Abstract
BackgroundRespiratory Syncytial Virus (RSV) causes significant disease in the elderly, in part, because immunosenescence impairs protective immune responses to infection in this population. Despite previous and current efforts, there is no RSV vaccine currently licensed in infants or elderly adults. Adjuvanted RSV subunit vaccines have the potential to boost waning immune responses and reduce the burden of RSV disease in the elderly population.ResultsWe used an aged BALB/c mouse model to evaluate immune responses to RSV Fusion (F) protein in the absence and presence of an alum adjuvant. We demonstrate that aged BALB/c mice immunized with alum-adjuvanted RSV F protein had significantly reduced lung viral titers at day 4 following challenge with wild-type (wt) RSV. Serum neutralizing antibody titers measured on day 27 correlated with protection in both young and aged vaccinated mice, although the magnitude of antibody titers was lower in aged mice. Unlike young mice, in aged mice, alum-adjuvanted RSV F did not induce lung TH2-type cytokines or eosinophil infiltration compared to non-adjuvanted F protein following wt RSV challenge.ConclusionOur studies demonstrate that neutralizing anti-RSV antibody titers correlate with protection in both young and aged BALB/c mice vaccinated with RSV F protein vaccines. The F + alum formulation mediated greater protection compared to the non-adjuvanted F protein in both young and aged mice. However, while alum can boost F-specific antibody responses in aged mice, it does not completely overcome the reduced ability of a senescent immune system to respond to the RSV F antigen. Thus, our data suggest that a stronger adjuvant may be required for the prevention of RSV disease in immunosenescent populations, to achieve the appropriate balance of protective neutralizing antibodies and effective TH1-type cytokine response along with minimal lung immunopathology.
Highlights
Respiratory Syncytial Virus (RSV) causes significant disease in the elderly, in part, because immunosenescence impairs protective immune responses to infection in this population
A dose titration of RSV F protein ranging from 0.03 – 3 μg was previously performed in young mice in our laboratory and demonstrated that partial protection against wt RSV challenge was achieved with a 0.3 μg dose of F
Young mice vaccinated with non-adjuvanted F alone showed partial viral clearance, while no detectable lung viral load was found in the F + alum vaccinated group or the live RSV group (Figure 1A)
Summary
Respiratory Syncytial Virus (RSV) causes significant disease in the elderly, in part, because immunosenescence impairs protective immune responses to infection in this population. Adjuvanted RSV subunit vaccines have the potential to boost waning immune responses and reduce the burden of RSV disease in the elderly population. RSV subunit vaccines have been plagued with poor immunogenicity in the elderly [10,11]. It has been shown that immunization with purified F protein enhanced pulmonary histopathology in cotton rats and mice [12,13]. It appears that RSV F protein alone is insufficient to show protection in aged mice due to poor immunogenicity. We hypothesized that adjuvant mixed with F protein may overcome poor immunogenicity, reduce histopathology, and induce protection in
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