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 and Zika that have reached late phase clinical testing. While we are still performing some exploratory studies on vaccine-elicited immunity following RSV vaccination, or 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 coronaviruses. Vaccines currently licensed for measles and mumps contain live-attenuated viruses. While these vaccines have had a remarkable impact of 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. 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 NHP, and development at the Vaccine Production Program is ongoing. We aim to apply the knowledge from this project to develop an enterovirus vaccine platform that can be used for vaccines against related enteroviruses. We have also produced and tested a VLP for enterovirus A71, another enterovirus associated with AFM. It elicits neutralizing antibodies and when codelivered with EV-D68 VLP, there was no reduction in the response to either virus. We are currently evaluating nanoparticle-based vaccine candidates for next-generation or pan-coronavirus vaccines.