TAGline - Volume 9 Issue 1 - January-February 2002

The week following the publication of the Merck studies, John Moore became the first researcher to speak up about another muffled controversy: the plans for two separate, massive phase III trials of Aventis Pasteur's canarypox-based HIV vaccine (ALVAC). Moore's commentary, also published in Nature, suggests that an excess of competitiveness between the two trial sponsors--the Department of Defense (DOD) and the National Institutes of Health (NIH)--is leading to duplicative trials that waste both human and financial resources.

The DOD's trial is to be conducted in Thailand, and plans to enroll 15,800 heterosexuals (the DOD's regulations don't allow them to work with gay men or intravenous drug users) into a trial of an ALVAC vector (vCP1521) encoding gp120 from a subtype E isolate, along with gp41 and gag/pro from subtype B. All volunteers will also receive two boosts with Vaxgen's bivalent subtype B/E recombinant gp120 vaccine. The estimated cost is $35-40 million and the current proposed start date is mid-2002. The NIH trial is being planned for the United States, the Caribbean and South America through the HIV Vaccine Trials Network (HVTN) and is slated to involve 11,080 volunteers comprising both gay men and high-risk heterosexuals. The protocol uses a slightly different ALVAC vector (vCP1452) encoding env, gag/pro and regions of pol and nef that are rich in CTL epitopes. One arm of the study includes a boost with Vaxgen's clade B gp120 vaccine. Estimated cost for the HVTN study is $60-80 million. (Plans for both studies are discussed in detail in the new IAVI Report, online at www.iavi.org.)

In addition to pointing out that the slender differences between these trials render them duplicative, John Moore also raises several scientific questions relating to the study designs. Chief among these is the notoriously poor immunogenicity of the ALVAC vector. In what must surely be a record for any experimental medical intervention, ALVAC's tortuous history has included over 40 phase I and II trials involving around 1900 volunteers. The vaccine has shown an ability to induce low-level HIV-specific CTL responses in about a third of participants at best, and these responses are rarely directed at more than one epitope. Moore also questions the scientific rationale for including a gp120 boosting component. No animal model study has shown an advantage to this approach, and recently presented data from Harriet Robinson's group at Emory reported that adding a gp120 booster to a DNA/MVA vaccine actually reduced efficacy rather than improving it. Moore points out that efficacy data from Vaxgen's phase III trial of gp120 will be available later this year, which will surely shed more light on this question.

To avoid duplication and wasted resources (and the potential of two huge failed trials further denting public confidence in the vaccine effort), Moore suggests that the DOD ALVAC trial go forward (perhaps with a more rational boost, for example, gag instead of gp120), while the HVTN concentrate on newer and more promising third-generation vaccine constructs such as Merck's adenovirus and the DNA/MVA prime-boost regimen being developed by the International AIDS Vaccine Initiative (IAVI). While a counter-argument is that these newer agents are not yet ready for phase III evaluation, it is entirely conceivable that they will reach this milestone within the next two years. And even if both proposed ALVAC trials begin as scheduled, enrollment is likely to be a lengthy process. Alternatively, Moore offers that the HVTN could assume responsibility for conducting a single ALVAC trial while DOD concentrates on bioterrorism defense. Although John Moore's advice is clearly not intended to be proscriptive, the overarching and long-overdue message of his commentary is clear: it's vital that the plans for both ALVAC trials are subjected to open public discussion before they are finalized. RJ

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