PRECLINICAL EFFICACY OF A GLUCURONOXYLOMANNAN-TETANUS TOXOID CONJUGATE VACCINE OF CRYPTOCOCCUS-NEOFORMANS IN A MURINE MODEL

The encapsulated yeast, Cryptococcus neoformans, causes life-threateni ng meningoencephalitis in immunocompromised humans, especially in AIDS patients. Fatality and relapse rates remain quite high despite aggres sive therapy, A conjugate vaccine composed of the cryptococcal capsula r glucuronoxylomannan covalently coupled to tetanus toxoid (GXM-TT) wa s constructed and evaluated. The vaccine elicited high levels of capsu lar antibodies rut mice by active and passive immunizations and confer red 70-80% protection against a moderate challenge with 10(3) C. neofo rmans. Monitoring of serum GXM and anti-GXM antibody levels and of inc idence of cryptococcal isolation from various organs of mice suggested that presence of vaccine-induced antibodies during the first 4-6 week s of infection is critical for clearance of cryptococci from various o rgans, for limiting serum GXM titers from reaching immunosuppressive l evels and ultimately for survival. GXM-TT is the first defined fungal vaccine to confer antibody-mediated protection against a systemic myco sis in an animal model. GXM-TT is being evaluated for safety and immun ogenicity in healthy and HIV-infected human volunteers at the National Institutes of Health.