Elicitation of broadly protective sarbecovirus immunity by receptor-binding domain nanoparticle vaccines

Abstract

Understanding vaccine-elicited protection against SARS-CoV-2 variants and other sarbecoviruses is key for guiding public health policies. We show that a clinical stage multivalent SARS-CoV-2 spike receptor-binding domain nanoparticle vaccine (RBD-NP) protects mice from SARS-CoV-2 challenge after a single immunization, indicating a potential dose-sparing strategy. We benchmarked serum neutralizing activity elicited by RBD-NP in non-human primates against a lead prefusion-stabilized SARS-CoV-2 spike (HexaPro) using a panel of circulating mutants. Polyclonal antibodies elicited by both vaccines are similarly resilient to many RBD residue substitutions tested although mutations at and surrounding position 484 have negative consequences for neutralization. Mosaic and cocktail nanoparticle immunogens displaying multiple sarbecovirus RBDs elicit broad neutralizing activity in mice and protect mice against SARS-CoV challenge even in the absence of SARS-CoV RBD in the vaccine. This study provides proof of principle that multivalent sarbecovirus RBD-NPs induce heterotypic protection and motivates advancing such broadly protective sarbecovirus vaccines to the clinic.

SARS-CoV-2 spike conformation determines plasma neutralizing activity

“…The identification of the RBD as the sole target of vaccine-elicited polyclonal antibodies broadly neutralizing SARS-CoV-2 variants is reminiscent of recent reports describing broadly neutralizing sarbecovirus monoclonal antibodies isolated from infected subjects (12-14, 16, 18, 64-67) and the rapid accumulations of mutations in the NTD (20,54,(61)(62)(63). These findings motivate the clinical development of RBD-based vaccines against SARS-CoV-2 (29, 74-77) and sarbecoviruses (78) for future pandemic preparedness. conformations (left to right).…”

“…The construct ends at residue K1211 and is followed by a TEV cleavage site, fold-on trimerization motif, and an 8× His tag in the CMVR vector. SARS-CoV-2 G614 S (YP 009724390.1), and Delta (B.1.617.2) S genes were all placed into the HDM vector with a 21 residue C-terminal deletion, as previously described (63,78,79). The plasmids encoding the SARS-CoV-2 Omicron (B.1.1.529) S variant was generated by overlap PCR mutagenesis of the wildtype plasmid, pcDNA3.1(+)-spike-D19 (80).…”

A broadly cross-reactive antibody neutralizes and protects against sarbecovirus challenge in mice

“…Moreover, existing therapeutic monoclonal antibodies against SARS-CoV, and SARS-CoV-2 mRNA vaccines do not fully protect against zoonotic SARS-related virus infection in vivo (6)(7)(8). Given the pandemic potential of SARS-related viruses, the development of broadly effective countermeasures, such as universal vaccination strategies (8)(9)(10) and coronavirus cross-reactive monoclonal antibodies, is a global health priority. Moreover, given the emergence of the SARS-CoV-2 variants that are partially or fully resistant to some neutralizing antibodies authorized for COVID-19 treatment (11)(12)(13), there is a need to develop mAb therapies that are broadly effective against existing SARS-CoV-2 variants and zoonotic SARS-related viruses that may emerge in the future.…”

An ultrapotent RBD-targeted biparatopic nanobody neutralizes broad SARS-CoV-2 variants

“…Recently, the variants Delta and Omicron have become the intensively concerned strains due to their unparalleled transmissibility. Several therapeutic antibody cocktails have been approved for postexposure treatment to reduce severe illness 12,13 . However, the potency of some antibodies is compromised by the emerging SARS-CoV-2 high-frequency mutation variants 32,35 , highlighting an urgent demand on developing next-generation antibodies with breadth and potency.…”

“…However, vaccines are unable to protect individuals with low immunity, autoimmune diseases, and low vaccination willingness. The emergency use authorization (EUA) has been issued for clinical utility of neutralizing antibodies to treat certain COVID-19 patients 12,13 . As the critical function for binding to the host receptor ACE2 and cell entry 14 , the receptor-binding domain (RBD) on SARS-CoV-2 Spike protein is the most preferred antigen target for neutralizing antibody-based countermeasures [15][16][17] .…”