TH1 Vaccines Based on Replication Attenuated Avirulent Uracil Auxotrophs of an Obligate Intracellular Apicomplexan

Toxoplasma gondii is an obligate intracellular parasite capable of infecting most warm-blooded vertebrates and most nucleated cell types. Parasite transmission occurs primarily by oral ingestion of tissue cysts in undercooked meat or sporozoites in contaminated soil, food, or water. Natural infection typically results in an asymptomatic primary infection that leads to a chronic latent infection.

Dartmouth researchers have now generated a replication attenuated avirulent uracil auxotroph mutant of T. gondii that lacks functional carbamoyl phosphate synthase II (cpsII) activity. The uracil auxotroph mutant cps1-1, in a single immunization, provides complete protection against acute and chronic infections by virulent strains of T. gondii.

The mechanism of the potent immune protection induced by immunization with cps1-1 is via the stimulation of potent and long-lasting (memory) Th-1 immune responses, which in this case is specific to T. gondii encoded antigens. The immune response to cps1-1 immunization is primarily local and induces little host inflammation. The immune response to cps1-1 immunization is unique in that systemic levels of interferon gamma (IFN-g) are very low and transient, and systemic levels of inflammatory cytokine IL-12p40 are also low. Surprisingly, immunization with cps1-1 induces significant levels of mature functional IL-12p70 both systemically as well as locally. This unique immune response is associated with the potent ability of this Th1 vaccine platform to efficiently and rapidly stimulate antigen-specific CD8+ T-cell responses that mature to long-lasting memory responses.

Accordingly, attenuated uracil auxotroph mutants of T. gondii are useful as a vaccine platform to develop Th1-based vaccines directed against parasites of the phylum Apicomplexa, as well as a delivery vector for exogenous antigens (for example, other diseases or cancer that require the elicitation of strong and long-lasting Th1 immune responses), thereby providing a multivalent vaccine against Apicomplexans and diseases associated with the exogenous antigen.

This technology is claimed in a pending patent application. We are seeking an industrial partner interested in its commercialization.

(Ref: J392)

Type of Offer: Licensing

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