A Zulu boy from Hlabisa Credit: Courtesy of Harry Connett

Despite the South African president's belief that human immunodeficiency virus (HIV) does not cause AIDS, the country's Medical Research Council (MRC) has announced that it will begin trials of an HIV vaccine in February 2001.

Ongoing preparations for such a trial in the rural South African village of Hlabisa emphasize the complexities of gearing up for a large efficacy study in the epicenter of the country's AIDS epidemic. After nearly two years of educating tribes and gaining their consent, researchers predict the site will be ready for a large-scale study by the end of next year—most probably sooner than large quantities of the vaccine will be ready for testing.

The Venezuelan equine encephalitis (VEE) virus vaccine to be tested is being produced at Greer Laboratories, North Carolina, on behalf of Alphavax, a company formed two years ago by University of North Carolina researchers. The South African AIDS Vaccine Initiative (SAAVI), in conjunction with the US National Institute of Allergy and Infectious Diseases (NIAID), has teamed with the International AIDS Vaccine Initiative (IAVI) to fund development. Quantities sufficient for phase I trials in the US and South Africa should be ready by the end the year, and phase III trials are scheduled for completion by 2005.

Developed with the help of the US Army, the vaccine uses an attenuated form of VEE virus inserted with genes selected from subtype C isolates of South African seroconverters, making it the first vaccine specific for clade C—the most prevalent HIV-1 subtype in Africa—to enter trials. According to Robert Olmsted, vice president of research at AlphaVax, the biological properties of the VEE virus make it an attractive AIDS vaccine delivery system because it targets lymphoid tissue.

The trial is expected to follow the type of fast-track course outlined in IAVI's Scientific Blueprint 2000: Accelerating Global Efforts in AIDS Vaccine Development. “We would really like to dramatically shorten timelines and that means a different kind of preparation for the large trials,” IAVI President Seth Berkley told Nature Medicine. “The worst thing we could do is have an exciting candidate and then say, 'Ah, how do we move to the next stage.'”

Community Educators discuss vaccination trials Credit: Courtesy of Harry Connett

Because vaccines have potential prophylactic rather than therapeutic value, informed consent is a delicate issue for any vaccine trial, even in Westernized countries. Testing an AIDS vaccine in rural South Africa requires the added challenge of gaining the trust of tribal leaders and winning their support. Social interaction and decision-making in Zulu culture is built on a hierarchical concept of togetherness called 'ubuntu'.

For the past three years, the South African MRC has been studying how such solidarity influences the highly individualized activity of consenting to a vaccine study. Researchers have learned that laying the groundwork for a vaccine trial can succeed only by going to tribal leaders first and getting their stamp of approval.

Primarily because of its high incidence rate—40% in pregnant women—Hlabisa, four hours northeast of Durban, has been chosen as a site for phase II and III trials of the VEE vaccine. The MRC gained access to Hlabisa villagers only after months of public-relations building with the chief of the tribal area, Inkosi Hlabisa, and his 25 'idunas', or cluster leaders, each of whom presides over 150 families. The Hlabisa chief eventually called together a community gathering of about 6,000 people to explain his reasons for supporting the MRC's research. “The head men cannot give consent for anybody's participation, but without their approval it would be difficult if not impossible to work in their communities,” explains Salim Karim, MRC director of HIV Prevention and Vaccination.

For the past 20 months, health workers have been recruiting and training young community educators to take vaccine trial information to the 12 clusters that make up the Hlabisa tribal area. On weekends, cluster leaders host community meetings at which the educators demonstrate how blood is drawn and medical histories are obtained. Tribal songs and dances also are used to spread the HIV-prevention message.

The level of vaccine preparedness in Hlabisa has been “excellent,” says Steve Self, senior biostatistician for the new international HIV Vaccine Trials Network, and professor of biostatistics at the University of Washington (Nature Med. 6, 488; 2000). “The kind of work going on there will have a huge impact on speeding up the process.” So far, efforts to identify and educate potential trial volunteers seem to be paying off. Working out of a trailer and a two-room research clinic surrounded by a security fence, field site manager Janet Frolich says participation in the vaccine preparedness trial has been high. Although results are not yet published, more than 95% of those surveyed so far agreed to participate in the study, and about 70% have agreed to be tested.

Despite ongoing research, including the recent completion of a large randomized STD intervention study that provided condoms and drugs for symptomatic patients visiting local health clinics, HIV infection rates have continued to rise in Hlabisa. Last year, 'detuned' assay surveillance revealed a double-digit annual infection rate. Such a high incidence rate will reduce the necessary sample size to around 4,000, says Salim Abdool Karim, director of HIV Prevention and Vaccine research for the MRC.

Although the vaccine preparedness study has received no funding from SAAVI or IAVI—NIAID is the primary supporter—work in Hlabisa has progressed so well that Karim expects to have the site ready for an efficacy trail by the end of 2001. “I don't expect there will be a phase III vaccine available by then,” he says, “but we should be ready to go with it.”

See Box 1: Lack of Subtype Vaccine Development.