ABSTRACT
The dominance of SARS-CoV-2 variants of concern (VoC), such as the Omicron subvariants, is a threat to the current vaccination scheme due to increased resistance to immune neutralization and greater transmissibility. To develop the next generation of prefusion SARS-CoV-2 spike protein (S-2P) subunit vaccine adjuvanted with CpG1018 and aluminum hydroxide, mice immunized with two doses of the adjuvanted ancestral Wuhan strain (W) followed by the third dose of the W or Omicron variants (BA.1 or BA.4/BA.5) S-2P, or a combination of the above bivalent S-2Ps. Antisera from mice were tested against pseudovirus neutralization assay of ancestral SARS-CoV-2 (WT) and Omicron BA.4/BA.5 subvariant. Boosting with bivalent mixture of Omicron BA.4/BA.5 and W S-2P achieved the highest neutralizing antibody titers against BA.4/BA.5 subvariant pseudovirus compared to other types of S-2P as boosters.
ABSTRACT
Background The use of variant-based severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine as a booster is being evaluated to overcome reduced neutralisation of variants induced by the original SARS-CoV-2 vaccine and waning protection over time. Methods This is a phase one, prospective, randomized, and open-labeled trial to study the safety and immunogenicity of a booster dose consisting of a subunit vaccine based on the stabilized prefusion SARS-CoV-2 spike protein, MVC-COV1901 or its Beta version, MVC-COV1901-Beta. One-hundred and seven participants aged [≥]18 and <55 years, who received two or three prior doses of MVC-COV1901 vaccines, were enrolled and were to receive a booster dose of either 15 mcg of MVC-COV1901, 15 mcg or 25 mcg of MVC-COV1901-Beta in 1:1:1 ratio. The primary endpoints were the incidences of adverse events and immunogenicity of the booster dose from Visit 2 (the day of the booster) to Visit 5 (four weeks after the booster). Cellular immunity was also investigated with memory B cell (MBC) and T cell assays. Findings Adverse reactions after either MVC-COV1901 or MVC-COV1901-Beta booster doses after two or three doses of MVC-COV1901 were comparable and mostly mild and transient. At four weeks after the booster dose, participants with two prior doses of MVC-COV1901 exhibited numerically higher levels of neutralising antibodies against SARS-CoV-2 or Beta variant than participants with three prior doses of MVC-COV1901 regardless of the type of booster used. However, compared to 15 mcg of MVC-COV1901, 25 mcg of MVC-COV1901-Beta significantly improved neutralising antibody titre against Beta variant and BA.4/BA.5 Omicron variant pseudoviruses. The booster dose also significantly increased the proportion of spike-specific MBCs, including those of Beta and Omicron variants. Interpretation MVC-COV1901-Beta can be effectively used as a booster dose against SARS-CoV-2, including the circulating BA.4/BA.5 Omicron variant. Funding Medigen Vaccine Biologics Corporation
Subject(s)
Coronavirus Infections , Lymphoma, B-CellABSTRACT
The current fight against COVID-19 is compounded by the Variants of Concern (VoCs), which can diminish the effectiveness of vaccines, increase viral transmission and severity of disease. MVC-COV1901 is a protein subunit vaccine based on the prefusion SARS-CoV-2 spike protein (S-2P) adjuvanted with CpG 1018 and aluminum hydroxide. Here we used the Delta variant to challenge hamsters innoculated with S-2P based on the ancestral strain or the Beta variant in two-dose or three-dose regimens. Two doses of ancestral S-2P followed by the third dose of Beta variant S-2P was shown to induce the highest neutralizing antibody titer against live SARS-CoV-2 of the ancestral strain as well as all VoCs. All regimens of vaccination were able to protect hamsters from SARS-CoV-2 Delta variant challenge and reduce lung live virus titer. Three doses of vaccination significantly reduced lung viral RNA titer, regardless of using the ancestral or Beta variant S-2P as the third dose. Based on the immunogenicity and viral challenge data, two doses of ancestral S-2P followed by the third dose of Beta variant S-2P could induce broad and potent immune response against the variants.
Subject(s)
COVID-19ABSTRACT
The COVID-19 pandemic caused by the novel coronavirus SARS-CoV-2 is a worldwide health emergency. The immense damage done to public health and economies has prompted a global race for cures and vaccines. In developing a COVID-19 vaccine, we applied technology previously used for MERS-CoV to produce a prefusion-stabilized SARS-CoV-2 spike protein by adding two proline substitutions at the top of the central helix (S-2P). To enhance immunogenicity and mitigate the potential vaccine-induced immunopathology, CpG 1018, a Th1-biasing synthetic toll-like receptor 9 (TLR9) agonist was selected as an adjuvant candidate. S-2P was combined with various adjuvants, including CpG 1018, and administered to mice to test its effectiveness in eliciting anti-SARS-CoV-2 neutralizing antibodies. S-2P in combination with CpG 1018 and aluminum hydroxide (alum) was found to be the most potent immunogen and induced high titer of spike-specific antibodies in sera of immunized mice. The neutralizing abilities in pseudotyped lentivirus reporter or live wild-type SARS-CoV-2 were measured with reciprocal inhibiting dilution (ID50) titers of 5120 and 2560, respectively. In addition, the antibodies elicited were able to cross-neutralize pseudovirus containing the spike protein of the D614G variant, indicating the potential for broad spectrum protection. A marked Th-1 dominant response was noted from cytokines secreted by splenocytes of mice immunized with CpG 1018 and alum. No vaccine-related serious adverse effects were found in the dose-ranging study in rats administered single- or two-dose regimens with up to 50 g of S-2P combined with CpG 1018 alone or CpG 1018 with alum. These data support continued development of CHO-derived S-2P formulated with CpG 1018/alum as a candidate vaccine to prevent COVID-19 disease.