Vectored co-delivery of human cytomegalovirus gH and gL proteins elicits potent complement-independent neutralizing antibodies

Neutralizing antibodies to several hCMV glycoproteins, and complexes thereof, have been identified in individuals following hCMV infection. Interestingly, a portion of the CMV-specific neutralizing antibody responses are directed to epitopes found on glycoprotein complexes but not the individual proteins. Using an alphavirus replicon particle (VRP) vaccine platform, we showed that bicistronic VRPs encoding hCMV gH and gL glycoproteins produce gH/gL complexes in vitro. Furthermore, mice vaccinated with these gH/gL-expressing VRPs produced broadly cross-reactive complement-independent neutralizing antibodies to hCMV. These neutralizing antibody responses were of higher titer than those elicited in mice vaccinated with monocistronic VRPs encoding gH or gL antigens, and they were substantially more potent than those raised by VRPs encoding gB. These findings underscore the utility of co-delivery of glycoprotein components such as gH and gL for eliciting potent, broadly neutralizing immune responses against hCMV, and indicate that the gH/gL complex represents a potential target for future hCMV vaccine development.