- A new analysis of an AIDS vaccine trial will help make future vaccines better.
- The methods used can be applied to study the AIDS vaccine that gained notoriety for modest success earlier this fall.
- Study coauthor and BYU prof Keith Crandall used advanced computational techniques to explore changes in the DNA of the virus that causes AIDS.
After early reports of a modestly successful experimental AIDS vaccine in Thailand this fall, a BYU researcher hopes his new analysis of an earlier AIDS vaccine trial will help researchers understand how to make the new vaccine work better.
In the mid-2000s a company called VaxGen conducted the world’s first phase III trial (a large, multi-center study for determining vaccine efficacy) on an AIDS vaccine. The vaccine, however, failed. Keith A. Crandall, chair of BYU’s Department of Biology, helped analyze the results.
“Why did it fail? How did it fail? How does the virus evolve a solution to the vaccine?” Crandall asked. “We want to find answers to those questions so we can develop better vaccines.”
Crandall and colleagues funded by the Gates Foundation sequenced a portion of the DNA from the virus collected from 349 patients infected with HIV. They developed powerful analytical approaches specifically for this study to compare and contrast those sequences with those sampled from participants who were not infected. Their approach and findings are reported in the journal Molecular Biology & Evolution.
By developing such methods for the world’s first phase III AIDS vaccine trial, they have established a road map for similar analyses of other AIDS vaccine trials, including the most recent Thai study.
“Now there is a way to analyze those data to pinpoint changes in the genome of the virus found in individuals who were vaccinated versus those given a placebo,” Crandall said. “That’s how you determine where in the genome the vaccine is really having an impact, and hopefully you can then fine-tune it to take advantage.”
For the newly published study, Crandall and fellow researchers sought to examine if the first vaccine, although ineffective at preventing infection, made any inroads against the virus at all. They looked for changes in one particular portion of the virus’s DNA and did not find any differences between placebo and vaccinated individuals. But new sequencing technologies can now allow them to sequence the virus’s entire genome and see if the vaccine made a dent elsewhere in the virus.
A genetic basis for developing an AIDS vaccine is especially important, Crandall said, because the virus changes so quickly.
“The vaccine whose effects we studied was based on an HIV sequence that was about 10 years old by the time of final clinical trial,” he said. “The virus that’s out there in the world by that point is very different from the virus that was being targeted during vaccine development.”
Another contribution of the new study is value of the data to future research. Crandall pointed out that it represents the first comprehensive survey of HIV genetic variation across the United States. Because the HIV-positive participants actually acquired the virus during the trial, their virus samples were captured very close to the time of infection. That’s a rarity in HIV genetic research, where researchers are often limited to studying viruses from blood samples taken years after the initial HIV infection, because the symptoms of AIDS often take some time to appear.
“The data reported in the paper represents one of the largest molecular epidemiologic surveys of HIV ever conducted,” said co-author Phillip W. Berman of UC-Santa Cruz. “The results of this trial will help scientists to better match vaccine antigens with the viruses currently in circulation.”
Crandall has previously collaborated with researchers at Johns Hopkins to study the relationship between genetic diversity of HIV and disease progression. He has also worked with a fellow BYU professor to peer into one of HIV’s hiding places in the human body.
The lead author on this paper is Marcos Pérez-Losada of the University of Porto. He and co-author David Posada of the University of Vigo previously worked in Crandall’s lab at BYU. Other co-authors are David V. Jobes and Faruk Sinangil of Global Solutions for Infectious Diseases, the nonprofit funded by the Gates Foundation to continue analysis of the original VaxXGen trial.