Safety and immunogenicity of a self-amplifying RNA vaccine against COVID-19: COVAC1, a phase I, dose-ranging trial

Katrina M Pollock; Hannah M Cheeseman; Alexander J Szubert; Vincenzo Libri; Marta Boffito; David Owen; Henry Bern; Jessica O'Hara; Leon R McFarlane; Nana-Marie Lemm; Paul F McKay; Tommy Rampling; Yee Ting N Yim; Ana Milinkovic; Cherry Kingsley; Tom Cole; Susanne Fagerbrink; Marites Aban; Maniola Tanaka; Savviz Mehdipour; Alexander Robbins; William Budd; Saul N Faust; Hana Hassanin; Catherine A Cosgrove; Alan Winston; Sarah Fidler; David T Dunn; Sheena McCormack; Robin J Shattock; COVAC1 study Group

doi:10.1016/j.eclinm.2021.101262

Safety and immunogenicity of a self-amplifying RNA vaccine against COVID-19: COVAC1, a phase I, dose-ranging trial

EClinicalMedicine. 2022 Feb:44:101262. doi: 10.1016/j.eclinm.2021.101262. Epub 2022 Jan 14.

Authors

Katrina M Pollock^{1

2}, Hannah M Cheeseman¹, Alexander J Szubert³, Vincenzo Libri⁴, Marta Boffito^{1

5}, David Owen², Henry Bern³, Jessica O'Hara¹, Leon R McFarlane¹, Nana-Marie Lemm¹, Paul F McKay¹, Tommy Rampling⁴, Yee Ting N Yim⁴, Ana Milinkovic⁵, Cherry Kingsley¹, Tom Cole², Susanne Fagerbrink², Marites Aban², Maniola Tanaka², Savviz Mehdipour², Alexander Robbins², William Budd², Saul N Faust⁶, Hana Hassanin⁷, Catherine A Cosgrove⁸, Alan Winston¹, Sarah Fidler¹, David T Dunn³, Sheena McCormack³, Robin J Shattock¹; COVAC1 study Group

Collaborators

COVAC1 study Group:
Kirsty Adams, Fahimah Amini, Nafisah B Atako, Amalina Bakri, Wendy Barclay, Elizabeth Brodnicki, Jonathan C Brown, Ruth Byrne, Rowena Chilvers, Sofia Coelho, Suzanne Day, Monica Desai, Eleanor Dorman, Tamara Elliott, Katie E Flight, James Fletcher, John Galang, Jagruti Gohil, Aneta Gupta, Chris Harlow, Kai Hu, Mahini Kalyan, Dominic Lagrue, Ely Liscano, Cecilia Njenga, Krunal Polra, Derecia A Powlette, Paul Randell, Mary Rauchenberger, Ianto Redknap, Maravic Ricamara, Paul Rogers, Hadijatou Sallah, Karnyart Samnuan, Michael Schumacher, Zareena Shah, Rachel Shaw, Thomas Shaw, Stefan Sivapatham, Susie Slater, Kim Sorley, Regina Storch, Elizabeth Tan, Tricia Tan, Lieze Thielemans, Sarah Whitely, Charlotte Valentine, Jeeva Varghese, Asha Vikraman, Martin Wilkins

Affiliations

¹ Department of Infectious Disease, Imperial College London.
² NIHR Imperial Clinical Research Facility and NIHR Imperial Biomedical Research Centre, London, UK.
³ MRC Clinical Trials Unit at UCL, London, UK.
⁴ NIHR UCLH Clinical Research Facility and NIHR UCLH Biomedical Research Centre, London, UK.
⁵ Chelsea & Westminster Hospital, London.
⁶ NIHR Southampton Clinical Research Facility and Biomedical Research Centre, University Hospital Southampton NHS Foundation Trust, Southampton, UK; Faculty of Medicine and Institute for Life Sciences, University of Southampton, Southampton, UK.
⁷ Surrey Clinical Research Facility, Faculty of Health and Medical Sciences, University of Surrey, Guildford, UK.
⁸ Centre for Infection, St George's, University of London, London, United Kingdom.

Abstract

Background: Lipid nanoparticle (LNP) encapsulated self-amplifying RNA (saRNA) is a novel technology formulated as a low dose vaccine against COVID-19.

Methods: A phase I first-in-human dose-ranging trial of a saRNA COVID-19 vaccine candidate LNP-nCoVsaRNA, was conducted at Imperial Clinical Research Facility, and participating centres in London, UK, between 19^th June to 28^th 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.

Keywords: AEs, adverse events; GOI, gene of Interest; LNP, lipid nanoparticle; NSP, non-structural protein; VEEV, Venezuelan equine encephalitis virus; saRNA, self-amplifying RNA.

Abstract

Grants and funding