Comparison of respiratory syncytial virus humoral immunity and response to infection in young and elderly adults

Human metapneumovirus (hMPV) is associated with respiratory tract infections among children and adults. Because hMPV induces significant morbidity and mortality in the elderly, a model of hMPV infection in aged BALB/c mice was established. Young (8 weeks old) and aged (18 months old) mice were intranasally inoculated with hMPV. The infected mice showed respiratory dysfunction, as measured by plethysmography, a marked loss in weight (up to 24%), and severe histopathological abnormalities including bronchiolitis obliterans organizing pneumonia. However, clinical severity was far higher in the aged mice, and none of the young infected mice died. Although virus replication in the lung was greater in the older mice, clearance of virus was not delayed compared to young mice. Production of virus-specific antibody as well as neutralizing antibody was lower. Gamma interferon and monocyte chemotactic protein-1 levels in bronchoalveolar lavage fluid were significantly lower in older mice, whereas interleukin-6 and interleukin-4 levels were significantly higher. We observed by flow cytometry a significant increase in the CD4 ؉ T lymphocytes (P < 0.05) of the aged mice and no difference in CD8 ؉ T-cell recruitment to the respiratory tract between the two groups. The present study investigated the effects of aging on the immunopathogenesis of hMPV infection and suggests that CD4 ؉ T lymphocytes, the cytokine response, or a defect in humoral response may be associated with the increased disease severity observed in the aged mice.

Section: Discussionmentioning

confidence: 99%

Age-Associated Aggravation of Clinical Disease after Primary Metapneumovirus Infection of BALB/c Mice

Darniot¹,

Pitoiset²,

Petrella³

et al. 2009

“…However, as discussed later, viral immune evasion strategies also may contribute to reinfection. Typical RSV-neutralizing serum antibody titers in adults are quite high (mean reciprocal titer of 1,450 in a 50%-infected-well-reduction assay), and following natural infection, they were increased fourfold or more in 64% of young adult and 79% of frail elderly patients, suggestive of good responses (41). While postinfection increases in antibody titers wane in most individuals within a year, this decay might not be unique to RSV (40), and the residual titers remain quite high.…”

Section: Protective and Pathogenic Features Of The Host Responsementioning

confidence: 99%

Viral and Host Factors in Human Respiratory Syncytial Virus Pathogenesis

Collins¹,

Graham

2008

422

478

Human respiratory syncytial virus (RSV) was first isolated in 1956 from a laboratory chimpanzee with upper respiratory tract disease (for general reviews, see references 21, 57, 102, and 145). RSV was quickly determined to be of human origin and was shown to be the leading worldwide viral agent of serious pediatric respiratory tract disease. In a 13-year prospective study of infants and children in the United States, RSV was detected in 43%, 25%, 11%, and 10% of pediatric hospitalizations for bronchiolitis, pneumonia, bronchitis, and croup, respectively (110). Approximately two-thirds of infants are infected with RSV during the first year of life, and 90% have been infected one or more times by 2 years of age. The rate of hospitalization for primary infection is approximately 0.5% but can vary by situation and ethnic group and can be as high as 25% (77).RSV also is a significant cause of morbidity and mortality in the elderly, with an impact approaching that of nonpandemic influenza virus (39). RSV readily infects severely immunocompromised individuals, most notably allogeneic bone marrow transplant recipients, causing high mortality. RSV also makes a substantial contribution to upper respiratory tract disease in individuals of all ages (59,65 Although RSV has a single serotype, reinfection can occur throughout life. RSV in yearly winter/early spring epidemics in temperate regions; elsewhere, the timing of RSV activity can vary widely with the locale. The RSV reservoir in the offseason is unknown. Strains circulate quickly around the earth (150). Neither a vaccine nor an effective antiviral therapy is available, although there is active research in both areas (23,78,138). However, infants at high risk for serious disease can receive passive immunoprophylaxis during the epidemic season by a monthly injection of a commercial RSV-neutralizing monoclonal antibody, palivizumab (Synagis), which provides a 55% reduction in RSV-associated hospitalization (17). THE VIRUSRSV (family Paramyxoviridae, order Mononegavirales) is an enveloped virus with a single-stranded negative-sense RNA genome of 15.2 kb (21). There are animal versions of RSV, including bovine RSV (BRSV) and pneumonia virus of mice (PVM), suggesting that species jumping occurred during the evolution of these viruses. However, there is no animal reservoir for human RSV.Efficient infection by RSV of established cell lines in vitro involves binding to cell-surface glycosaminoglycans (62). However, it is not known how closely this binding models attachment in vivo or whether it is an initial interaction that is followed by a second, higher-affinity step that remains to be identified. The nucleocapsid gains entry to the cytoplasm by membrane fusion; surprisingly, this may involve clathrin-mediated endocytosis rather than surface fusion typical of paramyxoviruses (85). Viral gene expression and RNA replication occur in the cytoplasm, and virions acquire a lipid envelope by budding through the plasmid membrane (Fig. 1). Virions are pleomorphic and include spheres ...

“…However, the relationship between antibody levels induced by HRSV and age in humans is still subject to speculation. Observations on the effect of age on the immune response to vaccine may be blurred since social behavior, environment, frailty, and a varying history of natural infections can influence the outcome of human studies (25,28,32,(37)(38)(39)(40). To clarify the effect of aging on the capacity to mount antibody production in response to HRSV vaccine, we analyzed the antibodies produced in response to vaccination with rHRSV, which induced suboptimal protection in old animals but fully protected young cotton rats.…”

Section: Fig 3 Rhrsv Vaccine-induced Serum Igg Cotton Rats At the Agmentioning

confidence: 99%

“…In contrast, clinical studies indicate that old humans express similar or even higher titers of RSV-specific IgG antibodies (28,31,39,41). However, several of those studies indicate that the functionality of these antibodies is inferior compared to that of the antibodies of younger people (28,39). Of note, old humans have been exposed more often to RSV infection during their lifespan than young people.…”

Section: Fig 3 Rhrsv Vaccine-induced Serum Igg Cotton Rats At the Agmentioning

confidence: 99%

“…The early booster effect was significantly lower in old animals, and this was most pronounced for the increase in the level of neutralizing antibodies, rather than the boost of IgG, indicating that aged individuals are less capable of mounting recall responses of functional antibodies to HRSV. This may explain why aged people have lower antibody functionality rather than lower levels of total IgG against HRSV in serum (18,38,39).…”

Section: Fig 3 Rhrsv Vaccine-induced Serum Igg Cotton Rats At the Agmentioning

confidence: 99%

See 1 more Smart Citation

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

Guichelaar

Hoeboer

Widjojoatmodjo

et al. 2014

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.