Broad immunity to SARS-CoV-2 variants of concern mediated by a SARS-CoV-2 receptor-binding domain protein vaccine

Abstract

The SARS-CoV-2 global pandemic has fuelled the generation of vaccines at an unprecedented pace and scale. However, many challenges remain, including: the emergence of vaccine-resistant mutant viruses, vaccine stability during storage and transport, waning vaccine-induced immunity, and concerns about infrequent adverse events associated with existing vaccines. Here, we report on a protein subunit vaccine comprising the receptor-binding domain (RBD) of the ancestral SARS-CoV-2 spike protein, dimerised with an immunoglobulin IgG1 Fc domain. These were tested in conjunction with three different adjuvants: a TLR2 agonist R4-Pam2Cys, an NKT cell agonist glycolipid alpha-Galactosylceramide, or MF59 squalene oil-in-water adjuvant. Each formulation drove strong neutralising antibody (nAb) responses and provided durable and highly protective immunity against lower and upper airway infection in mouse models of COVID-19. We have also developed an RBD-human IgG1 Fc vaccine with an RBD sequence of the highly immunoevasive beta variant (N501Y, E484K, K417N). This beta variant RBD vaccine, combined with MF59 adjuvant, induced strong protection in mice against the beta strain as well as the ancestral strain. Furthermore, when used as a third dose booster vaccine following priming with whole spike vaccine, anti-sera from beta-RBD-Fc immunised mice increased titres of nAb against other variants including alpha, delta, delta+, gamma, lambda, mu, and omicron BA.1 and BA.2. These results demonstrated that an RBD-Fc protein subunit/MF59 adjuvanted vaccine can induce high levels of broad nAbs, including when used as a booster following prior immunisation of mice with whole ancestral-strain Spike vaccines. This vaccine platform offers a potential approach to augment some of the currently approved vaccines in the face of emerging variants of concern, and it has now entered a phase I clinical trial.

A Polysaccharide-RBD-Fc-Conjugated COVID-19 Vaccine, SCTV01A, Showed High Immunogenicity and Low Toxicity in Animal Models

“…SCT-VA02B is a squalene-based oil-in-water emulsion similar to adjuvant systems 03 (AS03) and MF59 ® . Preclinical studies have proved that both adjuvant could enhance humoral and cellular immune responses and induce strong protection against SARS-CoV-2 challenge in RBD- or S-protein based vaccine [ 46 , 47 ]. SARS-CoV-2 recombinant protein vaccine with AS03 or MF59 ® adjuvant also showed acceptable safety and reactogenicity, and robust immunogenicity in clinical trials [ 48 , 49 , 50 ].…”

mRNA vaccines encoding membrane-anchored receptor-binding domains of SARS-CoV-2 mutants induce strong humoral responses and can overcome immune imprinting

“…A hamster challenge study was carried out according to the methods described in the Supplementary data file (Figure S7). This study was carried out in parallel with the evaluation of a protein Beta RBD-Fc adjuvanted by coadministration with MF59 ( 21 ). At doses of 3, 10 or 30μg, the RBD-TM vaccine was unable to induce full protection against infection with either ancestral or Beta SARS-CoV-2.…”

“…This candidate did not progress when the whole spike vaccine BNT162b2 was selected for its Phase 3 efficacy study( 2 ). The RBD-TM platform described here has been evaluated in a joint Phase 1 clinical trial using the Beta variant RBD-TM in parallel with an adjuvanted Beta RBD-Fc protein vaccine ( 19, 21 ). Given that the ancestral vaccines offered comparatively good neutralization of the Beta variant, as compared to Omicron variants, it was not clear how well the RBD-TM vaccine was able to overcome immune imprinting in humans.…”