A single dose of self-transcribing and replicating RNA-based SARS-CoV-2 vaccine produces protective adaptive immunity in mice

de Alwis, Ruklanthi; Gan, Esther S.; Chen, Shiwei; Leong, Yan Shan; Tan, Hwee Cheng; Zhang, Summer L.; Yau, Clement; Low, Jenny G.H.; Kalimuddin, Shirin; Matsuda, Daiki; Allen, Elizabeth C.; Hartman, Paula; Park, Kyoung-Joo Jenny; Alayyoubi, Maher; Bhaskaran, Hari; Dukanovic, Adrian; Bao, Yanjie; Clemente, Brenda; Vega, Jerel; Roberts, Scott; Gonzalez, Jose A.; Sablad, Marciano; Yelin, Rodrigo; Taylor, Wendy; Tachikawa, Kiyoshi; Parker, Suezanne; Karmali, Priya; Davis, Jared; Sullivan, Brian M.; Sullivan, Sean M.; Hughes, Steve G.; Chivukula, Pad; Ooi, Eng Eong

doi:10.1016/j.ymthe.2021.04.001

Cited by 193SARS-CoV-2 and COVID-19 ResearchAnimal Virus Infections StudiesImmunotherapy and Immune Responses

A single dose of self-transcribing and replicating RNA-based SARS-CoV-2 vaccine produces protective adaptive immunity in mice

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de Alwis, Ruklanthi, Gan, Esther S., Chen, Shiwei, Leong, Yan Shan, Tan, Hwee Cheng, Zhang, Summer L., Yau, Clement, Low, Jenny G.H. +25 more·2021·Molecular Therapy

DOI 10.1016/j.ymthe.2021.04.001PMC PMC8019652

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Abstract

A self-transcribing and replicating RNA (STARR)-based vaccine (LUNAR-COV19) has been developed to prevent SARS-CoV-2 infection. The vaccine encodes an alphavirus-based replicon and the SARS-CoV-2 full-length spike glycoprotein. Translation of the replicon produces a replicase complex that amplifies and prolongs SARS-CoV-2 spike glycoprotein expression. A single prime vaccination in mice led to robust antibody responses, with neutralizing antibody titers increasing up to day 60. Activation of cell-mediated immunity produced a strong viral antigen-specific CD8 + T lymphocyte response. Assaying for intracellular cytokine staining for interferon (IFN)γ and interleukin-4 (IL-4)-positive CD4 + T helper (Th) lymphocytes as well as anti-spike glycoprotein immunoglobulin G (IgG)2a/IgG1 ratios supported a strong Th1-dominant immune response. Finally, single LUNAR-COV19 vaccination at both 2 μg and 10 μg doses completely protected human ACE2 transgenic mice from both mortality and even measurable infection following wild-type SARS-CoV-2 challenge. Our findings collectively suggest the potential of LUNAR-COV19 as a single-dose vaccine.

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Depletion of CD8+ T cells following immunization with mRNA vaccine, prior to SARS-CoV-2 challenge, led to different outcomes in a transgenic mouse model, possibly due to the vaccine dose used and variability in nAb concentrations.
“Depletion of CD8+ T cells following immunization with mRNA vaccine, prior to SARS-CoV-2 challenge, led to different outcomes in a transgenic mouse model, possibly due to the vaccine dose used and variability in nAb concentrations14,35.”
From Efficacy of an unmodified bivalent mRNA vaccine against SARS-CoV-2 variants in female small animal models (2023) · cites this paper as [35]
The Results section (page unavailable) reports that CD8+ T-cell depletion before SARS-CoV-2 challenge caused breakthrough infection in vaccinated hACE2 transgenic mice, and specifies a reduced 1 μg vaccine dose. The paper does not attribute differing outcomes between studies to vaccine dose or variability in neutralizing-antibody concentrations; that proposed explanation is not supported by this source. (LLM, conf=0.85)
Experimental — accuracy not yet measured
Two different saRNA vaccines developed independently by Arcturus Therapeutics and Imperial College London have shown favorable immune responses against SARS-CoV-2, and have entered clinical trials.
“Recently, two different saRNA vaccines developed independently by Arcturus Therapeutics and Imperial College London have shown favorable immune responses against SARS-CoV-2, and have entered clinical trials.211–213”
From Advances in COVID-19 mRNA vaccine development (2022) · cites this paper as [213]
In transgenic mice expressing human angiotensin-converting enzyme 2, doses of 2 μg and 10 μg of ARCT-021 produced strong T cell responses, high IgG titres and protected mice from SARS-CoV-2 infection.
“In transgenic mice expressing human angiotensin-converting enzyme 2, doses of 2 µg and 10 µg produced strong T cell responses, high IgG titres and protected mice from SARS-CoV-2 infection137.”
From mRNA vaccines for infectious diseases: principles, delivery and clinical translation (2021) · cites this paper as [137]

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[32]Walsh E.E. Frenck R.W. Jr. Falsey A.R. Kitchin N. Absalon J. Gurtman A. Lockhart S. Neuzil K. Mulligan M.J. Bailey R. Safety and Immunogenicity of Two RNA-Based Covid-19 Vaccine Candidates N. Engl. J. Med. 383 2020 2439 2450 33053279 PMC7583697

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A self-amplifying RNA vaccine against COVID-19 with long-term room-temperature stability
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Complete substitution with modified nucleotides in self-amplifying RNA suppresses the interferon response and increases potency
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“The intermediate dose of 100 ng N1mΨ mRNA produces a weak antibody response in previous reports 31 https://doi.org/10.1038/s41587-024-02306-z early IFN response in mice, serum was collected from mice vaccinated with the 1,000-ng dose at 24 h and 48 h. Significantly reduced levels of serum IFNα1 are…”
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Controllable self-replicating RNA vaccine delivered intradermally elicits predominantly cellular immunity
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Authors: de Alwis, R., Gan, E. S., Chen, S., Leong, Y. S., Tan, H. C., Zhang, S. L., Yau, C., Low, J. G. H., Kalimuddin, S., Matsuda, D., Allen, E. C., Hartman, P., Park, K.-J. J., Alayyoubi, M., Bhaskaran, H., Dukanovic, A., Bao, Y., Clemente, B., Vega, J., Roberts, S., Gonzalez, J. A., Sablad, M., Yelin, R., Taylor, W., Tachikawa, K., Parker, S., Karmali, P., Davis, J., Sullivan, B. M., Sullivan, S. M., Hughes, S. G., Chivukula, P., & Ooi, E. E.
Affiliations: Duke-NUS Medical School (SG)
SingHealth (SG)
National University of Singapore (SG)
Arcturus Therapeutics (United States) (US)
Corresponding author: Sullivan, Sean M.
ORCID: Gan, Esther S.
Chen, Shiwei
Leong, Yan Shan
Tan, Hwee Cheng
Zhang, Summer L.
Yau, Clement
Low, Jenny G.H.
Kalimuddin, Shirin
Park, Kyoung-Joo Jenny
Bao, Yanjie
Vega, Jerel
Sullivan, Brian M.
Sullivan, Sean M.
Chivukula, Pad
Ooi, Eng Eong
Venue: Molecular Therapy
Publisher: Elsevier BV
Published: 2021-06
Volume: 29
Issue: 6
Pages: 1970-1983
ISSN: 1525-0016 (ISSN-L)
DOI: 10.1016/j.ymthe.2021.04.001
PMC: PMC8019652
OpenAlex: W3139674533
Cited by: 191
References: 53
Citations by year: 2026: 15 · 2025: 24 · 2024: 34 · 2023: 35 · 2022: 36 · 2021: 44 · 2020: 3
FWCI: 11.80
Type: journal article
Language: en
Open access: hybrid
doi.org
Licence: cc-by-nc-nd
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/legal/tdmrep-license (tdm)
creativecommons.org/licenses/by-nc-nd/4.0/ (vor)
Locations: Molecular Therapy (publishedVersion, cc-by-nc-nd)
bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
PubMed Central (publishedVersion, cc-by-nc-nd)
PubMed (publishedVersion)
Funders: National Medical Research Council
Economic Development Board - Singapore
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 › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
Keywords: COVID-19 vaccines, alphavirus replicon, spike protein, single-dose vaccination, neutralizing antibodies, CD8+ T cell responses, Th1 response, vaccine protection
MeSH terms: Angiotensin-Converting Enzyme 2, COVID-19, SARS-CoV-2, COVID-19 Vaccines, mRNA Vaccines, Alphavirus, Animals, Antibodies, Viral, Female, Humans, Immunity, Cellular, Interferon-gamma, Mice, Transgenic, Replicon, Vaccination, Vaccines, Synthetic, Interleukin-4, Gene Expression, Treatment Outcome, CD8-Positive T-Lymphocytes, Th1 Cells, Transgenes, Mice, Immunity, Humoral, Antibodies, Neutralizing, Spike Glycoprotein, Coronavirus

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A single dose of self-transcribing and replicating RNA-based SARS-CoV-2 vaccine produces protective adaptive immunity in mice

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