IgVH determined genetic restriction of a non-internal image monoclonal anti-idiotypic vaccine against Semliki Forest virus

Abstract

Two monoclonal anti-idiotypic antibodies (ab2 mAb), designated 1.13A112 (IgG2a) and 1.13A321 (IgG1) and induced against Semliki Forest virus (SFV)-neutralizing mAb UM 1.13, were investigated with regard to their vaccine potential. 1.13A321 was coupled with glutaraldehyde to keyhole limpet haemocyanin (KLH) and mixed with the adjuvant Quil A. Then when injected subcutaneously into BALB/c mice, it evoked high levels of SFV-neutralizing anti-anti-idiotypic antibodies in serum. In contrast, 1.13A112 had to be indirectly cross-linked to KLH with anti-mouse immunoglobulin to induce a low neutralizing antibody response. Competition binding assay revealed that 1.13A112 and 1.13A321 were completely competitive. Furthermore, SFV neutralization by UM 1.13 and anti-anti-idiotypic (ab3) serum was blocked equally well by either ab2 mAb. These results indicate that ab1 (UM 1.13) and ab3 share at least one antigen-combining site-related idiotope. Induction of SFV-neutralizing antibodies is genetically restricted. Rabbit anti-anti-idiotypic sera against 1.13A321 and 1.13A112 contained no SFV-neutralizing activity. Moreover, in DBA/2, C57BL/6J, CAL-20, and CB-20 mice 1.13A321 did not develop SFV-neutralizing ab3 antibodies in contrast to BALB.K, 129, SWISS, and BAB-14 mice. CAL-20, CB-20, and BAB-14 mice are congenic strains with an inbred background of BALB/c. CB-20 mice derived both IgCH and IgVH from donor strain C57BL/Ka, while BAB-14 mice derived IgCH from C57BL/Ka mice but retained IgVH from BALB/c mice. Clearly, induction of SFV-neutralizing antibodies by 1.13A321 in BAB-14 mice is dependent on IgVH of BALB/c origin. The results suggest that 1.13A321 binds to a paratope-associated recurring idiotope and almost certainly does not bear the internal image of the discontinuous neutralization epitope recognized by mAb UM 1.13. The latter suggestion is sustained by the observation that 1.13A112 and 1.13A321 do not bind to cell receptors.