Immunogenicity and protective efficacy of RSV G central conserved domain vaccine with a prefusion nanoparticle

Abstract

Respiratory syncytial virus (RSV) G glycoprotein has recently reemerged as a vaccine antigen due to its ability to elicit potent neutralizing antibodies and ameliorate disease in animal models. Here we designed three constructs to display the G central conserved domain (Gcc) focused on inducing broad and potent neutralizing antibodies. One construct displaying Gcc from both RSV subgroups trimerized via a C-terminal foldon (Gcc-Foldon) was highly immunogenic in mice and in MIMIC, a pre-immune human in vitro model. To explore an optimal RSV vaccine, we combined the Gcc-Foldon antigen with a stabilized pre-fusion-F nanoparticle (pre-F-NP) as a bivalent vaccine and detected no antigenic interference between the two antigens in the MIMIC model. In RSV-primed macaques, the bivalent vaccine elicited potent humoral responses. Furthermore, both Gcc-Foldon and the bivalent vaccine conferred effective protection against RSV challenge in mice. This two-component vaccine could potentially provide effective protection against RSV infection in humans and warrants further clinical evaluation.

Immune Prophylaxis Targeting the Respiratory Syncytial Virus (RSV) G Protein

“…RSV G protein is multifunctional mediating virus attachment to host cells, typically by G protein CX3C-CX3CR1 binding to ciliated respiratory epithelial cells [ 17 , 52 , 53 ], and by modifying immunity and disease pathogenesis [ 15 , 23 , 24 ]. Importantly, anti-G protein antibodies targeting the G protein CCD are protective when administered prophylactically or therapeutically in animal models [ 27 , 35 , 54 ]. Here, we examine anti-G protein mAb 2D10 for the first time in vivo and confirm mAbs 3D3 and palivizumab as neutralizing and disease protective [ 27 , 35 , 36 , 37 , 38 , 54 ].…”

“…Importantly, anti-G protein antibodies targeting the G protein CCD are protective when administered prophylactically or therapeutically in animal models [ 27 , 35 , 54 ]. Here, we examine anti-G protein mAb 2D10 for the first time in vivo and confirm mAbs 3D3 and palivizumab as neutralizing and disease protective [ 27 , 35 , 36 , 37 , 38 , 54 ]. The two broadly neutralizing human anti-G protein mAbs bind the RSV G protein CCD with high affinity (low picomolar-dissociation constant) at different, non-overlapping epitopes ( Figure 1 ) [ 40 ].…”

Experimental Validation of MHC Class I and II Peptide-Based Potential Vaccine Candidates for Human Papilloma Virus Using Sprague-Dawly Models

“…The strategy provides a timely analysis for vaccine development against different infectious agents. There are recent reports that peptide-based vaccines have been developed for SARS-CoV-2 [ 17 ], tuberculosis [ 18 ], respiratory syncytial virus (RSV) [ 19 ], Chikungunya virus [ 20 ], Streptococcus pneumoniae [ 21 ] and Neisseria meningitides [ 22 ].…”

Design and Preclinical Evaluation of a Nanoparticle Vaccine against Respiratory Syncytial Virus Based on the Attachment Protein G

“…The realization that the efficacy of viral vaccines does not necessarily depend on a strong response against the fusion protein was recognized for both influenza, where vaccine efficacy declined when the neuraminidase content was low [ 15 ], and for the paramyxovirus Hendra virus, for which an efficacious vaccine is approved based solely on the attachment protein H [ 16 , 17 ]. Although the G protein has been undervalued compared to F, the recent demonstration of strong neutralization in hAEC cultures of antibodies against G show the potential as a vaccine component [ 5 , 18 , 19 , 20 ], and protection from RSV challenge was demonstrated in mice after immunization with G [ 21 , 22 , 23 , 24 , 25 ]. Therefore, if durability and breadth of immunity elicited by current F-based RSV vaccines may turn out to be insufficient, inclusion of an additional RSV vaccine component based on the attachment protein G might increase the chance of durable and broad protection.…”