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

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.

Beta-containing bivalent SARS-CoV-2 protein vaccine elicits durable broad neutralization in macaques and protection in hamsters.

BACKGROUND: Since the beginning of the COVID-19 pandemic, several variants of concern (VOC) have emerged for which there is evidence of an increase in transmissibility, more severe disease, and/or reduced vaccine effectiveness. Effective COVID-19 vaccine strategies are required to achieve broad protective immunity against current and future VOC. METHODS: We conducted immunogenicity and challenge studies in macaques and hamsters using a bivalent recombinant vaccine formulation containing the SARS-CoV-2 prefusion-stabilized Spike trimers of the ancestral D614 and the variant Beta strains with AS03 adjuvant (CoV2 preS dTM-AS03) in a primary immunization setting. RESULTS: We show that a primary immunization with the bivalent CoV2 preS dTM-AS03 elicits broader and durable (1 year) neutralizing antibody responses against VOC including Omicron BA.1 and BA.4/5, and SARS-CoV-1 as compared to the ancestral D614 or Beta variant monovalent vaccines in naïve non-human primates. In addition, the bivalent formulation confers protection against viral challenge with SARS-CoV-2 prototype D614G strain as well as Alpha and Beta variant strains in hamsters. CONCLUSIONS: Our findings demonstrate the potential of a Beta-containing bivalent CoV2 preS dTM-AS03 formulation to provide broad and durable immunogenicity, as well as protection against VOC in naïve populations.

SARS-CoV-2 has changed over time, resulting in different forms of the virus called variants. These variants compromise the protection offered by the COVID-19 vaccines, which trigger an immune response against the viral Spike protein that allows the virus to attach and infect human cells, since their spike proteins are different. Here, we developed and tested a vaccine containing two different Spike proteins, one from the original Wuhan strain and another from the Beta variant. In macaques, the vaccine leads to the production of antibodies able to stop all variants tested from infecting human cells, including Omicron, with stable levels over one year. In hamsters, the vaccine protected against infection with the ancestral virus and the Alpha and Beta variants. Our findings have important implications for vaccine control of existing and future SARS-CoV-2 variants of concern.

Protein-based SARS-CoV-2 spike vaccine booster increases cross-neutralization against SARS-CoV-2 variants of concern in non-human primates.

The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants that partly evade neutralizing antibodies raises concerns of reduced vaccine effectiveness and increased infection. We previously demonstrated that the SARS-CoV-2 spike protein vaccine adjuvanted with AS03 (CoV2 preS dTM-AS03) elicits robust neutralizing antibody responses in naïve subjects. Here we show that, in macaques primed with mRNA or protein-based subunit vaccine candidates, one booster dose of CoV2 preS dTM-AS03 (monovalent D614 or B.1.351, or bivalent D614 + B.1.351 formulations), significantly boosts the pre-existing neutralizing antibodies against the parental strain from 177- to 370-fold. Importantly, the booster dose elicits high and persistent cross-neutralizing antibodies covering five former or current SARS-CoV-2 variants of concern (Alpha, Beta, Gamma, Delta and Omicron) and, unexpectedly, SARS-CoV-1. Interestingly, we show that the booster specifically increases the functional antibody responses as compared to the receptor binding domain (RBD)-specific responses. Our findings show that these vaccine candidates, when used as a booster, have the potential to offer cross-protection against a broad spectrum of variants. This has important implications for vaccine control of SARS-CoV-2 variants of concern and informs on the benefit of a booster with the vaccine candidates currently under evaluation in clinical trials.

Immunogenicity and efficacy of mRNA COVID-19 vaccine MRT5500 in preclinical animal models.

Emergency use authorization of COVID vaccines has brought hope to mitigate pandemic of coronavirus disease 2019 (COVID-19). However, there remains a need for additional effective vaccines to meet the global demand and address the potential new viral variants. mRNA technologies offer an expeditious path alternative to traditional vaccine approaches. Here we describe the efforts to utilize an mRNA platform for rational design and evaluations of mRNA vaccine candidates based on the spike (S) glycoprotein of SARS-CoV-2. Several mRNA constructs of S-protein, including wild type, a pre-fusion stabilized mutant (2P), a furin cleavage-site mutant (GSAS) and a double mutant form (2P/GSAS), as well as others, were tested in animal models for their capacity to elicit neutralizing antibodies (nAbs). The lead 2P/GSAS candidate was further assessed in dose-ranging studies in mice and Cynomolgus macaques, and for efficacy in a Syrian golden hamster model. The selected 2P/GSAS vaccine formulation, designated MRT5500, elicited potent nAbs as measured in neutralization assays in all three preclinical models and more importantly, protected against SARS-CoV-2-induced weight loss and lung pathology in hamsters. In addition, MRT5500 elicited TH1-biased responses in both mouse and non-human primate (NHP), thus alleviating a hypothetical concern of potential vaccine-associated enhanced respiratory diseases known associated with TH2-biased responses. These data position MRT5500 as a viable vaccine candidate for entering clinical development.