IAVI Report - October - November 2001
Patricia Kahn

As the three-year VaxGen trial in Bangkok approaches its midpoint (see article), Thailand is already deep in the midst of preparations for a second Phase III AIDS vaccine study. Slated to begin in the latter half of 2002, the trial will test whether a "prime-boost" strategy combining two vaccines--the first containing HIV genes in a canarypox virus vector (Aventis Pasteur's vCP1521 construct), followed by VaxGen's envelope (gp120) protein subunit--can protect against heterosexual transmission. If it proceeds as planned, the trial will be the only the third AIDS vaccine efficacy study worldwide, and the first to test a prime-boost strategy and to use a community-based population (rather than selected high-risk groups).

In the US, the HIV Vaccine Trials Network (HVTN) is planning a similar Phase III trial using vCP1452, a later version of the canarypox vaccine, which would start in 2003 at sites in the US and Latin America (see article). The two trials differ in design, and their teams are conferring on how to ensure that data can be pooled or compared.

In presentations at the meetings reported here, researchers involved with the Thai trial--a collaboration of the US and Thai Army vaccine programs, Mahidol University and Thailand's Ministry of Public Health--described plans for what will be an enormous logistical undertaking, involving over six times more volunteers than the ongoing VaxGen trial (16,000 versus 2,500). They also presented results from community-based cohort studies that shaped the trial design, as well as preliminary data from a Phase II trial that will guide the final "go-no go" decision on Phase III. And they made their case for moving ahead, provided that the final Phase II data meet scientific milestones set earlier--although there are conflicting opinions in the field as to whether the immunogenicity criteria (essentially the same as those for the US trial) are stringent enough, and the canarypox vaccines promising enough, to justify moving forward. The IAVI Report will continue to follow the pivotal decisions on these two trials as they unfold over the coming months.

The Road to Phase III

At the Bangkok meeting, Michel Klein of Aventis Pasteur summarized the long pathway that has brought the HIV-canarypox vaccines to the brink of efficacy trials. Developed from a vector that has been used successfully to make several veterinary vaccines, clinical testing began in the late 1980s, with more HIV components added to the vaccine over time. Cumulatively, HIV-canarypox constructs have now been tested in over 40 Phase I and II studies involving about 1900 volunteers, and show an excellent safety record. Over 700 of those volunteers have been in Thailand, where the US-Thai collaboration began testing these vaccines (with different protein boosts and immunization regimes) in 1995.

In terms of immune responses, clinical studies have looked mostly for CD8+ T-lymphocytes (CTLs) that specifically kill HIV-infected cells. Overall, CTLs are found in blood samples from 20-40% of canarypox-vaccinated people, and in some cases the CTLs are still detected 2-3 years after the last immunization, according to Klein. About two-thirds of vaccinees also show LPR (lymphoproliferative responses, which primarily detect T-helper cells) and neutralizing antibody responses to laboratory-grown HIV, but much less neutralization of primary HIV strains.

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%.

In a poster presentation at the Philadelphia conference, Mark de Souza of the US Army group in Bangkok (the Armed Forces Research Institute of Medical Sciences, or AFRIMS) presented preliminary results from RV135, which uses the exact vaccine combination and immunization regimen being proposed for the Thai efficacy study. The protocol calls for vCP1521 (which contains gp120 from an R5 subtype E HIV strain, plus gp41 and gag/pro from subtype B) to be given at weeks 0, 4, 12, and 24, along with a boost of VaxGen's bivalent B/E gp120 (at weeks 12 and 24, in two dosage groups) in 90 volunteers; another 30 received placebos. With the data still blinded and some late study visits and assays incomplete, De Souza reported cumulative HIV-specific (Env or Gag/Pro) CTL responses in 20 of 117 volunteers.

These numbers suggest that, even with the placebo group removed, it will be close in terms of meeting the 30% CTL milestone. And it is here that the controversy over moving to Phase III lies: the relatively low proportion of CTL responders in past trials, and the fact that responses often seem weak (although the CTL assay is poorly quantitative) has led some researchers to doubt the rationale for moving forward.

In their meeting presentations, and in conversations with the IAVI Report, Army researchers argued otherwise. John McNeil (Walter Reed Army Institute of Research) reminded the Philadelphia audience that the canarypox vaccines are the only ones sufficiently well-studied to move into Phase III within the next two years or so. Art Brown, who leads the AFRIMS group in Bangkok, sees potential limits on the CTL assay, which looks at cells from the peripheral blood rather than the lymph nodes. "It may not be the right way to sample," he says-although unfortunately it's the only feasible way for now. At the same time, Marta Marthas (University of California at Davis) has new data showing that-despite the lackluster CTL data in humans- a canarypox-based SIV vaccine protected 6/8 neonatal monkeys against multiple low-dose oral challenge with pathogenic SIV (see article).

And from the Thai perspective, Supachai Rerks Ngarm of the Ministry of Health, a principal investigator of the upcoming trial, points out that Thailand sees even a low-efficacy vaccine as a useful weapon in its battle against AIDS (see interview).

Since the Philadelphia meeting, the Phase II data have been completed and are under discussion among the collaborators, according to McNeil, although they have not yet been presented publicly. But as the IAVI Report went to press, he gave no hint of any change in plans, saying that "the Army remains committed to moving forward with the trial, together with our Thai partners."

Preparing Cohorts 

At the Bangkok conference, Mike Benenson (AFRIMS) presented results from cohort studies aimed at finding suitable and willing populations for the trial, and at developing the necessary infrastructure. With the rate of new infections in Thailand declining steadily throughout the late 1990s, that meant looking to the country's highest-incidence regions--which led researchers to the southern province of Chon Buri, where surveillance data showed 4-6% prevalence rates. The vaccine team also found very supportive staff at the district hospitals and local health centers, which became focal points for recruiting and following a cohort of 2,500 HIV-negative volunteers over 18 months for HIV incidence, risk behaviors and attitudes towards vaccine trials, while providing HIV counseling and education.

HIV prevalence at screening was 4.8%, (ranging from 3.8-7%). During follow-up, several factors were associated with higher infection risk. For men, these included low education level, IDU or recreational drug use, having tattoos, and work in temporary or unskilled jobs. Newly married women (< 5 years) emerged as one of the most vulnerable groups, with other risk factors for women including two or more sex partners and an early sexual debut (age 15 or less). Having syphilis or another STD was a risk factor in both genders.

Benenson also reported that willingness to participate in a 3-year vaccine study requiring four immunizations was extremely high, with 40% of volunteers saying they would definitely participate, 21% very likely and 33% somewhat likely. Only 6% said they were unlikely or definitely unwilling to participate. There were no significant differences between men and women, suggesting that this trial could be the first Phase III study to enroll significant numbers of women. (Both ongoing VaxGen trials target predominantly male risk groups, and the cohorts are >90% male). When volunteers were asked whom they most trust for information on health, the Ministry of Public Health was very high on the list, suggesting a strong foundation for recruitment.

Follow-up rates were lower than hoped for, Benenson said, at 80% over the entire study (88% at 6 months). Loss to follow-up was most often due to volunteers moving away from the region.

Veerachai Watanaveeradej (AFRIMS) and Sodsai Tovanabutra (Chiang Mai University) reported on the surveillance of subtypes in Thailand. About 27% of infections were with non-E subtypes, mostly B, but both B/E and C/E recombinants were also identified.

The Trial Design

Based on these findings, the trial team has devised a protocol to detect 50% or more vaccine efficacy over 2-3 years of follow-up. Enrollment will target 20-30 year olds, who showed an incidence of 0.68/100PY in the preparedness cohort, but the trial is designed around the lower figure of 0.2/100PY so it can retain statistical power even if infection rates continue to fall. Assuming a 5% loss to follow-up every six months and a two-arm trial (with half the volunteers getting vaccine and half placebo), this requires a cohort size of 15,800.

In Bangkok, Surasak Youngpairoj (Ministry of Public Health) reported that the study will build on the district hospital/local health center infrastructure that worked well in the preparedness work, expanding it to encompass eight hospitals and the 5-10 health centers affiliated with each one. Recruitment is expected to take one year, and several measures to improve follow-up rates, especially around the issue of volunteers who relocate, will be implemented.

The trial's primary endpoint is the prevention of infection in vaccinees. Participants who become infected will be monitored for viral load and CD4 counts, and their infecting virus compared genetically with the vaccine strains. They will be referred to the public health system for care, and the US Army has committed to providing them with triple drug therapy--the official national standard, but in practice out of reach for most Thais. Blood samples will be stored for possible immunological study later on, but at present there are no plans for systematic testing of cellular immune responses or correlates of protection.

Laboratory diagnostics for the trial will be carried out by the Royal Thai Army team in a new facility, which is seeking accreditation by the American College of Pathology--a first for the country, and the region.

Remaining Steps 

Before the trial can begin, it must go through myriad approval committees, including review boards at each of the participating institutions; at Thailand's AIDS vaccine sub-committee and ethics committee; and both the US and Thai FDA. That puts pressure on Thailand to re-convene an AIDS vaccine subcommittee, which was dissolved last year amid controversy over proposals for a therapeutic vaccine trial (see article) and has yet to be reconstituted. Final agreements with the vaccine manufacturers, Aventis Pasteur and VaxGen, also remain to be formalized; although both companies say they are committed to the trial, there remain unresolved issues with VaxGen concerning workload and finances, according to its vice president for international clinical research, William Heyward.

011010
IAVI2001-1004

©2001. The IAVI Report.

AEGiS is made possible through unrestricted grants from Boehringer Ingelheim, iMetrikus, Inc., John M. Lloyd Foundation, the National Library of Medicine, and donations from users like you. Always watch for outdated information. This article first appeared in 2001. This material is designed to support, not replace, the relationship that exists between you and your doctor.

AEGiS presents published material, reprinted with permission and neither endorses nor opposes any material. All information contained on this website, including information relating to health conditions, products, and treatments, is for informational purposes only. It is often presented in summary or aggregate form. It is not meant to be a substitute for the advice provided by your own physician or other medical professionals. Always discuss treatment options with a doctor who specializes in treating HIV.

Copyright ©1990, 2001. AEGiS. All materials appearing on AEGiS are protected by copyright as a collective work or compilation under U.S. copyright and other laws and are the property of AEGiS, or the party credited as the provider of the content.