小柯机器人

英国牛津大学Adrian V S Hill团队联合布基纳法索健康科学研究所Halidou Tinto团队研究了布基纳法索儿童季节性接种低剂量候选疟疾疫苗R21佐剂基质M的疗效。2021年5月5日，该研究发表在《柳叶刀》杂志上。

在控制恶性疟原虫疟疾方面进展缓慢，迫切需要一种有效和可部署的疫苗。迄今为止最有效的疟疾疫苗候选品RTS、S/AS01在非洲儿童中12个月内显示出56%的有效性。在此，研究组评估了一种新的候选疫苗的安全性和有效性。

在这项双盲、随机、对照、临床2b期试验中，研究组在布基纳法索纳诺罗（一个季节性疟疾传播频繁的地区）给5-17个月大的婴儿接种了低剂量的环子孢子蛋白疫苗R21，以及两种不同剂量的基质M佐剂（MM）。在疟疾季前每隔4周接种3次疫苗，1年后接种第4次。将这些儿童随机分为三组，所有疫苗都肌肉注射到大腿。第1组接种5 μg R21加25 μg MM，第2组接种5 μg R21加50 μg MM，第3组为对照组，接种狂犬病疫苗。疫苗安全性、免疫原性和有效性在1年内进行评估。主要目的是评估R21+MM（R21/MM）从第三次接种后14天到6个月的保护效果。

2019年5月7日至6月13日，共有498名5-17个月大的婴儿接受了筛查，48名被排除在外。450名婴儿至少接种了一次疫苗，每组150名。主要系列的最终疫苗接种于2019年8月7日进行。R21/MM具有良好的安全性，耐受性良好。大多数不良反应轻微，最常见的是发烧。7起严重不良事件均与疫苗无关。

在6个月的主要疗效分析中，第1组146名参与者中有43名（29%）、第2组146名参与者中有38名（26%）、第3组147名参与者中有105名（71%）患上了临床疟疾。6个月时，第1组的疫苗有效率为74%，第2组为77%。1年时，疫苗的有效性仍然很高，第1组为77%。

接种R21/MM疫苗的受试者在第三次接种后28天显示出高滴度的疟疾特异性抗Asn-Ala-Asn-Pro（NANP）抗体，随着佐剂剂量的增加，抗体滴度几乎增加了一倍。之后滴度下降，但在1年后第4次注射后，又升到与初级系列接种后的最高滴度相似的水平。

研究结果表明，R21/MM在非洲儿童中安全且具有很强的免疫原性，显示出有潜力的高水平疗效。

附：英文原文

Title: Efficacy of a low-dose candidate malaria vaccine, R21 in adjuvant Matrix-M, with seasonal administration to children in Burkina Faso: a randomised controlled trial

Author: Mehreen S Datoo, Magloire H Natama, Athanase Somé, Ousmane Traoré, Toussaint Rouamba, Duncan Bellamy, Prisca Yameogo, Daniel Valia, Moubarak Tegneri, Florence Ouedraogo, Rachidatou Soma, Seydou Sawadogo, Faizatou Sorgho, Karim Derra, Eli Rouamba, Benedict Orindi, Fernando Ramos Lopez, Amy Flaxman, Federica Cappuccini, Reshma Kailath, Sean Elias, Ekta Mukhopadhyay, Andres Noe, Matthew Cairns, Alison Lawrie, Rachel Roberts, Innocent Valéa, Hermann Sorgho, Nicola Williams, Gregory Glenn, Louis Fries, Jenny Reimer, Katie J Ewer, Umesh Shaligram, Adrian V S Hill, Halidou Tinto

Issue&Volume: 2021-05-05

Abstract:

Background

Stalled progress in controlling Plasmodium falciparum malaria highlights the need for an effective and deployable vaccine. RTS,S/AS01, the most effective malaria vaccine candidate to date, demonstrated 56% efficacy over 12 months in African children. We therefore assessed a new candidate vaccine for safety and efficacy.

Methods

In this double-blind, randomised, controlled, phase 2b trial, the low-dose circumsporozoite protein-based vaccine R21, with two different doses of adjuvant Matrix-M (MM), was given to children aged 5–17 months in Nanoro, Burkina Faso—a highly seasonal malaria transmission setting. Three vaccinations were administered at 4-week intervals before the malaria season, with a fourth dose 1 year later. All vaccines were administered intramuscularly into the thigh. Group 1 received 5 μg R21 plus 25 μg MM, group 2 received 5 μg R21 plus 50 μg MM, and group 3, the control group, received rabies vaccinations. Children were randomly assigned (1:1:1) to groups 1–3. An independent statistician generated a random allocation list, using block randomisation with variable block sizes, which was used to assign participants. Participants, their families, and the local study team were all masked to group allocation. Only the pharmacists preparing the vaccine were unmasked to group allocation. Vaccine safety, immunogenicity, and efficacy were evaluated over 1 year. The primary objective assessed protective efficacy of R21 plus MM (R21/MM) from 14 days after the third vaccination to 6 months. Primary analyses of vaccine efficacy were based on a modified intention-to-treat population, which included all participants who received three vaccinations, allowing for inclusion of participants who received the wrong vaccine at any timepoint. This trial is registered with ClinicalTrials.gov, NCT03896724.

Findings

From May 7 to June 13, 2019, 498 children aged 5–17 months were screened, and 48 were excluded. 450 children were enrolled and received at least one vaccination. 150 children were allocated to group 1, 150 children were allocated to group 2, and 150 children were allocated to group 3. The final vaccination of the primary series was administered on Aug 7, 2019. R21/MM had a favourable safety profile and was well tolerated. The majority of adverse events were mild, with the most common event being fever. None of the seven serious adverse events were attributed to the vaccine. At the 6-month primary efficacy analysis, 43 (29%) of 146 participants in group 1, 38 (26%) of 146 participants in group 2, and 105 (71%) of 147 participants in group 3 developed clinical malaria. Vaccine efficacy was 74% (95% CI 63–82) in group 1 and 77% (67–84) in group 2 at 6 months. At 1 year, vaccine efficacy remained high, at 77% (67–84) in group 1. Participants vaccinated with R21/MM showed high titres of malaria-specific anti-Asn-Ala-Asn-Pro (NANP) antibodies 28 days after the third vaccination, which were almost doubled with the higher adjuvant dose. Titres waned but were boosted to levels similar to peak titres after the primary series of vaccinations after a fourth dose administered 1 year later.

Interpretation

R21/MM appears safe and very immunogenic in African children, and shows promising high-level efficacy.

DOI: 10.1016/S0140-6736(21)00943-0

Source: https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(21)00943-0/fulltext

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