The immunization of goats with a synthetic peptide encompassing the G5 antigenic site of the rabies virus surface glycoprotein induces a strong humoral immune response in the absence of a carrier protein. The immunized animals mounted high antibody titers and showed a strong avidity maturation of the B cell immune response to both the G5-peptide and purified surface glycoprotein G. This antibody weakly neutralized rabies virus carrying the G5 epitope but failed to neutralize escape mutants carrying a single point mutation in this epitope. A putative T helper cell epitope, functional in the context of different caprine MHC haplotypes, was identified by structure analysis of the G5-peptide. This striking dichotomy between high titers and antibody of high avidity to the glycoprotein G and poor neutralizing activity strongly suggests that antibody binding assays such as ELISA cannot always reliably predict the neutralizing activity of sera as measured in functional assays.