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

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.

Figure 1

Consort diagram. Consort diagram demonstrating the eligibility assessment, enrolment, group allocation and follow-up of the n=192 participants in the dose escalation and randomised dose evaluation components of the study.

Figure 2

A. Solicited local injection site reactions that started within 7 days of administration of the vaccine with a frequency of at least 10%. Reactions are shown after the first injection in those who received, in columns from left to right 1.0μg, 2.5μg, 5.0μg, and 10.0μg. The upper row shows reports of any solicited local injection site reaction, the middle row pain at the injection site and the lower row tenderness at the injection site on the day of vaccination and for 7 days afterwards. Grade of adverse event is represented by colour on the bar chart as grade 1 (mild) in yellow, grade 2 (moderate) in orange and grade 3 (severe) in red. Figure 2B. Solicited systemic reactions that started within 7 days of administration of the vaccine with a frequency of at least 10%. Reactions are shown after the first injection in those who received in columns from left to right, 1.0μg, 2.5μg, 5.0μg, and 10.0μg. Rows show from the top any solicited systemic reaction, chills/shivering, myalgia, arthralgia, fatigue, headache and nausea. Grade of adverse event is represented by colour on the bar chart as grade 1 (mild) in yellow, grade 2 (moderate) in orange and grade 3 (severe) in red.

Figure 3

A. Anti-Spike (S) IgG (ng/mL) raised in sera from participants receiving two doses of LNP-saRNA. Responses are shown at 4 weeks, 6 weeks, and 8 weeks after enrolment in those who received 1.0μg (green dots), 2.5μg (blue dots), 5.0μg (orange dots), and 10.0μg (red dots). Responses from convalescent sera are shown as black dots – GM (95% CI): 718ng/mL (518, 996). Error bars detail the median and interquartile range amongst responders. Responses that did not meet criteria for a positive response are shown on the bottom row with numbers of participants <LOQ (limit of quantification). Figure 3B. Pseudoneutralising antibodies IC50 from participants receiving two doses of LNP-saRNA Responses are shown at 6 weeks and 8 weeks after enrolment in those who received 1.0μg (green dots), 2.5μg (blue dots), 5.0μg (orange dots), and 10.0μg (red dots). Responses from convalescent sera are shown as black dots - GM NT₅₀ (95% CI): 130 (74-229). Error bars detail the median and interquartile range amongst responders. Responses that did not meet criteria for a positive response are shown on the bottom row with numbers of participants <LOQ (limit of quantification).

Figure 4

A. Anti-Spike (S) IgG (ng/mL) raised in sera from participants at week 4 against week 6 after enrolment. Reponses from those who received 0.1 or 0.3 ug (green dots), 1.0 or 2.5 ug (orange dots) or 5.0 or 10.0 ug are shown (red dots). The dashed line represents an equivalent binding response at both week 4 and week 6, values above this line indicate an increased response (and a decreased response below this line) at week 6 in comparison to week 4. Figure 4B. Anti-Spike (S) IgG (ng/mL) raised in sera from participants at week 6 against week 8 after enrolment. Reponses from those who received 0.1 or 0.3 ug (green dots), 1.0 or 2.5 ug (orange dots) or 5.0 or 10.0 ug are shown (red dots). The dashed line represents an equivalent binding response at both week 6 and week 8, values above this line indicate an increased response (and a decreased response below this line) at week 8 in comparison to week 6.