HUMAN AND MURINE T-CELL RESPONSES TO ALLELIC FORMS OF A MALARIA CIRCUMSPOROZOITE PROTEIN EPITOPE SUPPORT A POLYVALENT VACCINE STRATEGY

Mouse models and a recent Vaccine trial have indicated the importance of T-cell immunity to the circumsporozoite protein (CSP) of malaria sp orozoites. One of the major impediments for the development of a CSP-b ased vaccine is that human T-cell epilopes, identified on the CSP, spa n regions of significant point mutational polymorphism. Studies with h uman and mouse T-tell clones have indicated that this polymorphism aff ects T-cell cross-reactivity to Th2R and Th3R, the two most polymorphi c and immunodominant epitopes. We extend this observation with polyclo nal human T-cell lines, from 11 donors, raised to known variants of Th 2R. These lines showed limited but variable cross-reactivity with the heterologous peptides. T cells from B10.A4(R) (I-A(k)) mice immunized with each of 18 natural variants of Th2R indicated a similar, limited, cross-reactivity. I-Ak competition assays showed that a number of pep tides were unable to bind because of a single polymorphic residue. In both the human and mouse assays, analysis of the sequences of immunoge nic cross-reactive and non-cross-reactive peptides suggested that the individual polymorphic residues affect the three-dimensional conformat ion of the peptide within the major histocompatibility complex (MHC) g roove in an, as yet, unpredictable way. These observations argue that design of an epitope able to generate broad cross-reactivity is, to da te, not possible. However, despite the limited cross-reactivity of the individual human T-cell lines, most of the donors had T-cell repertoi res capable of recognizing all or nearly all of the variants tested, w hich supports a strategy using a multivalent vaccine.