Since its discovery in 1981, HIV-1 has infected ~78 million people and killed ~39 million people. Developing an HIV-1 vaccine remains one of the top priorities in the fight against this devastating pandemic. The modest efficacy showed by the recent RV144 trial suggests that achieving this goal might be possible. As the search for an effective vaccine continues, the induction of antibodies that can neutralize a large number of antigenically distinct viruses from different clades remains a major goal. In recent years, a number of broadly neutralizing antibodies (bnAbs) that target the HIV-1 envelope have been isolated from virus-infected patients, offering hope for vaccine development. Of the different targets on the HIV-1 envelope, the membrane-proximal external region (MPER) of gp41 has been recognized as an attractive candidate for vaccine development. Besides playing a critical role in virus fusion, this domain also contains highly conserved linear epitopes recognized by some of the broadest neutralizing antibodies like 4E10 and 10E8. However, the lack of MPER structural details poses a significant challenge in designing MPER-based vaccines. In our attempts to induce MPER targeting bnAbs, we have designed and evaluated immunogenic properties of multiple antigens in rabbits. Our findings demonstrate that the immunogenicity of the MPER is strongly influenced by the presence or the absence of neighboring domains. Although we have not yet succeeded in inducing 4E10-/10E8-like antibodies, we have made significant progress towards targeting 4E10/10E8 epitope.