英国牛津大学Andrew J Pollard团队研究了ChAdOx1 nCoV-19（AZD1222）疫苗的单剂量给药和加强剂量给药间隔对免疫原性和有效性的影响。2021年2月19日，该研究发表在《柳叶刀》杂志上。
ChAdOx1 nCoV-19（AZD1222）疫苗已被英国药品和保健品管理局批准可紧急使用，标准两剂的方案间隔4-12周。目前英国计划推广该疫苗，包括立即给高危人群接种第一剂疫苗，并在12周后提供第二剂疫苗。研究组提供了ChAdOx1-nCoV-19试验的进一步预先指定的汇总分析，以及对免疫原性的影响和延长初次剂量和增强剂量间隔的疗效的探索性分析，此外还揭示了第一次注射的免疫原性和保护作用。
研究组提供了三个单盲随机对照试验的数据，其中一个是英国的临床1/2期研究（COV001），一个是英国的临床2/3期研究（COV002），一个是巴西的临床3期研究（COV003）；另外还提供了一个南非的双盲临床1/2期研究（COV005）。研究组招募18岁及以上的参与者，并将其按1：1随机分配，分别接受标准两剂的ChAdOx1-nCoV-19（5×1010病毒颗粒），或对照疫苗与生理盐水安慰剂。
在英国的试验中，一部分受试者初次接种较低剂量的ChAdOx1-nCoV-19（2.2×1010个病毒颗粒）。主要结局是经病毒学证实的症状性COVID-19病，定义为第二次接种后14天及以上核酸扩增试验（NAAT）拭子呈阳性，并至少有一种符合条件的症状（发烧≥37.8℃、咳嗽、呼吸急促或嗅觉缺失或味觉丧失）。次要疗效分析包括首次接种后22天以上的发病受试者。
2020年4月23日至12月6日，四项研究共招募了24422名参与者并接种了疫苗，其中17178名参与者被纳入初步分析（8597名参与者接种了ChAdOx1 nCoV-19，8581名参与者接种了对照疫苗），截止到2020年12月7日。第二次接种后14天以上，共有332例NAAT阳性感染符合症状性感染的主要结局。
第二次给药14天后的疫苗总有效率为66.7%，ChAdOx1-nCoV-19组8597名受试者中有84名（1.0%）患COVID-19，对照组8581名受试者中有248名（2.9%）。在最初的21天排除期后，ChAdOx1 nCoV-19组无一例因COVID-19入院，对照组有15例。ChAdOx1 nCoV-19组12282名参与者中有108名（0.9%）出现严重不良事件，对照组11962名参与者中有127名（1.1%）。
有7例死亡被认为与疫苗接种无关（2例在ChAdOx1-nCov-19组，5例在对照组），包括对照组中与COVID-19相关的1例死亡。探索性分析表明，从接种后第22天到第90天，单次标准剂量疫苗接种后的疫苗效力为76.0%。模型分析表明，在最初的3个月期间，保护作用没有减弱。同样，抗体水平在这段时间内保持不变，到第90天时下降幅度最小。
在接受两次标准剂量的受试者中，第二次接种后，初始增强间隔时间较长的受试者（疫苗有效期≥12周时为81.3%）的疗效高于间隔时间较短的受试者（疫苗有效期<6周时为55.1%）。免疫原性数据显示，年龄在18-55岁的人群在间隔12周或更长时间后，与间隔不到6周的人群相比，结合抗体反应高出2倍以上。
研究结果表明，两剂ChAdOx1-nCoV-19的初步分析结果与试验中期分析结果一致，证实疫苗有效，探索性分析的结果因剂量间隔时间而异，3个月的剂量间隔优于较短的剂量间隔方案。
附：英文原文
Title: 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
Author: Merryn Voysey, Sue Ann Costa Clemens, Shabir A Madhi, Lily Y Weckx, Pedro M Folegatti, Parvinder K Aley, Brian Angus, Vicky L Baillie, Shaun L Barnabas, Qasim E Bhorat, Sagida Bibi, Carmen Briner, Paola Cicconi, Elizabeth A Clutterbuck, Andrea M Collins, Clare L Cutland, Thomas C Darton, Keertan Dheda, Christina Dold, Christopher J A Duncan, Katherine R W Emary, Katie J Ewer, Amy Flaxman, Lee Fairlie, Saul N Faust, Shuo Feng, Daniela M Ferreira, Adam Finn, Eva Galiza, Anna L Goodman, Catherine M Green, Christopher A Green, Melanie Greenland, Catherine Hill, Helen C Hill, Ian Hirsch, Alane Izu, Daniel Jenkin, Carina C D Joe, Simon Kerridge, Anthonet Koen, Gaurav Kwatra, Rajeka Lazarus, Vincenzo Libri, Patrick J Lillie, Natalie G Marchevsky, Richard P Marshall, Ana V A Mendes, Eveline P Milan, Angela M Minassian, Alastair McGregor, Yama F Mujadidi, Anusha Nana, Sherman D Padayachee, Daniel J Phillips, Ana Pittella, Emma Plested, Katrina M Pollock, Maheshi N Ramasamy, Adam J Ritchie, Hannah Robinson, Alexandre V Schwarzbold, Andrew Smith, Rinn Song, Matthew D Snape, Eduardo Sprinz, Rebecca K Sutherland, Emma C Thomson
Issue&Volume: 2021-02-19
Abstract:
Background
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.
Methods
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).
Findings
Between April 23 and Dec 6, 2020, 24422 participants were recruited and vaccinated across the four studies, of whom 17178 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 12282 participants in the ChAdOx1 nCoV-19 group and 127 (1·1%) of 11962 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]).
Interpretation
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.
DOI: 10.1016/S0140-6736(21)00432-3
Source: https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(21)00432-3/fulltext
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