To support a coordinated, innovative approach to the development of an AIDS vaccine, Texas Biomedical Research Institute scientists, together with a multi-institutional coalition of experts from the United States and Europe, have received a grant for $23 million from the National Institute of Allergy and Infectious Diseases (NIAID) of the National Institutes of Health. The goal of this program is to establish a vaccine approach that targets a frontline defense at the mucosa, while simultaneously generating backup immune responses in the blood and tissues.
The new Program Project grant is led by Dr. Ruth Ruprecht, director of the Texas Biomed AIDS Research Program, as the principal investigator. She has brought together leaders in the fields of viral pathogenesis, molecular biology, whole body imaging, monoclonal antibody development, immunology, lymph node-targeted vaccine design and animal modeling.
“We are very excited about the potential of this project, which is the largest NIH Program Project grant received by Texas Biomed,” said Dr. Robert Gracy, president of Texas Biomed. “Ruth has assembled a quality team to tackle a vaccine approach that is both visionary and sensible in its design and is a great example of the type of research we deliver at Texas Biomed. This project embodies the mission of Texas Biomed, which is to enhance lives through discovery.”
The AIDS epidemic has been the worst infectious disease outbreak in modern history, killing 35 million people and continuing to infect 50,000 people in the U.S. each year. According to the U.S. Department of Health and Human Services, “developing a safe, effective and affordable vaccine to prevent HIV is the best hope for controlling or ending the HIV epidemic.”
“The basic idea of the new program project is to induce host defenses against HIV simultaneously at multiple levels, first at mucosal barriers, then in mucosal tissues, and finally in the systemic circulation and the rest of the body,” Ruprecht explained. “The first line of defense consists of mucosal antibodies – mostly IgA and IgG molecules in mucosal fluids – which trap incoming virus particles in a process called immune exclusion. The second line of defense consists of IgG antibodies in mucosal tissues and in blood that can both neutralize the virus and lead to the killing of infected, HIV envelope-producing target cells through antibody-dependent cell killing. The third line of defense involves specific immune T cells that can kill infected target cells expressing various viral proteins; such killer T cells circulate throughout the body.”
Ruprecht explained that the inspiration of this approach stems from the military strategy termed defense-in-depth which seeks to prevent a country from being overrun after the frontline has been penetrated by the enemy.
HIV transmission occurs in about 90 percent of all cases through mucosal exposures, including sexual contact and perinatal transmission. To mobilize and optimize the host defenses in mucosal fluids and tissues against the incoming virus, the scientists will use a highly interactive approach.
The five-year project, broken into three sub-projects, will begin with the basic analysis of virus movement through mucus, mucosal fluids and penetration through epithelial barriers and how virus-specific antibodies affect these processes. Through fluorescent labeling of virus particles and/or antibodies, scientists will be able to see exactly how and where the virus goes upon entering a mucosal barrier and how it interacts with antibodies. Dr. Thomas Hope, professor of cell and molecular biology at the Northwestern University Feinberg School of Medicine, will lead these studies.
Hope will collaborate closely with experts at the Research Imaging Institute (RII) of the University of Texas Health Science Center at San Antonio (UTHSCSA), where state-of-the-art imaging will be used to track virus and/or antibody movement across the epithelium and over time throughout the body. These imaging studies will be led by Dr. Peter Fox, director of the Research Imaging Institute, and Dr. Beth Goins, a professor at UTHSCSA.
The second part of the Program Project, led by Ruprecht, will pursue results from previous studies in which her team demonstrated the effectiveness of the process called immune exclusion, in which mucosal antibodies, specifically dimeric IgA1, can act as a trap to capture virus particles and crosslink them, thereby blocking their ability to cross the epithelial barrier. Her team, which includes Texas Biomed scientist Dr. Viraj Kulkarni, an expert in virology and immunology, plans to examine the structural requirements for optimal virus capture at the mucosal frontline in close collaboration with Dr. Antonio Lanzavecchia, director of the Swiss-based not-for-profit Institute for Research in Biomedicine (IRB), affiliated to the Università della Svizzera italiana. IRB will construct and produce monoclonal antibodies that can be tested in cell culture and in animal models as a first line of defense.
The third part of the project will be led by Dr. Darrell Irvine, professor of materials science and engineering and biological engineering, with Massachusetts Institute of Technology, who will be responsible for vaccine design and lymph node targeting for vaccines. Like Hope, Irvine will also work closely with Drs. Fox and Goins at RII/UTHSCSA to target his vaccines to the mucosal areas where the virus first enters the body. The scientists plan to follow vaccine delivery with PET and MRI imaging and analyze immune responses generated in mucosal fluids, tissues and blood.
The nonhuman primate research will be conducted at the Southwest National Primate Research Center at Texas Biomed and overseen by Texas Biomed scientists Drs. Samir Lakhashe and Sandeep Gupta. Work with the SNPRC will enable the team to further test these concepts and candidate vaccines in the appropriate nonhuman primate model. Dr. Sarah Ratcliffe, professor of biostatistics at the University of Pennsylvania, will provide biostatistical support for the collection and analysis of data on the primate studies.
Funding for this project comes from NIAID grant number 2P01_AI048240-12, as well as support from the Southwest National Primate Research Center’s NIH base grant P51 RR013986.
Source: Texas Biomedical Research Institute