Receptor-binding domain recombinant protein on alum-CpG induces broad protection against SARS-CoV-2 variants of concern

Abstract

We conducted preclinical studies in mice using a yeast-produced SARS-CoV-2 RBD219-N1C1 subunit vaccine candidate formulated with aluminum hydroxide (alum) and CpG deoxynucleotides. This vaccine formulation is similar to one that entered advanced phase 3 clinical development in India. We compared the immune response of mice vaccinated with RBD219-N1C1/alum to mice vaccinated with RBD219-N1C1/alum+CpG. We also evaluated mice immunized with RBD219-N1C1/alum+CpG and boosted with RBD219-N1C1/alum. Mice were immunized twice intramuscularly at a 21-day interval. Compared to two doses of the RBD219-N1C1/alum formulation, the RBD219-N1C1/alum+CpG vaccine induced a stronger and more balanced Th1/Th2 cellular immune response, with high levels of neutralizing antibodies against the original Wuhan isolate of SARS-CoV-2 as well as the B.1.1.7 (Alpha), B.1.351 (Beta) and B.1.617.1 (Kappa) variants. Notably, the sera from mice that received two 7 μg doses of RBD219-N1C1/alum+CpG showed more than 18 times higher neutralizing antibody titers against B.1.351, than the WHO International Standard for anti-SARS-CoV-2 immunoglobulin NIBSC 20/136. Interestingly, a booster dose did not require the addition of CpG to induce this effect. The data reported here reinforces that the RBD219-N1C1/alum+CpG vaccine formulation is suitable for inducing broadly neutralizing antibodies against SARS-CoV-2 including three variants of concern, B.1.1.7 (Alpha), B.1.351 (Beta), and B.1.617.1 (Kappa).

SARS-CoV-2 spike RBD and nucleocapsid encoding DNA vaccine elicits T cell and neutralising antibody responses that cross react with variants

“…In this study, these titres were higher than obtained with the NIBSC 20/136 reference control and those elicited by a DNA vaccine encoding whole S protein, which was also reflected in the ACE2 binding inhibition assay, suggesting that vaccination with RBD may elicit higher neutralising antibody titres than vaccination with the complete S antigen. Despite the fact that this may be linked to the protein expression levels from the vaccines in this study, these findings are concordant with other studies in mice in which the whole S protein or an RBD trimer have been delivered as recombinant protein, RNA or adenovirus vectors in prime boost regimes 19,46–51 . Our in vivo efficacy data demonstrate that the antibody titres and T cell responses induced were sufficient to protect mice from lethal viral challenge and promote survival.…”

Global regulatory reforms to promote equitable vaccine access in the next pandemic

“…When the COVID-19 genome was made available in January 2020, Texas Children's CVD coronavirus vaccine program pivoted to this new virus, and a prototype vaccine was developed and successfully tested including in a non-human primate virus challenge model [26]. Each step in the vaccine development process was published in the open access biomedical literature available on the PubMed National Library of Medicine database [27][28][29][30][31]. Baylor College of Medicine then non-exclusively licensed the vaccine technology on favorable terms and without patent protection to several LMIC vaccine producers.…”

Choice of adjuvant and antigen composition alters the immunogenic profile of a SARS-CoV-2 subunit vaccine

“…The RBD attaches to ACE-2 in human cells mediating infection (Tai et al, 2020). Compared to the RBD219-N1C1, RBD203-N1 was found to have increased production yields while maintaining equivalent biophysical and immunological properties (Chen et al, 2022;Pollet et al, 2022). The immunogenicity of this family of RBD antigens has primarily been tested using Alum as an adjuvant and formulation system, with or without the addition of either the TLR9 agonist CpG-1018 or the TLR7/8 agonist 3M-052 (Chen et al, 2020;Pino et al, 2021;Pollet et al, 2022).…”

“…Compared to the RBD219-N1C1, RBD203-N1 was found to have increased production yields while maintaining equivalent biophysical and immunological properties (Chen et al, 2022;Pollet et al, 2022). The immunogenicity of this family of RBD antigens has primarily been tested using Alum as an adjuvant and formulation system, with or without the addition of either the TLR9 agonist CpG-1018 or the TLR7/8 agonist 3M-052 (Chen et al, 2020;Pino et al, 2021;Pollet et al, 2022). It is of interest to understand how RBD203-N1 (hereafter RBD) interacts with other common adjuvant formulations and agonists, such as squalene emulsions, the synthetic TLR4 agonist glucopyranosyl lipid adjuvant (GLA), the murine TLR9 agonist CpG-1826 (CpG), the TLR7/8 agonist 3M-052, and the detoxified Escherichia coli double mutant heat-labile toxin (dmLT) LT(R192G/L211A), all of which are in either clinical or commercial stage use, to determine if there are synergies, or how these formulations influence the immune phenotype of the RBD vaccine.…”