Safety and immunogenicity of a synthetic multiantigen modified vaccinia virus Ankara-based COVID-19 vaccine (COH04S1): an open-label and randomised, phase 1 trial

Abstract

Background: COH04S1, a synthetic attenuated modified vaccinia virus Ankara vector co-expressing SARS-CoV-2 spike and nucleocapsid antigens, was tested for safety and immunogenicity in healthy adults.

Methods: This combined open-label and randomised, phase 1 trial was done at the City of Hope Comprehensive Cancer Center (Duarte, CA, USA). We included participants aged 18-54 years with a negative SARS-CoV-2 antibody and PCR test, normal haematology and chemistry panels, a normal electrocardiogram and troponin concentration, negative pregnancy test if female, body-mass index of 30 kg/m² or less, and no modified vaccinia virus Ankara or poxvirus vaccine in the past 12 months. In the open-label cohort, 1·0 × 10⁷ plaque-forming units (PFU; low dose), 1·0 × 10⁸ PFU (medium dose), and 2·5 × 10⁸ PFU (high dose) of COH04S1 were administered by intramuscular injection on day 0 and 28 to sentinel participants using a queue-based statistical design to limit risk. In a randomised dose expansion cohort, additional participants were randomly assigned (3:3:1), using block size of seven, to receive two placebo vaccines (placebo group), one low-dose COH04S1 and one placebo vaccine (low-dose COH04S1 plus placebo group), or two low-dose COH04S1 vaccines (low-dose COH04S1 group). The primary outcome was safety and tolerability, with secondary objectives assessing vaccine-specific immunogenicity. The primary immunological outcome was a four times increase (seroconversion) from baseline in spike-specific or nucleocapsid-specific IgG titres within 28 days of the last injection, and seroconversion rates were compared with participants who received placebo using Fisher's exact test. Additional secondary outcomes included assessment of viral neutralisation and cellular responses. This trial is registered with ClinicalTrials.gov, NCT046339466.

Findings: Between Dec 13, 2020, and May 24, 2021, 56 participants initiated vaccination. On day 0 and 28, 17 participants received low-dose COH04S1, eight received medium-dose COH04S1, nine received high-dose COH04S1, five received placebo, 13 received low-dose COH04S1 followed by placebo, and four discontinued early. Grade 3 fever was observed in one participant who received low-dose COH04S1 and placebo, and grade 2 anxiety or fatigue was seen in one participant who received medium-dose COH04S1. No severe adverse events were reported. Seroconversion was observed in all 34 participants for spike protein and 32 (94%) for nucleocapsid protein (p<0·0001 vs placebo for each comparison). Four times or more increase in SARS-CoV-2 neutralising antibodies within 56 days was measured in nine of 17 participants in the low-dose COH04S1 group, all eight participants in the medium-dose COH04S1 group, and eight of nine participants in the high-dose COH04S1 group (p=0·0035 combined dose levels vs placebo). Post-prime and post-boost four times increase in spike-specific or nucleocapsid-specific T cells secreting interferon-γ was measured in 48 (98%; 95% CI 89-100) of 49 participants who received at least one dose of COH04S1 and provided a sample for immunological analysis.

Interpretation: COH04S1 was well tolerated and induced spike-specific and nucleocapsid-specific antibody and T-cell responses. Future evaluation of this COVID-19 vaccine candidate as a primary or boost vaccination is warranted.

Funding: The Carol Moss Foundation and City of Hope Integrated Drug Development Venture programme.

Figure 1

Trial profile BMI=body-mass index. EUA=emergency use authorisation. *Ten participants opted to receive a second low-dose vaccination at day 56 (nine) or day 90 (one). †Day 90 post-last dose, the equivalent of day 120 for the normal 28-day interval schedule. ‡One participant received the first injection but was lost to follow-up (followed up for safety days 0-14), primary safety included up to that point. §One participant discontinued after the first dose and one subject discontinued at day 60 after the last dose (primary safety included up to that point). ¶One discontinued after day 56 so they were followed up and included in primary safety analysis up to day 56.

Figure 2

Serum SARS-CoV-2-specific binding and neutralising antibodies following COH04S1 vaccination with different dose levels and schedules Spike (A) and nucleocapsid (B) IgG endpoint titres following COH04S1 vaccination were quantified by ELISA. SARS-CoV-2-specific neutralising antibody titres (C) were evaluated using a SARS-CoV-2 pseudovirus based on the Wuhan spike sequence with Asp614Gly substitution. Box plots extend from the 25th to the 75th percentiles, median values are shown as a line (key geometric mean titres are discussed in the text), whiskers extend from minimum to maximum values. Individual values are superimposed. Reported are statistical testing results using Wilcoxon rank-sum paired test and comparing each timepoint to baseline (day 0). Exact p values are shown in appendix pp 92–94. Dashed lines represent the lower limit of quantification. Arrowheads represent time of vaccination. LD represents the low dose of COH04S1 (1·0 × 10⁷ PFU), MD represents the medium dose (1·0 × 10⁸ PFU), and HD represents the high dose (2·5 × 10⁸ PFU). P represents placebo. Indicated are spike and nucleocapsid endpoint titres and pseudovirus NT₅₀ titres measured in WHO reference panel 20/268 (ranked based on SARS-CoV-2 antibody titres: 20/150 indicates high, 20/148 indicates mid, 20/144 indicates low spike and high nucleocapsid, 20/140 indicates low, and 20/142 indicates negative). WHO assigned values are shown in appendix p 103). NT₅₀=50% neutralisation titre. PFU=plaque-forming unit. *p<0·05. †p<0·01. ‡p<0·001. §p<0·0001.

Figure 3

IFNγ-secreting T-cell responses following COH04S1 vaccination with different dose levels and schedules Spike-specific (A) and nucleocapsid-specific (B) IFNγ-secreting T-cell responses were quantified at the indicated timepoints by IFNγ:IL-4 ELISpot upon PBMC stimulation with spike and nucleocapsid peptide libraries in participants vaccinated with COH04S1. Box plots extend from the 25th to the 75th percentiles, median values are shown as a line, whiskers extend from minimum to maximum values. Individual values are superimposed. Reported are statistical testing results using Wilcoxon rank-sum paired test and comparing each timepoint to baseline (day 0). Exact p values are shown in appendix (pp 96–97). Dashed lines represent the arbitrary threshold for positive response (50 SFCs per 10⁶ PBMCs). Arrowheads represent time of vaccination. LD represents the low dose of COH04S1 (1·0 × 10⁷ PFU), MD represents the medium dose (1·0 × 10⁸ PFU), and HD represents the high dose (2·5 × 10⁸ PFU). P represents placebo. ELISpot=enzyme-linked immunospot. IFNγ=interferon-γ. IL-4=interleukin-4. PFU=plaque-forming unit. PBMCs=peripheral blood mononuclear cells. SFCs=spot-forming cells. *p<0·05. †p<0·01. ‡p<0·001. §p<0·0001.