Phase 1 Assessment of the Safety and Immunogenicity of an mRNA- Lipid Nanoparticle Vaccine Candidate Against SARS-CoV-2 in Human Volunteers

Abstract

There is an urgent need for vaccines to counter the COVID-19 pandemic due to infections with severe acute respiratory syndrome coronavirus (SARS-CoV-2). Evidence from convalescent sera and preclinical studies has identified the viral Spike (S) protein as a key antigenic target for protective immune responses. We have applied an mRNA-based technology platform, RNActive®, to develop CVnCoV which contains sequence optimized mRNA coding for a stabilized form of S protein encapsulated in lipid nanoparticles (LNP). Following demonstration of protective immune responses against SARS-CoV-2 in animal models we performed a dose-escalation phase 1 study in healthy 18-60 year-old volunteers.This interim analysis shows that two doses of CVnCoV ranging from 2 μg to 12 μg per dose, administered 28 days apart were safe. No vaccine-related serious adverse events were reported. There were dose-dependent increases in frequency and severity of solicited systemic adverse events, and to a lesser extent of local reactions, but the majority were mild or moderate and transient in duration. Immune responses when measured as IgG antibodies against S protein or its receptor-binding domain (RBD) by ELISA, and SARS-CoV-2-virus neutralizing antibodies measured by micro-neutralization, displayed dose-dependent increases. Median titers measured in these assays two weeks after the second 12 μg dose were comparable to the median titers observed in convalescent sera from COVID-19 patients. Seroconversion (defined as a 4-fold increase over baseline titer) of virus neutralizing antibodies two weeks after the second vaccination occurred in all participants who received 12 μg doses.Preliminary results in the subset of subjects who were enrolled with known SARS-CoV-2 seropositivity at baseline show that CVnCoV is also safe and well tolerated in this population, and is able to boost the pre-existing immune response even at low dose levels.Based on these results, the 12 μg dose is selected for further clinical investigation, including a phase 2b/3 study that will investigate the efficacy, safety, and immunogenicity of the candidate vaccine CVnCoV.

Nanomaterial Delivery Systems for mRNA Vaccines

“…In Syrian golden hamsters, two 10 µg doses (but not 2 µg) were able to reduce viral titers in the lungs (but not nasal turbinates) to baseline. In a phase 1 clinical trial examining 2–12 µg doses, neutralizing titers reaching the levels of convalescent sera were only found at the highest 12 µg dose, resulting in higher doses of 16 and 20 µg being included in the ongoing phase 2 trial [ 52 ]. All patients at the 12 µg dose experienced systemic adverse events after each dose, the majority being moderate and severe, while >80% experienced local injection site pain at the mild and moderate levels.…”

Self-assembled mRNA vaccines

“…The antibody response after the second dose was similar to the convalescent sera. [ 308 ] NCT04515147, NCT04449276 ChulaCoV19 mRNA vaccine Virus-specific antigen LNP IM Chulalongkorn University I NCT04566276

Fig. 9 (A) Structure of SARS-CoV-2 virus depicting a RNA genome and structural proteins [nucleocapsid (N), membrane (M), envelope (E) proteins, and spike (S) protein], (non-structural proteins are not shown).

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“…CVnCoV is an mRNA vaccine encoding the prefusion full-length spike protein and formulated with LNPs by their proprietary formulation (RNActive®). In the phase-I clinical trials (NCT04515147, NCT04449276), two doses of 2 μg to 12 μg each, were administered by an IM injection, 4 weeks apart [ 308 ]. In healthy adults (age of 18-60) with no history of prior SARS-CoV-2 infection, CVnCoV was well tolerated with mild to moderate side effects [ 308 ].…”

“…In the phase-I clinical trials (NCT04515147, NCT04449276), two doses of 2 μg to 12 μg each, were administered by an IM injection, 4 weeks apart [ 308 ]. In healthy adults (age of 18-60) with no history of prior SARS-CoV-2 infection, CVnCoV was well tolerated with mild to moderate side effects [ 308 ]. Local reactions and systemic adverse events displayed dose-dependent increases in frequency and severity, and no vaccine-related serious adverse events were observed [ 308 ].…”

“…In healthy adults (age of 18-60) with no history of prior SARS-CoV-2 infection, CVnCoV was well tolerated with mild to moderate side effects [ 308 ]. Local reactions and systemic adverse events displayed dose-dependent increases in frequency and severity, and no vaccine-related serious adverse events were observed [ 308 ]. CVnCoV elicited dose-dependent antibody responses, and the neutralizing antibody titers after the second 12 μg dose were similar to those observed in the convalescent sera [ 308 ].…”