Safety and immunogenicity of an mRNA-lipid nanoparticle vaccine candidate against SARS-CoV-2

Abstract

Summary Background We used the RNActive® technology platform (CureVac N.V., Tübingen, Germany) to prepare CVnCoV, a COVID-19 vaccine containing sequence-optimized mRNA coding for a stabilized form of SARS-CoV‑2 spike (S) protein encapsulated in lipid nanoparticles (LNP). Methods This is an interim analysis of a dosage escalation phase 1 study in healthy 18–60-year-old volunteers in Hannover, Munich and Tübingen, Germany, and Ghent, Belgium. After giving 2 intramuscular doses of CVnCoV or placebo 28 days apart we assessed solicited local and systemic adverse events (AE) for 7 days and unsolicited AEs for 28 days after each vaccination. Immunogenicity was measured as enzyme-linked immunosorbent assay (ELISA) IgG antibodies to SARS-CoV‑2 S‑protein and receptor binding domain (RBD), and SARS-CoV‑2 neutralizing titers (MN50). Results In 245 volunteers who received 2 CVnCoV vaccinations (2 μg, n = 47, 4 μg, n = 48, 6 μg, n = 46, 8 μg, n = 44, 12 μg, n = 28) or placebo (n = 32) there were no vaccine-related serious AEs. Dosage-dependent increases in frequency and severity of solicited systemic AEs, and to a lesser extent local AEs, were mainly mild or moderate and transient in duration. Dosage-dependent increases in IgG antibodies to S‑protein and RBD and MN50 were evident in all groups 2 weeks after the second dose when 100% (23/23) seroconverted to S‑protein or RBD, and 83% (19/23) seroconverted for MN50 in the 12 μg group. Responses to 12 μg were comparable to those observed in convalescent sera from known COVID-19 patients. Conclusion In this study 2 CVnCoV doses were safe, with acceptable reactogenicity and 12 μg dosages elicited levels of immune responses that overlapped those observed in convalescent sera.

Efficacy and safety of the CVnCoV SARS-CoV-2 mRNA vaccine candidate in ten countries in Europe and Latin America (HERALD): a randomised, observer-blinded, placebo-controlled, phase 2b/3 trial

“… 9 , 10 In a phase 1 dose-escalation study, two doses of CVnCoV administered 28 days apart were safe and immunogenic, with dose-dependent increases in anti-spike protein IgG antibodies and SARS-CoV-2-neutralising antibodies. 11 Median antibody titres against spike protein and its receptor binding domain after two 12 μg doses of CVnCoV were similar to those observed in convalescent serum samples from patients with COVID-19, with seroconversion observed 2 weeks after the second dose in all participants receiving this dosage. On the basis of these findings, the 12 μg dose was selected for further phase 2/3 testing.…”

Control of SARS-CoV-2 infection after Spike DNA or Spike DNA+Protein co-immunization in rhesus macaques

“…SARS-CoV-2 has infected to date more than 167 million individuals worldwide and is responsible for more than 3.5 million deaths to date (https://www.coronavirustraining.org/live-map). Several SARS-CoV-2 vaccines, approved under Emergency Use Authorization (EUA) and Conditional Marketing Authorization (for review see [1,2] and references therein), or that are being considered [3][4][5][6][7][8][9][10][11][12][13], have shown strong protective efficacy against the development of disease. Anti-Spike neutralizing antibodies (NAb) provide strong protection against infection in culture and in animal models, and correlate with protection in humans, supporting the notion that induction of strong humoral immunity is key to protection [1,2].…”

Targeting the Inside of Cells with Biologicals: Chemicals as a Delivery Strategy

“…Nucleic acid delivery has been performed in vivo with lipid- and polymer-based carriers [ 9 , 90 , 306 ], but approved gene therapies deliver DNA often with viral vectors [ 307 ], non-viral carriers for DNA delivery having reached clinical trials [ 64 , 307 ]. Lipid-based carriers for nucleic acids are clinically most advanced [ 302 , 308 , 309 ] and have been applied in vivo for siRNA [ 9 , 310 ], mRNA [ 10 – 14 ] and DNA [ 311 ]. Clinical trials or drugs based on RNA, including approved single-stranded antisense oligonucleotides, are reviewed, for example, by Kim, Dammes and Peer, and Roberts et al [ 312 – 314 ].…”

“…Delivery of mRNA for expressing proteins can be used to express antigens for eliciting an immune response, as known from the RNA-based coronavirus disease 2019 (COVID-19) vaccines [ 10 – 14 ], or it can be used with the intention to express therapeutic proteins, including antibodies [ 43 , 315 , 316 ].…”

“…Although naked RNA can induce an effect [ 42 , 45 ], lipid-based carriers are used for the mRNA-based COVID-19 vaccines [ 10 – 14 , 313 ]. The approved or most advanced mRNA-based COVID-19 vaccines from BioNTech, Moderna and CureVac use carriers with ionisable cationic lipids and a similar composition of helper lipids [ 13 ].…”