Design and evaluation of a multi-epitope HIV-1 vaccine based on human parvovirus virus-like particles.

The development of a protective HIV vaccine remains a challenge given the high antigenic diversity and mutational rate of the virus, which leads to viral escape and establishment of reservoirs in the host. Modern antigen design can guide immune responses towards conserved sites, consensus sequences or normally subdominant epitopes, thus enabling the development of broadly neutralizing antibodies and polyfunctional lymphocyte responses. Conventional epitope vaccines can often be impaired by low immunogenicity, a limitation that may be overcome by using a carrier system. In this work, Virus-Like Particles (VLPs) of the B19 human parvovirus were used as a carrier system for multiple HIV-1 epitopes displayed on the surface. Epitopes were selected based on being the binding site of broadly neutralizing antibodies (bnAbs) in patients. Full capsid assembly was confirmed by dynamic light scattering and morphology was confirmed by transmission electron imaging. The resulting chimeric VLPs were termed "VLP-MHIV-A". Antigenicity was confirmed by HIV+ patient sera binding to the chimeric VLP-MHIV-A. To evaluate immunogenicity, female C57bl/6 mice were immunized with the chimeric VLPs either via the intramuscular or subcutaneous route, specific humoral and cellular responses were evaluated, and neutralizing activity was measured in an in vitro reporter cell system. Substantial antibodies against whole-VLPs were induced in serum and vaginal lavages for both immunization routes. Antibody responses against the CD4 binding site, V3 loop and several epitopes of gp41 were detected. Both immunization routes demonstrated neutralizing activity; however, the I.M. route was more effective, showing significant neutralizing activity with up to 50 % inhibition of a tier 1 clade B virus infection. Taken as a whole, these results show that chimeric VLPs are an effective antigen capable of inducing HIV-1 specific antibodies with neutralizing activity.