The goal of the Viral Pathogenesis Laboratory (VPL) is to better understand basic aspects of viral pathogenesis and apply that knowledge toward development of safer and more effective vaccines. Defining how viruses cause disease requires investigation of functional and structural features of the viral pathogen, as well as studies to determine mechanisms for regulating the composition and timing of the host immune response. The studies encompass in vitro systems, animal models, and clinical trials. The major project areas include 1) respiratory syncytial virus (RSV) pathogenesis, 2) RSV vaccine development—including the study of immunity, antigen design, and delivery, and 3) RSV vaccine evaluation—both preclinical studies and endpoint analysis for candidate vaccines in clinical trials.
Major Project Areas
- Respiratory syncytial virus (RSV) pathogenesis
- RSV vaccine development—including the study of immunity, antigen design, and delivery
- RSV vaccine evaluation—both preclinical studies and endpoint analysis for candidate vaccines in clinical trials.
Sections and Units
The Viral Pathogenesis Laboratory includes the following sections and cores:
- Biodefense Research Section
Nancy Sullivan, Ph.D., Chief
- Viral Pathogenesis Laboratory and Translational Science Core
Barney Graham, M.D., Ph.D., Chief
Viral pathogenesis is determined by properties of the virus and the host response to the virus and is the basis for understanding immunity and guiding vaccine development. There are two major projects in the VPL focused on RSV pathogenesis. One involves exploring the determinants of viral tropism. The second is to define the functional properties of CD8 T cells and regulatory properties of CD4 T cells associated with efficient virus clearance and those associated with immunopathology. In particular, finding vaccine delivery approaches that can selectively induce distinct functional subsets of CD8 CTL in adults and neonates is a priority. These studies will inform our work on vaccine delivery as described below and are relevant to vaccine development in general.
RSV Vaccine Development
The focus of this work has been to identify and optimize vaccine antigens and to establish improved methods of antigen delivery. The antigen design work has been based on solving the structures of the postfusion and prefusion conformations of the RSV F trimer. This led to the structure-guided design of a stabilized prefusion trimeric RSV F immunogen that elicits potent neutralizing antibodies directed to antigenic site Ø located at the apex of the prefusion F trimer. This stabilized prefusion F can be delivered as a soluble subunit protein, displayed on a nanoparticle, or expressed from a gene-based vector. Various options for improved expression and formulations are being explored for manufacturing feasibility and advancement into clinical trials.
RSV Vaccine Evaluation
Another project area for the VPL is the support of clinical vaccine studies either through preclinical evaluation of candidate vaccines or by developing assays for endpoint analysis on clinical trial samples. Major projects include development of high throughput neutralization assays for subtype A and B viruses including both prototypic laboratory isolates and clinical isolates. In addition, assays for serological analysis of epitope-specific responses on prefusion and postfusion versions of the RSV F trimer are in development.