Safety and immunogenicity of heterologous versus homologous prime-boost schedules with an adenoviral vectored and mRNA COVID-19 vaccine (Com-COV): a single-blind, randomised, non-inferiority trial.
Safety and immunogenicity of heterologous versus homologous prime-boost schedules with an adenoviral vectored and mRNA COVID-19 vaccine (Com-COV): a single-blind, randomised, non-inferiority trial.
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DOI：
10.1016/s0140-6736(21)01694-9
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发表时间：
2021-09-04
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通讯作者：
Com-COV Study Group
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作者：
Liu X;Shaw RH;Stuart ASV;Greenland M;Aley PK;Andrews NJ;Cameron JC;Charlton S;Clutterbuck EA;Collins AM;Dinesh T;England A;Faust SN;Ferreira DM;Finn A;Green CA;Hallis B;Heath PT;Hill H;Lambe T;Lazarus R;Libri V;Long F;Mujadidi YF;Plested EL;Provstgaard-Morys S;Ramasamy MN;Ramsay M;Read RC;Robinson H;Singh N;Turner DPJ;Turner PJ;Walker LL;White R;Nguyen-Van-Tam JS;Snape MD;Com-COV Study Group
使用异源初免-加强COVID-19疫苗时间表可以促进大规模COVID-19免疫接种。然而，我们之前已经报道了以4周间隔掺入腺病毒载体疫苗（ChAdOx1 nCoV-19，AstraZeneca;下文称为ChAd）和mRNA疫苗（BNT 162b2，Pfizer-BioNTech;下文称为BNT）的异源方案比同源方案更具反应原性。在这里，我们报告了ChAd和BNT疫苗的异源时间表的安全性和免疫原性。Com-COV是一项评估疫苗安全性、反应原性和免疫原性的受试者设盲、随机、非劣效性试验。年龄在50岁及以上，无合并症或合并症控制良好，且经实验室确认既往无SARS-CoV-2感染的成年人符合条件，并在英国的8个地点招募。大多数合格的参与者被招募到一般队列（28天或84天的预充-加强间隔），他们被随机分配（1：1：1：1：1：1：1）接受ChAd/ChAd，ChAd/BNT，BNT/BNT或BNT/ChAd，以28天或84天的预充-加强间隔给药。一小部分合格的参与者（n = 100）被纳入免疫学队列，他们进行了额外的血液检查以评估免疫应答;这些参与者被随机分配（1：1：1：1）到四个时间表（仅28天间隔）。受试者对接受的疫苗设盲，但不对预充-加强间隔设盲。主要终点是在加强免疫后28天血清SARS-CoV-2抗刺突IgG浓度（通过ELISA测量）的几何平均值比（GMR），比较ChAd/BNT与ChAd/ChAd，BNT/ChAd与BNT/BNT。如果这些比较的GMR的单侧97.5%CI下限大于0.63，则认为异源方案不劣于批准的同源方案。主要分析在基线血清阴性的符合方案人群中进行。在接受至少一剂研究疫苗的参与者中进行安全性分析。该试验已在ISRCTN注册，编号69254139。在2021年2月11日至2月26日期间，830名参与者入组并随机分配，其中463名参与者的预充-加强间隔为28天，此处报告了他们的结果。参与者的平均年龄为57.8岁（SD 4.7），其中212名（46%）女性参与者和117名（25%）来自少数民族。加强后第28天，ChAd/BNT受体中SARS-CoV-2抗刺突IgG的几何平均浓度（12 906 ELU/mL）不劣于ChAd/ChAd受体（1392 ELU/mL），GMR为9·2（单侧97·5%CI 7·5至∞）。 在接受BNT预处理的受试者中，我们未显示异源方案（BNT/ChAd，7133 ELU/mL）相对于同源方案（BNT/BNT，14080 ELU/mL）的非劣效性，GMR为0.51（单侧97.5%CI 0.43至∞）。 所有组均发生了4起严重不良事件，认为均与免疫接种无关。尽管BNT/ChAd方案不符合非劣效性标准，但两种异源方案的SARS-CoV-2抗加标IgG浓度均高于已获许可的疫苗方案（ChAd/ChAd），该方案已证明对COVID-19疾病和住院有效。沿着与ChAD/ChAd相比ChAd/BNT的免疫原性更高，这些数据支持使用ChAd和BNT COVID-19疫苗的异源初免-加强疫苗接种的灵活性。英国疫苗工作组和国家卫生研究所。
Use of heterologous prime-boost COVID-19 vaccine schedules could facilitate mass COVID-19 immunisation. However, we have previously reported that heterologous schedules incorporating an adenoviral vectored vaccine (ChAdOx1 nCoV-19, AstraZeneca; hereafter referred to as ChAd) and an mRNA vaccine (BNT162b2, Pfizer–BioNTech; hereafter referred to as BNT) at a 4-week interval are more reactogenic than homologous schedules. Here, we report the safety and immunogenicity of heterologous schedules with the ChAd and BNT vaccines. Com-COV is a participant-blinded, randomised, non-inferiority trial evaluating vaccine safety, reactogenicity, and immunogenicity. Adults aged 50 years and older with no or well controlled comorbidities and no previous SARS-CoV-2 infection by laboratory confirmation were eligible and were recruited at eight sites across the UK. The majority of eligible participants were enrolled into the general cohort (28-day or 84-day prime-boost intervals), who were randomly assigned (1:1:1:1:1:1:1:1) to receive ChAd/ChAd, ChAd/BNT, BNT/BNT, or BNT/ChAd, administered at either 28-day or 84-day prime-boost intervals. A small subset of eligible participants (n=100) were enrolled into an immunology cohort, who had additional blood tests to evaluate immune responses; these participants were randomly assigned (1:1:1:1) to the four schedules (28-day interval only). Participants were masked to the vaccine received but not to the prime-boost interval. The primary endpoint was the geometric mean ratio (GMR) of serum SARS-CoV-2 anti-spike IgG concentration (measured by ELISA) at 28 days after boost, when comparing ChAd/BNT with ChAd/ChAd, and BNT/ChAd with BNT/BNT. The heterologous schedules were considered non-inferior to the approved homologous schedules if the lower limit of the one-sided 97·5% CI of the GMR of these comparisons was greater than 0·63. The primary analysis was done in the per-protocol population, who were seronegative at baseline. Safety analyses were done among participants receiving at least one dose of a study vaccine. The trial is registered with ISRCTN, 69254139. Between Feb 11 and Feb 26, 2021, 830 participants were enrolled and randomised, including 463 participants with a 28-day prime-boost interval, for whom results are reported here. The mean age of participants was 57·8 years (SD 4·7), with 212 (46%) female participants and 117 (25%) from ethnic minorities. At day 28 post boost, the geometric mean concentration of SARS-CoV-2 anti-spike IgG in ChAd/BNT recipients (12 906 ELU/mL) was non-inferior to that in ChAd/ChAd recipients (1392 ELU/mL), with a GMR of 9·2 (one-sided 97·5% CI 7·5 to ∞). In participants primed with BNT, we did not show non-inferiority of the heterologous schedule (BNT/ChAd, 7133 ELU/mL) against the homologous schedule (BNT/BNT, 14 080 ELU/mL), with a GMR of 0·51 (one-sided 97·5% CI 0·43 to ∞). Four serious adverse events occurred across all groups, none of which were considered to be related to immunisation. Despite the BNT/ChAd regimen not meeting non-inferiority criteria, the SARS-CoV-2 anti-spike IgG concentrations of both heterologous schedules were higher than that of a licensed vaccine schedule (ChAd/ChAd) with proven efficacy against COVID-19 disease and hospitalisation. Along with the higher immunogenicity of ChAd/BNT compared with ChAD/ChAd, these data support flexibility in the use of heterologous prime-boost vaccination using ChAd and BNT COVID-19 vaccines. UK Vaccine Task Force and National Institute for Health Research.