PreprintCited by 48SARS-CoV-2 and COVID-19 ResearchAnimal Virus Infections Studiesvaccines and immunoinformatics approaches

CVnCoV protects human ACE2 transgenic mice from ancestral B BavPat1 and emerging B.1.351 SARS-CoV-2

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Hoffmann, Donata, Corleis, Björn, Rauch, Susanne, Roth, Nicole, Mühe, Janine, Halwe, Nico Joel, Ulrich, Lorenz, Fricke, Charlie +12 more·2021·Nature Communications

Preprint — published as 10.1038/s41467-021-24339-7 · Paper page

Abstract

The ongoing severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) pandemic necessitates the fast development of vaccines as the primary control option. Recently, viral mutants termed “variants of concern” (VOC) have emerged with the potential to escape host immunity. VOC B.1.351 was first discovered in South Africa in late 2020, and causes global concern due to poor neutralization with propensity to evade preexisting immunity from ancestral strains. We tested the efficacy of a spike encoding mRNA vaccine (CVnCoV) against the ancestral strain BavPat1 and the novel VOC B.1.351 in a K18-hACE2 transgenic mouse model. Naive mice and mice immunized with formalin-inactivated SARS-CoV-2 preparation were used as controls. mRNA-immunized mice developed elevated SARS-CoV-2 RBD-specific antibody as well as neutralization titers against the ancestral strain BavPat1. Neutralization titers against VOC B.1.351 were readily detectable but significantly reduced compared to BavPat1. VOC B.1.351-infected control animals experienced a delayed course of disease, yet nearly all SARS-CoV-2 challenged naïve mice succumbed with virus dissemination and high viral loads. CVnCoV vaccine completely protected the animals from disease and mortality caused by either viral strain. Moreover, SARS-CoV-2 was not detected in oral swabs, lung, or brain in these groups. Only partial protection was observed in mice receiving the formalin-inactivated virus preparation. Despite lower neutralizing antibody titers compared to the ancestral strain BavPat1, CVnCoV shows complete disease protection against the novel VOC B.1.351 in our studies.

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Crossref · 10.1101/2021.03.22.435960

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  • 0.5 μg was the lowest tested dose of CV2CoV to induce detectable spike-specific IFNγ producing CD8+ cells.

    “This dosage was based on previous findings from comparative preclinical evaluations of CVnCoV and the current optimized candidate vaccine CV2CoV13, whereby 0.5 µg was the lowest tested dose to fully protect against lethality and induce abundant neutralizing antibodies (Fig. S1a) and induce detectable spike-specific interferon γ (IFNγ) producing CD8+ cells (Fig. S1b).”

    From Efficacy of an unmodified bivalent mRNA vaccine against SARS-CoV-2 variants in female small animal models (2023) · cites this paper as [13]

    The Results (page unavailable) say CV2CoV was tested at doses from 0.5 to 8 µg, establishing 0.5 µg as the lowest tested dose. They report antibody responses and protection at that dose, but do not report detectable spike-specific IFNγ-producing CD8+ cells; the Discussion mentions earlier CD8+ findings for CVnCoV, not CV2CoV. (LLM, conf=0.85)

    Experimental — accuracy not yet measured
  • CV2CoV is a second-generation mRNA vaccine containing non-modified nucleosides but with optimized non-coding regions and enhanced antigen expression.

    “CV2CoV is a second-generation mRNA vaccine containing non-modified nucleosides but with optimized non-coding regions and enhanced antigen expression.”

    From Optimization of non-coding regions for a non-modified mRNA COVID-19 vaccine (2022) · cites this paper as [2]

    Methods > Vaccination (page unavailable) describes CV2CoV as an mRNA vaccine without chemically modified nucleosides and specifies its untranslated regions. Results (page unavailable) says CV2CoV and CVnCoV encode the same protein but differ in their non-coding regions. Our copy does not establish that those regions are optimized or that they enhance antigen expression; its reported antibody responses do not directly measure antigen expression. (LLM, conf=0.84)

    Experimental — accuracy not yet measured
  • CV2CoV has different non-coding regions flanking the open reading frame, which have previously been shown to improve transgene expression and protection against SARS-CoV-2 in ACE2-transgenic mice.

    “CV2CoV has been engineered with different non-coding regions flanking the open reading frame, which have previously been shown to improve transgene expression3 and protection against SARS-CoV-2 in ACE2-transgenic mice2.”

    From Optimization of non-coding regions for a non-modified mRNA COVID-19 vaccine (2022) · cites this paper as [2]

    The Methods (Vaccination; page unavailable) describe CV2CoV’s different non-coding regions, and the Discussion reports that CV2CoV protected hACE2-transgenic mice against disease caused by both tested SARS-CoV-2 variants. The paper does not show that those regions improved protection relative to CVnCoV: the Discussion reports full protection with both vaccines. The transgene-expression claim is attached to a different citation and is not assessed here. (LLM, conf=0.84)

    Experimental — accuracy not yet measured
  • Protection in macaques was primarily observed in the lower respiratory tract.

    “However, protection in macaques was primarily observed in the lower respiratory tract23,24.”

    From Optimization of non-coding regions for a non-modified mRNA COVID-19 vaccine (2022) · cites this paper as [24]

    The Results (page unavailable) report near-complete protection in the lower respiratory tract but residual viral replication in the upper respiratory tract of vaccinated mice. The paper mentions protection in non-human primates in a previous study, but does not say that protection in macaques was primarily in the lower respiratory tract. (LLM, conf=0.85)

    Experimental — accuracy not yet measured
  • 0.5 μg was the lowest tested dose of CV2CoV to fully protect against lethality and induce abundant neutralizing antibodies.

    “This dosage was based on previous findings from comparative preclinical evaluations of CVnCoV and the current optimized candidate vaccine CV2CoV13, whereby 0.5 µg was the lowest tested dose to fully protect against lethality and induce abundant neutralizing antibodies (Fig. S1a) and induce detectable spike-specific interferon γ (IFNγ) producing CD8+ cells (Fig. S1b).”

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Authors
Hoffmann, D., Corleis, B., Rauch, S., Roth, N., Mühe, J., Halwe, N. J., Ulrich, L., Fricke, C., Schön, J., Kraft, A., Breithaupt, A., Wernike, K., Michelitsch, A., Sick, F., Wylezich, C., Müller, S. O., Mettenleiter, T. C., Petsch, B., Dorhoi, A., & Beer, M.
Affiliations
  • Friedrich-Loeffler-Institut (DE)
  • CureVac (Germany) (DE)
Corresponding author
  • Dorhoi, Anca
  • Beer, Martin
Venue
Nature Communications
Publisher
openRxiv
Published
2021-03-22
Volume
12
Issue
1
Pages
4048-4048
ISSN
2041-1723 (ISSN-L)
OpenAlex
W3175809015
Cited by
48
References
41
Citations by year
2025: 2 · 2024: 5 · 2023: 11 · 2022: 18 · 2021: 12
FWCI
3.64
Type
journal article
Language
en
Open access
Locations
  • Nature Communications (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • OpenAgrar (submittedVersion, cc-by)
Funders
  • Bundesministerium für Bildung und Forschung (01KI20703, SARS-CoV-2)
  • Bundesministerium für Ernährung und Landwirtschaft
Topics
  • Health Sciences › Medicine › Infectious Diseases › SARS-CoV-2 and COVID-19 Research
  • Life Sciences › Agricultural and Biological Sciences › Animal Science and Zoology › Animal Virus Infections Studies
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › vaccines and immunoinformatics approaches
Keywords
SARS-CoV-2, mRNA vaccines, B.1.351 variant, variants of concern, K18-hACE2 mice, neutralizing antibodies, spike RBD, vaccine efficacy
MeSH terms
Angiotensin-Converting Enzyme 2, COVID-19, SARS-CoV-2, COVID-19 Vaccines, Animals, Antibodies, Viral, Cell Line, Chlorocebus aethiops, Humans, Mice, Transgenic, Vero Cells, Genome, Viral, Mice, Antibodies, Neutralizing, Spike Glycoprotein, Coronavirus

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