Cnossen Victor M, van Leeuwen Rogier P, Mazur Natalie I, Vernhes Charlotte, Ten Voorde Wouter, Burggraaf Jacobus, de Visser Saco J, Roestenberg Meta, Kamerling Ingrid M C
Centre for Human Drug Research, Zernikedreef 8, 2333 CL Leiden, The Netherlands.
Centre for Human Drug Research, Leiden, The Netherlands.
Ther Adv Vaccines Immunother. 2024 Dec 19;12:25151355241308305. doi: 10.1177/25151355241308305. eCollection 2024.
Respiratory syncytial virus (RSV) causes high worldwide infant mortality, as well as a high disease burden in the elderly. Efforts in vaccine development over the past 60 years have recently delivered three approved vaccines and two monoclonal antibodies (mAbs). Looking back at the eventful history of RSV vaccine development, several factors can be identified that have hampered the developmental pathway, including the occurrence of enhanced RSV disease (ERD) in the first vaccine attempt and the difficulty in characterizing and stabilizing the pre-fusion F protein as a vaccine target. Moreover, the need for large trials to test vaccine efficacy, usually done late in development, and the lack of a correlate of protection (CoP) result in significant uncertainties in RSV vaccine development. The use of controlled human infection models (CHIMs) may provide a solution for some of these problems: through swift, cost-efficient and closely monitored assessment of vaccine safety and efficacy in early clinical phases, vaccines can either 'fail fast' or show results supporting further investments. Moreover, CHIMs facilitate the assessment of disease and could assist in the identification of a CoP supporting late-stage development. Although some factors may affect translatability to real-world vaccine efficacy, CHIMs can support the clinical development pathway in various ways. We advocate for, and demonstrate, a conceptual and rational design of RSV vaccine development. Assessing protective efficacy early on would result in the most cost-efficient pathway and identification of target populations should be done as early as possible. For RSV, elderly individuals and people in low- and middle-income countries are high-impact populations for RSV prevention. While RSV immunization is now available in certain regions, global access is not accomplished yet, and worldwide prevention does not seem within reach. Quick and cost-effective assessments of candidates currently in the pipeline could contribute to future successes in the battle against RSV.
呼吸道合胞病毒（RSV）在全球范围内导致婴儿高死亡率，同时也给老年人带来沉重的疾病负担。在过去60年的疫苗研发工作中，近期已有三种疫苗和两种单克隆抗体（mAb）获批。回顾RSV疫苗研发的曲折历程，可以确定有几个因素阻碍了研发进程，包括首次疫苗尝试中出现的增强型RSV疾病（ERD），以及将融合前F蛋白作为疫苗靶点进行表征和稳定化的困难。此外，需要进行大型试验来测试疫苗效力，而这类试验通常在研发后期进行，并且缺乏保护相关性（CoP），这导致RSV疫苗研发存在重大不确定性。使用受控人体感染模型（CHIM）可能为其中一些问题提供解决方案：通过在临床早期阶段对疫苗安全性和效力进行快速、经济高效且密切监测的评估，疫苗可以“快速失败”，或者显示出支持进一步投资的结果。此外，CHIM有助于疾病评估，并可协助确定支持后期研发的CoP。尽管某些因素可能会影响向实际疫苗效力的转化，但CHIM可以通过多种方式支持临床研发路径。我们倡导并展示了RSV疫苗研发的概念性和合理设计。尽早评估保护效力将带来最具成本效益的研发路径，并且应尽早确定目标人群。对于RSV而言，老年人以及低收入和中等收入国家的人群是预防RSV的高影响力人群。虽然目前某些地区已有RSV免疫接种，但尚未实现全球普及，全球预防似乎仍遥不可及。对目前正在研发的候选疫苗进行快速且经济高效的评估，可能有助于未来在抗击RSV的战斗中取得成功。
