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Cited by 464SARS-CoV-2 and COVID-19 ResearchRNA Interference and Gene DeliverySARS-CoV-2 detection and testing

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Self-amplifying RNA SARS-CoV-2 lipid nanoparticle vaccine candidate induces high neutralizing antibody titers in mice

Open access
McKay, Paul F., Hu, Kai, Blakney, Anna K., Samnuan, Karnyart, Brown, Jonathan C., Penn, Rebecca, Zhou, Jie, Bouton, Clément R., Rogers, Paul, Polra, Krunal, Lin, Paulo J. C., Barbosa, Christopher, Tam, Ying K., Barclay, Wendy S., Shattock, Robin J.·2020·Nature Communications
DOI 10.1038/s41467-020-17409-9PMC PMC7347890
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Abstract

The spread of the SARS-CoV-2 into a global pandemic within a few months of onset motivates the development of a rapidly scalable vaccine. Here, we present a self-amplifying RNA encoding the SARS-CoV-2 spike protein encapsulated within a lipid nanoparticle (LNP) as a vaccine. We observe remarkably high and dose-dependent SARS-CoV-2 specific antibody titers in mouse sera, as well as robust neutralization of both a pseudo-virus and wild-type virus. Upon further characterization we find that the neutralization is proportional to the quantity of specific IgG and of higher magnitude than recovered COVID-19 patients. saRNA LNP immunizations induce a Th1-biased response in mice, and there is no antibody-dependent enhancement (ADE) observed. Finally, we observe high cellular responses, as characterized by IFN-γ production, upon re-stimulation with SARS-CoV-2 peptides. These data provide insight into the vaccine design and evaluation of immunogenicity to enable rapid translation to the clinic.

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Fig. 1 Antibody quantification and neutralization of a SARS-CoV-2 saRNA vaccinated mice compared to COVID-19 recovered patients. a Schematic of vaccination of BALB/c mice with saRNA encoding pre-fusion stabilized spike protein in LNP, b SARS-CoV-2 specific IgG responses in mice vaccinated with doses of LNP-formulated saRNA ranging from 0.01–10 μg of saRNA with n = 7 biologically independent animals and COVID-19 recovered patients with n = 9 biologically independent samples, c SARS-CoV-2 pseudotyped virus neutralization of sera from BALB/c mice vaccinated with doses of LNP-formulated saRNA ranging from 0.01–10 μg of saRNA with n = 7 biologically independent animals and COVID-19 recovered patients with n = 9 biologically independent samples, d Correlation between SARS-CoV-2-specific IgG and SARS-CoV-2 neutralization IC50 for vaccinated mice (n = 7 biologically independent animals) and recovered COVID-19 patients (n = 9 biologically independent samples), e SARS-CoV-2 viral neutralization of sera from BALB/c mice vaccinated with doses of LNP-formulated saRNA ranging from 0.01 to 10 µg of saRNA with n = 7 biologically independent animals, f Correlation between SARS-CoV-2-specific IgG and SARS-CoV-2 wild type viral neutralization titers for vaccinated mice (n = 7 biologically independent animals). Electroporated pDNA (DNA + EP) was used as a positive control while saRNA encoding the rabies glycoprotein (RABV) in pABOL was used as a negative control (RABV control). * indicates significance of p < 0.05 using a two-way ANOVA adjusted for multiple comparisons. Line and error bars indicated mean ± SD. Components of this figure were created using Servier Medical Art templates, which are licensed under a Creative Commons Attribution 3.0 Unported License; https://creativecommons.org/licenses/by/3.0/.
Fig. 1 Antibody quantification and neutralization of a SARS-CoV-2 saRNA vaccinated mice compared to COVID-19 recovered patients. a Schematic of vaccination of BALB/c mice with saRNA encoding pre-fusion stabilized spike protein in LNP, b SARS-CoV-2 specific IgG responses in mice vaccinated with doses of LNP-formulated saRNA ranging from 0.01–10 μg of saRNA with n = 7 biologically independent animals and COVID-19 recovered patients with n = 9 biologically independent samples, c SARS-CoV-2 pseudotyped virus neutralization of sera from BALB/c mice vaccinated with doses of LNP-formulated saRNA ranging from 0.01–10 μg of saRNA with n = 7 biologically independent animals and COVID-19 recovered patients with n = 9 biologically independent samples, d Correlation between SARS-CoV-2-specific IgG and SARS-CoV-2 neutralization IC50 for vaccinated mice (n = 7 biologically independent animals) and recovered COVID-19 patients (n = 9 biologically independent samples), e SARS-CoV-2 viral neutralization of sera from BALB/c mice vaccinated with doses of LNP-formulated saRNA ranging from 0.01 to 10 µg of saRNA with n = 7 biologically independent animals, f Correlation between SARS-CoV-2-specific IgG and SARS-CoV-2 wild type viral neutralization titers for vaccinated mice (n = 7 biologically independent animals). Electroporated pDNA (DNA + EP) was used as a positive control while saRNA encoding the rabies glycoprotein (RABV) in pABOL was used as a negative control (RABV control). * indicates significance of p < 0.05 using a two-way ANOVA adjusted for multiple comparisons. Line and error bars indicated mean ± SD. Components of this figure were created using Servier Medical Art templates, which are licensed under a Creative Commons Attribution 3.0 Unported License; https://creativecommons.org/licenses/by/3.0/.CC BY · PubMed Central
Fig. 2 Th1/Th2 skew in response to SARS-CoV-2 saRNA LNP vaccine. a IgG1 and IgG2a responses in mice vaccinated with doses of LNP-formulated saRNA ranging from 0.01–10 μg of saRNA with n = 7 biologically independent animals, b Th1/Th2 skewing responses in mice vaccinated with doses of LNP-formulated saRNA ranging from 0.01–10 μg of saRNA with n = 7 biologically independent animals, and 10 μg of electroporated pDNA (EP pDNA) with n = 8 biologically independent animals. The asterisk (*) indicates significance of p < 0.05 as determined by a Kruskal–Wallis test. Line and error bars indicated mean ± SD.
Fig. 2 Th1/Th2 skew in response to SARS-CoV-2 saRNA LNP vaccine. a IgG1 and IgG2a responses in mice vaccinated with doses of LNP-formulated saRNA ranging from 0.01–10 μg of saRNA with n = 7 biologically independent animals, b Th1/Th2 skewing responses in mice vaccinated with doses of LNP-formulated saRNA ranging from 0.01–10 μg of saRNA with n = 7 biologically independent animals, and 10 μg of electroporated pDNA (EP pDNA) with n = 8 biologically independent animals. The asterisk (*) indicates significance of p < 0.05 as determined by a Kruskal–Wallis test. Line and error bars indicated mean ± SD.CC BY · PubMed Central
Fig. 3 Cellular and secreted cytokine responses to a SARS-CoV-2 saRNA LNP vaccine. a Quantification of IFN-γ splenocytes upon restimulation with SARS-CoV-2 peptides, expressed as spot forming units (SFU) per 106 cells with n = 7 biologically independent animals. Electroporated pDNA (EP pDNA) was used as a positive control while saRNA encoding the rabies glycoprotein (RABV) in pABOL was used as a negative control (RABV control). b–g Cytokine profile in sera of mice 4 h after vaccination with SARS-CoV-2 LNP vaccine with n = 7 biologically independent animals. Remaining cytokines can be found in Supplementary Fig. 5. The asterisk (*) indicates significance of p < 0.05 as determined by a Kruskal–Wallis test. Line and error bars indicated mean ± SD.
Fig. 3 Cellular and secreted cytokine responses to a SARS-CoV-2 saRNA LNP vaccine. a Quantification of IFN-γ splenocytes upon restimulation with SARS-CoV-2 peptides, expressed as spot forming units (SFU) per 106 cells with n = 7 biologically independent animals. Electroporated pDNA (EP pDNA) was used as a positive control while saRNA encoding the rabies glycoprotein (RABV) in pABOL was used as a negative control (RABV control). b–g Cytokine profile in sera of mice 4 h after vaccination with SARS-CoV-2 LNP vaccine with n = 7 biologically independent animals. Remaining cytokines can be found in Supplementary Fig. 5. The asterisk (*) indicates significance of p < 0.05 as determined by a Kruskal–Wallis test. Line and error bars indicated mean ± SD.CC BY · PubMed Central

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Authors
McKay, P. F., Hu, K., Blakney, A. K., Samnuan, K., Brown, J. C., Penn, R., Zhou, J., Bouton, C. R., Rogers, P., Polra, K., Lin, P. J. C., Barbosa, C., Tam, Y. K., Barclay, W. S., & Shattock, R. J.
Affiliations
  • Imperial College London (GB)
  • Acuitas Therapeutics (Canada) (CA)
Corresponding author
Shattock, Robin J.
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2020-07-09
Volume
11
Issue
1
Pages
3523-3523
ISSN
2041-1723 (ISSN-L)
DOI
10.1038/s41467-020-17409-9
PMC
PMC7347890
OpenAlex
W3041318796
Cited by
462
References
21
Citations by year
2026: 36 · 2025: 48 · 2024: 48 · 2023: 59 · 2022: 102 · 2021: 132 · 2020: 37
FWCI
10.83
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Communications (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Spiral (Imperial College London) (submittedVersion, cc-by)
Funders
  • European Commission (794059)
  • RCUK | Engineering and Physical Sciences Research Council (EP/R013764/1)
Topics
  • Health Sciences › Medicine › Infectious Diseases › SARS-CoV-2 and COVID-19 Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
  • Health Sciences › Medicine › Infectious Diseases › SARS-CoV-2 detection and testing
Keywords
SARS-CoV-2, COVID-19 vaccines, self-amplifying RNA, lipid nanoparticle vaccine, spike protein, neutralizing antibodies, Th1 response, antibody-dependent enhancement, interferon-gamma, cell-mediated immunity, vaccine immunogenicity
MeSH terms
Betacoronavirus, COVID-19, SARS-CoV-2, COVID-19 Vaccines, Animals, Antibodies, Viral, Disease Models, Animal, Humans, Immunoglobulin G, Immunity, Cellular, Mice, Inbred BALB C, Pneumonia, Viral, RNA, Viral, Vaccines, Synthetic, Viral Vaccines, Cytokines, Coronavirus Infections, Antibody-Dependent Enhancement, Mice, Nanoparticles, Antibodies, Neutralizing, Pandemics, Spike Glycoprotein, Coronavirus

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