Development of a nanoparticle-based vaccine for prevention of acute and recurrent Herpes Simplex Virus infections

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Human Herpes Simplex Virus (HSV) infections belong to the most frequently occurring virus-associated diseases worldwide. The ability of the virus to successfully avoid clearance by the immune system by spreading directly from cell to cell and establishing latency leads to lifelong infection. Subsequently, periodic reactivations from latency result in recurrent symptomatic infections at the site of primary infection. Although many strategies have been tried, no successful vaccine against HSV infections was developed so far. The major problem of controling HSV-infections are the various mechanisms HSV uses to avoid the immune response. Particularly, HSV migrates directly between adjacent cells over the the cell-to-cell spread mechanism during acute or recurrent infections without beeing disturbed by cellular or humoral immune compounds. Obviously, conventional vaccine approaches failed to circumvent this obstacle. Because of the urgent need of an effective vaccine for the prevention of new infections and for therapeutic approaches, a novel vaccine strategy should be investigated in the present study. Recently, we showed that the presence of the highly neutralizing antibody mAb hu2c, which is capable of inhibiting the cell-to-cell spread mechanism, mediated complete protection from the establishment of an otherwise lethal infection in highly immunocompromized NOD/SCID mice. Moreover, an already established mucosal infection was neutralized and the neuronal spread of the virus from the periphery to the brain could be completely aborted. The results indicate that a vaccine capable of inducing a humoral response containing antibodies with equal specificities as mAb hu2c should be effective in preventing new HSV infections and reactivations. Based on these findings, the focus of this research project is the design and pre-clinical evaluation of an innovative mimotope-based nanoparticle vaccine designed to induce highly neutralizing antibodies capable of preventing HSV infections and limiting the frequency of reactivations by inhibiting the cell-to-cell transmission of the virus. Therefore, peptides exhibiting high avidity to mAb hu2c will be selected for the generation of capsid-like particles (CLPs) or calcium-phosphate nanoparticles (CaPs. Subsequently, the efficacy of these nanoparticles in mediating protective humoral responses containing highly neutralizing and cell-to-cell spread inhibiting antibodies will be investigated in mice. Candidates inducing the highest levels of neutralizing as well as cell-to-cell spread inhibiting antibodies will then be considered for subsequent challenge experiments in animals. Mouse experiments will be performed to investigate the impact of the vaccine on a new HSV infection, whereas guinea pigs will serve for examination of the efficacy of the vaccine on HSV reactivations. The planned experiments shall make an important contribution to the development of an effective prophylactic and therapeutic HSV vaccine.