Max Essex, chairman of the Botswana-Harvard AIDS Institute Partnership

A major step in the fight against AIDS was taken in June at the Princess Marina Hospital in Gaborone, Botswana. There, not far from the country's first public HIV-care ward where patients regularly battle AIDS-induced death, the first prophylactic HIV vaccine trial conducted in southern Africa was launched. Two healthy volunteers who had undergone a rigorous screening and education process received a non-infectious HIV preventive vaccine candidate as part of a larger, international clinical trial.

"Each human trial we undertake advances our understanding of the development of HIV vaccines," said Max Essex, principal investigator of the Botswana arm of the clinical trial and chairman of the Botswana-Harvard AIDS Institute Partnership (BHP). The Harvard AIDS Institute is based at HSPH. "HIV, a particularly variable virus, makes an already complicated vaccine development process more challenging. Clinical trials are integral to our efforts to achieve a working vaccine to prevent HIV infection."

A Staggering Problem
The AIDS epidemic in southern Africa is dramatically different from patterns in the West. About 20 percent of adults in southern Africa are infected with HIV, compared to about half of one percent in the U.S. and one-quarter of one percent in Western Europe, said Essex. In addition, transmission in Africa is largely heterosexual, as opposed to a transmission pattern among homosexuals and IV drug users that is more typical in the West.

Botswana has been particularly hard hit, with one of the highest HIV/AIDS rates in the world. The adult HIV prevalence rate in the country has more than tripled to nearly 36 percent since 1992, according to UNAIDS. Not all the news is bad, though. The Botswana government has taken the epidemic seriously and is building collaborations with companies, universities and organizations to help curb the spread of infection.

In 1996, the Botswana government established BHP with the Harvard AIDS Institute. In addition to undertaking HIV-related research relevant to Botswana, BHP engages in large-scale training programs for the country's health care personnel. In 2001, BHP opened a state-of-the-art HIV reference laboratory in Botswana. It is the largest laboratory of its kind in Africa, with advanced HIV/AIDS disease diagnosis and monitoring, research and training efforts.

A Milestone Vaccine Trial
The Botswana study is part of a larger international clinical trial launched by the HIV Vaccine Trials Network (HVTN), which links scientists, community organizations, governments and industry from different countries working on HIV vaccine development. HVTN is funded through the National Institutes of Health (NIH) and is headquartered at the Fred Hutchinson Cancer Research Center in Seattle, WA.

The experiment is a Phase 1 clinical trial, meaning that it will test the safety of the drug as well as effects on the immune system.

The clinical trial has three main sites: Boston, St. Louis and Gaborone. The Botswana HIV Vaccine Trial Unit, headed by Essex under the auspices of BHP, is in charge of the Gaborone study. This is the first time that a HVTN trial is beginning simultaneously in the U.S. and in Africa.

Research nurse Keemenao Matshediso (r) draws blood from a potential volunteer as part of the Phase I screening process.

A total of 42 volunteers will participate in the clinical trial, dispersed evenly among the three sites. Recruitment in Botswana has gone well, said Peninah Thumbi, who oversees the running of the vaccine clinic in Botswana.

"The response has been very positive," she said. "We have more volunteers than slots available in the study."

All participants are HIV-negative. A few will receive a placebo, while the remainder will receive the experimental vaccine.

The clinical trial is expected to last 18 months and is designed as a "dose escalation" experiment. The first group of volunteers from among the 42 recruits will receive a low dose of the vaccine. Then, researchers will allow time to carefully gauge effects. If all goes as expected, the next group of volunteers will receive a higher dose, followed by another waiting period. A final third group of volunteers comprised of the remaining recruits from the original 42 participants will be given the highest dose planned by the trial.

Participants in each of the three groups are expected to receive a total of four injections over the course of the trial.

Partners in the trial's design and implementation are the Botswana Ministry of Health, Harvard AIDS Institute, NIH, Harvard Medical School, HVTN, St. Louis University, and the pharmaceutical products company Epimmune. Preparations for HIV vaccine trials in Botswana were aided by the National HIV Vaccine Committee, appointed by the Ministry of Health, and a Community Advisory Board.

A Disappointing Vaccine Development History
The track record for HIV vaccine development is discouraging. Since 1987, more than 30 experimental vaccines have been tested in human trials and, so far, none has proven effective. Only one or two have progressed from the stage of testing for safety to the stage of testing for efficacy, noted Essex. One of those, an eagerly anticipated vaccine recently developed by a California-based company, did not protect people at high risk and gave indications that need further research of possible protection for African Americans and Asians. The company released its study results in February.

A vaccine is proving hard to develop for several reasons. "HIV is far more variable in a genomic sense than any other virus or bacteria we have worked to make vaccines against," said Essex. An analogy would be the flu shot, which needs reconfiguring each year to protect against the easily mutable influenza virus. HIV by comparison is even more variable, said Essex.

Beyond that, no known viable animal model exists for HIV/AIDS in which a vaccine can be tested. Animals typically used in scientific experiments, such as mice, rats and rabbits, simply don't get infected with HIV. Chimpanzees, increasingly rare and expensive to purchase for research, can be injected with HIV and sustain an infection, but they don't get sick in the same way that people do, said Essex.

As a result, vaccines must be tested in humans, which takes considerably longer due to necessary safety, health and informed consent considerations.

A Unique Vaccine Candidate
The drug being tested in the clinical trial is called EP HIV-1090 and is made by the company Epimmune. Its design is unique, which is why Essex is hopeful that this vaccine may prove more useful than previous candidates.

EP HIV-1090 is a DNA vaccine using a "polyepitope" design. Previous vaccine candidates have used larger pieces of the virus that causes AIDS, sometimes an entire gene or two of HIV, to try to train the immune system to recognize and attack the virus.

In the polyepitope design, only the fragments of HIV already known to stimulate immune responses are included. These fragments are much smaller than genes, which allows scientists to pack the vaccine with components that have a demonstrated usefulness in triggering a response instead of wasting space with unnecessary ingredients.

The design theoretically should also allow researchers to make adjustments to the vaccine to target specific subtypes of HIV. This feature is critical because different subtypes are dominant in different parts of the world. In the U.S. and Western Europe, the HIV B subtype is most prevalent whereas in southern Africa the HIV C subtype is dominant.

No infectious components of HIV are used in EP HIV-1090, so trial volunteers cannot become HIV-infected from being injected with the vaccine candidate, said Essex. Furthermore, unlike other vaccine candidates, EP HIV-1090 will not cause false-positive results on HIV tests.

To evaluate the safety of EP HIV-1090, vaccinated volunteers will be carefully monitored for possible side effects such as fever, malaise and swelling. To monitor the effects on the immune system, blood lymphocytes from vaccinated volunteers will be evaluated in the laboratory to see if the cells recognize the vaccine epitopes. The vaccine is not designed to illicit antibodies, only cell-mediated immunity involving lymphocytes called killer T cells.

Outreach in Botswana
In Gaborone, a team of scientists and educational outreach staff are bustling as the Botswana study takes off. The site director is Tonya Villafana, a PhD immunologist who graduated from HSPH in 2000 with an MPH. She has witnessed the devastating effects of HIV/AIDS in the country.

"No one has gone unaffected," said Villafana. "Everyone knows either someone personally or of someone who has become infected with HIV."

The epidemic has undermined the country's economy, too, as workers in the prime of their lives waste away from AIDS.

Educational outreach is integral to the Botswana study. Staff members regularly conduct community meetings to discuss HIV/AIDS prevention in general, as well as vaccines, said Villafana. (See sidebar) Some people do not wish to know their HIV status because coping with the aftermath is too overwhelming. Others mistakenly fear that taking AIDS medications will only make them sicker.

The Botswana study team formed a Community Advisory Board to help direct their efforts. The board has community leaders, including tribal chiefs, and representatives from human rights organizations, women's groups and ethics groups.

Even if EP HIV-1090 is unsuccessful, Villafana believes the efforts have been worthwhile. "Significant clinical and laboratory infrastructure, regulatory capacity, training of personnel and community education has been put into place," she said, "making this a prime site where much more can be done related to vaccine trials and other research efforts to address the AIDS epidemic."

Villafana and Essex agree that a vaccine presents the best promise to eventually slowing the spread of AIDS. Noted Essex, it is better to prevent infection or disease altogether than to treat the sickness with complicated drug strategies that may be difficult to execute in developing countries.

"Drug treatment is important, but do not assume that it is a long-term solution, whereas an effective vaccine could be," said Essex.

--cr

On the Road in Botswana Raising Awareness about HIV/AIDS On a February afternoon in Botswana, Gillian Goodwin and Rupert Hambira journeyed on the Lobatse Road from the capital Gaborone to the village of Otse on an unusual mission. They were sent to the country's new Botswana Police College to educate the young men and women training there about a threat posed not by a villain but instead by a virus--HIV. While Botswana enjoys prosperity and a stable government, nearly 36 percent of the adult population is HIV-infected, according to UNAIDS. Funerals have become a regular part of Saturday routines. Rupert Hambira (l) and Gillian Goodwin The Botswana Police College is a collaborator in an HIV vaccine preparedness study, part of a larger effort by the Botswana-Harvard AIDS Institute Partnership (BHP). The Partnership is working with the HIV Vaccine Trials Network (HVTN) and others to conduct the vaccine preparedness study, which gathers information about a population's infection rates and risk behaviors. The study also enables researchers to refine their recruitment and retention strategies for potential large-scale (Phase II and Phase III) studies involving hundreds of volunteers. BHP and HVTN in addition are working together on a separate Phase 1 study to test an HIV vaccine candidate. The vaccine preparedness study is progressing through its early stages, with recruiters and educators now working to build cohorts. One cohort is being developed at one of Botswana's diamond mines; another is being developed at the Botswana Police College. Through the cohorts, researchers hope to recruit the volunteers needed for the next stages of the preparedness study. Recruitment and enrollment will begin in September. Botswana citizens, Goodwin and Hambira's job is to educate potential HIV vaccine preparedness study volunteers--among them the police recruits--about HIV generally and vaccines specifically. Goodwin, the study's recruitment officer, is a social worker who has served at voluntary HIV counselling and testing centers. Hambira, the study's senior community educator, is a well-known minister and community leader. At the Botswana Police College, they faced 50 trainees crowded into a classroom. When Goodwin asked what the trainees knew about HIV and AIDS, one responded with simple poignancy: "HIV is killing us in Botswana." Another knew that the prevalence among pregnant women in his hometown was 42 percent. Others were aware of two national programs--one to prevent transmission from mother to child and the other to distribute free anti-retroviral drugs to people with AIDS. Currently, six hospital and clinic-based sites can dispense the medications. To volunteer for the vaccine preparedness study, subjects must be HIV-negative and therefore must be tested before enrollment. Goodwin discussed the benefits of testing, such as the ability to get treatment, change risky behaviors and plan for the future. She was met with some skepticism. With infection rates so high, the possibility of getting a positive HIV test result is not lightly dismissed. One trainee commented that being tested may be more of an exercise in preparing to die than one of planning for the future. Another asked what was the point of being tested if one didn't live near a site that dispenses free anti-retroviral therapies. Goodwin noted that the government is ramping up to open more sites in the very near future. This kind of community discussion and education is an integral part of the vaccine preparedness study and the separate Phase I HIV vaccine study. HSPH alumna Tonya Villafana, who is involved in conducting both studies, gives media interviews and briefings, including to Botswana's President Festus Mogae, members of Parliament, and the House of Chiefs, an upper house in the government consisting of 15 traditional tribal leaders. Hambira and Goodwin regularly present to women factory workers, health care workers, labor union members, local councilmen, church attendees and health fair participants. They work with a Community Advisory Board and develop educational materials for the study. Leaving the Botswana Police College after her presentation, Goodwin was hopeful that some of the police trainees would volunteer for the vaccine preparedness study. Despite the skepticism and resistance they had voiced, she reflected, "They want to help." --Carisa Cunningham