Impaired Immune Response to Vaccination against Infection with Human Respiratory Syncytial Virus at Advanced Age

Abstract

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. IMPORTANCEHRSV 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.

Innate immune responses in the ageing lung

“…Studies examining the impact of advanced age on the immune response to RSV infection have demonstrated that viral titres are higher and the virus persists longer in aged compared to younger hosts. Interestingly, some studies have shown an early delay in viral replication in older hosts, which the authors hypothesize is due possibly to changes in the pulmonary epithelium due to ageing . Contributing to the enhanced mortality is that elderly individuals do not respond to influenza virus vaccinations as well as younger individuals, and a Food and Drug Administration (FDA)‐approved RSV vaccination does not currently exist .…”

Effect of aging on immunogenicity and efficacy of inactivated influenza vaccines in cotton rats Sigmodon hispidus

“…Cotton rats over 9 months of age were used to model human elderly, based on the earlier demonstration of immunosenescent antiviral responses in animals of that age. [41][42][43][44] Results of this work allow us to reconcile some of the seemingly contradictory findings of reduced immunogenicity and comparable efficacy of influenza vaccines in the elderly.…”

“…Choice of females was guided by the fact that all aged animals were retired female breeders and young female animals had to be used as appropriate controls. Additionally, delayed dynamics of respiratory infection and disease in immunosenescent animals needs to be taken into account, 34,[41][42][43][44][62][63][64] and more numerous time points may need to be included for a more comprehensive analysis of responses with regards to aging. Finally, the estimation of antiviral efficacy in cotton rats was based on quantification of viral load/gene expression in the lung and nose homogenates, not in swabs or washes collected from nasopharyngeal and throat surfaces, as in humans.…”

“…37,40 These animals reproduce the effect of advanced age and immunosenescence on respiratory viral infections. [41][42][43][44] In this study, we compared antibody response to and efficacy of inactivated split-virion influenza vaccine FluLaval in young and aged cotton rats Sigmodon hispidus. Cotton rats over 9 months of age were used to model human elderly, based on the earlier demonstration of immunosenescent antiviral responses in animals of that age.…”

Shp‐2 contributes to anti‐RSV activity in human pulmonary alveolar epithelial cells by interfering with the IFN‐α‐induced Jak/Stat1 pathway

“…Respiratory syncytial virus infections are related to severe lower respiratory tract inflammation in infants and young children [1], particularly for those born preterm [2]. To date, there is no specific chemotherapy or licensed vaccine available for RSV [3,4]. The pathogenesis of RSV and the interacting between the virus and host immune responses appear to be complicated and are not fully understood.…”