Centre for Clinical Vaccinology and Tropical Medicine, The Jenner Institute, University of Oxford and the NIHR Oxford Biomedical Research Centre, Oxford, UK.
Unité de Recherche Clinique de Nanoro, Institut de Recherche en Sciences de la Santé, Nanoro, Burkina Faso.
Lancet Infect Dis. 2022 Dec;22(12):1728-1736. doi: 10.1016/S1473-3099(22)00442-X. Epub 2022 Sep 7.
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.
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 μg R21/25 μg Matrix-M, 5 μg R21/50 μg 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.
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 μg R21 adjuvanted with 25 μg Matrix-M, 137 received 5 μg R21 adjuvanted with 50 μg 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 μg) 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 ρ -0·32 [95% CI -0·45 to -0·19]; p=0·0001) and second year of follow-up (-0·20 [-0·34 to -0·06]; p=0·02).
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.
European and Developing Countries Clinical Trials Partnership 2 (EDCTP2), Wellcome Trust, and NIHR Oxford Biomedical Research Centre.
For the French translation of the abstract see Supplementary Materials section.
疟疾是全世界发病率和死亡率的主要原因之一。我们之前报告了 R21/Matrix-M 疟疾疫苗的疗效，该疫苗在非洲儿童目标人群中达到了世卫组织规定的 12 个月时 75%或更高的疗效目标。在此，我们报告了在接种加强疫苗后 12 个月时的安全性、免疫原性和疗效结果。
这是一项在布基纳法索纳诺罗进行的 5-17 月龄儿童的双盲 1/2b 随机对照试验。合格的儿童被纳入并随机分配（1:1:1）接受三种疫苗接种，即 5μg R21/25μg Matrix-M、5μg R21/50μg Matrix-M 或对照疫苗（狂犬病疫苗 Rabivax-S），在疟疾季节前接种，随后 12 个月加强一剂。如果父母或监护人可以提供书面知情同意书，儿童就有资格入组。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。一个独立的统计学家使用具有可变块大小的区组随机化生成了一个随机分配列表。牛津大学的一名研究助理根据该列表准备了密封的信封，并将其提供给研究药剂师，以便为参与者分配疫苗。所有疫苗均由研究药剂师使用相同类型的注射器制备，内容物用不透明标签覆盖。在接种加强疫苗后 1 年，对疫苗安全性、疗效以及与免疫原性相关的潜在疗效预测指标（抗 NANP 抗体滴度）进行了评估。疗效分析人群包括接受了初级系列疫苗接种和加强疫苗接种的所有参与者。如果参与者在接种加强疫苗后的前 2 周内退出试验，则将其排除在疗效分析之外。这项试验在 ClinicalTrials.gov （NCT03896724）上注册，并将继续进行另外 2 年，以评估额外加强疫苗剂量的潜在价值和长期安全性。
2020 年 6 月 2 日至 7 月 2 日，409 名儿童返回接受加强疫苗接种。每个孩子都接种了与初级系列疫苗相同的疫苗作为加强疫苗；132 名参与者接种了 5μg R21 佐剂与 25μg Matrix-M，137 名参与者接种了 5μg R21 佐剂与 50μg 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（50μg）组的疫苗疗效仍然很高，与初级系列疫苗接种后 1 年的疗效相似。在加强疫苗接种后，接受低剂量佐剂的 132 名儿童中有 67 名（51%）、接受高剂量佐剂的 137 名儿童中有 54 名（39%）和接受狂犬病疫苗的 140 名儿童中有 121 名（86%）在 12 个月时发生了临床疟疾。低剂量佐剂组的疫苗效力为 71%（95%CI 60 至 78），高剂量佐剂组为 80%（72 至 85）。在高剂量佐剂组中，针对多次疟疾发作的疫苗效力为 78%（95%CI 71 至 83），在接种儿童第二年的随访中，每 1000 名儿童年可预防 2285 例（95%CI 1911 至 2568）疟疾。在这些参与者中，在最后一次接种 R21/Matrix-M 后 28 天，疟疾特异性抗 NANP 抗体的滴度与第一年（Spearman's ρ-0·32 [95%CI -0·45 至 -0·19]；p=0·0001）和第二年（-0·20 [-0·34 至 -0·06]；p=0·02）的疟疾保护呈正相关。
在初级三剂方案接种后 1 年加强一剂 R21/Matrix-M 可保持对首次和多次临床疟疾发作的高疗效。此外，加强疫苗诱导的抗体浓度与疫苗效力相关。该试验正在进行中，以评估这些参与者的长期随访结果和进一步加强疫苗接种的价值。
欧洲和发展中国家临床试验伙伴关系 2（EDCTP2）、惠康信托基金和牛津大学国家卫生研究院生物医学研究中心。
