Beyond the state of the art of reverse vaccinology: predicting vaccine efficacy with the Universal Immune System Simulator for influenza

Abstract When it was first introduced in 2000, reverse vaccinology was defined as an in silico approach that begins with the pathogen's genomic sequence and concludes with a list of potential protein and/or peptide candidates that need to be experimentally confirmed for vaccine production. During the subsequent years, reverse vaccinology has dramatically changed: now it consists of a large number of bioinformatics tools and processes namely subtractive proteomics, computational vaccinology, immunoinformatics, and in silico related procedures. However, the state of the art of reverse vaccinology still misses the ability to predict the efficacy of the proposed vaccine formulation. Here, we describe how to fill the gap introducing an advanced immune system simulator able to test the efficacy of a vaccine formulation against the disease for which it has been designed. As a working example, we present a fully application of this advanced reverse vaccinology approach to design and predict the efficacy of a potential vaccine formulation against influenza H5N1. Climate change and melting glaciers are critical issues due to reactivating frozen viruses and emerging new pandemics. H5N1 is one of the potential strains present in frozen lakes that can raise a pandemic. Investigating structural antigen protein is the most profitable therapeutic pipeline to generate an effective vaccine against H5N1. In particular, we designed a multi-epitope vaccine based on predicted epitopes of hemagglutinin and neuraminidase proteins that potentially trigger B-cells, CD4, and CD8 T-cell immune responses. Antigenicity and toxicity of all predicted CTL, Helper T-lymphocytes, and B-cells epitopes were evaluated, and both antigenic and non-allergenic epitopes were selected. In the perspective of advanced reverse vaccinology, the Universal Immune System Simulator, an in silico trial computational framework, was applied to estimate vaccine efficacy using a cohort of 100 digital patients.