25,000 volunteers to be sought for vaccine trials

Two large US-funded vaccine efficacy trials are now in late planning stages and likely to begin in 2002. Both would test canarypox vaccines made by Aventis Pasteur as “primers” followed by gp120 products from VaxGen which are already being studied in Phase III trials. Between them, they will be looking to recruit 25,000 volunteers across 5 or more countries.

Networking in the Americas

The US National Institutes of Health is shortly to make a decision, with the two vaccine companies, about sponsoring its first Phase III trial through the NIH HIV Vaccine Trials Network, with sites in the USA, Brazil, Haiti and Trinidad. This would enrol more than 11,000 volunteers at a cost of between US $60 million and $80 million. Speaking for NIH, Dr Margaret Johnston said she saw no problem in finding this money from the $2.5 billion annual AIDS research budget that NIH is now promised.

The vaccines to be tested are Aventis Pasteur’s ALVAC-HIV vCP1452 and VaxGen’s AIDSVAX B/B; a combination already studied in Phase I/II trials. A final decision to go ahead will be taken before the end of 2001, when an international Phase II trial is concluded and the immune responses of volunteers can be assessed.

ALVAC-HIV vCP1452 uses a strain of canarypox, a bird virus which cannot establish ongoing infection in humans, engineered to express several HIV proteins based on subtype B viruses. It is impossible, however, for this vaccine to “give anyone HIV”.

Specifically, the HIV genes used are part of env (for he HIV envelope protein gp120), and elements of gag, pro, pol and nef – structural and regulatory genes.

The trial will be a double-blinded, three-armed design, in which one group receives vCP1452 only, a second one receives both vaccines, and the third receives placebo, in the ration 3:3:2. Volunteers will therefore have a 25 per cent chance of receiving only placebos.

Thai Partnership Leads Again

The US Army’s medical research division is building on ten years of HIV research with the government of Thailand and the Royal Thai Army to plan for a full scale trial starting in 2002 which closely parallels the NIAID effort, while using subtly different vaccines based in part on Thai “subtype E” HIV strains.

As explained by Dr John McNeil, from the Walter Reed Army Institute of Research, current plans are to recruit 15,800 volunteers from 50 health centres based in eight districts across two south-eastern provinces of Thailand: Chon Buri and Rayong.

Like the NIH trial, this will use a canarypox primer followed by a gp120 booster. It differs in having only two arms, with equal numbers: half receiving both vaccines and the other half receiving only placebos.

The canarypox vaccine is ALVAC-HIV vCP1521, which is similar to a previous ALVAC product vCP205, tested in a number of US trials. In this case the HIV genes are env based on a primary isolate of a Thai “subtype E” virus, alongside subtype B gag/pro elements.

The gp120 booster will be AIDSVAX B/E from VaxGen, which is a mixture of genetically engineered surface proteins from subtype B and subtype E viruses, both of which circulate in Thailand.

Immunological “milestones” to be met in the ongoing Phase I/II trials comprise:

• 30% showing CTL responses at one or more of 6 visits
• 70% showing neutralising antibodies
• 60% showing lymphoproliferative responses to vaccine antigens

Ironically, one of several possible “show stoppers” listed by Dr McNeil would be evidence that one or both of VaxGen’s products currently in clinical trials actually work. If this happened, the need to redesign the trial to show equivalence would mean expanding the trial to between 75,000 and 100,000 participants, which would make it impractical.

There has been some reported questioning in US Department of Defense circles of whether the US Army should be engaged in medical research. However, Dr McNeil said at a press briefing that this was no longer in question. The proposed trial will, nonetheless, depend on the approval of Thai authorities and final agreements being signed with the two vaccine companies involved.

Into Africa

What Dr McNeil didn’t say, but which was implicit in his comments on Thailand, is that once vaccine trials have to show equivalence, those trials will need to shift into populations at higher risk than can readily be identified in Thailand. More positively, there is a clear moral imperative to ensure that the value of any genuinely promising vaccines to those countries and regions which are worst affected by the pandemic is fully and urgently explored.

There were several progress reports during the meeting on a developing partnership between the US Army and vaccine researchers from Kenya, Tanzania and Uganda. This has already involved a number of full-length virus sequences to define the range of subtypes and recombinants circulating in the region, already known to have many people living with subtypes A, C and D with a number of recombinant forms. This opens up the possibility of testing cross-subtype protection with future vaccines, an issue which should be explored experimentally rather than being taken for granted.

The National Institute of Allergy and Infectious Diseases, which is NIH’s lead agency for AIDS research, now has a long-term grants scheme called the Comprehensive International Program of Research on AIDS (CIPRA) which “supports … research and development efforts at organizations located in eligible [specified, low-income] nations to develop practical, affordable, and acceptable methods to prevent and treat HIV/AIDS in adults and children.” Full details are at the website below.

* Technically subtype E is now known as HIV CRF01-AE where CRF stands for “circulating recombinant form”

Further Information

HIV Vaccine Trials Network

CIPRA grants scheme details