Viral Shedding and Immune Responses to Respiratory Syncytial Virus Infection in Older Adults

Walsh, Edward E.; Peterson, Derick R.; Kalkanoglu, Aja E.; Lee, Frances Eun-Hyung; Falsey, Ann R.

doi:10.1093/infdis/jit038

Cited by 122 publications

(96 citation statements)

References 36 publications

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“…This is a general finding in cotton rats (15,17) and has also been described in humans (31). Observed differences in viral loads between nose and lungs might partly be due to differences between sampling methods.…”

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

confidence: 71%

“…Since rHRSV is a live virus (17), rHRSV immunization can be regarded as a mild HRSV infection, and challenge with wtHRSV can be regarded as a boosting reinfection. A booster effect in previously immunized individuals becomes apparent by the quick and steep increase of the antibody titer during the recall immune response to infection within 5 to 7 days, as shown in our cotton rat studies (our unpublished data), lambs (42), young children (43), and aged humans (31). 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.…”

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

confidence: 59%

“…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).…”

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

confidence: 99%

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

Guichelaar

Hoeboer

Widjojoatmodjo

et al. 2014

J Virol

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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.

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

confidence: 71%

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

confidence: 59%

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

J Virol

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“…In a human challenge model using healthy adult volunteers, RSV nasal viral load is closely correlated with clinical symptoms and recovery [18]. Observational studies have shown that RSV viral load is higher and viral shedding more protracted in hospitalised adults compared to outpatients [19], and that a high viral load in hospitalised adults is a risk factor for the development of complications including respiratory failure and the need for mechanical ventilation [20,21]. In human challenge models of asthma and COPD exacerbation, using challenge with rhinovirus, viral load measured in sputum correlates with the degree of host inflammatory response [22,23].…”

Section: Introductionmentioning

confidence: 99%

Viral load is strongly associated with length of stay in adults hospitalised with viral acute respiratory illness

Clark

Ewings

Medina

et al. 2016

Journal of Infection

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“…Studies in BALB/c mice have demonstrated that although both CD4 and CD8 T cells mediate viral clearance, CD4 and CD8 T cells also contribute to RSVassociated disease (8). Furthermore, several human studies have demonstrated that the increased presence of T cells is correlated to severe RSV disease in both children and the elderly (9)(10)(11)(12).…”

mentioning

confidence: 99%

Determining the Breadth of the Respiratory Syncytial Virus-Specific T Cell Response

McDermott

Knudson

Varga

2014

J Virol

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Respiratory syncytial virus (RSV) is the most common cause of viral lower respiratory tract infections in infants and children under the age of 5. Studies examining RSV infection in susceptible BALB/c mice indicate that both CD4 and CD8 T cells not only contribute to viral clearance but also facilitate RSV-induced disease. However, efforts to understand the mechanisms by which RSV-specific T cells mediate disease following acute RSV infection have been hampered by the lack of defined RSV-specific T cell epitopes. Using an overlapping peptide library spanning each of the RSV-derived proteins, intracellular cytokine staining for gamma interferon was utilized to identify novel RSV-specific CD4 and CD8 T cell epitopes. Five novel CD8 T cell epitopes were revealed within the RSV fusion (F) protein and glycoprotein (G). In addition, five previously unidentified CD4 T cell epitopes were discovered, including epitopes in the phosphoprotein (P), polymerase protein (L), M2-1 protein, and nucleoprotein (N). Though the initial CD4 T cell epitopes were 15 amino acids in length, synthesis of longer peptides increased the frequency of responding CD4 T cells. Our results indicate that CD4 T cell epitopes that are 17 amino acids in length result in more optimal CD4 T cell stimulation than the commonly used 15-mer peptides. IMPORTANCE Respiratory syncytial virus (RSV) is the leading cause of hospitalization for lower respiratory tract infection in children. T cells play a critical role in clearing an acute RSV infection, as well as contributing to RSV-induced disease.Here we examined the breadth of the RSV-specific T cell response, using for the first time an overlapping peptide library spanning the entire viral genome. We identified 5 new CD4 and 5 new CD8 T cell epitopes, including a CD8 T cell epitope within the G protein that was previously believed not to elicit a CD8 T cell response. Importantly, we also demonstrated that the use of longer, 17-mer peptides elicits a higher frequency of responding CD4 T cells than the more commonly used 15-mer peptides. Our results demonstrate the breadth of the CD4 and CD8 T cell response to RSV and demonstrate the importance of using longer peptides when stimulating CD4 T cell responses. R espiratory syncytial virus (RSV), a single-stranded negativesense RNA paramyxovirus, is the leading cause of hospitalizations for lower respiratory tract infections in young children (1). RSV is a ubiquitous pathogen, infecting 30 to 60% of children during their first year of life and up to 90% of children by their second year of life (2-4). Furthermore, approximately 3% of RSVinfected children require hospitalization (5). In total, it is estimated that worldwide, RSV is responsible for 3.4 million acute lower respiratory tract infections annually in children under the age of 5, resulting in up to 196,000 yearly fatalities (6). In addition to children, the elderly are also susceptible to severe RSV-induced disease (7).BALB/c mice are susceptible to RSV infection and have been used extensively to ...

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Viral Shedding and Immune Responses to Respiratory Syncytial Virus Infection in Older Adults

Abstract: Multiple factors, but not older age, are independently associated with severe RSV infection in adults. The presence of underlying medical conditions had the greatest influence on disease severity.

Cited by 122 publications

References 36 publications

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

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

Viral load is strongly associated with length of stay in adults hospitalised with viral acute respiratory illness

Determining the Breadth of the Respiratory Syncytial Virus-Specific T Cell Response

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