Vaccine's $40 million boost

The Bill & Melinda Gates Foundation has awarded two grants totaling $40 million to Fred Hutchinson Cancer Research Center as part of a larger international effort to speed the development of effective HIV vaccines. The Center will play a pivotal role — including overall data management and analysis — in this $287 million HIV-vaccine discovery network.

Collectively known as the Collaboration for AIDS Vaccine Discovery, or CAVD, the network brings together more than 165 investigators from 19 countries to design and evaluate promising HIV-vaccine candidates. The network will address research priorities identified by the Global HIV Vaccine Enterprise, an international alliance of organizations dedicated to accelerating HIV-vaccine development by implementing a shared scientific plan.

Two Hutchinson Center investigators received five-year funding from the Gates Foundation to participate in the consortia: Clinical researcher Dr. Julie McElrath received $30.1 million to lead a research consortium to develop vaccine adjuvants that boost cellular immunity, and biostatistician Dr. Steven Self received $9.9 million to lead the network's data and statistical management center. In addition, structural biologist Dr. Roland Strong is a collaborator on a Gates Foundation grant awarded to Seattle Biomedical Research Institute (SBRI) to help develop antibody-based vaccines. Strong will receive $4.1 million from SBRI to collaborate on this project.

As new vaccine candidates are created, the network's researchers will test the vaccines using standardized protocols, share data in real time and compare results so that the most promising vaccine strategies can be quickly prioritized for further development, including clinical trials in humans.

"Thanks to the Gates Foundation's extraordinary generosity and vision, this international research network promises to be a pipeline for the next generation of HIV vaccines," said McElrath, an investigator in the Clinical Research Division and associate head of the Program in Infectious Diseases at the Center. "The efforts that are going into this are definitely going to jump-start the next round of vaccine development."

Improving cellular memory

McElrath will lead a consortium dedicated to testing the effectiveness of compounds called adjuvants, which are added to vaccines to increase their ability to elicit a potent innate immune response, which in turn improves adaptive immunity or cellular memory. "When a person's immune cells see the pathogen again, they recall seeing it before and can mount a better immune response against it," McElrath said.

Although adjuvants often make vaccines more effective, very little is understood about how they work. "A lot of the molecular interactions are just unfolding," said McElrath, also a professor of medicine at the University of Washington School of Medicine.

McElrath and colleagues from the Center, the UW, the Institute for Systems Biology, Emory University, Oregon Health Sciences University and New York University will use both laboratory and preclinical studies to explore the molecular pathways by which adjuvants enhance cellular immune responses. The researchers will compare multiple existing and new adjuvants to try to understand how they work and, ultimately, evaluate new compounds in clinical trials to determine the best ways to use them in combination with HIV vaccines. Such clinical trials will be conducted primarily through the federally funded HIV Vaccine Trials Network (HVTN), which is headquartered at the Center. HVTN principal investigator Dr. Lawrence Corey, head of the Center's Program in Infectious Diseases and UW's Virology Division, will collaborate on the project as will immunologist Dr. Phillip Greenberg, an investigator in the Clinical Research Division and professor of medicine and immunology at UW.

Most infectious-disease vaccines on the market are preventive; they depend on neutralizing antibodies to bind pathogens and prevent them from entering cells. So far, however, research researchers have been unable to effectively develop a protein or any kind of vaccine that will make HIV-neutralizing antibodies. "HIV has a really complicated envelope structure that evades the immune system, which has prevented us from developing an effective antibody-based vaccine," McElrath said.

T-cell and antibody-based vaccines

Instead, McElrath's team will focus on adjuvants to be used in conjunction with T-cell vaccines, which aim to control the spread of HIV within the body and prevent the virus from progressing to full-blown AIDS. T-cell vaccines are designed to recognize HIV-infected CD4 immune cells and destroy them by enhancing the CD8 killer-cell response. In addition to preventing HIV from developing into AIDS, such vaccines may prove to potentially decrease HIV transmissibility, McElrath said.

"Ultimately we hope to use both T-cell and antibody-based vaccines together, and the adjuvants we'll be studying to induce innate immune responses could actually work for inducing the T-cell response as well as the antibody response," said McElrath, who also directs the HVTN Laboratory Program and is principal investigator of the Seattle HIV Vaccine Trials Unit (a joint program of the Center and UW).

On a practical level, the use of adjuvants to optimize cellular immunity may permit fewer immunizations and lower the antigen dosage, which potentially will improve the success rate of completing the immunization series and reduce the cost of the vaccine.

The CAVD network's Vaccine Immunology Statistical Center will be housed within the Hutchinson Center's Statistical Center for HIV/AIDS Research and Prevention, or SCHARP. Under the leadership of SCHARP director Dr. Steven Self, Center statisticians and data-operations experts will establish a standardized central repository for storing, comparing and sharing statistical data generated by preclinical and clinical studies of HIV-vaccine candidates. SCHARP investigators also will provide consultation on study design and statistical analyses for all of the network's vaccine-discovery consortia.

The data repository will include a Web-based interface that will provide researchers throughout the network with real-time, secure access to laboratory data. "We'll offer an electronic, collaborative environment for all of the scientists throughout the network to share data securely," said Self, head of the Program in Biostatistics and Biomathematics in the Public Health Sciences Division.

Unique opportunity

In addition to serving as the statistical and data-management center for the Gates-funded network, SCHARP is the statistical coordinating center for ongoing federally funded vaccine trials and related field studies in more than 20 countries run by the HIV Vaccine Trials Network (HVTN) and the Duke University-based Center for HIV/AIDS Vaccine Immunology (CHAVI).

"With preclinical data coming in from the Gates-funded CAVD consortia and clinical-trial data coming in from HVTN and CHAVI, this centralized data repository will allow researchers, for the first time, to compare standardized data across candidate immunogens from both preclinical studies and human trials to more quickly identify the most promising vaccine candidates and accelerate their development. That's going to be a unique opportunity," Self said.

Designing proteins to fight HIV

Highly effective vaccines, such as those that protect against polio, work by eliciting an immune response, or the production of antibodies, in vaccinated individuals similar to what occurs during natural infection. A major obstacle to vaccine design for HIV is that it has been difficult to develop a vaccine that causes the human immune system to produce protective antibodies.

Studies have shown that parts of the viral coating, or envelope, can trigger the development of broadly reactive neutralizing antibodies in some rare individuals. To exploit this potential for vaccine development, Dr. Roland Strong, an investigator in the Center's Basic Sciences Division, is collaborating on a project led by Dr. Leonidas Stamatatos of SBRI to design and build proteins that resemble parts of these viral envelopes.

"Our approach, rather than working with the whole virus particle or a large fragment of it, is to try and identify just the key bits of the virus — which, when targeted by antibodies, stop HIV infection — and then design, computationally, protein-based molecular 'scaffolds' to present those key bits in a way that will generate an ideal immune response," said Strong, whose lab will be using X-ray crystallography and other imaging tools to analyze the structure of these rare antibodies to better understand how they work. His lab will also analyze these designer proteins to make sure they work as planned in both the laboratory and in preclinical settings.

"Our goal is to engineer proteins that can elicit a strong immune response against the AIDS-causing virus, which could form the basis for a vaccine to prevent HIV infection," Strong said. Other Center collaborators on the project will include Corey and Greenberg.