Supplement The original grant seeks to develop a novel conjugate vaccine based on synthetic and natural oligosaccharides for Cryptococcus neoformans. This supplement changes the scope to a human clinical trial with the overall goal to investigate novel applications of human convalescent plasma in the prevention and therapy of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which causes coronavirus disease (COVID-19). This is necessary before a vaccine is realized for COVID-19. Thus, the central hypothesis of this project is that COVID-19 convalescent plasma can be successfully used as a treatment strategy to mitigate the spread and mortality of the ongoing COVID-19 pandemic. This randomized open label trial will assess the efficacy and safety of Anti-SARS-CoV-2 convalescent plasma in hospitalized patients with acute respiratory symptoms as well as in high risk exposures as prevention of infection. Serological assays specific for SARS-CoV-2 will be used to assess the amount of antibodies that are present in the blood of plasma donors and recipients. Project Summary (from Parent Grant): ?FIRST 4 sentences truncated?. 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.
Supplement Although the COVID-19 virus appears to be a new human pathogen without known vaccines, monoclonal antibodies or drugs available for treatment, there is robust historical precedent to anticipate that human convalescent plasma is a viable option for mitigation and treatment of COVID-19 disease. This supplement changes to a human plasma therapy to a viral cause of lethal pneumonia. Serological assays specific for SARS-CoV-2 will be used to assess the amount of protective antibodies that are present in the blood of plasma donors and recipients. Project Narrative (from Parent Grant): There are currently no vaccines against any fungal disease. This application 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.
