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The goal of the work described here was to use a targeted multiparameter evaluation of the RSV F-specific T cell response to further characterize the cellular response to RSV in these vaccinated subjects. A higher dose of 120 μg RSV sF + 5 μg GLA-SE induced similar rates of humoral and slightly higher rates of cellular immune responses. At the 80 ug RSV sF + 2.5 μg GLA-SE dose tested, 100% of recipients demonstrated a > threefold rise in humoral responses and 74% demonstrated a > threefold rise in cellular responses. Humoral and cellular responses were measured in > 60 year olds following vaccine dosing. This vaccine consists of RSV soluble fusion protein formulated without or with the adjuvant Glucopyranosyl Lipid A in 2% stable emulsion (GLA-SE). Īn investigational adjuvanted RSV vaccine that aimed to induce both neutralizing antibodies and virus-specific T cells was evaluated in dose-finding Phase 1 trials in > 60 year old subjects.
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It has been proposed that a successful vaccine for the elderly would need to induce both protective neutralizing antibodies and virus clearing T cells. There is currently no approved vaccine for RSV though the incidence of RSV illness in older adults is on par with that of influenza illness. Those meant for elderly subjects may benefit from inclusion of an adjuvant or an increased antigen dose. Vaccines have been only partially successful in reversing declining immune responses in older adults. Though neutralizing antibody titers to RSV are similar between elderly and young adult populations, the elderly have decreased RSV-specific T cell responses compared to young adults.
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Pre-existing influenza-specific CD4 + T cells were associated with decreased illness severity following influenza challenge of healthy volunteers lacking neutralizing antibodies. In an elderly adult population, T cell IFNγ responses to influenza could distinguish between those protected by vaccination and those who subsequently developed influenza illness. T cells in combination with neutralizing antibodies may have a key role in controlling respiratory viruses such as influenza and respiratory syncytial virus (RSV) that can cause more acute infections in the elderly versus healthy young adults. Increased background inflammation, decreased antigen presenting cell function, a higher threshold of T cell activation, decreased naïve T cell numbers, a loss of T cell receptor diversity, a loss of central memory CD8 T cells and reduced CD8 T cell priming are all mechanisms identified that impact T cell responses in older adults. Extensive research on immune senescence in the elderly has identified multiple pathways by which aging mechanisms adversely affect immune responses, particularly T cell responses. Waning adaptive immunity can be seen in adults as young as 50 years old. High parameter CyTOF can help profile immune components associated with differential vaccine responsiveness.Īged adults have decreased immune responses compared to younger adults and are more prone to acute infections as well as reactivation of latent viruses. Using viSNE to analyze RSV-responsive CD4 + and CD8 + T cells, we also found increased expression of HLA-DR, CCR7, CD127 and CD69 in non-responders versus responders. Principal components analysis revealed baseline differences between responders and non-responders, including differences in activated (HLA-DR +) CD4 + and CD8 + T cells, which were higher in non-responders versus responders. Resultsīoth CD4 + and CD8 + T cell antigen-specific IFNγ responses were observed. Here, CyTOF was used to characterize the cellular response profile of ELISPOT responders and non-responders in this vaccine dose cohort. Antigen-specific T cell responses to RSV by IFNγ ELISPOT had been observed in most but not all recipients in the highest dose cohort in this trial. In this study, we applied CyTOF to comprehensively characterize the circulating immune cell populations in elderly individuals both before and after administration of an investigational adjuvanted protein vaccine against respiratory syncytial virus (RSV) in a Phase 1a trial. Mass cytometry, or CyTOF (Cytometry by Time-of-Flight), permits the simultaneous detection of over 40 phenotypic and functional immune markers in individual cells without the issues of spectral overlap seen in traditional flow cytometry.