Single-dose administration and the influence of the timing of the booster dose on immunogenicity and efficacy of ChAdOx1 nCoV-19 (AZD1222) vaccine: a pooled analysis of four randomised trials.
Single-dose administration and the influence of the timing of the booster dose on immunogenicity and efficacy of ChAdOx1 nCoV-19 (AZD1222) vaccine: a pooled analysis of four randomised trials.
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DOI：
10.1016/s0140-6736(21)00432-3
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发表时间：
2021-03-06
期刊：
影响因子：
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通讯作者：
Oxford COVID Vaccine Trial Group
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作者：
Voysey M;Costa Clemens SA;Madhi SA;Weckx LY;Folegatti PM;Aley PK;Angus B;Baillie VL;Barnabas SL;Bhorat QE;Bibi S;Briner C;Cicconi P;Clutterbuck EA;Collins AM;Cutland CL;Darton TC;Dheda K;Dold C;Duncan CJA;Emary KRW;Ewer KJ;Flaxman A;Fairlie L;Faust SN;Feng S;Ferreira DM;Finn A;Galiza E;Goodman AL;Green CM;Green CA;Greenland M;Hill C;Hill HC;Hirsch I;Izu A;Jenkin D;Joe CCD;Kerridge S;Koen A;Kwatra G;Lazarus R;Libri V;Lillie PJ;Marchevsky NG;Marshall RP;Mendes AVA;Milan EP;Minassian AM;McGregor A;Mujadidi YF;Nana A;Padayachee SD;Phillips DJ;Pittella A;Plested E;Pollock KM;Ramasamy MN;Ritchie AJ;Robinson H;Schwarzbold AV;Smith A;Song R;Snape MD;Sprinz E;Sutherland RK;Thomson EC;Török ME;Toshner M;Turner DPJ;Vekemans J;Villafana TL;White T;Williams CJ;Douglas AD;Hill AVS;Lambe T;Gilbert SC;Pollard AJ;Oxford COVID Vaccine Trial Group
ChAdOx 1 nCoV-19（AZD 1222）疫苗已被英国药品和保健品管理局批准紧急使用，方案为两次标准剂量，间隔4-12周。计划在英国推出的疫苗将包括立即为高危人群接种第一剂疫苗，并在12周后接种第二剂疫苗。在这里，我们提供了ChAdOx 1 nCoV-19试验的进一步预先规定的汇总分析，以及延长初免和加强剂量之间的间隔对免疫原性和疗效影响的探索性分析。此外，我们还显示了在提供加强剂量之前，第一剂疫苗的免疫原性和保护作用。我们提供了三项单盲随机对照试验的数据-一项在英国进行的1/2期研究（COV 001），一项在英国进行的2/3期研究（COV 002），一项在巴西进行的3期研究（COV 003）-以及一项在南非进行的双盲1/2期研究（COV 005）。如前所述，18岁及以上的个体以1：1的比例随机分配接受两种标准剂量的ChAdOx 1 nCoV-19（5 × 1010个病毒颗粒）或对照疫苗或生理盐水安慰剂。 在英国的试验中，一部分参与者接受了较低剂量（2.2 × 1010个病毒颗粒）的ChAdOx 1 nCoV-19作为第一剂。 主要结局是病毒学证实的症状性COVID-19疾病，定义为核酸扩增试验（NAAT）阳性拭子伴至少一种合格症状（发热≥37·8°C、咳嗽、呼吸急促或嗅觉丧失或味觉丧失），第二剂给药后超过14天。次要疗效分析包括首次给药后至少22天发生的病例。通过免疫测定和假病毒中和测定的抗体应答是探索性结局。所有NAAT阳性拭子的COVID-19病例均由设盲的独立终点审查委员会裁定纳入分析。主要分析包括所有基线时SARS-CoV-2 N蛋白血清阴性的参与者，第二次给药后至少随访14天，并且NAAT拭子没有既往SARS-CoV-2感染的证据。在所有接受至少一次剂量的参与者中评估安全性。这四项试验在ISRCTN 89951424（COV 003）和ClinicalTrials.gov、NCT 04324606（COV 001）、NCT 04400838（COV 002）和NCT 04444674（COV 005）上注册。在2020年4月23日至12月6日期间，四项研究共招募了24422名参与者并接种了疫苗，其中17178名参与者被纳入主要分析（8597名接受ChAdOx 1 nCoV-19，8581名接受对照疫苗）。 这些分析的数据截止日期为2020年12月7日。332例NAAT阳性感染者在第二次给药后超过14天满足症状性感染的主要终点。第二次接种后超过14天的总体疫苗有效性为66.7%（95% CI 57.4 - 74.0），ChAdOx 1 nCoV-19组8597例受试者中有84例（1.0%），对照组8581例受试者中有248例（2.9%）。在最初的21天排除期后，ChAdOx 1 nCoV-19组没有因COVID-19住院，对照组有15人。ChAdOx 1 nCoV-19组12282例受试者中有108例（0.9%）和对照组11962例受试者中有127例（1.1%）发生严重不良事件。 有7例死亡被认为与疫苗接种无关（ChAdOx 1 nCov-19组2例，对照组5例），包括对照组1名参与者的1例COVID-19相关死亡。探索性分析显示，接种后第22天至第90天单次标准剂量疫苗后的疫苗有效率为76.0%（59.3 - 85.9）。我们的建模分析表明，在最初的3个月期间，保护并没有减弱。类似地，在此期间抗体水平得以维持，至第90天抗体水平最小程度下降（几何平均值比[GMR] 0·66 [95% CI 0·59-0·74]）。在接受两次标准剂量的受试者中，在第二次剂量后，具有较长预充-加强间隔的受试者的有效性（≥12周的疫苗有效性为81.3%[95%CI 60.3 - 91.2]）高于具有短间隔的受试者（<6周的疫苗有效性为55.1%[33.0 - 69.9]）。这些观察结果得到免疫原性数据的支持，免疫原性数据显示，在18-55岁的受试者中，间隔12周或更长时间后的结合抗体应答是间隔小于6周的2倍以上（GMR 2·32 [2·01-2·68]）。两种剂量ChAdOx 1 nCoV-19的初步分析结果与试验中期分析中观察到的结果一致，证实疫苗有效，探索性分析中的结果因剂量间隔而异。3个月的给药间隔可能比短给药间隔的计划更有优势，以便在供应稀缺时尽早推出大流行疫苗，以保护人口中最大数量的个体，同时在接受第二剂疫苗后也能提高保护。英国研究和创新，国家卫生研究院（NIHR），流行病防范创新联盟，比尔和梅林达盖茨基金会，莱曼基金会，雷德D 'Or，布拉瓦和Telles基金会，NIHR牛津生物医学研究中心，泰晤士河谷和南米德兰的NIHR临床研究网络，以及阿斯利康。
The ChAdOx1 nCoV-19 (AZD1222) vaccine has been approved for emergency use by the UK regulatory authority, Medicines and Healthcare products Regulatory Agency, with a regimen of two standard doses given with an interval of 4–12 weeks. The planned roll-out in the UK will involve vaccinating people in high-risk categories with their first dose immediately, and delivering the second dose 12 weeks later. Here, we provide both a further prespecified pooled analysis of trials of ChAdOx1 nCoV-19 and exploratory analyses of the impact on immunogenicity and efficacy of extending the interval between priming and booster doses. In addition, we show the immunogenicity and protection afforded by the first dose, before a booster dose has been offered. We present data from three single-blind randomised controlled trials—one phase 1/2 study in the UK (COV001), one phase 2/3 study in the UK (COV002), and a phase 3 study in Brazil (COV003)—and one double-blind phase 1/2 study in South Africa (COV005). As previously described, individuals 18 years and older were randomly assigned 1:1 to receive two standard doses of ChAdOx1 nCoV-19 (5 × 1010 viral particles) or a control vaccine or saline placebo. In the UK trial, a subset of participants received a lower dose (2·2 × 1010 viral particles) of the ChAdOx1 nCoV-19 for the first dose. The primary outcome was virologically confirmed symptomatic COVID-19 disease, defined as a nucleic acid amplification test (NAAT)-positive swab combined with at least one qualifying symptom (fever ≥37·8°C, cough, shortness of breath, or anosmia or ageusia) more than 14 days after the second dose. Secondary efficacy analyses included cases occuring at least 22 days after the first dose. Antibody responses measured by immunoassay and by pseudovirus neutralisation were exploratory outcomes. All cases of COVID-19 with a NAAT-positive swab were adjudicated for inclusion in the analysis by a masked independent endpoint review committee. The primary analysis included all participants who were SARS-CoV-2 N protein seronegative at baseline, had had at least 14 days of follow-up after the second dose, and had no evidence of previous SARS-CoV-2 infection from NAAT swabs. Safety was assessed in all participants who received at least one dose. The four trials are registered at ISRCTN89951424 (COV003) and ClinicalTrials.gov, NCT04324606 (COV001), NCT04400838 (COV002), and NCT04444674 (COV005). Between April 23 and Dec 6, 2020, 24 422 participants were recruited and vaccinated across the four studies, of whom 17 178 were included in the primary analysis (8597 receiving ChAdOx1 nCoV-19 and 8581 receiving control vaccine). The data cutoff for these analyses was Dec 7, 2020. 332 NAAT-positive infections met the primary endpoint of symptomatic infection more than 14 days after the second dose. Overall vaccine efficacy more than 14 days after the second dose was 66·7% (95% CI 57·4–74·0), with 84 (1·0%) cases in the 8597 participants in the ChAdOx1 nCoV-19 group and 248 (2·9%) in the 8581 participants in the control group. There were no hospital admissions for COVID-19 in the ChAdOx1 nCoV-19 group after the initial 21-day exclusion period, and 15 in the control group. 108 (0·9%) of 12 282 participants in the ChAdOx1 nCoV-19 group and 127 (1·1%) of 11 962 participants in the control group had serious adverse events. There were seven deaths considered unrelated to vaccination (two in the ChAdOx1 nCov-19 group and five in the control group), including one COVID-19-related death in one participant in the control group. Exploratory analyses showed that vaccine efficacy after a single standard dose of vaccine from day 22 to day 90 after vaccination was 76·0% (59·3–85·9). Our modelling analysis indicated that protection did not wane during this initial 3-month period. Similarly, antibody levels were maintained during this period with minimal waning by day 90 (geometric mean ratio [GMR] 0·66 [95% CI 0·59–0·74]). In the participants who received two standard doses, after the second dose, efficacy was higher in those with a longer prime-boost interval (vaccine efficacy 81·3% [95% CI 60·3–91·2] at ≥12 weeks) than in those with a short interval (vaccine efficacy 55·1% [33·0–69·9] at <6 weeks). These observations are supported by immunogenicity data that showed binding antibody responses more than two-fold higher after an interval of 12 or more weeks compared with an interval of less than 6 weeks in those who were aged 18–55 years (GMR 2·32 [2·01–2·68]). The results of this primary analysis of two doses of ChAdOx1 nCoV-19 were consistent with those seen in the interim analysis of the trials and confirm that the vaccine is efficacious, with results varying by dose interval in exploratory analyses. A 3-month dose interval might have advantages over a programme with a short dose interval for roll-out of a pandemic vaccine to protect the largest number of individuals in the population as early as possible when supplies are scarce, while also improving protection after receiving a second dose. UK Research and Innovation, National Institutes of Health Research (NIHR), The Coalition for Epidemic Preparedness Innovations, the Bill & Melinda Gates Foundation, the Lemann Foundation, Rede D’Or, the Brava and Telles Foundation, NIHR Oxford Biomedical Research Centre, Thames Valley and South Midland's NIHR Clinical Research Network, and AstraZeneca.