A phase 3 randomized controlled trial of a COVID-19 recombinant vaccine S-268019-b versus ChAdOx1 nCoV-19 in Japanese adults

Abstract

We assessed S-268019-b, a recombinant spike protein vaccine with a squalene-based adjuvant, for superiority in its immunogenicity over ChAdOx1 nCoV-19 vaccine among adults in Japan. In this multicenter, randomized, observer-blinded, phase 3 study, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-naïve participants (aged ≥ 18 years, without prior infection or vaccination against SARS-CoV-2) were randomized (1:1) to receive either S-268019-b or ChAdOx1 nCoV-19 as two intramuscular injections given 28 days apart. Participants who provided consent for a booster administration received S-268019-b at Day 211. The primary endpoint was SARS-CoV-2 neutralizing antibody (NAb) titer on Day 57; the key secondary endpoint was the seroconversion rate for SARS-CoV-2 NAb titer on Day 57. Other endpoints included anti-SARS-CoV-2 S-protein immunoglobulin (Ig)G antibody titer and safety. The demographic and baseline characteristics were generally comparable between S-268019-b (n = 611) and ChAdOx1 nCoV-19 (n = 610) groups. S-268019-b showed superior immunogenicity over ChAdOx1 nCoV-19, based on their geometric mean titers (GMTs) and GMT ratios of SARS-CoV-2 NAb on Day 57 by cytopathic effect assay (GMT [95% confidence interval {CI}] 19.92 [18.68, 21.23] versus 3.63 [3.41, 3.87]; GMT ratio [95% CI] 5.48 [5.01, 6.00], respectively; two-sided p-values < 0.0001). Additionally, NAb measured using a cell viability assay also showed similar results (GMT [95% CI] 183.25 [168.04, 199.84] versus 24.79 [22.77, 27.00]; GMT ratio [95% CI] 7.39 [6.55, 8.35] for S-268019-b versus ChAdOx1 nCoV-19, respectively; p < 0.0001). The GMT of anti-SARS-CoV-2 S-protein IgG antibody was 370.05 for S-268019-b versus 77.92 for ChAdOx1 nCoV-19 on Day 57 (GMT ratio [95% CI] 4.75 [4.34, 5.20]). Notably, immune responses were durable through the end of the study. S-268019-b elicited T-helper 1 skewed T-cell response, comparable to that of ChAdOx1 nCoV-19. After the first dose, the incidence of solicited systemic treatment-related adverse events (TRAEs) was higher in the ChAdOx1 nCoV-19 group, but after the second dose, the incidence was higher in the S-268019-b group. Headache, fatigue, and myalgia were the most commonly reported solicited systemic TRAEs, while pain at the injection site was the most frequently reported solicited local TRAE following both doses in both groups. No serious treatment-related adverse serious TRAEs events were reported in the two groups. S-268019-b was more immunogenic than ChAdOx1 nCoV-19 vaccine and was well tolerated (jRCT2051210151).

Figure 1

Participant disposition. Safety analysis population included randomized participants who received at least one dose of study intervention. Immunogenicity subset population included participants selected from all randomized participants who were included in the mITT population and had at least 1 valid immunogenicity result after the first dose of vaccination. mITT, modified intent-to-treat. One participant who received ChAdOx1 nCoV-19 was excluded due to double enrolment; therefore, the safety analysis population for ChAdOx1 nCoV-19 included 610 participants.

Figure 2

GMTs for SARS-CoV-2 neutralizing antibody: immunogenicity subset using two different methods: (a) cytopathic effect assay; (b) cell viability assay; and (c) GMTs for SARS-CoV-2 neutralizing antibody measured using the cytopathic effect assay in the S-268019-b group: immunogenicity subset in subgroups by age. CI, confidence interval; GMT, geometric mean titer; GMTR, geometric mean titer ratio; LLoQ, lower limit of quantification; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2. Wilcoxon rank-sum test was applied as a post hoc analysis for both methods because there was a certain level of proportion of neutralizing antibody titer below the LLoQ in the ChAdOx1 nCoV-19 group in the results of both methods.

Figure 3

(a) Incidence of solicited systemic TRAEs by severity within 7 days after the first dose of the vaccine in the safety analysis set; (b) Incidence of solicited systemic TRAEs by severity within 7 days after the second dose of the vaccine in the safety analysis set; (c) Incidence of solicited local TRAEs by severity within 7 days after the first dose of the vaccine in the safety analysis set; (d) Incidence of solicited local TRAEs by severity within 7 days after the second dose of the vaccine in the safety analysis set. TRAE, treatment-related adverse event.

Figure 4

Neutralizing antibodies against the virus variants in the serum samples collected from vaccinated individuals at Day 57. Neutralizing antibody titers against (a) spike protein-bearing pseudoviruses and (b) live virus variants are shown. Selected samples from the immunogenicity subset (n = 24/group) were assessed for neutralizing antibody titer testing, and the sampling ensured no significant differences in age and neutralizing antibody titer against live wildtype virus on Day 57 compared with the entire cohort. The solid and open circles represent individual values for the S-268019-b and ChAdOx1 nCoV-19 groups, respectively. Titer values reported as below the LLoQ were replaced with 0.5 × LLoQ. Each bar represents the GMT with error bars indicating 95% CI. Samples were selected from the immunogenicity subset (n = 24/group) assessed on Day 57, and sampling ensured no significant differences in age and neutralizing antibody titer against live wildtype virus on Day 57 compared with the entire cohort. The 95% CIs were constructed using Student’s t distribution for log-transformed titers. CI, confidence interval; GMT, geometric mean titer; LLoQ, lower limit of quantification; NT50, serum titers at which 50% neutralization was achieved.