Safety and immunogenicity of a self-amplifying RNA vaccine against COVID-19: COVAC1, a phase I, dose-ranging trial
Open accessAbstract
BACKGROUND: Lipid nanoparticle (LNP) encapsulated self-amplifying RNA (saRNA) is a novel technology formulated as a low dose vaccine against COVID-19. METHODS: October 2020. Participants received two intramuscular (IM) injections of LNP-nCoVsaRNA at six different dose levels, 0.1-10.0μg, given four weeks apart. An open-label dose escalation was followed by a dose evaluation. Solicited adverse events (AEs) were collected for one week from enrolment, with follow-up at regular intervals (1-8 weeks). The binding and neutralisation capacity of anti-SARS-CoV-2 antibody raised in participant sera was measured by means of an anti-Spike (S) IgG ELISA, immunoblot, SARS-CoV-2 pseudoneutralisation and wild type neutralisation assays. (The trial is registered: ISRCTN17072692, EudraCT 2020-001646-20). FINDINGS: 192 healthy individuals with no history or serological evidence of COVID-19, aged 18-45 years were enrolled. The vaccine was well tolerated with no serious adverse events related to vaccination. Seroconversion at week six whether measured by ELISA or immunoblot was related to dose (both p<0.001), ranging from 8% (3/39; 0.1μg) to 61% (14/23; 10.0μg) in ELISA and 46% (18/39; 0.3μg) to 87% (20/23; 5.0μg and 10.0μg) in a post-hoc immunoblot assay. Geometric mean (GM) anti-S IgG concentrations ranged from 74 (95% CI, 45-119) at 0.1μg to 1023 (468-2236) ng/mL at 5.0μg (p<0.001) and was not higher at 10.0μg. Neutralisation of SARS-CoV-2 by participant sera was measurable in 15% (6/39; 0.1μg) to 48% (11/23; 5.0μg) depending on dose level received. INTERPRETATION: Encapsulated saRNA is safe for clinical development, is immunogenic at low dose levels but failed to induce 100% seroconversion. Modifications to optimise humoral responses are required to realise its potential as an effective vaccine against SARS-CoV-2. FUNDING: This study was co-funded by grants and gifts from the Medical Research Council UKRI (MC_PC_19076), and the National Institute Health Research/Vaccine Task Force, Partners of Citadel and Citadel Securities, Sir Joseph Hotung Charitable Settlement, Jon Moulton Charity Trust, Pierre Andurand, Restore the Earth.
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The current understanding of the field is that incorporating modified NTPs into saRNA abrogates downstream efficacy.
“However, the current understanding of the field is that incorporating modified NTPs into saRNA abrogates downstream efficacy, as reported by multiple independent groups5,19–28.”
From Complete substitution with modified nucleotides in self-amplifying RNA suppresses the interferon response and increases potency (2025) · cites this paper as [24]
The Discussion (page unavailable) says that the compatibility of modified bases with saRNA has not been established and that the bases would be rapidly lost during amplification. This supports a concern about their usefulness, but it does not establish that incorporating modified NTPs abrogates downstream efficacy. (LLM, conf=0.85)
Experimental — accuracy not yet measuredTwo 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 [212]
Compared with the dose of mRNA in the Moderna vaccine (100 μg) and that of Pfizer-BioNTech vaccine (30 μg), the amount of saRNA required for vaccine development is within a range of 0.1~10 μg.
“Compared with the dose of mRNA in the Moderna vaccine (100 μg) and that of Pfizer-BioNTech vaccine (30 μg), the amount of saRNA required for vaccine development is within a range of 0.1~10 μg.212”
From Advances in COVID-19 mRNA vaccine development (2022) · cites this paper as [212]
LNP-nCoVsaRNA showed seroconversion rate from 8% to 61% by ELISA when 0.1-10.0 μg was administered per dose group, and demonstrated inferior immunogenicity in humans compared to mice.
“the saRNA vaccine LNP-nCoVsaRNA developed by the Imperial College London showed seroconversion rate from 8% to 61% as determined by ELISA when 0.1–10.0 μg was administered per dose group, demonstrated inferior immunogenicity in humans compared to that observed in mice.212”
From Advances in COVID-19 mRNA vaccine development (2022) · cites this paper as [212]
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- Authors
- Pollock, K. M., Cheeseman, H. M., Szubert, A. J., Libri, V., Boffito, M., Owen, D., Bern, H., McFarlane, L. R., O'Hara, J., Lemm, N.-M., McKay, P., Rampling, T., Yim, Y. T. N., Milinkovic, A., Kingsley, C., Cole, T., Fagerbrink, S., Aban, M., Tanaka, M., Mehdipour, S., Robbins, A., Budd, W., Faust, S., Hassanin, H., Cosgrove, C. A., Winston, A., Fidler, S., Dunn, D., McCormack, S., Shattock, R. J., Adams, K., Amini, F., Atako, N. B., Bakri, A., Barclay, W., Brodnicki, E., Brown, J. C., Byrne, R., Chilvers, R., Coelho, S., Day, S., Desai, M., Dorman, E., Elliott, T., Flight, K. E., Fletcher, J., Galang, J., Gohil, J., Gupta, A., Harlow, C., Hu, K., Kalyan, M., Lagrue, D., Liscano, E., Njenga, C., Polra, K., Powlette, D. A., Randell, P., Rauchenberger, M., Redknap, I., Ricamara, M., Rogers, P., Sallah, H., Samnuan, K., Schumacher, M., Shah, Z., Shaw, R., Shaw, T., Sivapatham, S., Slater, S., Sorley, K., Storch, R., Tan, E., Tan, T., Thielemans, L., Whitely, S., Valentine, C., Varghese, J., Vikraman, A., & Wilkins, M.
- Affiliations
- NIHR Imperial Biomedical Research Centre (GB)
- Imperial College London (GB)
- MRC Clinical Trials Unit at UCL (GB)
- UCL Biomedical Research Centre (GB)
- Chelsea and Westminster Hospital (GB)
- University Hospital Southampton NHS Foundation Trust (GB)
- University of Surrey (GB)
- St George's, University of London (GB)
- Corresponding author
- Shattock, Robin J.
- ORCID
- Pollock, Katrina M.
- Cheeseman, Hannah M.
- Szubert, Alexander J.
- Libri, Vincenzo
- Boffito, Marta
- Owen, David
- Bern, Henry
- McFarlane, Leon R.
- McKay, Paul
- Rampling, Tommy
- Yim, Yee Ting N.
- Milinkovic, Ana
- Robbins, Alexander
- Faust, Saul
- Hassanin, Hana
- Cosgrove, Catherine A.
- Winston, Alan
- Fidler, Sarah
- Dunn, David
- McCormack, Sheena
- Shattock, Robin J.
- Adams, Kirsty
- Amini, Fahimah
- Brodnicki, Elizabeth
- Brown, Jonathan C
- Coelho, Sofia
- Desai, Monica
- Dorman, Eleanor
- Elliott, Tamara
- Flight, Katie E
- Hu, Kai
- Randell, Paul
- Rauchenberger, Mary
- Rogers, Paul
- Sallah, Hadijatou
- Samnuan, Karnyart
- Shaw, Thomas
- Tan, Elizabeth
- Tan, Tricia
- Wilkins, Martin
- Venue
- eClinicalMedicine
- Publisher
- Elsevier BV
- Published
- 2022-02
- Volume
- 44
- Pages
- 101262
- ISSN
- 2589-5370 (ISSN-L)
- PMC
- PMC8759012
- OpenAlex
- W4220898781
- Cited by
- 173
- References
- 31
- Citations by year
- 2026: 23 · 2025: 37 · 2024: 31 · 2023: 40 · 2022: 40 · 2021: 2
- FWCI
- 8.95
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- EClinicalMedicine (publishedVersion, cc-by-nc-nd)
- SSRN Electronic Journal (publishedVersion)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- ePrints Soton (University of Southampton) (acceptedVersion)
- St George's Online Research Archive (St George's University of London) (acceptedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- UCL Discovery (University College London) (submittedVersion)
- Spiral (Imperial College London) (submittedVersion)
- Funders
- Medical Research Council (MC_PC_19076, MC_UU_12023/23, MC_UU_00004/04)
- Engineering and Physical Sciences Research Council (EP/R013764/1)
- James B. Pendleton Charitable Trust
- National Institute for Health Research
- NIHR Imperial Biomedical Research Centre
- 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 › COVID-19 Clinical Research Studies
- Keywords
- self-amplifying RNA vaccine, COVID-19 vaccines, SARS-CoV-2, lipid nanoparticles, dose escalation, vaccine safety, immunogenicity, anti-spike IgG, neutralizing antibodies, seroconversion, dose-response relationship, intramuscular injection, healthy volunteers, vaccine adjuvants, SARS-CoV-2 spike protein
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