Efficacy and immunogenicity of R21/Matrix-M vaccine against clinical malaria after 2 years' follow-up in children in Burkina Faso: a phase 1/2b randomised controlled trial
Efficacy and immunogenicity of R21/Matrix-M vaccine against clinical malaria after 2 years' follow-up in children in Burkina Faso: a phase 1/2b randomised controlled trial
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DOI：
10.1016/s1473-3099(22)00442-x
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发表时间：
2022-11-23
影响因子：
56.3
通讯作者：
Tinto, Halidou
中科院分区：
文献类型：
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作者：
Datoo, Mehreen S.;Natama, Hamtandi Magloire;Tinto, Halidou
背景疟疾是世界范围内发病率和死亡率的主要原因。我们以前报告了R21/Matrix-M疟疾疫苗的效力，它达到了世卫组织规定的在12个月内在非洲儿童目标人群中取得75%或更高效力的目标。在这里，我们报告了加强疫苗接种后12个月的安全性、免疫原性和有效性结果。方法这项1/2b期双盲随机对照试验在布基纳法索纳诺罗的5-17个月大的儿童中进行。符合条件的儿童被登记并随机分配(1：1：1)，在疟疾季节之前接种三种疫苗，分别为5mgR21/25mgMatrix-M、5mgR21/50mgMatrix-M或对照疫苗(兔瘟-S狂犬病疫苗)，并在12个月后加强接种。如果父母或监护人能够提供书面知情同意，儿童就有资格被纳入。排除标准包括任何现有的临床显著合并症或接受其他研究产品。通过使用具有可变区块大小的区块随机化，由独立统计学家生成随机分配列表。牛津大学的一名研究助理独立于试验团队，使用这份清单准备了密封的信封，然后提供给研究药剂师分配参与者。所有疫苗都是由研究药剂师使用相同类型的注射器制备的，内容物用不透明的标签覆盖。在第一次加强接种后一年多的时间里，对疫苗的安全性、有效性以及有效性与免疫原性的潜在相关性(以抗NANP抗体滴度衡量)进行了评估。进行疗效分析的人群包括所有接受初级系列疫苗接种和加强免疫接种的参与者。如果参与者在接种加强疫苗后的头两周内退出试验，则被排除在疗效分析之外。这项试验已在ClinicalTrials.gov(NCT03896724)注册，并将继续进行两年，以评估额外加强疫苗剂量的潜在价值和长期安全性。研究发现，在2020年6月2日至7月2日期间，409名儿童返回接受加强疫苗接种。每个儿童都接受了与他们在初级系列疫苗接种中相同的强化免疫接种；132名参与者接受了5亩R21佐剂25微克Matrix-M，137名参与者接种了5微克R21佐剂50微克Matrix-M，140名参与者接种了对照疫苗。R21/Matrix-M具有良好的安全性，耐受性良好。高佐剂剂量(50微克)组的疫苗效力仍然很高，与先前在初级系列疫苗接种后1年的研究结果相似。加强免疫后，132名接受低剂量佐剂的R21/Matrix-M儿童中有67名(51%)，137名接受大剂量佐剂的R21/Matrix-M儿童中54名(39%)，以及接受狂犬病疫苗接种的140名儿童中121名(86%)在12个月后出现临床疟疾。低剂量佐剂组疫苗有效率为71%(95%CI为60~78)，高剂量佐剂组为80%(72~85)。在大剂量佐剂组中，第二年接种疫苗的儿童对多发疟疾的疫苗效力为78%(95%可信区间71到83)，每1000名高危儿童在第二年的随访中避免了2285例疟疾病例(95%可信区间1911到2568)。在这些参与者中，在最后一次接种R21/Matrix-M疫苗后的28天，疟疾特异性抗NANP抗体的滴度与第一年的疟疾防治呈正相关(Spearman‘s.-0中心点32[95%CI-0中心点45到0中心点19]；P=0中心点0001)和第二年随访(-0中心点20[-0中心点34至-0中心点06]；p=0中心点02)。解释R21/Matrix-M在最初的三剂方案后1年的加强剂量对首次和多次临床疟疾发作保持了高的疗效。此外，加强疫苗诱导的抗体浓度与疫苗效力相关。这项试验正在进行中，以评估这些参与者的长期随访和进一步加强接种的价值。版权所有(C)2022，作者(S)。由Elsevier Ltd出版。这是一篇CC BY-NC-ND 4.0许可证下的开放获取文章。
Background Malaria is a leading cause of morbidity and mortality worldwide. We previously reported the efficacy of the R21/Matrix-M malaria vaccine, which reached the WHO-specified goal of 75% or greater efficacy over 12 months in the target population of African children. Here, we report the safety, immunogenicity, and efficacy results at 12 months following administration of a booster vaccination. Methods This double-blind phase 1/2b randomised controlled trial was done in children aged 5-17 months in Nanoro, Burkina Faso. Eligible children were enrolled and randomly assigned (1:1:1) to receive three vaccinations of either 5 mu g R21/25 mu g Matrix-M, 5 mu g R21/50 mu g Matrix-M, or a control vaccine (the Rabivax-S rabies vaccine) before the malaria season, with a booster dose 12 months later. Children were eligible for inclusion if written informed consent could be provided by a parent or guardian. Exclusion criteria included any existing clinically significant comorbidity or receipt of other investigational products. A random allocation list was generated by an independent statistician by use of block randomisation with variable block sizes. A research assistant from the University of Oxford, independent of the trial team, prepared sealed envelopes using this list, which was then provided to the study pharmacists to assign participants. All vaccines were prepared by the study pharmacists by use of the same type of syringe, and the contents were covered with an opaque label. Vaccine safety, efficacy, and a potential correlate of efficacy with immunogenicity, measured as anti-NANP antibody titres, were evaluated over 1 year following the first booster vaccination. The population in which the efficacy analyses were done comprised all participants who received the primary series of vaccinations and a booster vaccination. Participants were excluded from the efficacy analysis if they withdrew from the trial within the first 2 weeks of receiving the booster vaccine. This trial is registered with ClinicalTrials.gov (NCT03896724), and is continuing for a further 2 years to assess both the potential value of additional booster vaccine doses and longer-term safety. Findings Between June 2, and July 2, 2020, 409 children returned to receive a booster vaccine. Each child received the same vaccination for the booster as they received in the primary series of vaccinations; 132 participants received 5 mu g R21 adjuvanted with 25 mu g Matrix-M, 137 received 5 mu g R21 adjuvanted with 50 mu g Matrix-M, and 140 received the control vaccine. R21/Matrix-M had a favourable safety profile and was well tolerated. Vaccine efficacy remained high in the high adjuvant dose (50 mu g) group, similar to previous findings at 1 year after the primary series of vaccinations. Following the booster vaccination, 67 (51%) of 132 children who received R21/Matrix-M with low-dose adjuvant, 54 (39%) of 137 children who received R21/Matrix-M with high-dose adjuvant, and 121 (86%) of 140 children who received the rabies vaccine developed clinical malaria by 12 months. Vaccine efficacy was 71% (95% CI 60 to 78) in the low-dose adjuvant group and 80% (72 to 85) in the high-dose adjuvant group. In the high-dose adjuvant group, vaccine efficacy against multiple episodes of malaria was 78% (95% CI 71 to 83), and 2285 (95% CI 1911 to 2568) cases of malaria were averted per 1000 child-years at risk among vaccinated children in the second year of follow-up.Among these participants, at 28 days following their last R21/Matrix-M vaccination, titres of malaria-specific anti-NANP antibodies correlated positively with protection against malaria in both the first year of follow-up (Spearman's. -0 center dot 32 [95% CI -0 center dot 45 to -0 center dot 19]; p=0 center dot 0001) and second year of follow-up (-0 center dot 20 [-0 center dot 34 to -0 center dot 06]; p=0 center dot 02). Interpretation A booster dose of R21/Matrix-M at 1 year following the primary three-dose regimen maintained high efficacy against first and multiple episodes of clinical malaria. Furthermore, the booster vaccine induced antibody concentrations that correlated with vaccine efficacy. The trial is ongoing to assess long-term follow-up of these participants and the value of further booster vaccinations.Copyright (c) 2022 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license.