We engineered an antibody expressing in the third complementarity-determining region of its heavy chain variable region a "foreign" epitope, the repetitive tetrapeptide Asn-Ala-Asn-Pro (NANP) of the circumsporozoite protein of Plasmodiumfalciparum parasite, one of the etiologic agents of malaria in humans. A monoclonal antibody to P. falciparum specific for the (NANP Immunoglobulins are the main effector of humoral immunity, a property linked with their ability to bind antigens. A second general property is the immunogenicity of their antigenic determinants (idiotypes) whereby they can regulate the immune system in a predictable way (1). The sequence ofevents antigen -* idiotype --anti-idiotype (2-4) and the ability of the latter to mimic peptide (5) and carbohydrate epitopes (6, 7) (internal image anti-idiotypes) (8) constitute a framework for the specific and rational manipulation of the immune system. Structurally, the immunogenic property of immunoglobulins resides in the complementarity-determining regions (CDRs) of their variable (V) domains, sites where changes in sequence and conformation are tolerated with little, if any, effect on the framework of the molecule (9). For instance, the CDRs of one antibody grafted into another immunoglobulin molecule maintain in the new molecular environment the antigen-binding property of the donor antibody (10-12).Mimicry of antigens by antibodies has been reported in many systems and internal image antibodies generated through a conventional idiotypic cascade served to immunize animals against bacteria, viruses, and parasites (131 14).Whereas the structural basis for this phenomenon remains by and large unclear, few reports exist to suggest that functional mimicry can be associated with shared primary structure between an antibody's CDR and the respective nominal antigen (15)(16)(17).In the study presented here we used protein engineering techniques to verify whether an antibody expressing a "foreign" peptide epitope as an integral part of a V region could be used to induce immunity of predetermined specificity in vivo. We tested this hypothesis using a chimeric mouse/ human antibody (y1NANP) constructed to express three copies of the tetrapeptide Asn-Ala-Asn-Pro (NANP) of malaria's Plasmodium falciparum circumsporozoite (CS) protein in the CDR3 of the heavy (H) chain. The rationale to this experiment was 2-fold. On one hand, we chose to engineer the CDR3 of the H chain as studies from this laboratory indicated that the CDR3 loop of the murine VH (18) used expresses an immunodominant idiotype at the surface of the molecule (19). On the other hand, we selected the NANP sequence, an oligopeptide that occurs as 37 tandem repeats interspersed with 4 repeats of the variant sequence Asn-ValAsp-Pro (NVDP), because it is immunodominant in humans and correlates with protective immunity (20). Monoclonal antibodies (mAbs) that passively protect animals against sporozoite infection bind to the repeat region of the CS protein (10). Immunization of mice and rabbits with the ...