Advanced Live Attenuated Vaccines for the Prevention of Respiratory Syncytial Virus Infections in Young Children.
Advanced Live Attenuated Vaccines for the Prevention of Respiratory Syncytial Virus Infections in Young Children.
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用于预防幼儿呼吸道合胞病毒感染的先进减毒活疫苗。
DOI：
10.1093/infdis/jiz409
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发表时间：
2020
期刊：
影响因子：
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通讯作者：
Mejias,Asuncion
中科院分区：
文献类型：
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作者：
Ramilo,Octavio;Rodriguez-Fernandez,Rosa;Peeples,MarkE;Mejias,Asuncion
呼吸道合胞病毒（RSV）感染与世界各地的重大疾病负担有关，特别是在儿童中。据估计，RSV每年在5岁以下儿童中造成3300万例新发急性下呼吸道感染，并造成约12万人死亡。在婴儿中，呼吸道合胞病毒是全球住院的主要原因，也是低收入和中等收入国家的第二大死亡原因[1,2]。经过60年的研究，仍然没有获得许可的RSV疫苗。对20世纪60年代研制的福尔马林灭活疫苗进行了评估，这些婴儿在随后暴露于自然感染后出现呼吸道疾病加重，导致住院人数增加和2例死亡。这一经历阻碍了研制呼吸道合胞病毒疫苗的努力，特别是那些为幼儿设计的疫苗。为了克服这些挑战，有人提出，鼻内给药减毒活疫苗可能是一种安全的策略，可以使幼儿免疫对抗呼吸道合胞病毒。几十年来，研究人员在幼儿中开发并测试了几种RSV减毒活疫苗。最初，这些候选疫苗是使用传统的传代技术在次优条件下开发的，以减毒。研究表明，选择在给幼儿接种时耐受性良好而不引起明显症状的候选疫苗是困难的，同时显示出足够的复制以诱导保护性免疫反应，所有这些都不会逆转减毒突变。然而，在过去20年里，结合反向遗传学来靶向在疾病发病机制中起作用的特定基因，使得有目的地设计候选疫苗以实现所需的衰减、免疫原性和遗传稳定性，从而取得更一致的进展。在本期的《传染病杂志》上，Karron等人报道了一种有希望的RSV减毒活疫苗候选物的首次人体研究结果/ΔNS2/Δ1313/I1314L。该疫苗包含2个独特元素：(1)缺失NS2基因；(2)缺失聚合酶蛋白(L)密码子L1313和一个稳定错义突变I1314L。这些变化为病毒提供了重要的特性。NS2基因是一种干扰素拮抗剂，它可以促进受感染上皮细胞的脱落，可能导致小气道阻塞[5]。NS2基因的缺失导致干扰素反应增加，从而减少病毒复制，减少呼吸道上皮损伤，并可能增强适应性免疫反应。L1313的缺失也提供了病毒复制的衰减和温和的温度敏感性。由于这种疫苗病毒在动物实验中是减毒的和免疫原性的[6,7]，研究者将他们的研究扩展到血清阳性和血清阴性的儿童。在这项I期研究中，他们给12-59个月的血清阳性儿童（n= 15）注射单剂疫苗（随机分为2组：1组与安慰剂组），剂量为106个菌斑形成单位（pfu），随后给6-22个月的血清阴性儿童注射2剂：105个（n= 22）和106个（n= 30） pfu。在血清阳性儿童（n= 15）中，2例出现上呼吸道症状，1例出现咳嗽，2例均在发病时检测到鼻病毒。重要的是，接种疫苗的人都没有传播疫苗病毒。此外，没有一个血清阳性儿童表现出抗rsv F或中和抗体增加≥4倍。
Respiratory syncytial virus (RSV) infections are associated with significant disease burden across the world, especially among children. It is estimated that RSV causes 33 new million episodes of acute lower respiratory tract infection in children< 5 years of age, and approximately 120 000 deaths annually. Among infants, RSV represents the leading cause of hospitalization worldwide, and the second cause of death in low-and middleincome countries [1, 2]. After> 60 years of research, there are still no licensed RSV vaccines. A formalin-inactivated vaccine developed in the 1960s was evaluated in RSV-naive infants, who after subsequent exposure to natural infection developed enhanced respiratory tract disease that resulted in increased hospitalizations and 2 deaths [3]. This experience discouraged efforts to develop RSV vaccines, especially those designed for young children. To overcome these challenges, it has been proposed that a live attenuated vaccine administered intranasally might represent a safe strategy to immunize young children against RSV. Over several decades, investigators have developed and tested several RSV live attenuated vaccine candidates in young children. Initially, these vaccine candidates were developed using traditional techniques of passage under suboptimal conditions to attenuate the virus. Studies have illustrated the difficulties of selecting vaccine candidates that were well tolerated without causing significant symptoms when administered to young children and at the same time showed adequate replication to induce a protective immune response, all without reversion of the attenuating mutations. In the last 2 decades, however, the incorporation of reverse genetics to target specific genes with a role in disease pathogenesis has allowed the development of vaccine candidates purposefully designed to achieve the desired attenuation, immunogenicity and genetic stability, leading to more consistent progress. In the present issue of the Journal of Infectious Diseases, Karron et al [4] report the results of the first-in-human study of one promising live attenuated vaccine candidate RSV/ΔNS2/Δ1313/I1314L. This vaccine contains 2 unique elements:(1) deletion of the NS2 gene and (2) deletion of codon L1313 of the polymerase protein (L) and a stabilizing missense mutation, I1314L. These changes provide the virus with important properties. The NS2 gene is an interferon antagonist, and it enhances shedding of the infected epithelial cells, likely contributing to small airway obstruction [5]. Deletion of the NS2 gene results in increased interferon responses that diminish virus replication, reduce damage to the respiratory tract epithelium, and, possibly, enhance of adaptive immune responses. The L1313 deletion also provides attenuation of viral replication and mild temperature sensitivity. Because this vaccine virus was attenuated and immunogenic in animal experiments [6, 7], the investigators advanced their studies to seropositive and seronegative children. In this phase I study, they administered a single dose of the vaccine (randomized in all groups 2: 1 vs placebo) initially to seropositive children, aged 12–59 months (n= 15) at a dose of 106 plaque-forming units (PFUs), and subsequently to seronegative children, aged 6–22 months, at 2 doses: 105 (n= 22) and 106 (n= 30) PFUs. Among seropositive children (n= 15), upper respiratory tract symptoms developed in 2 and 1 cough in 1, and in both rhinovirus was detected at the time of illness. Importantly, none of the vaccine recipients shed vaccine virus. In addition, none of the seropositive children demonstrated a≥ 4-fold increase in anti-RSV F or neutralizing antibodies …