A Mouse Model for Betacoronavirus Subgroup 2c Using a Bat Coronavirus Strain HKU5 Variant

Agnihothram, Sudhakar; Yount, Boyd L.; Donaldson, Eric F.; Huynh, Jeremy; Menachery, Vineet D.; Gralinski, Lisa E.; Graham, Rachel L.; Becker, Michelle M.; Tomar, Sakshi; Scobey, Trevor D.; Osswald, Heather L.; Whitmore, Alan; Gopal, Robin; Ghosh, Arun K.; Mesecar, Andrew; Zambon, Maria; Heise, Mark; Denison, Mark R.; Baric, Ralph S.

Importantly, the BtCoV HKU5-SE chimera was fully susceptible to a SARS-CoV S-based vaccine, and polyclonal serum raised against SARS-CoV S completely neutralized the virus in vitro. The difference in neutralization titers between young and aged animals likely reflects the gradient of immune response that occurs in aged animals following emerging CoV infections (49) . These data demonstrate that the S glycoprotein retains key neutralization epitopes critical for protective immunity (16) . In contrast, none of the VRPs expressing S proteins from BtCoV HKU4, BtCoV HKU5, or MERS-CoV conferred protection in vivo, demonstrating the divergence between other group 2b and 2c CoV S proteins. These findings argue that vaccine design for any novel emerging CoV should involve S protein from the respective virus or a chimeric multivalent vaccine containing neutralizing epitopes from the S proteins of different CoVs.