Vaccine Research and Development for Endemic, Emerging, and Resurgent Viruses

National Institute Of Allergy And Infectious Diseases

Investigators

Linked publications & trials

Abstract

Our previous work has led to the development of vaccines against respiratory syncytial virus (RSV) and Zika virus that have reached late phase clinical testing. While we are still performing exploratory studies on immune responses to RSV in humans, our work on emerging and resurgent viruses has shifted to focus on vaccines for paramyxoviruses (primarily measles and mumps), enteroviruses (primarily enterovirus D68 and A71), and herpesviruses. Vaccines currently licensed for measles and mumps contain live-attenuated viruses. While these vaccines have had a remarkable impact on disease burden, they have several shortcomings. Live-attenuated vaccines are neutralized by maternal antibodies, dampening responses in early life and to booster vaccinations. They also have several contraindications and have been associated with adverse events that contribute to vaccine hesitancy. As a result, measles and mumps are resurgent particularly in clusters of susceptible people. We have been working on optimized vaccine antigens based on viral surface glycoproteins. Structure-based design is used to stabilize the viral fusion proteins in the prefusion conformation and co-deliver with the attachment proteins, either separately or as chimeric fusion proteins. Vaccine candidates for measles and mumps have been shown to elicit neutralizing antibodies in mice and nonhuman primates, and provide a strong boost to immunity elicited by live-attenuated vaccines. Enterovirus D68 is a respiratory enterovirus that causes biannual respiratory illnesses in pediatric populations and has been associated with outbreaks of acute flaccid myelitis (AFM). We are designing and evaluating virus-like particle (VLP) vaccines that expresses the structural proteins of EV-D68. We have demonstrated immunogenicity and the elicitation of cross-neutralizing antibodies across multiple virus subclades following VLP immunization. We have demonstrated that passively transferred antibodies confer protection from replication of mouse-adapted virus following respiratory challenge of susceptible immunodeficient AG129 mice. We are currently testing different doses and formulations in nonhuman primates, and exploring multiple vaccine modalities. We aim to apply the knowledge from this project to develop an enterovirus vaccine platform that can be used for vaccines against related enteroviruses such as enterovirus A71, another enterovirus associated with AFM. We are also working on the development of effective medical countermeasures for herpesviruses such as Epstein-Barr virus (EBV) and have structurally characterized potently neutralizing monoclonal antibodies that mimic the interaction between EBV and cellular receptors.