Guichelaar Teun, Hoeboer Jeroen, Widjojoatmodjo Myra N, Reemers Sylvia S N, van Els Cécile A C M, Otten Rob, van Remmerden Yvonne, Boes Jolande, Luytjes Willem
Centre for Infectious Disease Control Netherlands, National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands
Centre for Infectious Disease Control Netherlands, National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands.
J Virol. 2014 Sep 1;88(17):9744-50. doi: 10.1128/JVI.01101-14. Epub 2014 Jun 11.
Elderly humans are prone to severe infection with human respiratory syncytial virus (HRSV). The aging of today's human population warrants the development of protective vaccination strategies aimed specifically at the elderly. This may require special approaches due to deteriorating immune function. To design and test vaccination strategies tailored to the elderly population, we need to understand the host response to HRSV vaccination and infection at old age. Moreover, the preclinical need for testing of candidate vaccines requires translational models resembling susceptibility to the (unadapted) human pathogen. Here, we explored the effects of aging on immunity and protection induced by a model HRSV vaccine candidate in a translational aging model in cotton rats (Sigmodon hispidus) and examined possibilities to optimize vaccination concepts for the elderly. We immunized young and aged cotton rats with a live-attenuated recombinant HRSV vaccine candidate and analyzed the induced immune response to and protection against challenge with HRSV. In old cotton rats, HRSV infection persisted longer, and vaccination induced less protection against infection. Aged animals developed lower levels of vaccine-induced IgG, virus-neutralizing serum antibodies, and IgA in lungs. Moreover, booster responses to HRSV challenge were impaired in animals vaccinated at an older age. However, increased dose and reduced attenuation of vaccine improved protection even in old animals. This study shows that cotton rats provide a model for studying the effects of aging on the immune response to the human respiratory pathogen HRSV and possibilities to optimize vaccine concepts for the elderly.
HRSV infection poses a risk for severe disease in the elderly. The aging of the population warrants increased efforts to prevent disease at old age, whereas HRSV vaccines are only in the developmental phase. The preclinical need for testing of candidate human vaccines requires translational models resembling susceptibility to the natural human virus. Moreover, we need to gain insight into waning immunity at old age, as this is a special concern in vaccine development. In this study, we explored the effect of age on protection and immunity against an experimental HRSV vaccine in aged cotton rats (Sigmodon hispidus), a rodent species that provides a model representing natural susceptibility to human viruses. Older animals generate fewer antibodies upon vaccination and require a higher vaccine dose for protection. Notably, during the early secondary immune response to subsequent HRSV infection, older animals showed less protection and a slower increase of the virus-neutralizing antibody titer.
老年人容易感染人呼吸道合胞病毒（HRSV）。当今人口老龄化促使人们开发专门针对老年人的保护性疫苗接种策略。由于免疫功能下降，这可能需要特殊方法。为了设计和测试针对老年人群体的疫苗接种策略，我们需要了解老年人对HRSV疫苗接种和感染的宿主反应。此外，临床前对候选疫苗进行测试需要类似于对（未适应的）人类病原体易感性的转化模型。在这里，我们在棉鼠（棉鼠属）的转化衰老模型中探索了衰老对一种HRSV候选疫苗诱导的免疫和保护的影响，并研究了优化针对老年人的疫苗接种概念的可能性。我们用一种减毒活重组HRSV候选疫苗免疫年轻和老年棉鼠，并分析诱导的免疫反应以及对HRSV攻击的保护作用。在老年棉鼠中，HRSV感染持续时间更长，疫苗接种诱导的抗感染保护作用更小。老年动物产生的疫苗诱导IgG、病毒中和血清抗体和肺中IgA水平较低。此外，老年时接种疫苗的动物对HRSV攻击的加强反应受损。然而，增加疫苗剂量和降低疫苗减毒程度即使在老年动物中也能改善保护作用。这项研究表明，棉鼠为研究衰老对人类呼吸道病原体HRSV免疫反应的影响以及优化针对老年人的疫苗接种概念提供了一个模型。
HRSV感染对老年人构成严重疾病风险。人口老龄化促使人们加大力度预防老年疾病，而HRSV疫苗仅处于研发阶段。临床前对候选人类疫苗进行测试需要类似于对天然人类病毒易感性的转化模型。此外，我们需要深入了解老年时免疫力的下降情况，因为这在疫苗开发中是一个特别需要关注的问题。在这项研究中，我们在老年棉鼠（棉鼠属）中探索了年龄对针对实验性HRSV疫苗的保护和免疫的影响，棉鼠是一种代表对人类病毒天然易感性的啮齿动物物种。老年动物接种疫苗后产生的抗体较少，需要更高的疫苗剂量来提供保护。值得注意的是，在对随后的HRSV感染的早期二次免疫反应期间，老年动物显示出的保护作用较小，病毒中和抗体滴度上升较慢。
