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Infection and Immunity, September 2006, p. 5075-5084, Vol. 74, No. 9
0019-9567/06/$08.00+0     doi:10.1128/IAI.00815-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Vaccinations with Recombinant Variants of Aspergillus fumigatus Allergen Asp f 3 Protect Mice against Invasive Aspergillosis{dagger}

James I. Ito,1 Joseph M. Lyons,1 Teresa B. Hong,2 Daniel Tamae,2 Yi-Kuang Liu,2 Sharon P. Wilczynski,3 and Markus Kalkum2*

Department of Infectious Diseases,1 Division of Immunology,2 Department of Anatomic Pathology, City of Hope National Medical Center and Beckman Research Institute, Duarte, California3

Received 19 May 2006/ Returned for modification 16 June 2006/ Accepted 23 June 2006

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 predominately 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.

* Corresponding author. Mailing address: Immunology Division, City of Hope National Medical Center and Beckman Research Institute, 1500 E. Duarte Rd., Duarte, CA 91010-3000. Phone: (626) 471-7131. Fax: (626) 301-8186. E-mail: mkalkum{at}coh.org.

{dagger} Supplemental material for this article may be found at http://iai.asm.org/.

Editor: A. Casadevall

Infection and Immunity, September 2006, p. 5075-5084, Vol. 74, No. 9
0019-9567/06/$08.00+0     doi:10.1128/IAI.00815-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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