An adjuvanted respiratory syncytial virus fusion protein induces protection in aged BALB/c mice

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.

Adults 65 Years Old and Older Have Reduced Numbers of Functional Memory T Cells to Respiratory Syncytial Virus Fusion Protein

“…Moreover, RSV-specific CD8 ϩ T cells have been detected in the peripheral blood of previously infected adults in whom these responses have been associated with decreased clinical symptoms (34,35). The contribution of the different antigen-specific T cell subsets to recovery from RSV infection has been extensively studied in mouse models, and long-lived RSVspecific cytotoxic T cell function has been demonstrated to be critical for the accelerated clearance of virus from the lungs of infected animals (36)(37)(38)(39)(40). Recently, it was demonstrated that RSV-specific CD8 ϩ T cells induced upon vaccination protected mice against RSV infection and pathogenesis, and the authors reported that waning protection correlated with reduced CD8 ϩ T cell cytokine expression (41).…”

Palivizumab epitope–displaying virus-like particles protect rodents from RSV challenge

“…On days 0 and 14, mice (n = 5) were immunized intramuscularly with 40 μg of the VLP to be tested or PBS (50 μl total volume) mixed with 50 μl IFA (Imject from Pierce) or 100 μg of VLP plus 250 μg AdjuPhos (Brenntag Biosector) or 40 μg of VLP (50 μl total volume) mixed with 50 μl of GLA-SE (39) (Immune Design Corp.) or 50 to 400 μg of VLP in 100 μl saline. RSV sF protein as described in Cherukuri et al (8) was used as a positive control, and mice were injected with 0.5 μg in the various adjuvants. A final cohort of mice received 1 dose of 10 6 PFU WT RSV A2 (100 μl total volume) intranasally on day 0.…”

“…Development of an RSV vaccine has been hampered by the incidence of enhanced respiratory disease (ERD) following vaccination with formalininactivated RSV in the 1960s (5-7). Subsequent approaches have been to identify key neutralizing RSV proteins or epitopes to which a protective immune response can be safely generated, and development of modern pre-and postfusion RSV fusion (F) protein subunit vaccines is ongoing (8)(9)(10). Alternatively, an immunogen targeted to a single neutralizing epitope may provide protection as a stand-alone vaccine or serve to boost a specific protective immune response after priming with an RSV F vaccine.…”

Impact of formulation and particle size on stability and immunogenicity of oil-in-water emulsion adjuvants

“…18 Mice were randomly assigned into 12 groups (n D 5 mice per group), primed at day 0 and boosted at day 14 intramuscularly (i.m.) with 1.5 mg of RSV F and different combinations of emulsions C/¡ 20 mg of CpG 2395 (Invivogen, San Diego, CA), and AddaVax (Invivogen) C/¡ 20 mg of CpG 2395 (Invivogen).…”