5/13/2008

Lemons to lemonade: unique database recovers new insights from unsuccessful HIV vaccine trial

By Branwyn Wagman, QB3 UC Santa Cruz

Phil Berman

The ending of a clinical trial for an unsuccessful AIDS vaccine in 2003 marked the beginning of a new opportunity for researching how the virus evolves to infect new victims. The University of California Santa Cruz and Global Solutions for Infectious Diseases (GSID) have announced a new HIV data browser, modeled on the UCSC Genome Browser, that will give researchers access to the wealth of data collected during the trial.

The GSID HIV Data Browser was the brainchild of Philip Berman, chair of the biomolecular engineering department at UCSC and former senior vice president for research and development at VaxGen, the company that developed the vaccine.

Berman said, “After the trial failed, I spent a couple of years trying to think what was the most important thing I could do for HIV research. I concluded it was using new technology to preserve the data from these clinical trials and presenting it in a form useful to the scientific community.”

In 2004, Berman co-founded GSID, a nonprofit research organization dedicated to combining knowledge and expertise from the biotechnology industry and the public health sector to address infectious disease problems in the developing world.

Berman said, “Despite the fact that the vaccine trial didn’t work, a huge amount of useful information was obtained. The trial represented the only up-to-date nation-wide survey of virus sequences from new infections that had ever been carried out.” The trial spanned about 60 different clinical sites across the United States and one site in Europe.

“Every time there was a new infection in the vaccine or placebo group, the virus was sequenced,” Berman said. “The sequence information provides the best picture we have about what the immune system sees when there is a new infection.”

This is important, Berman said, because other major repositories of HIV sequence data are not annotated for the time after infection, the clinical status of the patient, or the histories of the specimens sequenced—a problem for studying such a rapidly-evolving virus.

Berman explained, “A current hypothesis in HIV vaccine research is that the antigenic structures of HIV viruses that mediate new infections differ from those recovered from people long after infection.” While the viral forms responsible for new infections were selected for effective transmission, viruses recovered years after initial infection—the type included in all vaccines tested to date—have evolved to thwart the immune system.

“The specimens in this set represent the largest group from new infections that have ever been collected,” Berman said, explaining that a vaccine should be targeted at the virus when it is in its most infectious form.

In addition, Berman said, “This is the first time that an HIV sequence database has been linked to a specimen repository and a database of clinical information.” Besides viral genome sequence data, the database links to a repository of existing specimens—blood and cryopreserved cells—that researchers can access for further study.

Berman said, “These clinical specimens are longitudinal, collected from the same person during a two-year follow-up period. This will allow investigators to study the evolution of the virus and the evolution of the immune response and clinical outcomes.”

At UCSC, Berman teamed up with the UCSC Genome Browser group to develop a browser for the sensitive clinical data from the vaccine trial.

Jim Kent, associate research scientist for the UCSC Genome Browser and principal investigator on the project, said, “This was our first time to work with clinical data from participants. This data must be handled differently, with great care taken with confidentiality. We learned from this project how to build the infrastructure to cope with that.”

Kent said, “This will be useful for other medical projects, such as cancer genomics, in the future.”

Fan Hsu, director of proteomics for the UCSC Genome Browser said, “Before, everything we have worked on is totally open, totally public. With the GSID project, only authorized users can access the data. We needed to set up special controls, like online banking.”

Another challenge was how to display the very large number of HIV sequences on the browser. Hsu said, “Our original genome browser has only one reference genome. For this HIV database, we are talking about close to 400 infected people—more than 1000 sequences.”

Hsu and software developer Galt Barber adapted the genome browser software to accommodate the large number of HIV sequences and the data security along with interactive selection criteria for viewing the data.

As the project evolved, Hsu also coordinated the transfer of the software to GSID with others on the UCSC team who worked nights and weekends to bring the new browser online. “Erich Weiler provided the system layer—he recommended a server, brought up the physical machine at GSID, and brought up the Linux operating system,” Hsu said. Robert Kuhn and Ann Zweig from the genome browser quality assurance group developed software documentation and a tutorial.

The resulting HIV Data Browser, hosted by GSID, is a customized version of the UCSC Genome Browser. It provides researchers with searchable demographic and clinical data from volunteers who became HIV infected during the VaxGen clinical trial. The browser allows users to align viral sequences with one another and with reference or consensus sequences.

Kent said, “This is something where the university can make a difference, because the private sector is not so interested in vaccines—they’re not so profitable. Vaccine efforts are more targeted toward the developing world. There is very little economic incentive to develop an AIDS vaccine, but there is a tremendous humanitarian incentive.”

Berman said, “A lot of thought- and opinion-leaders believed it would be impossible to do large scale HIV vaccine efficacy (phase three) trials—recruiting and retaining volunteers at high risk for HIV infection for a three-year trial and providing risk avoidance counseling. They underestimated the target group—people enrolled for altruistic reasons.”

Although the vaccine proved ineffective, the trial may have helped some participants. Berman said, “The rate of infection of everybody in the trial declined, demonstrating that counseling had an effect. The people in these trials who became infected did so through high-risk behavior despite intensive counseling on how to avoid becoming infected with HIV.”

Kent hopes that just as the UCSC Genome Browser has continued to build the collaborative nature of the genomics research community, this HIV data browser will help motivate the AIDS research community to work together and pool their research.

“Our role was to put up information gathered during the course of one of the failed vaccine trials, so that future researchers could build upon and learn from the mistakes,” Kent said.

In addition to the VaxGen vaccine, another HIV vaccine candidate developed by the NIH and Merck & Co., Inc. also failed in clinical trials. Berman said, “The recent failure of the Merck/NIH HIV vaccine has thrown the field in turmoil, all the best ideas for an HIV vaccine in the past 25 years have failed. The information in this database is now more critical than anyone could have imagined. It tells us what’s being transmitted.”

The next phase of this project involves releasing the sequence data from infected participants in the parallel clinical trial of the VaxGen vaccine conducted in Thailand.

“In the future, the database will be expanded to allow associations between virus sequences, clinical data, immune response data, and host genetics,” Berman said. He added, “We hope to eventually include data from other HIV vaccine trials sponsored by the NIH, private companies, and other HIV vaccine research organizations.”

GSID is making these data and serological samples available to the HIV research community through an agreement with VaxGen and with funding provided by the Bill and Melinda Gates Foundation.

For information on accessing the GSID HIV Data Browser and background on the clinical trials, visit www.gsid.org/index02.html.