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Factors Associated with the Development of Neonatal Tolerance After the Administration of a Plasmid DNA Vaccine¹

Motohide Ichino^*, Gil Mor^*, Jackie Conover^*, Walter R. Weiss, Mitsuhiro Takeno^*, Ken J. Ishii^* and Dennis M. Klinman^2,*

^* Section of Retroviral Immunology, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, MD 20892; and Malaria Program, Naval Medical Research Institute, Bethesda, MD 20889

A plasmid DNA vaccine encoding the circumsporozoite protein of malaria (pCSP) induces tolerance rather than immunity when administered to newborn mice. We find that this tolerance persists for >1 yr after neonatal pCSP administration and interferes with the induction of protective immunity in animals challenged with live sporozoites. Susceptibility to tolerance induction wanes rapidly with age, disappearing within 1 wk of birth. Higher doses of plasmid are more tolerogenic, and susceptibility to tolerance is not MHC-restricted. CD8⁺ T cells from tolerant mice suppress the in vitro Ag-specific immune response of cells from adult mice immunized with pCSP. Similarly, CD8⁺ T cells from tolerant mice transfer nonresponsiveness to naive syngeneic recipients. These findings clarify the cellular basis and factors contributing to the development of DNA vaccine-induced neonatal tolerance.

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