A
vaccine that effectively protects immunocompromised patients against invasive
aspergillosis is a novel approach to a universally fatal disease. Here we present a rationale for selection and in vivo testing of potential
protein vaccine candidates, based on the modification of an immunodominant fungal
allergen for which we demonstrate immunoprotective properties. Pulmonary exposure to viable Aspergillus fumigatus conidia as well as vaccination with crude hyphal extracts protects
corticosteroid-immunosuppressed mice against invasive
aspergillosis (J. I. Ito and J. M. Lyons, J. Infect. Dis. 186:869-871, 2002). Sera from the latter animals contain
antibodies with numerous and diverse
antigen specificities, whereas sera from conidium-exposed mice contain
antibodies predominantly against
allergen Asp f 3 (and some against Asp f 1), as identified by mass spectrometry. Subcutaneous immunization with recombinant Asp f 3 (rAsp f 3) but not with Asp f 1 was protective. The lungs of Asp f 3-vaccinated survivors were free of hyphae and showed only a patchy low-density infiltrate of mononuclear cells. In contrast, the nonimmunized animals died with invasive hyphal elements and a compact peribronchial infiltrate of predominantly polymorphonuclear leukocytes. Three truncated versions of rAsp f 3, spanning
amino acid residues 15 to 168 [rAsp f 3(15-168)], 1 to 142, and 15 to 142 and lacking the known bipartite sequence required for
IgE binding, were also shown to be protective. Remarkably, vaccination with either rAsp f 3(1-142) or rAsp f 3(15-168) drastically diminished the production of
antigen-specific
antibodies compared to vaccination with the full-length rAsp f 3(1-168) or the double-truncated rAsp f 3(15-142) version. Our findings point to a possible mechanism in which Asp f 3 vaccination induces a cellular immune response that upon
infection results in the activation of lymphocytes that in turn enhances and/or restores the function of
corticosteroid-suppressed macrophages to clear fungal elements in the lungs.