A novel STING agonist-adjuvanted pan-sarbecovirus vaccine elicits potent and durable neutralizing antibody and T cell responses in mice, rabbits and NHPs

Zezhong Liu,Meiyu Wang,Changfa Tao ,Yanqun Wang,Jianrong Dong ,Chuan Qin,Jincun Zhao,Zhenghong Yuan,Xinling Wang,Youhua Xie,Lixiao Xing,Ming Kun Hsieh ,Qin Wang ,Jie Zhou,Miaoling He,Shibo Jiang,Wei Deng,Youchun Wang,Wei Xu,Yilong Zhang,Weijin Huang,Lu Lu

doi:10.1038/s41422-022-00612-2

Abstract

The emergence of SARS-CoV-2 variants and potentially other highly pathogenic sarbecoviruses in the future highlights the need for pan-sarbecovirus vaccines. Here, we discovered a new STING agonist, CF501, and found that CF501-adjuvanted RBD-Fc vaccine (CF501/RBD-Fc) elicited significantly stronger neutralizing antibody (nAb) and T cell responses than Alum- and cGAMP-adjuvanted RBD-Fc in mice. Vaccination of rabbits and rhesus macaques (nonhuman primates, NHPs) with CF501/RBD-Fc elicited exceptionally potent nAb responses against SARS-CoV-2 and its nine variants and 41 S-mutants, SARS-CoV and bat SARSr-CoVs. CF501/RBD-Fc-immunized hACE2-transgenic mice were almost completely protected against SARS-CoV-2 challenge, even 6 months after the initial immunization. NHPs immunized with a single dose of CF501/RBD-Fc produced high titers of nAbs. The immunized macaques also exhibited durable humoral and cellular immune responses and showed remarkably reduced viral load in the upper and lower airways upon SARS-CoV-2 challenge even at 108 days post the final immunization. Thus, CF501/RBD-Fc can be further developed as a novel pan-sarbecovirus vaccine to combat current and future outbreaks of sarbecovirus diseases.

Highlights

Global public health is continuously threatened by emerging viruses.[1]
receptorbinding domain (RBD)-Fc group were still significantly higher than those in mice in. These results suggest that the stimulator of interferon genes (STING) agonist CF501 can be used as the cGAMP/RBD-Fc and Alum/RBD-Fc groups (Fig. 3c, d)
We found that CF501/RBD-Fc induced a significantly higher number of Th1-biased IFN-γ+ and TNF-α+ splenocytes than that induced by Alum/RBD-Fc or cGAMP/ RBD-Fc (Fig. 3a, b)

Summary

INTRODUCTION

Global public health is continuously threatened by emerging viruses.[1]. Coronaviruses, especially sarbecoviruses, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). CF501/ RBD-Fc-elicited sera exhibited high potency against RsSHC014 S-mediated cell–cell fusion (IT50: 2618), about 2.7- and 10.3-fold more potent than those from rabbits immunized with Alum/RBDFc and cGAMP/RBD-Fc, respectively (Supplementary information, Fig. S6i) Together, these results suggest that CF501 can enhance the capacity of the RBD-Fc vaccine to elicit highly potent crossnAbs in rabbits against divergent sarbecoviruses, including SARSCoV-2 and its variants and natural mutants, as well as SARS-CoV and bat SARSr-CoVs. Robust and durable immune responses and protection elicited by CF501/RBD-Fc in rhesus macaques Subsequently, we further assessed the immunogenicity of CF501/ RBD-Fc in rhesus macaques. All above results suggest that CF501/RBD-Fc can induce durable protection in NHPs tested against the SARS-CoV-2 challenge

DISCUSSION

Findings

MATERIALS AND METHODS