Cryptococcosis is an invasive mycotic disease caused by the fungus Cryptococcus neoformans. In the second half of the 20th century, cryptococcosis increased dramatically in medical importance because of its association with HIV infection, organ transplantation and immunosuppression caused by medical advances. Therapy with antifungal drugs remains unsatisfactory, particularly in non-HIV cases, as the infection tends to be chronic, difficult to eradicate and recur after therapy. There are no vaccines available for the prevention of cryptococcosis, or for any other mycoses. Host defense against C. neoformans infection involves both humoral and cellular mechanisms. C. neoformans is unusual in that it is the only encapsulated human pathogen and the polysaccharide capsule is an absolute requirement for virulence. The major capsular polysaccharide is glucuronoxylomannan (GXM). Antibodies to the capsular polysaccharide are protective providing a strong rationale for the development of vaccines that target this antigen. This proposal seeks funds to develop a novel conjugate vaccine based on synthetic and natural oligosaccharides, which will focus the resulting immune response into making only protective antibodies. Conjugate vaccines have been remarkably successful in reducing the incidence of several bacterial encapsulated pathogens and the same should be possible for cryptococcosis. We plan to take advantage of all that we have learned about antibody-mediated immunity against C. neoformans to develop a novel conjugate vaccine against a major human fungal pathogen. In addition, two new developments provide a new approach to this problem: 1) advances in synthetic organic chemistry have led to the generation of chemically defined oligosaccharides representing GXM motifs; and 2) the discovery that C. neoformans makes large amounts of oligosaccharides in culture that are raw materials for vaccine construction. The availability of new materials in the form of natural and synthetic oligosaccharides for the polysaccharide component of the conjugate vaccine bring the promise of making highly immunogenic compounds that focus the immune response to elicit only protective antibodies.
Three aims are proposed: 1. To establish the epitopes in C. neoformans GXM recognized by protective and non-protective antibodies; 2. To generate a set of novel protein-polysaccharide conjugate vaccines based on natural and synthetic oligosaccharides of expressing C. neoformans GXM structural motifs; 3. To establish the immunogenicity and efficacy novel conjugate vaccines against experimental C. neoformans infection.

Public Health Relevance

There are currently no vaccines against any fungal disease. This application is proposes to develop a vaccine for the prevention of Cryptococcosis, a serious and life-threatening disease caused by the fungus Cryptococcus neoformans. Our goal is to take advantage of recent advances to create a novel polysaccharide-protein conjugate that will elicit protective antibody responses and be useful for the prevention and therapy of cryptococcosis.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
3R01AI152078-02S1
Application #
10265635
Study Section
Vaccines Against Microbial Diseases Study Section (VMD)
Program Officer
Zou, Lanling
Project Start
2020-06-17
Project End
2025-02-28
Budget Start
2021-03-01
Budget End
2022-02-28
Support Year
2
Fiscal Year
2021
Total Cost
Indirect Cost
Name
Johns Hopkins University
Department
Microbiology/Immun/Virology
Type
Schools of Public Health
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218