Beta variant COVID-19 protein booster vaccine elicits durable cross-neutralization against SARS-CoV-2 variants in non-human primates

Abstract

The rapid spread of the SARS-CoV-2 Omicron subvariants, despite the implementation of booster vaccination, has raised questions about the durability of protection conferred by current vaccines. Vaccine boosters that can induce broader and more durable immune responses against SARS-CoV-2 are urgently needed. We recently reported that our Beta-containing protein-based SARS-CoV-2 spike booster vaccine candidates with AS03 adjuvant (CoV2 preS dTM-AS03) elicited robust cross-neutralizing antibody responses at early timepoints against SARS-CoV-2 variants of concern in macaques primed with mRNA or protein-based subunit vaccine candidates. Here we demonstrate that the monovalent Beta vaccine with AS03 adjuvant induces durable cross-neutralizing antibody responses against the prototype strain D614G as well as variants Delta (B.1.617.2), Omicron (BA.1 and BA.4/5) and SARS-CoV-1, that are still detectable in all macaques 6 months post-booster. We also describe the induction of consistent and robust memory B cell responses, independent of the levels measured post-primary immunization. These data suggest that a booster dose with a monovalent Beta CoV2 preS dTM-AS03 vaccine can induce robust and durable cross-neutralizing responses against a broad spectrum of variants.

Fig. 1. Study schema.

In the mRNA-primed cohort (left), three groups of four cynomolgus macaques were immunized intramuscularly with mRNA COVID-19 (ancestral D614) vaccine candidates on day 0 (D0) and on day 21 (D21). In subunit-primed cohort (right), three groups of five rhesus macaques were immunized intramuscularly with CoV2 preS dTM-AS03 (ancestral D614) vaccine candidates on D0 and D21. Both cohorts were boosted 7 months post-dose 1 with monovalent (ancestral or Beta) or bivalent (ancestral + Beta) CoV2 preS dTM-AS03. Humoral immune responses were assessed up to 6 months post-booster.

Fig. 2. Kinetics of booster-neutralizing antibody responses in primed macaques.

Pseudovirus-neutralizing antibody against a the prototype D614G, variants of concern b Beta, c Delta, and d Omicron (BA.1), and e SARS-CoV-1 were assessed up to D176 (mRNA-primed macaques, n = 4) or day 178 (protein-primed macaques, n = 5) post-booster with ancestral D614 vaccine, Beta vaccine, or bivalent ancestral + Beta vaccine. Individual macaque data are shown. Connecting lines represent geometric mean titers (GMTs). Horizontal dotted lines represent the limit of quantification of the assay. *Timepoints relative to booster injection day.

Fig. 3. Neutralizing antibody responses against SARS-CoV-2 Omicron BA.4/5 at 6 months post-booster in primed macaques.

Pseudovirus-neutralizing antibodies against Omicron BA.4/5 variant were assessed at a day 176 (mRNA-primed macaques, n = 4) or b day 178 (protein-primed macaques, n = 5) post-booster with ancestral D614 vaccine, Beta vaccine, or bivalent ancestral + Beta vaccine. Individual macaque data were shown with geometric mean titers (GMTs). Horizontal dotted lines represent the limit of quantification of the assay.

Fig. 4. Spike-specific IgG memory B cell ELISpot responses in PBMCs from immunized macaques.

Spike-specific memory B cell ELISpot results before booster (5 or 6 days before) and at day 84 following booster with ancestral D614 vaccine, Beta vaccine or bivalent ancestral + Beta vaccine in macaques previously immunized with a mRNA vaccine candidate (n = 4) or b protein-subunit vaccine candidate (n = 5). Bars = Medians.