Participants
Demographic and Clinical Characteristics of the Participants at Baseline (Intention-to-Treat Population).
Between December 12, 2020, and December 15, 2021, a total of 28,904 participants were enrolled and underwent randomization at 32 clinical centers across 5 countries (China, Uzbekistan, Indonesia, Pakistan, and Ecuador). The demographic and clinical characteristics of the participants were similar in the two trial groups and in the subgroups defined according to age, body-mass index, race, and the presence of coexisting medical conditions (Table 1). Among these participants, 27,065 (93.6%) were 18 to 59 years of age, 1,839 (6.4%) were 60 years of age or older, and 9,383 (32.5%) were female. A total of 78.5% of the participants were Asian, and 17.7% were multiracial. More than 99.9% of the participants were negative for SARS-CoV-2 exposure or vaccination. At baseline, 13.2% of the participants had a coexisting medical condition.
Screening, Randomization, Follow-up, and Analyzes Performed up to the Second Data Cutoff Date of December 15, 2021.
Eight participants who had been randomly assigned to receive placebo and instead received at least one dose of ZF2001 (protocol violation) were included in the ZF2001 group in the safety analysis. Covid-19 denotes coronavirus disease 2019.
At the first data cutoff date (June 30, 2021), a total of 28,470 participants had received at least one dose of vaccine or placebo, and 14,681 were included in the modified full analysis set for efficacy (Fig. S1 and Tables S3 and S6 ). At the second data cutoff date (December 15, 2021), a total of 28,873 participants had received at least one dose of ZF2001 or placebo and were included in the safety analysis set. The modified full analysis set for efficacy included 25,193 participants (Figure 1 and Table S7).
Efficacy after Short-Term Follow-up
Vaccine Efficacy of ZF2001 against Covid-19 According to Analysis Groups.
At the first data cutoff date, 663 Covid-19 cases were confirmed on real-time PCR assay after the first dose; 224 of these cases had an onset at least 7 days after the third dose and were analyzed as primary end-point cases. The mean (±SD) duration of follow-up, starting 7 days after the third dose, was 50.4±37.1 days in the ZF2001 group and 50.6±37.1 days in the placebo group. A total of 36 cases occurred among 7359 participants in the ZF2001 group, and 188 cases occurred among 7322 participants in the placebo group. These results yielded a vaccine efficacy of 81.4% (95% confidence interval [CI]73.3 to 87.3) (Table 2).
Kaplan–Meier Plots of the Cumulative Incidence of Symptomatic Covid-19 in the Trial Groups.
The cumulative incidence of symptomatic Covid-19, as confirmed on real-time polymerase-chain-reaction (PCR) assay, with an onset of at least 7 days after the third dose of ZF2001 or placebo (the primary end point) in the modified full analysis set for efficacy is shown at the first data cutoff date of June 30, 2021 (Panel A) and at the second data cutoff date of December 15, 2021 (Panel B). The cumulative incidence of real-time PCR–confirmed symptomatic Covid-19, with an onset after the first dose of ZF2001 or placebo, in the full analysis set for efficacy is shown at the first data cutoff date of June 30, 2021 (Panel C ) and at the second data cutoff date of December 15, 2021 (Panel D). In each panel, the inset shows the same data on an enlarged and axis.
The cumulative incidence of Covid-19 events over time among the participants in the ZF2001 group and those in the placebo group diverged immediately after the beginning of follow-up for the primary end-point analysis, a result indicating the start of protection (Figure 2A). Among the participants who received at least one dose of vaccine or placebo in the full analysis set for efficacy, a late onset of protection and low vaccine efficacy were observed before the third dose (Figure 2C and Tables S10 and S11).
A total of 14 cases met the criteria for severe-to-critical Covid-19 in the modified full analysis set for efficacy. One case occurred in the ZF2001 group, and 13 occurred in the placebo group. These results yielded a vaccine efficacy of 92.9% (95% CI, 52.4 to 99.8). A total of five Covid-19–related deaths occurred — all in the placebo group (Table 2). Among the participants with coexisting medical conditions that were risk factors for severe Covid-19, vaccine efficacy was 84.4% (95% CI, 41.8 to 97.2). Among the participants 18 to 59 years of age, vaccine efficacy was 81.2% (95% CI, 72.8 to 87.3), and among those 60 years of age or older, vaccine efficacy was 87.6% (95% CI, 2.5 to 99.7). Two lots of ZF2001 vaccine were used in this trial. Lot 1 was used in the Uzbekistan cohort, and lot 2 was used in the other countries. Both lots had an efficacy of more than 80%.
In a post hoc exploratory analysis of the primary end-point cases, 185 SARS-CoV-2–positive swab samples yielded genotyping results, all of which showed variants. The three major variants were the delta (B.1.617.2, AY.4, AY.6, and AY.12) variant of concern (130 cases), the alpha (B.1.1.7) variant of concern (29 cases ), and the kappa (B.1.617.1) variant of interest plus the B.1.617.3 variant (15 cases). Vaccine efficacy was 81.4% (95% CI, 70.1 to 88.9) against the delta variant, 92.7% (95% CI, 70.9 to 99.2) against the alpha variant, and 84.8% (95% CI, 32.9 to 98.3) against the kappa variant plus the B.1.617.3 variant (Table 2).
Efficacy after Long-Term Follow-up
At the second data cutoff date, 1255 Covid-19 cases had been confirmed after the first dose. Among these confirmed cases, 738 had an onset of at least 7 days after the third dose and were evaluated as primary end-point cases. The mean (±SD) duration of follow-up, starting 7 days after the third dose, was 178.6±56.9 days in the ZF2001 group and 177.8±56.4 days in the placebo group. A total of 158 cases occurred among 12,625 participants in the ZF2001 group, and 580 cases occurred among 12,568 participants in the placebo group. These results yielded a vaccine efficacy of 75.7% (95% CI, 71.0 to 79.8) (Table 2).
A time-to-event plot showed that the incidence of Covid-19 in the ZF2001 group and in the placebo group diverged immediately after the beginning of follow-up for the primary end-point analysis, a result indicating the start of protection (Figure 2B). Among the participants who received at least one dose in the full analysis set for efficacy, a late onset of protection and low efficacy before the third dose were observed (Figure 2D and Tables S10 and S11).
Vaccine efficacy against severe-to-critical Covid-19 was 87.6% (95% CI, 70.6 to 95.7), with confirmed cases of Covid-19 occurring in 6 participants in the ZF2001 group and in 43 participants in the placebo group. Vaccine efficacy against Covid-19–related death was 86.5% (95% CI, 38.9 to 98.5), with death occurring in 2 participants in the ZF2001 group and in 12 participants in the placebo group. Among the participants with coexisting medical conditions that were risk factors for severe Covid-19, vaccine efficacy was 61.6% (95% CI, 29.5 to 79.9). Among younger participants (18 to 59 years of age), vaccine efficacy was 76.0% (95% CI, 71.2 to 80.1), and among older participants (≥60 years of age), vaccine efficacy was 67.6% (95% CI, 21.9 to 87.8).
In a post hoc exploratory analysis of the 738 primary end-point cases, 626 swab samples yielded genotyping results, all of which showed SARS-CoV-2 variants. The three major variants were the delta (454 cases) and alpha (35 cases) variants of concern and the kappa variant of interest plus the B.1.617.3 variant (68 cases). Vaccine efficacy was 76.1% (95% CI, 70.0 to 81.2) against the delta variant, 88.3% (95% CI, 66.8 to 97.0) against the alpha variant, and 75.2% (95% CI, 55.3 to 87.0) against the kappa variant (Table 2).
Safety
Adverse Events at the Second Data Cutoff Date of December 15, 2021.
Panel A shows the incidence of adverse events, both overall and according to age group, among the participants who received at least one dose of ZF2001 or placebo. Panel B shows the overall incidence of local and systemic adverse reactions. A total of 28,873 participants were included in the safety analysis set (14,448 in the ZF2001 group and 14,425 in the placebo group); 8 participants who had been randomly assigned to receive placebo and instead received at least one dose of ZF2001 (protocol violation) were included in the ZF2001 group for the safety analysis.
A total of 28,873 participants were included in the safety analysis set (14,448 in the ZF2001 group and 14,425 in the placebo group); 8 participants who had been randomly assigned to receive placebo and instead received at least one dose of ZF2001 (protocol violation) were included in the ZF2001 group in the safety analysis. At least one adverse event was reported by 11,957 (41.4%) participants — 6073 (42.0%) in the ZF2001 group and 5884 (40.8%) in the placebo group (Figure 3A). Adverse events reported by 9588 participants (33.2%) were related to the investigational products, as determined by the trial investigators; the incidence of these events was similar in the trial groups (34.1% [4922 participants] in the ZF2001 group and 32.4% [4666 participants] in the placebo group). Within 7 days after each dose, 4730 participants (32.7%) in the ZF2001 group and 4481 participants (31.1%) in the placebo group reported having solicited reactions. Among the 4730 participants in the ZF2001 group, the incidence of local reactions was 18.8%, and the incidence of systemic reactions was 25.1%. The incidence of unsolicited reactions was low and similar in the two groups (5.5% in the ZF2001 group and 5.3% in the placebo group). In the ZF2001 group, the most common solicited local and systemic reactions were injection-site pain (in 17.3%) and headache (in 12.9%) (Figure 3B).
The overall reactogenicity was consistent with that reported in a phase 2 clinical trial of ZF2001.12 In the current trial, 98.5% of the adverse reactions in the ZF2001 group were of grade 1 and 2, according to the criteria of the National Medical Products Administration (Tables S17 through S20), and 1.5% were of grade 3 or higher. The second and third injections did not further increase the incidence of adverse reactions (Table S21).
Serious adverse events were reported by 463 participants (1.6%) — 199 (1.4%) in the ZF2001 group and 264 (1.8%) in the placebo group (Table S23). A total of 4 participants (2 ZF2001 recipients and 2 placebo recipients) reported serious adverse events that were determined by the trial investigators to be related to the investigational products in terms of hypersensitivity. All symptoms resolved after medical treatment without sequelae (Table S24). A total of 48 deaths were documented, but none were attributed to the investigational products (Table S25). No cases of antibody-dependent enhancement or vaccine-enhanced disease were confirmed.
The incidence of adverse events was lower among the participants 60 years of age or older than among those 18 to 59 years of age (28.8% vs. 42.3%), as were the incidences of unsolicited and solicited adverse events and local and systemic reactions (Figure 3A). Among the participants 60 years of age or older in the ZF2001 group, reactogenicity events were mainly grade 1 and 2 (96.7% of events), and no vaccine-related serious adverse events occurred.
