAIDS) Vaccine Advisory Committee (VAC) endorsed the proposed R144 trial and protocol (but not unanimously). Full comments provided to Thai Subcommittee on HIV/AIDS Vaccines (but are not made available publicly on the WHO-UNAIDS Web site).
WHO-UNAIDS consultation (conducted together with the U.S. Centers for Disease Control [CDC]) to discuss “Implications of forthcoming results from the first Phase III trial of an HIV vaccine for ongoing and future trials.” They decide that if efficacy is not demonstrated in the AIDSVAX trials, proceeding with RV144 is appropriate “because of the independent scientific rationale of the prime-boost strategy.” Of the 23 participants at this meeting, none were independent experts in antibody or cell-mediated immune responses, or HIV vaccine science in general. The three scientists from the U.S. CDC were epidemiologists, as were all but one of the other six scientists not involved with the RV144 study (the remaining independent scientist was a bioethicist). One of the participants was from Cooney-Waters, a PR firm that represents Aventis-Pasteur. The ability of this panel to comment authoritatively on the “scientific rationale” of the RV144 trial is therefore extremely questionable.
The report from the WHO-UNAIDS consultation was “presented to and accepted by” the WHO-UNAIDS Vaccine Advisory Committee. Minutes from this meeting are also not publicly available.
Failure of AIDSVAX B/B to protect against sexual transmission of HIV infection reported.
Screening for RV144 begins, the only public announcement in the U.S. is a brief, little-noticed release on the U.S. Military HIV Research Program’s Web site.
First RV144 volunteers vaccinated.
Failure of AIDSVAX B/E to protect against HIV infection in a trial that recruited Thai injection drug users is reported. A Science article by Jon Cohen reports the start of the RV144 trial, still no public announcement made by the sponsors.
A group of AIDS vaccine researchers publishes a perspective article in Science critiquing the launch of RV144. (“A Sound Rationale Needed for Phase III HIV-1 Vaccine Trials” by Dennis Burton, Ron Desrosiers, Robert Doms, Mark Feinberg, Robert Gallo, Beatrice Hahn, James Hoxie, Eric Hunter, Bette Korber, Alan Landay, Michael Lederman, Judy Lieberman, Joseph McCune, John P. Moore, Neal Nathanson, Louis Picker, Douglas Richman, Charles Rinaldo, Mario Stevenson, David Watkins, Steven Wolinsky and Jerome A. Zack). NIAID issues a press release in response (www2.niaid.nih.gov/newsroom/releases/rv144.htm), representing the first public announcement from NIAID acknowledging that the trial has started.
Science publishes a rebuttal, “HIV Vaccine Trial Justified” authored by representatives of the trial’s sponsors, John McNeil, Peggy Johnston, Debbie Birx and Ed Tramont.
The Division of AIDS advisory body on vaccine research, the AIDS Vaccine Research Working Group (AVRWG), makes recommendations for improving and streamlining RV144.
The Journal of Infectious Diseases (JID) publishes immunogenicity results from the phase II prime-boost trial (RV135), demonstrating that even by the most optimistic (and widely criticized) assessment of “cumulative” CTL responses (e.g., adding together all participants showing a CTL response at any timepoint), only 24% of participants showed a response, suggesting that the 30% milestone was not met. DAIDS later states that the 30% milestone referred to bulk unfractionated PBMC (including CD4 and CD8 T cells) and that, based on this criteria, 31.25% of participants showed evidence of CTL activity at some point during RV135. These data are not mentioned in the JID article, and none of the RV144 trial sponsors and investigators cite these responses in the face of skeptical questions about the CTL data at a subsequent FDA hearing (see below).
JID also publishes a study by researchers from the HIV Vaccine Trials Network (HVTN) reporting breakthrough infections among participants in phase I and II trials of the ALVAC prime/envelope protein boost approach and showing no evidence of enhanced post-infection control of viremia or CD4 T-cell preservation among vaccinees compared to placebo recipients.
Science publishes a series of letters both supporting and criticizing the trial, including a critique from TAG and support from a group of AIDS vaccine researchers led by Veffa Franchini and Martha Marthas.
Jorge Flores from NIAID presents the response of the RV144 investigators to the AVRWG recommendations at a meeting in Lausanne. Some of the recommendations were adopted, but the investigators refuse to contemplate reducing the sample size of the study.
The FDA’s Vaccine and Related Biological Products Advisory Committee holds a hearing on the RV144 trial, which is criticized by several committee members (see “AIDS Vaccine Low Efficacy Rate Makes Cmte. Skeptical About Phase III Potential”). TAG also submits oral and written testimony critiquing the study. Presentations and a transcript from the September 23rd hearing are available on the FDA Web site: www.fda.gov/ohrms/dockets/ac/cber04.html#VaccinesandRelatedBiological.
In explaining the investigator’s reluctance to halve the sample size by slightly reducing the statistical power to detect protection against acquisition of HIV infection, Colonel Debbie Birx states: “I think this trial will answer a critical military question about acquisition, and I can’t minimize that. When a soldier becomes positive, he’s non-deployable. So a critical aspect is the acquisition.”
Enrollment as of October 5, 2004:
6,200 volunteers enrolled (10,800 screened).