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

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.

A Five-Helix-Based SARS-CoV-2 Fusion Inhibitor Targeting Heptad Repeat 2 Domain against SARS-CoV-2 and Its Variants of Concern

“…Cells were re-fed in a fresh medium after 12 h. The luminescence detection was performed at 48 h post-infection. A luminescence value ten-fold higher than the untreated cell control was considered as positive [ 14 ]. TCID 50 was determined by using the Reed-Muench method.…”

Effect of Different Adjuvants on Immune Responses Elicited by Protein-Based Subunit Vaccines against SARS-CoV-2 and Its Delta Variant

“…Generation of both pseudotyped wildtype SARS-CoV-2 and its Delta variant was performed as previously described [ 11 , 16 , 17 , 18 ]. Briefly, the backbone plasmid of pNL4-3.Luc.R-E- was co-transfected with the plasmid of pcDNA3.1-SARS-CoV-2-S (D614G)/pcDNA3.1-SARS-CoV-2-S (Delta) into HEK-293T cells by using VigoFect transfection reagent (Vigorous Biotechnology, Beijing, China).…”

“…Detection of nAbs against pseudotyped SARS-CoV-2 and its Delta variant was conducted as previously described [ 11 , 19 ]. Briefly, the mouse sera from all 12 groups were inactivated at 56 °C for 30 min.…”

“…Recently, we found a new stimulator of interferon gene (STING) agonist and named it CF501. The CF501-adjuvanted RBD-Fc vaccine (CF501/RBD-Fc) was shown to elicit potent neutralizing antibodies (nAbs) against SARS-CoV-2 and its 9 variants and 41 S-mutants, SARS-CoV and bat SARSr-CoVs in mice, rabbits and rhesus macaques [ 11 ]. Nanoparticle manganese adjuvant, also a STING agonist, was shown to facilitate antigen presentation, virus-specific memory T cell development and host-adaptive immunity [ 12 , 13 ].…”

Innovative adjuvant augments potency of a SARS-CoV-2 subunit vaccine

“…In a recent study, Liu et al 7 compared STING agonists with several well-known adjuvants, such as Alum and cGAMP. They found that the STING agonist CF501-adjuvanted RBD-Fc vaccine (CF501/RBD-Fc) elicited significantly stronger nAb and T cell responses than Alum- and cGAMP-adjuvanted RBD-Fc vaccine in mice.…”