Combining agent based-models and virtual screening techniques to predict the best citrus-derived vaccine adjuvants against human papilloma virus

Marzio Pennisi,Silvia Ravalli,Francesco Pappalardo,Giulia Russo

doi:10.1186/s12859-017-1961-9

Abstract

BackgroundHuman papillomavirus infection is a global social burden that, every year, leads to thousands new diagnosis of cancer. The introduction of a protocol of immunization, with Gardasil and Cervarix vaccines, has radically changed the way this infection easily spreads among people. Even though vaccination is only preventive and not therapeutic, it is a strong tool capable to avoid the consequences that this pathogen could cause. Gardasil vaccine is not free from side effects and the duration of immunity is not always well determined. This work aim to enhance the effects of the vaccination by using a new class of adjuvants and a different administration protocol. Due to their minimum side effects, their easy extraction, their low production costs and their proven immune stimulating activity, citrus-derived molecules are valid candidates to be administered as adjuvants in a vaccine formulation against Hpv.ResultsWith the aim to get a stronger immune response against Hpv infection we built an in silico model that delivers a way to predict the best adjuvants and the optimal means of administration to obtain such a goal. Simulations envisaged that the use of Neohesperidin elicited a strong immune response that was then validated in vivo.ConclusionsWe built up a computational infrastructure made by a virtual screening approach able to preselect promising citrus derived compounds, and by an agent based model that reproduces HPV dynamics subject to vaccine stimulation. This integrated methodology was able to predict the best protocol that confers a very good immune response against HPV infection. We finally tested the in silico results through in vivo experiments on mice, finding good agreement.

Highlights

Human papillomavirus infection is a global social burden that, every year, leads to thousands new diagnosis of cancer
They predominantly belong to the epidermis rather than to the immune system machinery, they play an important role as innate immune system tools: they act as non-professional Antigen Presenting Cells (APC), being able to present peptides in association with MHC I/II [6, 7]; they are able to secrete pro-inflammatory cytokines and chemokines (IL-1, IL-6, IL-10, IL-18, TNF) and can express Toll-like receptors (TLR), located both on cell surface (TLR1, TLR2, TLR4, TLR5, TLR6) and in endosomes (TLR3 and TLR9)
The starting point of the model: virtual screening approach To narrow the identification of potential citrus-derived adjuvants candidates to be used in vaccine formulation against Human papillomavirus (Hpv), we initially used virtual screening method starting from a set of molecules present in the essential oil of orange peel

Summary

Introduction

Human papillomavirus infection is a global social burden that, every year, leads to thousands new diagnosis of cancer. This work aim to enhance the effects of the vaccination by using a new class of adjuvants and a different administration protocol. Due to their minimum side effects, their easy extraction, their low production costs and their proven immune stimulating activity, citrus-derived molecules are valid candidates to be administered as adjuvants in a vaccine formulation against Hpv. Human papillomavirus (Hpv) is a member of the Papovaviridae family, a successful infectious group of small, non-lytic, non-enveloped viruses with over 180 genotypes identified. Hpv infection has become the most common sexually transmitted disease all over the world, because of its peculiar mechanism to escape the immune system; it represents a global social burden. They predominantly belong to the epidermis rather than to the immune system machinery, they play an important role as innate immune system tools: they act as non-professional Antigen Presenting Cells (APC), being able to present peptides in association with MHC I/II [6, 7]; they are able to secrete pro-inflammatory cytokines and chemokines (IL-1, IL-6, IL-10, IL-18, TNF) and can express Toll-like receptors (TLR), located both on cell surface (TLR1, TLR2, TLR4, TLR5, TLR6) and in endosomes (TLR3 and TLR9)

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