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Fall 2008  
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h “We learned how extraordinary
our volunteer community is—
they understand the research process and remain committed
to participating in research
to help fight HIV.”— Mark Mulligan,
executive director of the Hope Clinic (shown above)
  The Trouble with Vaccine Trials
Emory researchers take stock after a promising HIV vaccine falters

By Sylvia Wrobel

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Hope that scientists had finally developed a vaccine to protect against HIV infection took a giant step backward last fall when a large, international phase 2B efficacy trial was halted abruptly, throwing the worldwide HIV vaccine community into shock and dismay.

Most vaccine candidates against the ever-mutating AIDS virus never make it past phase 1 into phase 2 trials, which assess safety (1) and protection against disease (2). The HIV vaccine being tested at 30 STEP trial sites worldwide had passed earlier tests with flying colors. Study participants tolerated the vaccine well, and it induced strong T-cell response to HIV proteins.
     Excitement had grown at Merck, developer of the drug; the National Institute of Allergy and Infectious Diseases (NIAID), co-sponsor of the clinical trial; the NIH-funded HIV Vaccine Trials Network (HVTN), coordinator of the trial; and HIV/AIDS scientific and lay communities worldwide. Never had an HIV vaccine candidate seemed more promising.
     But two years into the study, the independent Data and Safety Monitoring Board recommended halting further vaccinations following analysis of interim data. By then, more than 3,000 volunteers—men and women ages 18 to 45 from diverse racial groups—had been inoculated, half of them with the vaccine. All had been chosen because they were at high risk of exposure to infection through sexual and other behaviors. It was not surprising that some receiving placebo became infected, despite safe sex counseling and free condoms from investigators. It was disappointing that some volunteers became infected, despite having been vaccinated. It was shocking—and completely unexpected—that a subgroup of those receiving vaccine appeared more, not less, susceptible to HIV infection.
     Worldwide, investigators halted vaccinations overnight, unblinded study volunteers as to whether they received vaccine or placebo, and began the discouraging task of telling volunteers what the results might mean to their own disease risk if their activities had exposed them to HIV. The trial involved 130 Atlanta volunteers at the Hope Clinic, the clinical trial arm of the Emory Vaccine Center, an HVTN member and a world leader in vaccine research. Carlos del Rio, co-director of the Emory Center for AIDS Research, led the testing at the Atlanta site.

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      What happened

Why did the Merck vaccine prove to be so disappointing? It contained only three genes from the virus, assuring that the vaccine itself could not infect volunteers. The vaccine vector (designed to carry these genes into the body and present HIV proteins to the immune system) consisted of three adenoviruses, weakened and altered to render them unable to replicate and cause the common colds or upper respiratory infections for which they are known.
     Those who acquired HIV infection after vaccination were more often people with pre-existing immunity to the adenovirus used as a vector. Participants with the highest risk of infection had this pre-existing immunity and were uncircumcised.
     Mark Mulligan, executive director of the Hope Clinic, believes that when the immune system recognized the adenovirus in the carrier, it may have attracted more T cells to mucosal surfaces, providing an environment more susceptible to HIV acquisition. However, “It’s still an unfolding study,” he says. “The results will likely provide more insight into how HIV infection works and how it can be combated.”
     In the meantime, the Hope Clinic continues to follow its STEP study volunteers, tracking the longevity of immune response to the vaccine, counseling about safe sex, and testing for infection. Support from volunteers has not wavered. This past spring, the Atlanta Gay and Lesbian Chamber of Commerce presented its Guardian Angel award to the clinic for its commitment to community involvement in HIV research.
     Despite the STEP trial setback, the study offers lessons for researchers and study participants alike. “We learned how extraordinary our volunteer community is,” says Mulligan, who counseled volunteers with del Rio after Merck halted the study. “They understand the research process and remain committed to participating in research to help fight HIV.” The STEP trial also “reminds us that no matter how much we dislike the results, clinical trials efficiently yield the truth, giving new meaning to the word ‘re-search.’”
     As Mulligan points out, polio vaccine researchers went through a similar process of hope, failure, and renewal before the Salk/Sabin vaccines proved successful. Further analysis of the adenovirus-vectored AIDS vaccine trial will help determine whether some people actually were protected (i.e., those without pre-existing response to the vector) and the exact nature of any protective immune response, a question that researchers still seek to answer in terms of protection against either HIV infection or disease. STEP data also reaffirmed several earlier studies showing the protective impact of circumcision.
     Two upcoming HIV vaccine trials at the Hope Clinic have been postponed, possibly halted, until researchers fully understand what happened in the STEP trial. Still other trials using different approaches will move forward this year. Participating centers will be named for an upcoming phase 2 clinical trial of a promising HIV vaccine developed by Harriet Robinson and NIH and CDC collaborators. Robinson directed the microbiology and immunology division at Yerkes National Primate Research Center and is a co-founder of GeoVax, an Atlanta biotech company that licensed the vaccine. She recently left Emory to lead GeoVax research and development.
     Currently, the Hope Clinic is recruiting for a phase 1 study to test the safety and tolerability of a microbicide gel, using what Mulligan calls “woman-controlled technology” to potentially prevent vaginal HIV transmission. The clinic—one of NIAID’s Vaccine and Treatment Evaluation Units, also is beginning trials for prevention of avian flu, malaria, and other infectious diseases.
     Mulligan and other AIDS experts at Emory recently gave voice to the need for continued HIV/AIDS vaccine research in an Atlanta Journal-Constitution editorial. They responded to a previous editorial advocating that all vaccine research be halted in order to allocate more resources for prevention, routine testing, and universal access to treatment. The editorial cited the halted Merck trial as one reason. Mulligan and his colleagues countered with the polio vaccine. Nearly 25 years passed between discovery of the polio virus in the 1930s until an effective vaccine became widely available in 1955.
     “Persistence, sustained scientific effort, and increased collaboration will drive the quest for an HIV vaccine forward,” wrote Mulligan and his co-authors, “just as they did for the polio vaccine.”
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