Neutralization of SARS-CoV-2 Omicron BA.4/BA.5 subvariant by a booster dose of bivalent adjuvanted subunit vaccine containing Omicron BA.4/BA.5 and BA.1 subvariants

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.

Intranasal Nanoemulsion Adjuvanted S-2P Vaccine Demonstrates Protection in Hamsters and Induces Systemic, Cell-Mediated and Mucosal Immunity in Mice

With the rapid progress made in the development of vaccines to fight the SARS-CoV-2 pandemic, almost >90% of vaccine candidates under development and a 100% of the licensed vaccines are delivered intramuscularly (IM). While these vaccines are highly efficacious against COVID-19 disease, their efficacy against SARS-CoV-2 infection of upper respiratory tract and transmission is at best temporary. Development of safe and efficacious vaccines that are able to induce robust mucosal and systemic immune responses are needed to control new variants. In this study, we have used our nanoemulsion adjuvant (NE01) to intranasally (IN) deliver stabilized spike protein (S-2P) to induce immunogenicity in mouse and hamster models. Data presented demonstrate the induction of robust immunity in mice resulting in 100% seroconversion and protection against SARS-CoV-2 in a hamster challenge model. There was a significant induction of mucosal immune responses as demonstrated by IgA- and IgG-producing memory B cells in the lungs of animals that received intranasal immunizations compared to an alum adjuvanted intramuscular vaccine. The efficacy of the S-2P/NE01 vaccine was also demonstrated in an intranasal hamster challenge model with SARS-CoV-2 and conferred significant protection against weight loss, lung pathology, and viral clearance from both upper and lower respiratory tract. Our findings demonstrate that intranasal NE01-adjuvanted vaccine promotes protective immunity against SARS-CoV-2 infection and disease through activation of three arms of immune system: humoral, cellular, and mucosal, suggesting that an intranasal SARS-CoV-2 vaccine may play a role in addressing a unique public health problem and unmet medical need.

Protection of Hamsters Challenged with SARS-CoV-2 after Two Doses of MVC-COV1901 Vaccine Followed by a Single Intranasal Booster with Nanoemulsion Adjuvanted S-2P Vaccine

Intramuscular vaccines have greatly reduced hospitalization and death due to severe COVID-19. However, most countries are experiencing a resurgence of infection driven predominantly by the Delta and Omicron variants of SARS-CoV-2. In response, booster dosing of COVID-19 vaccines has been implemented in many countries to address waning immunity and reduced protection against the variants. However, intramuscular boosting fails to elicit mucosal immunity and therefore does not solve the problem of persistent viral carriage and transmission, even in patients protected from severe disease. In this study, two doses of stabilized prefusion SARS-CoV-2 spike (S-2P)-based intramuscular vaccine adjuvanted with Alum/CpG1018, MVC-COV1901, were used as a primary vaccination series, followed by an intranasal booster vaccination with nanoemulsion (NE01)-adjuvanted S-2P vaccine in a hamster model to demonstrate immunogenicity and protection from viral challenge. Here we report that this vaccination regimen resulted not only in the induction of robust immunity and protection against weight loss and lung pathology following challenge with SARS-CoV-2, but also led to increased viral clearance from both upper and lower respiratory tracts. Our findings showed that intramuscular MVC-COV1901 vaccine followed by a booster with intranasal NE01-adjuvanted vaccine promotes protective immunity against both viral infection and disease, suggesting that this immunization protocol may offer a solution in addressing a significant, unmet medical need for both the COVID-19 and future pandemics.

The age-dependent immunogenicity after two doses of MVC-COV1901 vaccine.

A post-hoc analysis of the phase 2 data was performed for the SARS-COV-2 subunit protein vaccine MVC-COV1901. Anti-spike IgG, neutralization assays with live virus and pseudovirus were used to demonstrate age-dependent vaccine-induced antibody response to the vaccine. Results showed that an association exists between age and immune responses to the vaccine, providing further support for the need of booster shots, especially for the older age groups.

Protection of Hamsters Challenged with SARS-CoV-2 Variants of Concern by Two Doses of MVC-COV1901 Vaccine Followed by a Single Dose of Beta Variant Version of MVC-COV1901

The current fight against COVID-19 is compounded by the Variants of Concern (VoCs), which can diminish the effectiveness of vaccines and potentially 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) and is adjuvanted with CpG 1018 and aluminum hydroxide. In this study, we used the Delta variant to challenge hamsters inoculated with S-2P from the Wuhan wildtype and the Beta variant in two-dose or three-dose regimens. Two doses of wildtype S-2P followed by the third dose of Beta variant was shown to induce the highest neutralizing antibody titer against live SARS-CoV-2 of the wildtype and all current VoCs, as well as improved neutralization against Omicron variant pseudovirus compared to three doses of wildtype S-P. All regimens of vaccination were able to protect hamsters from SARS-CoV-2 Delta variant challenge and resulted in reduced lung live virus titer and pathology. Three doses of vaccination also significantly reduced lung viral RNA titer, regardless of whether the wildtype or Beta variant S-2P was used as the third dose. Based on the immunogenicity and viral challenge data, two doses of wildtype S-2P followed by the third dose of Beta variant S-2P induced potent antibody immune responses against the VoCs.

First-in-Human Trial of a Recombinant Stabilized Prefusion SARS-CoV-2 Spike Protein Vaccine with Adjuvant of Aluminum Hydroxide and CpG 1018

DesignThis is a phase 1, dose-escalation open-label trial to evaluate the safety and immunogenicity of MVC-COV1901, a recombinant stabilized prefusion SARS-CoV-2 spike (S-2P) protein vaccine with adjuvant of aluminum hydroxide and CpG 1018. MethodsWe enrolled 45 healthy adults from 20 to 49 years of age to be administered with two vaccinations of MVC-COV1901 in a low dose (LD), middle dose (MD), and high dose (HD) of spike protein at 28 days apart. There were 15 participants in each dose group, and all of them were followed up for 28 days after the second vaccination at the time of interim analysis. Adverse events (AEs) and laboratory data were recorded for safety evaluation. Blood samples were collected for wild-type SARS-CoV-2 and pseudovirus neutralization assays as well as SARS-CoV-2 spike-specific immunoglobulin G (IgG) at various times. Overall, the study duration will be 7 months. ResultsSolicited events were mostly mild and similar in the participants of all three dose groups. No subject experienced fever. There were no serious nor adverse events of special interest at the time point of this interim report. After the second vaccination, the SARS-CoV-2 spike specific IgG titers increased with peak geometric mean titers at 7178.245 (LD), 7746.086 (MD), and 11220.58 (HD), respectively. Serum neutralizing activity was detected by two methods in all participants of MD and HD groups, with geometric mean values generally comparable to those of a panel of control convalescent serum specimens. All of the participants in the MD and HD groups were seroconverted after the second vaccination. ConclusionsThe MVC-COV1901 vaccine is safe and elicits remarkable immune responses especially in the MD and HD groups. Trial RegistrationClinicalTrials.gov NCT 04487210

Evaluating the neutralizing ability of a CpG-adjuvanted S-2P subunit vaccine against SARS-CoV-2 Variants of Concern

Vaccination is currently the best weapon to control the COVID-19 pandemic. However, an alarming number of novel variants termed Variants of Concern (VoC) were found to harbor mutations that diminished the neutralizing capacity of antibodies elicited by the vaccines. We have investigated the neutralizing titers of antibodies from sera of humans and rats immunized with the MVC-COV1901 vaccine against pseudoviruses coated with the wildtype, D614G, B.1.1.7, or B.1.351 spike proteins. Rats vaccinated with two doses of adjuvanted S-2P retained neutralization activities against the B.1.351 variant, albeit with a slight reduction compared to wildtype. Phase 1 vaccinated subjects showed more reduced neutralization abilities against the B.1.351 variant. The study is among the first, to our knowledge, to demonstrate dose-dependent neutralizing responses against VoCs, particularly against B.1.351, from different doses of antigen in a clinical trial for a subunit protein COVID-19 vaccine. The appearance of vaccine escape variants is a growing concern facing many current COVID-19 vaccines and therapeutics. Strategies should be adopted against the ever-changing nature of these variants. The observations of this study grant us valuable insight into preemptive strikes against current and future variants.

CpG-adjuvanted stable prefusion SARS-CoV-2 spike protein protected hamsters from SARS-CoV-2 challenge

The COVID-19 pandemic presents an unprecedented challenge to global public health. Rapid development and deployment of safe and effective vaccines are imperative to control the pandemic. In the current study, we applied our adjuvanted stable prefusion SARS-CoV-2 spike (S-2P)-based vaccine, MVC-COV1901, to hamster models to demonstrate immunogenicity and protection from virus challenge. Golden Syrian hamsters immunized intramuscularly with two injections of 1 {micro}g or 5 {micro}g of S-2P adjuvanted with CpG 1018 and aluminum hydroxide (alum) were challenged intranasally with SARS-CoV-2. Prior to virus challenge, the vaccine induced high levels of neutralizing antibodies with 10,000-fold higher IgG level and an average of 50-fold higher pseudovirus neutralizing titers in either dose groups than vehicle or adjuvant control groups. Six days after infection, vaccinated hamsters did not display any weight loss associated with infection and had significantly reduced lung pathology and most importantly, lung viral load levels were reduced to lower than detection limit compared to unvaccinated animals. Vaccination with either 1 g or 5 g of adjuvanted S-2P produced comparable immunogenicity and protection from infection. This study builds upon our previous results to support the clinical development of MVC-COV1901 as a safe, highly immunogenic, and protective COVID-19 vaccine.