Abstract
Life-threatening, invasive fungal infections (IFIs) cause over 1.5 million deaths worldwide and are a major public health concern with high mortality rates even with medical treatment. Infections with the opportunistic fungal pathogen, Aspergillus fumigatus are among the most common. Despite the growing clinical need, there are no licensed vaccines for IFIs. Here we evaluated the immunogenicity and protective efficacy of an A. fumigatus recombinant protein vaccine candidate, AF.KEX1, in experimental murine models of drug-induced immunosuppression. Immunization of healthy mice with AF.KEX1 and adjuvant induced a robust immune response. Following AF.KEX1 or sham immunization, mice were immunosuppressed by treatment with either cortisone acetate or hydrocortisone and the calcineurin inhibitor, tacrolimus. To test vaccine efficacy, immunosuppressed mice were intranasally challenged with A. fumigatus conidia (Af293) and weight and body temperature were monitored for 10 days. At study termination, organism burden in the lungs was evaluated by quantitative PCR and Gomori’s methanamine silver staining. In both models of immunosuppression, AF.KEX1 vaccinated mice experienced decreased rates of mortality and significantly lower lung organism burden compared to non-vaccinated controls. The lung fungal burden was inversely correlated with the peak anti-AF.KEX1 IgG titer achieved following vaccination. These studies provide the basis for further evaluation of a novel vaccine strategy to protect individuals at risk of invasive aspergillosis due to immunosuppressive treatments.
Highlights
Aspergillus infections are estimated to affect over 3 million people and contribute to nearly 500,000 deaths per year [1, 2]
These results demonstrate that antibodies recognizing AF.KEX1 are naturally generated during experimental A. fumigatus infection in immunocompromised mice
This study examined the immunogenicity and protective efficacy of a recombinant Aspergillus fumigatus protein AF.KEX1 in two murine models of invasive pulmonary aspergillosis (IPA)
Summary
Aspergillus infections are estimated to affect over 3 million people and contribute to nearly 500,000 deaths per year [1, 2]. Aspergillus colonization is a major cause of allergic diseases, which can contribute to severity and exacerbations of chronic pulmonary diseases such as asthma and cystic fibrosis. AF.KEX1 Vaccination Prevents Aspergillosis sensitization in severe asthma may affect over 6 million people [3]. The most severe infection due to Aspergillus is invasive pulmonary aspergillosis (IPA) which is one of the most frequent, life-threatening infections of immunosuppressed individuals. Despite the increases in morbidity and mortality due to IPA and increasing concerns for an emerging trend in azole resistance [6], there are no anti-fungal vaccines approved for clinical use and few options have been presented in the field as candidates [7].
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