Design and Testing of Novel Vaccines Against Epstein-Barr Virus

Epstein-Barr virus (EBV) is one of the most common human viruses. It is a causative agent of infectious mononucleosis and is associated with ~200 000 new cases of cancer and ~140,000 deaths annually. It is thought that a vaccine that prevents EBV infection and/or associated pathologies would have a significant clinical benefit. However, the kinds of immune responses a protective EBV vaccine would need to elicit have not been defined. Consequently it is not clear which viral antigens are ideal candidates for an EBV vaccine.

To get a better understanding of what types of antibodies a protective EBV vaccine should elicit, we isolate monoclonal antibodies targeting multiple viral proteins from people naturally infected with EBV and evaluate their ability to neutralize, or block infection of multiple cell types, and to block experimental EBV infection in animal models. We couple this with structural information to define critical sites of vulnerability on the virus. We then use this information to design and optimize  next-generation vaccine antigens that can focus the immune response on key antigenic sites and evaluate their ability to elicit protective antibodies in animal models. To do so, we employ next-generation nanoparticle antigen display, mRNA vaccine technologies, and machine-learning design approaches.

Developing Novel RSV Vaccine Immunogens

Respiratory syncytial virus (RSV) causes lower respiratory tract infections leading to significant morbidity and mortality at the extremes of age. While three vaccines were recently approved for use in adults over 60, a vaccine that can prevent infection in the infant population is lacking. In fact, recent early phase trials have faced substantial setbacks and have been placed on hold by the FDA. To address this global health priority, we engineered a vaccine to target a reproducible class of antibodies that arise from the chromosomally-encoded VH3-21/VL1-40 antibody genes that are structurally pre-configured to neutralize RSV without undergoing affinity maturation. We developed a non-viral immunogen derived from anti-idiotypic monoclonal antibodies (ai-mAbs) that can selectively recognize and activate RSV-neutralizing VH3-21/VL1-40 B cells. Because this immunogen is structurally unrelated to RSV it may prevent vaccine-associated enhanced disease outcomes that have been seen in previous attempts to vaccinate against RSV in infants. We are currnetly developing and evaluating a bespoke small animal model that will  allow us to evaluate the immunogenic efficacy of the ai-mAb in vivo. Success in this project will provide compelling proof-of-concept for use of the ai-mAb as an RSV vaccine candidate and support progression towards clinical trials.

Defining Humoral Immunity to Kaposi sarcoma associated herpesvirus 

Kaposi sarcoma associated herpesvirus (KSHV) is a herpesvirus related to EBV. Like EBV, KSHV causes cancer in several cell types, primarily in immunocompromised individuals. Because these cancers are caused by a virus, they may be preventable by a vaccine or treated by biologics or immune therapies. Also similar to EBV, the types of immune responses that can prevent KSHV infection and/or KSHV-driven cancer are poorly defined. Our work on KSHV is similar to that for EBV; we isolate monoclonal antibodies targeting multiple viral proteins from people naturally infected with KSHV and evaluate their ability to neutralize, of multiple cell types. We are working to establish better animal models of KSHV infection to evaluated antibody-mediated prevention and test vaccines and antibodies as therapeutic agents.