Focusing immune response on key neutralizing epitopes of HIV- 1 through immune complex vaccination

Since its discovery in 1981, HIV-1 has infected almost 78 million people, and ~39 million people have died. An effective vaccine for HIV-1 remains an utmost priority. In the past several years, tremendous progress has been made in designing different immunogens and employing vaccination strategies, with the common goal of eliciting broadly neutralizing antibodies (bnAbs) and/or T cell responses against HIV infection. Several bnAbs have been isolated from patients, suggesting that the humoral immune system is capable of making such antibodies. Unfortunately, none of the immunogens and vaccination strategies has elicited bnAbs till date, and thus a tremendous amount of work still lies ahead. Here, we evaluated an immune complexing vaccination strategy in rabbits to focus the immune response towards critical neutralizing epitopes on HIV-1 by masking the hypervariable, immunodominant V3 loop on gp120 with a rabbit monoclonal antibody (mAb). Our findings indicate that although the humoral immune response did not increase in immune complex vaccinated rabbits as compared to gp120 alone group, we still suppressed the V3-specific antibody, as seen by antigen specific antibody titer and fine linear epitope mapping. Also, competition of immune complex sera against V3 loop-neutralizing antibodies (nAbs) confirm repressed antibody activity towards this epitope. Although, immune complex vaccinated rabbits failed to elicit neutralizing antibodies, we have demonstrated the proof of concept and feasibility of this approach. Further evaluation of this strategy using alternate immunogens like BG505 SOSIP gp140 and eOD-GT8 will be carried out in the near future.