Macaque studies to optimize vaccine strategies
Early this year IAVI launched a pre-clinical program aimed at optimizing vaccine design, dosage and immunization regimen and prime-boost combinations with its current crop of candidates. So far it has launched the first vaccination studies in macaques and established a core lab at the pharmaceutical company Becton Dickinson (San Diego), where the analyses of immune responses in these studies will be carried out.
Ongoing studies are working out the best dosing regimes with DNA/MVA and the adeno-associated virus (AAV), and testing whether responses to AAV can be boosted with either AAV (using a different subtype than the prime) or with MVA. Future experiments will analyze which HIV genes are necessary for protective immunity, compare different viral vectors head-to-head, and examine the ability of adjuvants to enhance the immunogenicity of DNA vaccines. The findings of these studies will be published, and should help guide the design of future vaccines.
These efforts are being led by Alan Schultz at IAVI and Shiu-Lok Hu from the University of Washington. Collaborating non-human primate centers include the Oregon Health and Science University, Children’s Research Institute, and the University of Pittsburgh—with possible future collaborations to include the Tulane National Primate Research Center and the Air Force Research Institute for Medical Science in Bangkok.
Neutralizing antibody consortium update
In 2002, IAVI, the National Institutes of Health Vaccine Research Center (VRC), and a number of leading academic and industry laboratories joined forces to create the Neutralizing Antibody Consortium (NAC) (see IAVI Report, May-Jun 2002). In the year since its inception, NAC members have made steady progress towards the design of immunogens that elicit broadly neutralizing antibodies to HIV.
Members of the consortium are taking a systematic approach to developing effective immunogens. The first stage involves gathering information on key aspects of the structures involved in neutralization. This is done through crystallization of HIV envelope proteins and monoclonal antibodies, which is now being executed by a robotic system from Syrrx (San Diego, California), at the Scripps Research Institute (La Jolla, California) in collaboration with the Joint Center for Structural Genomics (a California-based consortium). The automated high-throughput platform can produce crystals in as little as two weeks, in contrast to the usual manual procedures, which generally take months and are far more costly. This system has now been used successfully to determine the structure of several broadly neutralizing monoclonal antibodies, including IgG1 b12, which recognizes the CD4 binding site, and 2G12, a highly unusual antibody that recognizes a cluster of carbohydrates on gp120, among others directed at gp41 or the V3 loop.
The next step is the modification or enhancement of envelope proteins to expose important regions for neutralization. One design approach is to mimic the native trimeric form of envelope spikes that occur on the virus surface. One such candidate immunogen (gp140 GCN4) previously developed by the group of Joseph Sodroski (Harvard University, Cambridge), an NAC member, has been shown to induce neutralizing antibodies in rabbits and is being modified further to increase its immunogenicity. Sera from rabbits immunized with these novel immunogens will be tested against a broad range of viruses, using ViroLogic’s high-throughput pseudovirion assay. Another ongoing study is comparing immune responses induced by DNA vaccines encoding env with responses to the envelope protein itself, since vaccines using DNA are potentially cheaper and easier to manufacture.
The consortium has also established a repository to store and distribute key reagents, such as the various envelope proteins and monoclonal antibodies used in the crystallization studies. Looking ahead, NAC members plan continued structural studies and production of new immunogens, along with head-to-head immunogenicity studies in animals.