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Researchers halt HIV vaccine trial — What's the next step?
Study shuttered after interim data showed vaccine was ineffective
Progress toward an effective HIV vaccine has encountered a major roadblock with the cessation of a HIV vaccine clinical trial sponsored by Merck & Co. Meanwhile, the need for an effective vaccine continues to grow: The number of new infections in 2006 rose to 4.3 million around the globe, 400,000 more than in 2004.1
"While we are very disappointed that this vaccine candidate did not demonstrate protection, the data from this trial will provide critical insights into this disease and future vaccine development," says Lawrence Corey, MD, principal investigator of the HIV Vaccine Trials Network (HVTN), which co-sponsored the Merck trial.
The study had enrolled 3,000 participants at sites in Australia, Brazil, Canada, the Dominican Republic, Haiti, Jamaica, Peru, Puerto Rico, and the United States since its initiation in late 2004. U.S. study sites included Boston; Birmingham, AL; Chicago; Decatur, GA; Denver; Houston; Los Angeles; Miami; New York City; Newark, NJ; Philadelphia; Rochester, NY; St. Louis; San Francisco; and Seattle. Study volunteers all were HIV-negative, between 18 and 45 years of age, and at high risk of HIV infection. Enrollment for the study was closed in March 2007.
The trial was designed to test Merck's candidate HIV vaccine, the MRKAd5 trivalent vaccine. Made with a weakened version of adenovirus Type 5, which was used as a delivery vector, the vaccine included three synthetically produced HIV genes, gag, pol, and nef. Its design was aimed to stimulate production of immune system T cells to kill HIV-infected cells. During a scheduled interim efficacy analysis of the study, an independent monitoring group reviewed safety data from some 1,500 volunteers who were expected to have the best response to the vaccine due to their low levels of pre-existing immunity to the adenovirus.
The interim analysis concluded that the vaccine did not prevent infection. In volunteers who received at least one dose of the three-dose vaccine series, 24 cases of HIV infection were observed in the 741 volunteers who received vaccine, and 21 cases of HIV infection were observed in the 762 participants in the placebo group. In the subgroup that had received at least two vaccinations and who were HIV negative for at least the first 12 weeks of the trial, 19 cases of HIV infection were observed in the 672 volunteers in the vaccine arm, and 11 cases were observed in the 691 volunteers in the placebo arm. Data also indicated the vaccine did not reduce the amount of virus in the bloodstream of those who became infected. HIV RNA levels were similar in the vaccine and the placebo arms about eight to 12 weeks after diagnosis of infection.2
Study volunteers were followed for about 13 months. Overall adverse event rates generally were similar among the two groups, except for a higher rate of local injection site-related reactions in the vaccine group.
Researchers also have halted a second Phase II trial of the Merck vaccine candidate, known as the Phambili trial, as well as two additional Phase I trials. The Phambili trial was begun earlier in 2007 in South Africa by the HVTN to see whether the Merck vaccine would be effective at preventing infection, reducing viral levels, or both from HIV subtype C, which is more common in southern Africa.
"The next step is really to learn as much as we can about why this vaccine didn't work and then continue to work with the vaccines in the pipeline to keep testing until we find one that will," says Sarah Alexander, HVTN spokeswoman.
More vaccines on way
In a conventional vaccine, the immune system is triggered into manufacturing antibodies against an infectious organism. Scientists have been stymied in developing an effective vaccine against the rapidly mutating HIV.
Over the past decade, science has focused on the T cell approach, stimulating T lymphocytes that can identify and kill HIV-infected cells in an effort to prevent/limit viral replication and delay disease progression.3 Researchers have zeroed in on this approach after results of early studies showed that monkeys receiving such vaccines against simian immunodeficiency virus (similar to HIV) lived longer or had lower than usual viral levels.3
One vaccine using this premise is nearing an efficacy trial, says Alexander. Developed by the Dale and Betty Bumpers Vaccine Research Center (VRC), part of the National Institutes of Health (NIH), the vaccine uses a recombinant DNA as a prime and then an adenoviral vector vaccine as a boost. The vaccine contains synthetic versions of four HIV genes: gag, pol, nef, and env. The gag, pol, and nef genes come from HIV subtype B, the primary virus found in Europe and North America. Env, the fourth gene, codes for an HIV coat protein that allows the virus to recognize and attach to human cells.4 The first portion of the vaccine strategy uses DNA to prime an immune response to internal HIV proteins and external HIV proteins, with the booster portion designed to stimulate specific antibody responses to HIV envelope proteins and internal proteins.3
The DNA components of the vaccine were manufactured by Vical in San Diego; the adenovirus vector was developed by the VRC in collaboration with GenVec of Gaithersburg, MD, which also manufactured the adenovirus vector vaccine.4
Funding pushes search
An Atlanta-based biotechnology company, GeoVax Labs, has just been awarded an estimated $15 million grant from the NIH's National Institute of Allergy & Infectious Disease to support its HIV/AIDS vaccine program. How does GeoVax's vaccine differ from the Merck candidate? There are multiple differences, says Harriet Robinson, PhD, chief scientific advisor for the company and chief of microbiology and immunology at the Yerkes National Primate Research Center based at Emory University in Atlanta.
"The Merck vaccine used a recombinant adenovirus to introduce HIV proteins into cells," she explains. "We use recombinant DNA, followed by a recombinant poxvirus, so the platforms are different."
GeoVax scientists believe that the company's vaccine raises a form of protection not seen in the Merck candidate, says Robinson. Also, while both candidates raise a T cell response, the GeoVax vaccine includes high frequencies of T cells associated with good long-term control of HIV, she says. "We feel that we have raised a type of T cell that has greater potential for protective responses for battle," Robinson says. Consider the analogy of soldiers, she says. "You want your soldiers to demobilize and rest, and you can't keep them continually in the field," Robinson says.
The government grant will propel GeoVax's research, says Robinson. At this point in time, the company's research team is moving along through its clinical trials to build up its safety and immune response data, she reports. "The next most important result we will have from our vaccine is when we get to the point that Merck is, and at that point, we'll know whether or not we protected humans or not," states Robinson.