Universal peptide vaccines - optimal peptide vaccine design based on viral sequence conservation

Rapidly mutating viruses such as the hepatitis C virus (HCV), the human immunodeficiency virus (HIV), or influenza viruses (Flu) call for highly effective universal peptide vaccines, i.e. vaccines that do not only yield broad population coverage but also broad coverage of various viral strains. The efficacy of such vaccines is determined by multiple properties of the epitopes they comprise. Beyond the specific properties of each epitope, properties of the corresponding source antigens are of great importance. If a response is mounted against viral proteins with a low copy number within the cell or against proteins expressed very late, this response may fail to induce lysis of the infected cells before budding can take place. We here propose a novel methodology to optimize the epitope composition and assembly in order to induce maximum protection. In order for a peptide vaccine to yield the best possible universal protection, several conditions should be met: (a) an optimal choice of target antigens, (b) an optimal choice of highly conserved epitopes, (c) maximum coverage of the target population, and (d) the proper ordering of the epitopes in the final vaccine to ensure favorable cleavage. We propose a mathematical formalism for epitope selection and ordering that balances the constraints imposed by these different conditions. Focusing on HCV, HIV, and Flu, we show that not all of the conditions can be satisfied for all viruses. Depending on the virus, different constraints are harder to fulfill: for Flu, the conservation constraint is violated first, while for HIV, it is difficult to focus the response at the optimal target antigens. The proposed methodology can be applied to any virus to assess the feasibility of optimally combining the above-mentioned constraints.