Department of Infectious Disease, Imperial College London, London, UK.
National Heart and Lung Institute, Imperial College London, London, UK.
Curr Top Microbiol Immunol. 2024;445:41-68. doi: 10.1007/82_2022_257.
Despite considerable momentum in the development of RSV vaccines and therapeutics, there remain substantial barriers to the development and licensing of effective agents, particularly in high-risk populations. The unique immunobiology of RSV and lack of clear protective immunological correlates has held back RSV vaccine development, which, therefore, depends on large and costly clinical trials to demonstrate efficacy. Studies involving the deliberate infection of human volunteers offer an intermediate step between pre-clinical and large-scale studies of natural infection. Human challenge has been used to demonstrate the potential efficacy of vaccines and antivirals while improving our understanding of the protective immunity against RSV infection. Early RSV human infection challenge studies determined the role of routes of administration and size of inoculum on the disease. However, inherent limitations, the use of highly attenuated/laboratory-adapted RSV strains and the continued evolutionary adaptation of RSV limits extrapolation of results to present-day vaccine testing. With advances in technology, it is now possible to perform more detailed investigations of human mucosal immunity against RSV in experimentally infected adults and, more recently, older adults to optimise the design of vaccines and novel therapies. These studies identified defects in RSV-induced humoral and CD8+ T cell immunity that may partly explain susceptibility to recurrent RSV infection. We discuss the insights from human infection challenge models, ethical and logistical considerations, potential benefits, and role in streamlining and accelerating novel antivirals and vaccines against RSV. Finally, we consider how human challenges might be extended to include relevant at-risk populations.
尽管在 RSV 疫苗和疗法的开发方面取得了相当大的进展，但在开发和许可有效药物方面仍然存在重大障碍，特别是在高风险人群中。RSV 的独特免疫生物学以及缺乏明确的保护性免疫相关性阻碍了 RSV 疫苗的开发，因此，这取决于大型和昂贵的临床试验来证明其疗效。涉及故意感染人类志愿者的研究为临床前和自然感染的大规模研究之间提供了一个中间步骤。人体挑战已被用于证明疫苗和抗病毒药物的潜在疗效，同时提高了我们对 RSV 感染保护性免疫的理解。早期 RSV 人体感染挑战研究确定了给药途径和接种剂量大小对疾病的影响。然而，由于固有局限性、使用高度减毒/实验室适应的 RSV 株以及 RSV 的持续进化适应，限制了将结果外推到当今的疫苗测试。随着技术的进步，现在可以对实验性感染的成年人和最近的老年人进行更详细的 RSV 诱导的粘膜免疫研究，以优化疫苗和新型疗法的设计。这些研究确定了 RSV 诱导的体液和 CD8+ T 细胞免疫缺陷，这可能部分解释了对复发性 RSV 感染的易感性。我们讨论了人体感染挑战模型的见解、伦理和后勤考虑、潜在益处以及在简化和加速针对 RSV 的新型抗病毒药物和疫苗方面的作用。最后，我们考虑如何将人体挑战扩展到包括相关的高危人群。
