Szczepionka przeciw COVID-19 (rekombinowana, z adiuwantem, adsorbowana)

Pharmacotherapeutic group: vaccines, COVID-19 vaccines, RNA-based vaccine, ATC code: J07BN01 Mechanism of action Kostaive contains self-amplifying mRNA encoding the SARS-CoV-2 spike protein, encapsulated in lipid nanoparticles. The self-amplifying mRNA is designed so that, following intramuscular injection, additional copies of mRNA are generated in host cells to achieve enhanced expression of the spike protein antigen. This elicits a neutralising antibody and cellular immune response against the spike antigen, contributing to protection against COVID-19. The mRNA self-amplification process is transient and does not generate infectious particles. Clinical efficacy Trial ARCT-154-01 was a randomised, observer-blinded, controlled, multicentre clinical trial conducted in participants aged 18 years and older in Vietnam at a time when the delta variant was dominant. Efficacy was assessed in the analysed mITT set and included 15,458 participants, 7,762 in the Kostaive (zapomeran) group and 7,696 in the placebo group. Randomisation was stratified by age (< 60 or ≥ 60 years) and, in participants aged < 60 years, by risk of severe COVID-19 (those with asthma, cancer, cerebrovascular disease, chronic kidney/liver/lung disease, cystic fibrosis, type 1 or type 2 diabetes mellitus, cardiovascular disease, mental health conditions, smoking, pulmonary fibrosis, Down syndrome, obesity, sickle cell disease, or substance use disorder). All participants aged ≥ 60 years were considered to be at high risk of severe COVID-19. Among participants who received Kostaive, 5.5% (n = 485) had a serious underlying condition, including cardiovascular disease, diabetes, obesity, hepatic disorders, chronic obstructive pulmonary disease (COPD) and asthma. Participants who were immunocompromised, including those known to have a diagnosis of human immunodeficiency virus (HIV) or taking immunosuppressive medication, and those with prior clinical or microbiological diagnosis of COVID-19, were excluded from the trial. Participants with pre-existing acute or chronic illness, including those known to be infected with hepatitis C virus (HCV) or hepatitis B virus (HBV), were eligible for enrolment. Demographic and baseline characteristics were similar between groups across the 2 age cohorts and risk groups. Of the total participants who received Kostaive, 49% were male and 51% were female, 99.6% were Asian and 0.4% were described as "other" race. The mean age of the population at the time of vaccination was 46.4 years (age range 18–89 years). The overall primary efficacy endpoint was vaccine efficacy (VE), defined as the first occurrence of protocol-defined virologically confirmed COVID-19 with onset between Day 36 (7 days after Dose 2) and Day 92, inclusive. In participants without evidence of SARS-CoV-2 infection prior to 7 days after Dose 2, vaccine efficacy against confirmed COVID-19 at least 7 days after Dose 2 was 56.7% (95% confidence interval: 48.8% to 63.4%). The number of COVID-19 cases was 200 in the Kostaive group and 440 in the placebo group. At the time of the primary efficacy analysis, participants were followed for symptomatic COVID-19 for a total of 1,146 person-years in the Kostaive group and 1,120 person-years in the placebo group. Information on the overall vaccine efficacy assessment is presented in Table 2. Table 2 Vaccine efficacy against protocol-defined virologically confirmed COVID-19 between Day 36 and Day 92 – modified intent-to-treat population (mITT) Subgroup Kostaive Placebo VE % (95% CI) a All participants N 7,762 7,696 56.7 (48.8–63.4) Number of confirmed COVID-19 cases, n (%) 200 (2.6) 440 (5.7) Follow-up time b (person-years) 1,146.2 1,120.2 Healthy participants aged ≥ 18 to < 60 years N 3,882 3,896 49.8 (37.8–59.5) Number of confirmed COVID-19 cases, n (%) 126 (3.2) 246 (6.3) Follow-up time b (person-years) 572.1 566.1 At-risk participants aged ≥ 18 to < 60 years N 2,519 2,471 69.7 (57.6–78.3) Number of confirmed COVID-19 cases, n (%) 46 (1.8) 138 (5.6) Follow-up time b (person-years) 372.9 359.5 Participants aged ≥ 60 years N 1,361 1,329 53.5 (26.8–70.5) Number of confirmed COVID-19 cases, n (%) 28 (2.1) 56 (4.2) Follow-up time b (person-years) 201.2 194.5 Abbreviations: CI, confidence interval; COVID-19, coronavirus disease 2019; HR, hazard ratio; N, number of at-risk participants; n, number of participants with reported cases; RR, relative risk; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; VE, vaccine efficacy. mITT, modified intent-to-treat (includes all participants who received all doses of the trial vaccine required by the protocol (Kostaive or placebo) up to the time of evaluation and who had no evidence of SARS-CoV-2 infection on Day 1 or up to 7 days after the second vaccination in the trial). "At-risk participants" were defined as individuals considered to be at high risk of developing severe COVID-19. a VE is calculated as 1-HR from a Cox regression model adjusted for risk group and trial site region. b Follow-up time refers to the total person-years at risk for the given endpoint. Efficacy against severe COVID-19 The efficacy of Kostaive was evaluated for the prevention of virologically confirmed severe COVID-19, including death (Table 3). Severe COVID-19 included any of the following: respiratory rate ≥ 30 per minute, heart rate ≥ 125 per minute, oxygen saturation (SpO2) ≤ 93% on room air at sea level or partial pressure of arterial oxygen (PO2)/fraction of inspired oxygen (FiO2) < 300 mm Hg, respiratory failure (defined as the need for high-flow oxygen, non-invasive ventilation, mechanical ventilation, or extracorporeal membrane oxygenation (ECMO)), shock (defined as systolic blood pressure < 90 mm Hg, diastolic blood pressure < 60 mm Hg, or requirement for vasopressors), severe acute renal, hepatic or neurological dysfunction, admission to an intensive care unit, or death. The endpoint was the first occurrence of protocol-defined confirmed severe COVID-19 with onset between Day 36 and Day 92, inclusive. Table 3 Vaccine efficacy against protocol-defined virologically confirmed severe COVID-19 between Day 36 and Day 92 – modified intent-to-treat population (mITT) Subgroup Kostaive Placebo VE % (95% CI) a All participants N 7,762 7,696 95.3 (80.5–98.9) Number of confirmed COVID-19 cases, n (%) 2 (0.0) 41 (0.5) Follow-up time b (person-years) 1,162.9 1,154.7 Healthy participants aged ≥ 18 to < 60 years N 3,882 3,896 100.0 (NE) Number of confirmed COVID-19 cases, n (%) 0 (0.0) 15 (0.4) Follow-up time b (person-years) 582.7 585.8 At-risk participants aged ≥ 18 to < 60 years N 2,519 2,471 91.9 (37.9–98.9) Number of confirmed COVID-19 cases, n (%) 1 (0.0) 9 (0.4) Follow-up time b (person-years) 376.9 370.9 Participants aged ≥ 60 years N 1,364 1,329 94.4 (58.2–99.3) Number of confirmed COVID-19 cases, n (%) 1 (0.1) 17 (1.3) Follow-up time b (person-years) 203.4 197.9 Abbreviations: CI, confidence interval; COVID-19, coronavirus disease 2019; HR, hazard ratio; N, number of at-risk participants; n, number of participants with a reported case; NE, not estimable; RR, relative risk; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; VE, vaccine efficacy. mITT, modified intent-to-treat (includes all participants who received all doses of the trial vaccine required by the protocol (Kostaive or placebo) up to the time of evaluation and who had no evidence of SARS-CoV-2 infection on Day 1 or up to 7 days after the second vaccination in the trial) a VE is calculated as 1-HR from a Cox regression model adjusted for risk group and trial site region, or 1-RR when the number of confirmed cases in the Kostaive group is 0. b Follow-up time refers to the total person-years at risk for the given endpoint. Immunogenicity in participants aged 18 years and older following a booster dose Evaluation of booster-dose immunogenicity is based on results from study ARCT-154-J01, conducted in Japan, which compared the immune response after a booster dose of Kostaive (zapomeran) with a comparator vaccine (tozinameran, BNT162b2) in adults who had previously completed primary vaccination and received 1 booster dose of authorised mRNA COVID-19 vaccines. In this trial, immunogenicity was assessed using a virus neutralisation assay against the original SARS-CoV-2 strain and the omicron BA.4/5 variant. The primary objective of study ARCT-154-J01 was to demonstrate non-inferiority of Kostaive versus the comparator vaccine in terms of geometric mean antibody titre (GMT) ratio and difference in seroresponse rate (SRR) against the original SARS-CoV-2 strain on Day 29 post-vaccination. If non-inferiority for the original strain was demonstrated, similar testing was to be performed for the omicron BA.4/5 variant. Once the second non-inferiority was demonstrated, superiority of Kostaive versus the comparator vaccine for the omicron BA.4/5 variant was tested. Additional GMT testing through 12 months was conducted to evaluate the durability of the antibody response. A total of 828 participants were enrolled and randomised (1:1) to the Kostaive group and the comparator vaccine group. The mean age at the time of vaccination was 45.7 years (age range 18–77 years). Of the 828 participants randomised and dosed with the trial vaccine, 759 participants were included in the per-protocol set 1 (PPS-1), the analysis set for the primary immunogenicity endpoint. Results of study ARCT-154-J01 are presented in Table 4. Kostaive demonstrated non-inferiority to the comparator vaccine against the original SARS-CoV-2 strain and superiority against the omicron BA.4/5 variant one month after vaccination. Longer-term immunogenicity data showed that neutralising antibodies persisted, with approximately 2-fold higher GMTs observed for Kostaive versus the comparator vaccine for both strains at 3, 6 and 12 months post-vaccination. Table 4 Summary of immune response against the original SARS-CoV-2 strain and the omicron BA.4/5 variant through 12 months following the booster dose Strain Time point Endpoint GMT/SRR (95% CI) GMT ratio / SRR difference (95% CI) Na Kostaive Na Comparator vaccine* Original strain (Wuhan-Hu-1) Pre-vaccination GMT 385 813 (716, 924) 374 866 (755, 993) 0.94 (0.78, 1.13) 1 month GMT 385 5,641 (4,321, 7,363) 374 3,934 (2,993, 5,169) 1.43 b (1.26, 1.63) 1 month SRR 385 65.2 (60.2, 69.9) 374 51.6 (46.4, 56.8) 13.6 b (6.8, 20.5) 3 months GMT 369 5,928 (5,414, 6,491) 356 2,899 (2,648, 3,175) 2.04 c (1.80, 2.32) 6 months GMT 332 4,119 (3,723, 4,557) 313 1,861 (1,667, 2,078) 2.21 c (1.91, 2.57) 12 months GMT 272 3,396 (3,019, 3,821) 266 1,771 (1,532, 2,047) 1.92 c (1.59, 2.31) Omicron BA.4/5 Pre-vaccination GMT 385 275 (227, 335) 374 292 (236, 360) 0.94 (0.71, 1.26) 1 month GMT 385 2,551 (1,687, 3,859) 374 1,958 (1,281, 2,993) 1.30 d (1.07, 1.58) 1 month SRR 385 69.9 (65.0, 74.4) 374 58.0 (52.8, 63.1) 11.6 d (4.9, 18.3) 3 months GMT 369 1,892 (1,646, 2,175) 356 888 (764, 1,031) 2.13 c (1.74, 2.61) 6 months GMT 332 1,119 (960, 1,305) 313 495 (413, 595) 2.26 c (1.78, 2.86) 12 months GMT 272 881 (735, 1,057) 266 467 (376, 580) 1.89 c (1.42, 2.50) Abbreviations: CI – confidence interval; GMT – geometric mean titre; SARS-CoV-2 – severe acute respiratory syndrome coronavirus; SRR – seroresponse rate. The log-transformed neutralising antibody titre value for Day 29 (1 month) was analysed using an analysis of covariance (ANCOVA) model. Sex and time since the last (3rd) vaccination (< 5 months, ≥ 5 months) were used as pre-specified factors in the protocol. GMTs at baseline and at 3, 6 and 12 months are unadjusted. If the measured antibody titre is below the lower limit of quantification, the value was imputed as 1/2 of the limit of quantification. Seroresponse is defined as at least a 4-fold increase in neutralising antibody titres after the booster dose from the baseline titre, or from one half of the lower limit of quantification when undetectable at baseline. a N = number of participants with valid analysis results for the specific analysis at the given sampling time. b Pre-specified criteria were met for non-inferiority: the lower limit (LL) of the 95% confidence interval (CI) for the GMT ratio (Kostaive / comparator vaccine) exceeds 0.67 and the LL of the 95% CI for the SRR difference (Kostaive minus comparator vaccine) exceeds –10%. Superiority testing for the original strain was not pre-specified. The analysis was performed according to PPS-1. c The analysis was performed according to PPS-1-ic, a modified version of PPS-1 in which participants with a positive nucleocapsid antibody test were excluded from all subsequent immunogenicity analyses. d Pre-specified criteria were met for both non-inferiority and superiority. Superiority criteria: the LL of the 95% CI for the GMT ratio exceeds 1.0 and the LL of the 95% CI for the SRR difference exceeds 0%. The analysis was performed according to PPS-1. * Comparator vaccine: tozinameran (BNT162b2) Paediatric population The European Medicines Agency has deferred the obligation to submit the results of studies with Kostaive in one or more subsets of the paediatric population in the prevention of COVID-19 (see section 4.2 for information on paediatric use).