Phase 1 Assessment of the Safety and Immunogenicity of an mRNA- Lipid Nanoparticle Vaccine Candidate Against SARS-CoV-2 in Human Volunteers
Open accessPreprint — published as 10.1007/s00508-021-01922-y · Paper page
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.
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Phase I clinical data showed CVnCoV has acceptable tolerance and high immunogenicity.
“Phase I clinical data showed that CVnCoV has acceptable tolerance and high immunogenicity.29,427”
From Advances in COVID-19 mRNA vaccine development (2022) · cites this paper as [29]
The favorable safety profile of the CVnCoV vaccine candidate was confirmed at up to a 12 μg dose.
“The favorable safety profile of the CVnCoV vaccine candidate126,127 using the RNActive mRNA vaccine platform developed by CureVac128 was confirmed at up to a 12 μg dose,129”
From COVID-19 mRNA vaccines: Platforms and current developments (2022) · cites this paper as [129]
CVnCoV induced anti-spike IgG, anti-RBD IgG and serum-neutralization titres comparable to convalescent serum.
“anti-spike IgG, anti-RBD IgG and serum-neutralization titres comparable to convalescent serum133”
From mRNA vaccines for infectious diseases: principles, delivery and clinical translation (2021) · cites this paper as [133]
CVnCoV uses lipid nanoparticles formulated using an ionizable lipid from Acuitas Therapeutics (potentially ALC-0315) and an unmodified mRNA sequence encoding a full-length spike protein with the two proline substitutions.
“CVnCoV uses LNPs formulated using an ionizable lipid from Acuitas Therapeutics (potentially ALC-0315) and an unmodified mRNA sequence encoding a full-length spike protein with the two proline substitutions133.”
From mRNA vaccines for infectious diseases: principles, delivery and clinical translation (2021) · cites this paper as [133]
In phase I clinical trials, primer and booster injections of a 12 μg dose of CVnCoV administered 28 days apart generated neutralizing antibodies similar to those in plasma from patients convalescing from COVID-19 and was well tolerated.
“In phase I clinical trials, primer and booster injections of a 12 μg dose of CVnCoV administered 28 days apart generated neutralizing antibodies similar to those in plasma from patients who were convalescing from COVID-19 and was well tolerated133.”
From mRNA vaccines for infectious diseases: principles, delivery and clinical translation (2021) · cites this paper as [133]
Two vaccine doses of CVnCoV (12 μg mRNA dose) induced SARS-CoV-2 neutralizing antibody titers in all participants at levels comparable to those found in individuals who had recovered from natural infection.
“two vaccine doses of CVnCoV (12 μg mRNA dose) induced SARS-CoV-2 neutralizing antibody titers in all participants at levels that were comparable to those found in individuals who had recovered from natural infection [57]”
From The dawn of mRNA vaccines: the COVID-19 case (2021) · cites this paper as [57]
No details on T cell activation were reported in the first clinical data of the phase 1 trial of CVnCoV.
“nor were any details on T cell activation reported in the first clinical data of the phase 1 trial of this mRNA vaccine [57].”
From The dawn of mRNA vaccines: the COVID-19 case (2021) · cites this paper as [57]
CVnCoV's capacity to elicit robust CD8+ T cell responses could not yet be confirmed in humans.
“this capacity of CVnCoV to elicit robust CD8+ T cell responses could not yet be confirmed in humans”
From The dawn of mRNA vaccines: the COVID-19 case (2021) · cites this paper as [57]
Fever was reported by 57% of participants after the first dose of CVnCoV, but the incidence did not further increase after the boost vaccine.
“fever was reported by 57% of the participants after the first dose, but the incidence of this AE did not further increase after the boost vaccine [57].”
From The dawn of mRNA vaccines: the COVID-19 case (2021) · cites this paper as [57]
The mRNA dose selected for phase 2b/3 clinical testing of CureVac's CVnCoV vaccine candidate was 12 μg, substantially lower than what is used in the nucleoside-modified mRNA vaccines.
“The mRNA dose selected for phase 2b/3 clinical testing of CureVac's CVnCoV vaccine candidate was 12 μg, substantially lower than what is used in the nucleoside-modified mRNA vaccines.”
From The dawn of mRNA vaccines: the COVID-19 case (2021) · cites this paper as [57]
Despite the high incidence of systemic AEs after a single dosage of CVnCoV, no major toxicities were reported and all AEs resolved within 2 days after dosing.
“Despite the high incidence of systemic AEs after a single dosage, no major toxicities were reported and all AEs resolved within 2 days after dosing.”
From The dawn of mRNA vaccines: the COVID-19 case (2021) · cites this paper as [57]
Even at the low 12 μg dose, systemic AEs occurred more frequently in response to a prime dose of CVnCoV compared to the modified mRNA vaccines.
“Even at this low dose, systemic AEs occurred more frequently in response to a prime dose compared to the modified mRNA vaccines.”
From The dawn of mRNA vaccines: the COVID-19 case (2021) · cites this paper as [57]
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Self-citation
- Authors
- Kremsner, P., Mann, P., Bosch, J., Fendel, R., Gabor, J. J., Kreidenweiss, A., Kroidl, A., Leroux-Roels, I., Leroux-Roels, G., Schindler, C., Schunk, M., Velavan, T. P., Fotin-Mleczek, M., Müller, S., Quintini, G., Schönborn-Kellenberger, O., Vahrenhorst, D., Verstraeten, T., Walz, L., Wolz, O.-O., & Oostvogels, L.
- Affiliations
- Universitätsklinikum Tübingen (DE)
- CureVac (Germany) (DE)
- Medizinische Hochschule Hannover (DE)
- German Center for Infection Research (DE)
- Ghent University Hospital (BE)
- Corresponding author
- Mann, Philipp
- ORCID
- Venue
- Wiener klinische Wochenschrift
- Publisher
- openRxiv
- Published
- 2020-11-09
- Volume
- 133
- Issue
- 17-18
- Pages
- 931-941
- ISSN
- 0043-5325 (ISSN-L)
- PMC
- PMC8354521
- OpenAlex
- W3188147052
- Cited by
- 199
- References
- 32
- Citations by year
- 2026: 6 · 2025: 16 · 2024: 25 · 2023: 25 · 2022: 47 · 2021: 73 · 2020: 5 · 2013: 2
- FWCI
- 13.46
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- cc-by
- Locations
- Wiener klinische Wochenschrift (publishedVersion, cc-by)
- medRxiv (acceptedVersion, cc-by-nd)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Ghent University Academic Bibliography (Ghent University) (submittedVersion, cc-by)
- Funders
- Coalition for Epidemic Preparedness Innovations (RRCU2001)
- Topics
- Health Sciences › Medicine › Infectious Diseases › SARS-CoV-2 and COVID-19 Research
- Health Sciences › Medicine › Infectious Diseases › COVID-19 Clinical Research Studies
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Keywords
- COVID-19 vaccines, SARS-CoV-2 spike protein, mRNA vaccines, lipid nanoparticles, vaccine safety, immunogenicity, dose escalation, reactogenicity, neutralizing antibodies, receptor binding domain, IgG, seroconversion
- MeSH terms
- Immunogenicity, Vaccine, COVID-19, SARS-CoV-2, COVID-19 Vaccines, COVID-19 Serotherapy, Adolescent, Adult, Antibodies, Viral, Double-Blind Method, Humans, Immunization, Passive, Lipids, Middle Aged, RNA, Messenger, Vaccines, Nanoparticles, Young Adult
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