Lancet：非洲试验证实埃博拉DNA疫苗有效

今年早些时候有研究报道，预防埃博拉病毒及其近缘马尔堡病毒的两种实验性DNA疫苗是有效的，会在健康的乌干达成年人中产生相似的免疫反应。这些研究结果，来自于非洲的第一个丝状病毒疫苗试验，发表的12月22日的《柳叶刀》杂志（The Lancet）。

本文第一作者、美国国立卫生研究院国家过敏和传染病研究所（NIAID）的Julie Ledgerwood博士指出：“这是首次有研究在非洲人口中显示一种实验性埃博拉疫苗具有相当的安全性和免疫反应。这特别令人鼓舞，因为那些埃博拉病毒风险最大的人群主要生活在非洲。”

来自于NIAID的科学家开发了DNA疫苗，其编码来自扎伊尔和苏丹菌株的埃博拉病毒蛋白和马尔堡病毒蛋白。这种疫苗含有病毒外表面蛋白质的编码指令。对这些蛋白质的免疫反应，已被表明在非人类灵长类动物模型中是高度保护性的。

在这项1期试验中，马凯雷雷大学Walter Reed项目在2009年11月至2010年四月之间，招募了来自于坎帕拉、乌干达的108名健康成年人（年龄在18到50岁之间）。在研究开始时，每名志愿者被随机分配接种一次埃博拉病毒疫苗（30人）、或马尔堡病毒疫苗（30人）、或两种疫苗（30人）或安慰剂（18人），然后在4周后和8周后再次注射。

该疫苗单独和共同注射都是安全的，并能以中和抗体和T细胞的形式，刺激一种免疫反应对抗病毒蛋白质。第三次注射后的四周内，只有超过半数的志愿者（57%，30人里面有17人）对埃博拉扎伊尔蛋白有抗体反应，而接受埃博拉和马尔堡病毒疫苗的30名志愿者中有14人有抗体反应。然而，该抗体是不持久的，在接种11个月内返回到检测不到的水平。

这两种DNA疫苗在乌干达成人中都耐受性良好，在所有组中都报告了相同数目的局部和全身反应。只有一种严重的不良反应（嗜中性粒细胞减少症；低的白细胞计数），在只接受马尔堡病毒疫苗的患者中有报道，但不认为与疫苗有关。

根据Ledgerwood博士介绍：“这些发现构成了一种更有效疫苗的基础，这种更有效的疫苗使用一种无害的黑猩猩感冒病毒进行传递，目前该疫苗正在美国、英国、乌干达进行试验，以应对正在暴发的埃博拉病毒疫情。”

牛津大学Jenner 研究所的Saranya Sridhar博士在一篇相关评论中写道：“这项研究应该成为疫苗开发的更广泛问题所围绕的焦点，尤其是非洲，必须解决疫苗开发这个问题。考虑到后见之明对不断变化的2014埃博拉暴发的益处，我们必须问我们自己：是否一种丝状病毒疫苗应该进行更先进的临床研究。目前国际对暴发的埃博拉疫情所作出的反应，是临床疫苗开发速度和目标的一个典范，已经设立了未来疫苗研制必须判断的基准。这项研究是在非洲部署丝状病毒疫苗成功之路上的第一步，肯定有助于清除阻碍我们接近这一目标的障碍。”

英文阅读：

Safety and immunogenicity of Ebola virus and Marburg virus glycoprotein DNA vaccines assessed separately and concomitantly in healthy Ugandan adults: a phase 1b, randomised, double-blind, placebo-controlled clinical trial

Summary

Background

Ebola virus and Marburg virus cause serious disease outbreaks with high case fatality rates. We aimed to assess the safety and immunogenicity of two investigational DNA vaccines, one (EBO vaccine) encoding Ebola virus Zaire and Sudan glycoproteins and one (MAR) encoding Marburg virus glycoprotein.

Methods

RV 247 was a phase 1b, double-blinded, randomised, placebo-controlled clinical trial in Kampala, Uganda to examine the safety and immunogenicity of the EBO and MAR vaccines given individually and concomitantly. Healthy adult volunteers aged 18–50 years were randomly assigned (5:1) to receive three injections of vaccine or placebo at weeks 0, 4, and 8, with vaccine allocations divided equally between three active vaccine groups: EBO vaccine only, MAR vaccine only, and both vaccines. The primary study objective was to investigate the safety and tolerability of the vaccines, as assessed by local and systemic reactogenicity and adverse events. We also assessed immunogenicity on the basis of antibody responses (ELISA) and T-cell responses (ELISpot and intracellular cytokine staining assays) 4 weeks after the third injection. Participants and investigators were masked to group assignment. Analysis was based on the intention-to-treat principle. This trial is registered at ClinicalTrials.gov, number NCT00997607.

Findings

108 participants were enrolled into the study between Nov 2, 2009, and April 15, 2010. All 108 participants received at least one study injection (including 100 who completed the injection schedule) and were included in safety and tolerability analyses; 107 for whom data were available were included in the immunogenicity analyses. Study injections were well tolerated, with no significant differences in local or systemic reactions between groups. The vaccines elicited antibody and T-cell responses specific to the glycoproteins received and we detected no differences between the separate and concomitant use of the two vaccines. 17 of 30 (57%, 95% CI 37–75) participants in the EBO vaccine group had an antibody response to the Ebola Zaire glycoprotein, as did 14 of 30 (47%, 28–66) in the group that received both vaccines. 15 of 30 (50%, 31–69) participants in the EBO vaccine group had an antibody response to the Ebola Sudan glycoprotein, as did 15 of 30 (50%, 31–69) in the group that received both vaccines. Nine of 29 (31%, 15–51) participants in the MAR vaccine groups had an antibody response to the Marburg glycoprotein, as did seven of 30 (23%, 10–42) in the group that received both vaccines. 19 of 30 (63%, 44–80) participants in the EBO vaccine group had a T-cell response to the Ebola Zaire glycoprotein, as did 10 of 30 (33%, 17–53) in the group that received both vaccines. 13 of 30 (43%, 25–63) participants in the EBO vaccine group had a T-cell response to the Ebola Sudan glycoprotein, as did 10 of 30 (33%, 17–53) in the group that received both vaccines. 15 of 29 (52%, 33–71) participants in the MAR vaccine group had a T-cell response to the Marburg glycoprotein, as did 13 of 30 (43%, 25–63) in the group that received both vaccines.

Interpretation

This study is the first Ebola or Marburg vaccine trial done in Africa, and the results show that, given separately or together, both vaccines were well tolerated and elicited antigen-specific humoral and cellular immune responses. These findings have contributed to the accelerated development of more potent Ebola virus vaccines that encode the same wild-type glycoprotein antigens as the EBO vaccine, which are being assessed during the 2014 Ebola virus disease outbreak in west Africa.