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

COVAC1 study Group

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3 Citations (Scopus)

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 19th June to 28th 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.

Original languageEnglish
Article number101262
JournalEClinicalMedicine
Volume44
DOIs
Publication statusPublished - Feb 2022
Externally publishedYes

Bibliographical note

Funding Information:
We wish to acknowledge the COVAC1 participants who took part in this first in human vaccine trial, the dedication of the clinic, laboratory and administrative teams, and the oversight that the governance committees provided as the study evolved, including Jonathan Weber who represented the Sponsor, Sue Marlow as Qualified Person, the members who represented the Patients and Public (PPI) and the members of the Independent Data Monitoring Committee established to oversee the planned efficacy trial. Manufacture studies were additionally supported by the NIHR Imperial Biomedical Research Centre (BRC) and the MRC Imperial confidence in Concept. Preclinical toxicology was funded by Department of Health and Social Care using UK Aid funding, managed by the Engineering and Physical Sciences Research Council (EPSRC, grant number: EP/R013764/1). Infrastructure support was provided by the NIHR Imperial Biomedical Research Centre and the NIHR Imperial Clinical Research Facility. We also acknowledge Fondation Dormeur, Vaduz and a gift from the James B. Pendleton Charitable Trust for providing funds to purchase equipment used in these studies. DTD and SMc were supported by a Medical Research Council grant, MC_UU_12023/23 & MC_UU_00004/04. KMP was supported by the NIHR Imperial BRC. We would like to acknowledge also members of the COVAC1 Governance (Independent members): Trial Steering Committee: Robert Lechler (Chair), Janet Darbyshire (Vice Chair), Jeff Almond, Ben Cromarty (PPI), Stuart Elborn;

Funding Information:
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.

Funding Information:
Data will be made available when the trial is complete, upon requests directed to the corresponding author and after approval of a proposal. We wish to acknowledge the COVAC1 participants who took part in this first in human vaccine trial, the dedication of the clinic, laboratory and administrative teams, and the oversight that the governance committees provided as the study evolved, including Jonathan Weber who represented the Sponsor, Sue Marlow as Qualified Person, the members who represented the Patients and Public (PPI) and the members of the Independent Data Monitoring Committee established to oversee the planned efficacy trial. Manufacture studies were additionally supported by the NIHR Imperial Biomedical Research Centre (BRC) and the MRC Imperial confidence in Concept. Preclinical toxicology was funded by Department of Health and Social Care using UK Aid funding, managed by the Engineering and Physical Sciences Research Council (EPSRC, grant number: EP/R013764/1). Infrastructure support was provided by the NIHR Imperial Biomedical Research Centre and the NIHR Imperial Clinical Research Facility. We also acknowledge Fondation Dormeur, Vaduz and a gift from the James B. Pendleton Charitable Trust for providing funds to purchase equipment used in these studies. DTD and SMc were supported by a Medical Research Council grant, MC_UU_12023/23 & MC_UU_00004/04. KMP was supported by the NIHR Imperial BRC. We would like to acknowledge also members of the COVAC1 Governance (Independent members): Trial Steering Committee: Robert Lechler (Chair), Janet Darbyshire (Vice Chair), Jeff Almond, Ben Cromarty (PPI), Stuart Elborn;, Independent Data Monitoring Committee (for planned COVAC2): Peter Smith (Chair), George Griffin, Phil Minor, Moira Whyte; PPI representative on the Trial Management Group: Pro Chatzikyriakou. 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.

Publisher Copyright:
© 2021 The Authors

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