Clinical trials march on

AIDS vaccine researchers provide clinical updates and details on planned trials

The Keystone symposium on HIV Vaccines is a major meeting on the calendar of HIV researchers from various scientific disciplines. For one week each year it offers them a chance to share ideas, discuss, and often debate, their work. A practical and crucial part of this work is the progress made in conducting clinical trials with AIDS vaccine candidates to test their safety, immunogenicity, and possible efficacy. This year's Keystone meeting provided a comprehensive roundup of ongoing AIDS vaccine trials and related activities and showcased the work of several collaborating organizations that are expanding existing trials or unveiling plans for new ones.

Trial partnerships

Barney Graham of the Vaccine Research Center (VRC) at the US National Institutes of Health (NIH) kicked off this series of updates with a look at a series of ongoing trials with their lead vaccine candidates—a DNA plasmid vaccine and an adenovirus serotype 5 (Ad5)-based vaccine containing fragments of HIV's genetic material from multiple virus clades—administered sequentially in a "prime-boost" manner. These candidates entered Phase II testing late last year and are now in ongoing clinical trials in several countries in partnership with the HIV Vaccine Trials Network (HVTN), IAVI, and the Walter Reed Army Institute of Research (WRAIR; see VAX October 2005 Global News).

Both WRAIR and IAVI are testing these candidates in four east African countries. WRAIR and partners recently began recruitment at their sites in Kampala, Uganda and Kericho, Kenya, and enrollment will begin in May at another site in Tanzania, according to an update provided by Nelson Michael of WRAIR. His organization has been working in Tanzania on a three year study to measure HIV incidence there. The trial staff at both of the IAVI trial sites in Kigali, Rwanda and Nairobi, Kenya is now preparing to increase the total number of volunteers receiving these candidates (see Global News, this issue).

Another trial WRAIR is conducting in partnership with the VRC is in Kampala, Uganda and involves giving 31 volunteers, who have already received the VRC's DNA candidate in a previously completed trial, a booster vaccination with the Ad5 candidate. Results from a series of completed Phase I trials suggest that administering these candidates as a prime and boost is a more effective way of inducing strong immune responses.

These immune responses may face an even greater test soon in a preliminary efficacy trial involving thousands of volunteers. Preparations for a Phase IIb "test of concept" trial are now underway for the VRC's DNA/Ad5 candidate and Michael says WRAIR sites in Uganda, Kenya, and Tanzania are beginning preparations for this larger trial.

An important consideration for this and other larger trials will be the criteria used to determine if healthy, HIV-uninfected volunteers can participate. For the initial WRAIR trial with the VRC's DNA candidate alone (RV 156), 223 potential volunteers were screened to enroll just 31. Michael said many individuals were excluded from the trial because their results from general laboratory tests, including blood tests, differed significantly from the standard reference ranges used to determine trial eligibility. But these ranges were mostly developed based on North American or European populations, where the average background health of individuals differs significantly from that in developing countries where sanitation standards are not as high and there is increased exposure to pathogenic bacteria and viruses. Michael concluded that many eligible people were unnecessarily prevented from joining this trial. He therefore suggested that studies should be conducted to determine relevant reference ranges in the populations where vaccines will be tested to help alleviate this problem in future vaccine trials.

Michael also reported on the progress of other trials at the WRAIR. Enrollment is now complete in the only ongoing Phase III trial, taking place in Thailand, evaluating the efficacy of a prime-boost administration of two vaccine candidates: the ALVAC canarypox vaccine and the VaxGen gp120 vaccine, the latter having already been tested in a previous efficacy trial. The final round of immunizations with this combination will occur in July and volunteers will be followed for an additional three years.

A hard look at MVA

Michael also reported on a series of clinical trials planned by WRAIR to test other prime-boost regimens. Many of these will involve using different DNA constructs developed by other groups as a prime, followed by a booster vaccination with a modified vaccinia Ankara (MVA) vaccine candidate that was developed by WRAIR and the NIH. These trials will take place at WRAIR sites in the US, Thailand, and Africa. The results from an already ongoing Phase I trial with WRAIR's MVA vaccine candidate will be presented later this year at the 2006 AIDS vaccine meeting in Amsterdam.

In the meantime, this same candidate is also being evaluated in another series of clinical trials at the Karolinska Institute in Stockholm, Sweden. These Phase I trials are designed to compare the safety and immunogenicity of either intramuscular or intradermal injections of a DNA plasmid vaccine candidate developed at the Swedish Institute for Infectious Disease Control, followed by a boost with WRAIR's MVA vaccine candidate. The 40 participants receive either three DNA immunizations followed by a single MVA boost, or an inert substance known as placebo.

The final volunteer in this trial will complete the vaccination schedule in May and Eric Sandström, a researcher at the Karolinska Institute, says results on these candidates will also be presented in Amsterdam. "We look forward to a very pleasant presentation," he says, modestly hinting at the results. Previous clinical trials with MVA-based vaccine candidates have produced disappointing results but Sandström suggests this combination may be different. "Both immunizations have been safe and well tolerated and, compared to published results on this approach, we are encouraged by the data."

Sandström and his colleagues in Tanzania, Sweden, Germany, South Africa, and the US are also starting a trial with the same vaccines in 60 volunteers in Dar es Salaam, Tanzania, once final approval from the local authorities is received.

IIb take II

Detailed plans for another new trial were also presented at Keystone by John Hural of the HVTN. The US-based company Merck and the HVTN are now completing site preparations for an additional Phase II "test of concept" trial with Merck's Ad5 vaccine candidate. This candidate is already being tested in a Phase IIb trial, known as the STEP study, in North and South America, the Caribbean, and Australia. But the South African trial marks the first time this candidate will be evaluated in a population where the predominantly circulating clade of HIV is different from that in the vaccine. The HIV antigens in the vaccine are from clade B, while the epidemic in South Africa is mainly clade C. Although there is still uncertainty about how important this clade matching is, Merck wants to find out early on if this vaccine will be effective against different HIV clades.

This South African trial will enroll 3000 volunteers at 5 HVTN sites, 40% of whom are required to have low levels of pre-existing Ad5 immunity, which occurs after someone is exposed to this naturally-circulating virus that causes cold-like symptoms (see VAX February 2005 Primer on Understanding Pre-Existing Immunity). Due to the high prevalence of pre-existing immunity to this serotype of adenovirus in South Africa, initial expectations are that 6000 people will need to be screened across the sites in order to enroll just 1200 volunteers that meet this criterion. Hural acknowledges that this will be a huge task but emphasizes that all of the South African HVTN sites are now undergoing expansion in order to handle this number of volunteers. And by the time it begins, Hural says each site will also be capable of processing volunteer specimens and preparing them for shipment.

Recruitment efforts for the South African trial, HVTN 503, will also focus more on women. In the STEP study only 800-900 of the 3000 total participants are women, but in this second Phase II trial, HVTN plans to enroll equal numbers of male and female volunteers. This is reflective of the high number of infections among women in South Africa. A study of almost 12,000 15-24 year olds living in South Africa in 2003 reported that HIV prevalence in women was 15.5%, compared to only 4.8% in men of the same age group (AIDS 19, 1525, 2005). And this may not be the only country where women are disproportionately infected with HIV. "I don't think there's a case from Africa where you don't see this gut-wrenching stratification by gender," says Michael.

This study is expected to start once Merck's assay, which will be used to determine baseline eligibility for the trial, is successfully transferred to the South African sites. Merck expects that enrollment will begin before the end of the year.