Safety and immunogenicity of ChAdOx1 nCoV-19 vaccine administered in a prime-boost regimen in young and old adults (COV002): a single-blind, randomised, controlled, phase 2/3 trial.
Safety and immunogenicity of ChAdOx1 nCoV-19 vaccine administered in a prime-boost regimen in young and old adults (COV002): a single-blind, randomised, controlled, phase 2/3 trial.
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DOI：
10.1016/s0140-6736(20)32466-1
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发表时间：
2021-12-19
期刊：
影响因子：
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通讯作者：
Oxford COVID Vaccine Trial Group
中科院分区：
文献类型：
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作者：
Ramasamy MN;Minassian AM;Ewer KJ;Flaxman AL;Folegatti PM;Owens DR;Voysey M;Aley PK;Angus B;Babbage G;Belij-Rammerstorfer S;Berry L;Bibi S;Bittaye M;Cathie K;Chappell H;Charlton S;Cicconi P;Clutterbuck EA;Colin-Jones R;Dold C;Emary KRW;Fedosyuk S;Fuskova M;Gbesemete D;Green C;Hallis B;Hou MM;Jenkin D;Joe CCD;Kelly EJ;Kerridge S;Lawrie AM;Lelliott A;Lwin MN;Makinson R;Marchevsky NG;Mujadidi Y;Munro APS;Pacurar M;Plested E;Rand J;Rawlinson T;Rhead S;Robinson H;Ritchie AJ;Ross-Russell AL;Saich S;Singh N;Smith CC;Snape MD;Song R;Tarrant R;Themistocleous Y;Thomas KM;Villafana TL;Warren SC;Watson MEE;Douglas AD;Hill AVS;Lambe T;Gilbert SC;Faust SN;Pollard AJ;Oxford COVID Vaccine Trial Group
老年人（年龄≥70岁）如果患上COVID-19，罹患严重疾病和死亡的风险会增加，因此，如果开发出有效的疫苗，应优先进行免疫接种。由于免疫衰老，老年人疫苗的免疫原性往往较差。我们已经报道了一种新型黑猩猩腺病毒载体疫苗ChAdOx1 nCoV-19 （AZD1222）在年轻人中的免疫原性，现在描述了这种疫苗在更广泛的参与者（包括70岁及以上的成年人）中的安全性和免疫原性。在这项单盲、随机、对照、2/3期试验（COV002）的2期组成部分的报告中，18岁及以上的健康成年人在两个英国临床研究机构以年龄递增的方式入组，分为18 - 55岁、56-69岁和70岁及以上的免疫原性亚组。如果参与者没有严重或无法控制的医疗合并症或高虚弱评分（年龄≥65岁），则符合条件。首先，参与者被招募到一个低剂量队列，在每个年龄组中，参与者被随机分配接受肌肉注射ChAdOx1 nCoV-19（2·2 × 1010病毒颗粒）或对照疫苗MenACWY，采用块随机化并按年龄、剂量组和研究地点分层，使用以下比例：在18-55岁组中，1:1接种两剂ChAdOx1 nCoV-19或两剂MenACWY；56 ~ 69岁组，1剂ChAdOx1 nCoV-19、1剂MenACWY、2剂ChAdOx1 nCoV-19或2剂MenACWY的比例为3:1:3:1；在70岁及以上的人群中，1剂ChAdOx1 nCoV-19、1剂MenACWY、2剂ChAdOx1 nCoV-19或2剂MenACWY的比例为5:1:5:1。初始强化方案间隔28天。然后将参与者招募到标准剂量队列（ChAdOx1 nCoV-19的3.5 - 6·5 × 1010病毒颗粒），并遵循相同的随机化程序，但18-55岁组以5:1的比例分配到两剂ChAdOx1 nCoV-19或两剂MenACWY。参与者和调查人员，而不是管理疫苗的工作人员，对疫苗分配不知情。本报告的具体目的是评估55岁以上成人单剂量和双剂量方案的安全性、体液和细胞免疫原性。使用内部标准化ELISA、多重免疫测定和活体严重急性呼吸综合征冠状病毒2型（SARS-CoV-2）微量中和测定（MNA80）评估基线时和每次疫苗接种后直至加强后1年的体液应答。使用体外IFN-γ酶联免疫斑点法评估细胞反应。该试验的主要结局是疗效（通过症状性病毒学确诊的COVID-19病例数来衡量）和安全性（通过严重不良事件的发生来衡量）。对接种疫苗的参与者进行分组分析。在这里，我们报告了安全性、反应原性以及细胞和体液免疫反应的初步结果。该研究正在进行中，注册号为ClinicalTrials.gov, NCT04400838， ISRCTN, 15281137。在2020年5月30日至8月8日期间，共招募了560名参与者：160名年龄在18-55岁之间（100名分配给ChAdOx1 nCoV-19, 60名分配给MenACWY）， 160名年龄在56-69岁之间（120名分配给ChAdOx1 ncov - 19,40名分配给MenACWY）， 240名年龄在70岁及以上（200名分配给ChAdOx1 ncov - 19,40名分配给MenACWY）。7名参与者没有接受他们指定的两剂方案的加强剂量，1名参与者接种了错误的疫苗，3名参与者由于错误标记的样本而被排除在免疫原性分析之外。552名可分析的参与者中有280名（50%）是女性。局部和全身反应在接种ChAdOx1 nCoV-19疫苗的参与者中比接种对照疫苗的参与者更常见，并且在性质上与先前报道的反应相似（注射部位疼痛、感觉发烧、肌肉疼痛、头痛），但在老年人（年龄≥56岁）中比年轻人更少见。在接受两次标准剂量ChAdOx1 nCoV-19疫苗接种后，18-55岁组49名参与者中有43名（88%）发生局部反应，56-69岁组30名（73%）发生局部反应，70岁及以上组49名（61%）发生全身反应，18-55岁组42名（86%），56-69岁组23名（77%），70岁及以上组32名（65%）发生全身反应。截至2020年10月26日，在研究期间发生了13起严重不良事件，其中没有一起被认为与两种研究疫苗有关。在接受两剂疫苗的参与者中，三个年龄队列（标准剂量组：18-55岁，20713任意单位[AU]/mL [IQR 13 898-33 550]， n=39； 56-69岁，16 170 AU/mL [10 233-40 353], n=26；≥70岁，17561 AU/mL [9705-37 796], n=47; p= 0.68）的中位抗刺升SARS-CoV-2 IgG应答相似。各年龄组增强剂量后的中和抗体效价相似（标准剂量组第42天的中位MNA80: 18-55岁，193 [IQR 113-238], n=39； 56-69岁，144 [119-347],n=20；≥70岁，161 [73-323],n=47; p= 0.40）。在增强剂量14天后，209名增强参与者中有208人（bbb99%）产生了中和抗体反应。单次标准剂量ChAdOx1 nCoV-19后，t细胞应答在第14天达到峰值（18-55岁：每百万外周血单个核细胞中位数为1187个斑点形成细胞[sfc] [IQR 841-2428]， n=24； 56-69岁：797个sfc [383-1817]， n=29；≥70岁：977个sfc [458-1914]， n=48）。ChAdOx1 nCoV-19在老年人中的耐受性似乎比在年轻人中更好，并且在增加剂量后，所有年龄组的免疫原性相似。有必要在所有年龄组和有合并症的个体中进一步评估该疫苗的疗效。英国研究与创新，国家卫生研究院（NIHR），流行病防范创新联盟，NIHR牛津生物医学研究中心，泰晤士河谷和南米德兰兹NIHR临床研究网络，以及阿斯利康。
Older adults (aged ≥70 years) are at increased risk of severe disease and death if they develop COVID-19 and are therefore a priority for immunisation should an efficacious vaccine be developed. Immunogenicity of vaccines is often worse in older adults as a result of immunosenescence. We have reported the immunogenicity of a novel chimpanzee adenovirus-vectored vaccine, ChAdOx1 nCoV-19 (AZD1222), in young adults, and now describe the safety and immunogenicity of this vaccine in a wider range of participants, including adults aged 70 years and older. In this report of the phase 2 component of a single-blind, randomised, controlled, phase 2/3 trial (COV002), healthy adults aged 18 years and older were enrolled at two UK clinical research facilities, in an age-escalation manner, into 18–55 years, 56–69 years, and 70 years and older immunogenicity subgroups. Participants were eligible if they did not have severe or uncontrolled medical comorbidities or a high frailty score (if aged ≥65 years). First, participants were recruited to a low-dose cohort, and within each age group, participants were randomly assigned to receive either intramuscular ChAdOx1 nCoV-19 (2·2 × 1010 virus particles) or a control vaccine, MenACWY, using block randomisation and stratified by age and dose group and study site, using the following ratios: in the 18–55 years group, 1:1 to either two doses of ChAdOx1 nCoV-19 or two doses of MenACWY; in the 56–69 years group, 3:1:3:1 to one dose of ChAdOx1 nCoV-19, one dose of MenACWY, two doses of ChAdOx1 nCoV-19, or two doses of MenACWY; and in the 70 years and older, 5:1:5:1 to one dose of ChAdOx1 nCoV-19, one dose of MenACWY, two doses of ChAdOx1 nCoV-19, or two doses of MenACWY. Prime-booster regimens were given 28 days apart. Participants were then recruited to the standard-dose cohort (3·5–6·5 × 1010 virus particles of ChAdOx1 nCoV-19) and the same randomisation procedures were followed, except the 18–55 years group was assigned in a 5:1 ratio to two doses of ChAdOx1 nCoV-19 or two doses of MenACWY. Participants and investigators, but not staff administering the vaccine, were masked to vaccine allocation. The specific objectives of this report were to assess the safety and humoral and cellular immunogenicity of a single-dose and two-dose schedule in adults older than 55 years. Humoral responses at baseline and after each vaccination until 1 year after the booster were assessed using an in-house standardised ELISA, a multiplex immunoassay, and a live severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) microneutralisation assay (MNA80). Cellular responses were assessed using an ex-vivo IFN-γ enzyme-linked immunospot assay. The coprimary outcomes of the trial were efficacy, as measured by the number of cases of symptomatic, virologically confirmed COVID-19, and safety, as measured by the occurrence of serious adverse events. Analyses were by group allocation in participants who received the vaccine. Here, we report the preliminary findings on safety, reactogenicity, and cellular and humoral immune responses. This study is ongoing and is registered with ClinicalTrials.gov, NCT04400838, and ISRCTN, 15281137. Between May 30 and Aug 8, 2020, 560 participants were enrolled: 160 aged 18–55 years (100 assigned to ChAdOx1 nCoV-19, 60 assigned to MenACWY), 160 aged 56–69 years (120 assigned to ChAdOx1 nCoV-19: 40 assigned to MenACWY), and 240 aged 70 years and older (200 assigned to ChAdOx1 nCoV-19: 40 assigned to MenACWY). Seven participants did not receive the boost dose of their assigned two-dose regimen, one participant received the incorrect vaccine, and three were excluded from immunogenicity analyses due to incorrectly labelled samples. 280 (50%) of 552 analysable participants were female. Local and systemic reactions were more common in participants given ChAdOx1 nCoV-19 than in those given the control vaccine, and similar in nature to those previously reported (injection-site pain, feeling feverish, muscle ache, headache), but were less common in older adults (aged ≥56 years) than younger adults. In those receiving two standard doses of ChAdOx1 nCoV-19, after the prime vaccination local reactions were reported in 43 (88%) of 49 participants in the 18–55 years group, 22 (73%) of 30 in the 56–69 years group, and 30 (61%) of 49 in the 70 years and older group, and systemic reactions in 42 (86%) participants in the 18–55 years group, 23 (77%) in the 56–69 years group, and 32 (65%) in the 70 years and older group. As of Oct 26, 2020, 13 serious adverse events occurred during the study period, none of which were considered to be related to either study vaccine. In participants who received two doses of vaccine, median anti-spike SARS-CoV-2 IgG responses 28 days after the boost dose were similar across the three age cohorts (standard-dose groups: 18–55 years, 20 713 arbitrary units [AU]/mL [IQR 13 898–33 550], n=39; 56–69 years, 16 170 AU/mL [10 233–40 353], n=26; and ≥70 years 17 561 AU/mL [9705–37 796], n=47; p=0·68). Neutralising antibody titres after a boost dose were similar across all age groups (median MNA80 at day 42 in the standard-dose groups: 18–55 years, 193 [IQR 113–238], n=39; 56–69 years, 144 [119–347], n=20; and ≥70 years, 161 [73–323], n=47; p=0·40). By 14 days after the boost dose, 208 (>99%) of 209 boosted participants had neutralising antibody responses. T-cell responses peaked at day 14 after a single standard dose of ChAdOx1 nCoV-19 (18–55 years: median 1187 spot-forming cells [SFCs] per million peripheral blood mononuclear cells [IQR 841–2428], n=24; 56–69 years: 797 SFCs [383–1817], n=29; and ≥70 years: 977 SFCs [458–1914], n=48). ChAdOx1 nCoV-19 appears to be better tolerated in older adults than in younger adults and has similar immunogenicity across all age groups after a boost dose. Further assessment of the efficacy of this vaccine is warranted in all age groups and individuals with comorbidities. UK Research and Innovation, National Institutes for Health Research (NIHR), Coalition for Epidemic Preparedness Innovations, NIHR Oxford Biomedical Research Centre, Thames Valley and South Midlands NIHR Clinical Research Network, and AstraZeneca.