It is generally agreed that the recombinant gp120 (rgp120) of HIV-1 could be developed as an antibody-mediated subunit vaccine against HIV-1. Unfortunately, Connor and co-workers have provided direct experimental evidence that rgp120 (monomer) does not protect individuals from HIV-1 infection1. In addition, Moore has reviewed studies of rgp120 subunit vaccines and proposed that a new strategy is needed to develop an effective vaccine against HIV-1 (Ref. 2). An epitope vaccine might be such a strategy. The epitope vaccine against HIV-1 uses much of the principal neutralizing determinant (PND) of the envelope (Env) protein (gp160) and belongs to a special type of synthetic peptide vaccine. Several epitopes on gp160 have been characterized as PNDs, for example, GPGRAF (Env aa316-321) on the V3 loop of gp120, ELDKWA (aa669-674) on the C-domain of gp41 and RILAVERYLKD (Env aa586-596) on the N-domain of gp41. It has been demonstrated that crossneutralizing antibodies elicited by peptides of the V3 loop bind to epitope GPGRAF, which undergoes restricted mutation from GPGRAF to GPG(R/K/Q)AF (Ref. 3). ELDKWA is a relatively conserved epitope. Recent sequence analysis of primary isolates from different HIV-1 subtypes suggests that the major determinant of monoclonal antibody (mAb) 2F5 corresponds to the amino acid sequence LDKW. Naturally occurring and in vitro-selected neutralization-resistant viruses contained D to N, D to E and K to N changes in the ELDKWA motif. These amino acid changes caused abrogation of 2F5-binding to ELDKWA (Ref. 4). Recent studies have attested the breadth of reactivity of 2F5 by the antibody's significant neutralization potency against African, Asian, American and European strains from clades A, B and E. Most of the viruses investigated were neutralized by 90% (Ref. 4). The epitope RILAVERYLKD has been shown to induce protective activity5. We have designed candidate synthetic peptide vaccines and compared immunogenicity of: (1) the recombinant gp160 and gp41 subunit vaccines; (2) peptide vaccines of the C-domain on gp41 (EnvIIIB aa646-674: C-TSLIHSLIEESQNQQEKNEQELLELDKWA) and the gp120 V3 loop (EnvIIIB aa301-328: C-TRPNNNTRKSIRIQRGPGRAFYTIGKI); and (3) epitope vaccines of ELDKWA on the C-domain of gp41 [C-(ELDKWAG)4-BSA] and GPGRAFY on gp120 [C-(GPGRAFY)4-P24EC]. In mice, the rgp160 subunit vaccine induced a very weak antibody response to both epitopes (ELDKWA and GPGRAFY), whereas both synthetic peptides conjugated with carrier protein BSA or carrier peptide P24EC (GPKEPFRDYVDRFYK-C) increased the epitope-specific antibody responses (increased antibody titre by two- to fourfold) to ELDKWA and GPGRAFY. Interestingly, both the ELDKWA and the GPGRAFY tetramer epitope vaccines induced a strong epitope-specific antibody response against ELDKWA and GPGRAFY, respectively, and the levels of ELDKWA- and GPGRAFY-specific antibodies increased two- to fourfold, compared with levels induced with the synthetic peptide vaccines (Table 1). These results indicate that the epitope vaccine could provide a new strategy to develop an effective vaccine against HIV-1 infection. Crystallographic analysis indicates that the binding of gp120 to both CD4 and a chemokine receptor induces conformational changes in gp41 from the native structure to the fusion-active structure. The exposed coiled coils create a fusion intermediate, in which the C-domain and N-domain are exposed6. Recent studies have demonstrated that a fusion-competent vaccine with broad neutralization of HIV primary isolates is associated with these fusion intermediates7,8, suggesting that