“Developing a Mycosis Vaccine” – November Graduate Student Research Forum
My research is about making a vaccine to protect against pathogenic fungi. These fungi, particularly Aspergillus fumigatus and Candida albicans, generally only infect immunocompromised patients, such as those receiving hematopoietic stem cell transplants at City of Hope. Around 4 percent of these patients will incur fungal infections with a 50 percent mortality rate. Of course, some fungi, such as Coccidioides, which is prevalent in Southern California, can attack immunocompetent hosts and occasionally cause life-threatening infections.
There are indications that a vaccine may help prevent fungal infection in our patients, despite their immunocompromised condition. In an immunosuppressed mouse model, the lab of Markus Kalkum, Ph.D., (associate professor in City of Hope’s Department of Immunology) showed that a vaccine based on recombinant Asp f 3 (pmp20) provided a significant level of protection against pulmonary Aspergillus infection. While the primary mechanism of protection against the fungus is likely to be through CD4+ T cells, antibodies may enhance vaccine efficacy if their target is on the cell surface (at least according to a diagram I made). Thus, we are attempting to create a recombinant cell wall protein vaccine.
In order to identify additional vaccine targets, mass spectrometry was used to analyze the proteome of Aspergillus and other infectious fungi, particularly their cell walls. Several cell wall proteins highly expressed in A. fumigatus were made recombinantly and tested as vaccines in the mouse model. Some of them seemed to provide protection, but further studies have been hampered by chronic failures in the mouse model. Extensive troubleshooting is now underway.
While Aspergillus and Candida are responsible for most fungal infections, more rare species are in fact more deadly. Thus, we hope to eventually create a vaccine that is cross-protective against multiple species of fungi. Such a vaccine would take the form of a recombinant protein composed of several epitopes from different fungal proteins. To promote efficient immune processing, these epitopes would be connected with linkers containing optimal cathepsin cut sites. While each epitope would only confer protection against one or a small number of species, taken together they would provide strong protection against many different pathogenic fungal species.