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Principal Investigator: Xiaorong Lin
Organization: UNIVERSITY OF GEORGIA
Fiscal Year: 2023
Award: $166,248
Funding agency: National Institute of Allergy and Infectious Diseases
Cryptococcus neoformans and C. gattii cause life threatening cryptococcal meningoencephalitis, the most
common fungal infection of the central nervous system in the world today. The 12-month mortality rate for
individuals with cryptococcal meningoencephalitis is 60% even with the current antifungal treatment.
Developing vaccines against cryptococcosis to treat high risk patients remains one of the most urgent and
challenging goals to combat this devastating fungal infection. So far, inactivated whole cell vaccines and
recombinant protein subunit vaccines are being investigated in preclinical studies. Both inactivated whole cell
vaccines or protein subunit vaccines have issues (e.g., safety, technical, cost, and efficacy concerns) and none
have made it to clinical trials yet.
The emerging and clinically proven vaccine technology based on delivering stabilized mRNAs encoding
immunogens packaged in lipid nanoparticles (LNPs) has not been developed for any bacterial or fungal
infections. Here we will investigate this technology to develop vaccines against cryptococcal infections. Our
research group has experience with liposomes and nucleic acids, and have been working with together on
dectin-decorated liposomes for targeted antifungal drug delivery for years. The targeted antifungal delivery with
dectin-decorated liposomes has shown great promise in both in vitro and animal models. We have also
experience with vaccination against Cryptococcus infection using inactivated cryptococcal mutants.
Capitalizing on these experiences, our goal is to produce a highly effective mRNA LNP vaccine for
cryptococcosis. We have incorporated several new strategies into our novel mRNA vaccine design. For
example, encoded immunogens to be tested are selected based on prior demonstrated efficacy of recombinant
proteins to be protective immunogens, high in vivo transcript abundance, extracellular localization, and their
roles in fungal pathogenesis. Because each extracellular protein will be produced from an mRNA in the host
cell, it will be glycated, and hence, more closely resemble proteins produced by the fungus C. neoformans as
compared to recombinant proteins produced by E. coli. To meet our goal, we propose to accomplish the
following two specific aims: (i) Construct LNPs carrying the mRNAs encoding distinct candidate C. neoformans
protein immunogens. (ii) Test the immunogenicity and durable host protection provided by each mRNA
nanoparticle vaccine and a combinatorial vaccine in mouse models of cryptococcosis. Completion of this
proposal will likely provide a successful platform for mRNA vaccine against cryptococcosis and in the future
other fungal diseases. The exploratory nature of the proposed work and the potential impact it could have on
our ability to fight this and other deadly fungal pathogens make this application perfectly fit for the R21
mechanism.
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