Pre-clinical Vaccine Development for Respiratory Viruses

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Human paramyxoviruses and pneumoviruses are widespread pathogens, cause considerable disease burden. Parainfluenza virus types 1-4 (PIV1-4) are highly infectious human pathogens, of which PIV3 is most commonly responsible for severe respiratory illness in newborns, elderly, and immunocompromised individuals. Based on a cryoelectron microscopy structure of an engineered PIV3 F prefusion-stabilized trimer, we engineered in additional mutations different from our previous published modifications in each of the four PIV fusion (F) glycoproteins to further stabilize their metastable prefusion states. The vaccine candidates were able to elicit murine PIV type-specific response, with little cross-neutralization of other PIVs. We evaluated the neutralization responses of the vaccine candidates in nonhuman primates (NHPs). We applied similar concept and designs to hMPV F proteins. In the past year, we designed various mutations to further stabilize the PIV F prefusion trimers and hMPV prefusion trimers. In addition, we designed expression the modified trimers on the surface of different nanoparticles as vaccine immunogens. We are now trying to evaluate the antigenicity of the modified trimers and we selected the most stable ones for mice and NHP animal immunogenicity study. The animal studies are actively going on.