Predicting the artificial immunity induced by RUTI® vaccine against tuberculosis using universal immune system simulator (UISS)

BACKGROUND: Tuberculosis (TB) represents a worldwide cause of mortality (it infects one third of the world's population) affecting mostly developing countries, including India, and recently also developed ones due to the increased mobility of the world population and the evolution of different new bacterial strains capable to provoke multi-drug resistance phenomena. Currently, antitubercular drugs are unable to eradicate subpopulations of Mycobacterium tuberculosis (MTB) bacilli and therapeutic vaccinations have been postulated to overcome some of the critical issues related to the increase of drug-resistant forms and the difficult clinical and public health management of tuberculosis patients. The Horizon 2020 EC funded project "In Silico Trial for Tuberculosis Vaccine Development" (STriTuVaD) to support the identification of new therapeutic interventions against tuberculosis through novel in silico modelling of human immune responses to disease and vaccines, thereby drastically reduce the cost of clinical trials in this critical sector of public healthcare

Moving forward through the in silico modeling of tuberculosis : a further step with UISS-TB

In 2018, about 10 million people were found infected by tuberculosis, with approximately 1.2 million deaths worldwide. Despite these numbers have been relatively stable in recent years, tuberculosis is still considered one of the top 10 deadliest diseases worldwide. Over the years, Mycobacterium tuberculosis has developed a form of resistance to first-line tuberculosis treatments, specifically to isoniazid, leading to multi-drug-resistant tuberculosis. In this context, the EU and Indian DBT funded project STriTuVaD-In Silico Trial for Tuberculosis Vaccine Development-is supporting the identification of new interventional strategies against tuberculosis thanks to the use of Universal Immune System Simulator (UISS), a computational framework capable of predicting the immunity induced by specific drugs such as therapeutic vaccines and antibiotics. Here, we present how UISS accurately simulates tuberculosis dynamics and its interaction within the immune system, and how it predicts the efficacy of the combined action of isoniazid and RUTI vaccine in a specific digital population cohort. Specifically, we simulated two groups of 100 digital patients. The first group was treated with isoniazid only, while the second one was treated with the combination of RUTI vaccine and isoniazid, according to the dosage strategy described in the clinical trial design. UISS-TB shows to be in good agreement with clinical trial results suggesting that RUTI vaccine may favor a partial recover of infected lung tissue. In silico trials innovations represent a powerful pipeline for the prediction of the effects of specific therapeutic strategies and related clinical outcomes. Here, we present a further step in UISS framework implementation. Specifically, we found that the simulated mechanism of action of RUTI and INH are in good alignment with the results coming from past clinical phase IIa trials

Protective efficacy in a hamster model of a multivalent vaccine for human visceral leishmaniasis (Mulevaclin) consisting of the kmp11, leish-f3+, and ljl143 antigens in virosomes, plus gla-se adjuvant

Visceral leishmaniasis (VL) is the most severe clinical form of leishmaniasis, fatal if untreated. Vaccination is the most cost-effective approach to disease control; however, to date, no vaccines against human VL have been made available. This work examines the efficacy of a novel vaccine consisting of the Leishmania membrane protein KMP11, LEISH-F3+ (a recombinant fusion protein, composed of epitopes of the parasite proteins nucleoside hydrolase, sterol-24-c-methyltransferase, and cysteine protease B), and the sand fly salivary protein LJL143, in two dose ratios. The inclusion of the TLR4 agonist GLA-SE as an adjuvant, and the use of virosomes (VS) as a delivery system, are also examined. In a hamster model of VL, the vaccine elicited antigen-specific immune responses prior to infection with Leishmania infantum. Of note, the responses were greater when higher doses of KMP11 and LEISH-F3+ proteins were administered along with the GLA-SE adjuvant and/or when delivered within VS. Remarkably, hamsters immunized with the complete combination (i.e., all antigens in VS + GLA-SE) showed significantly lower parasite burdens in the spleen compared to those in control animals. This protection was underpinned by a more intense, specific humoral response against the KMP11, LEISH-F3+, and LJL143 antigens in vaccinated animals, but a significantly less intense antibody response to the pool of soluble Leishmania antigens (SLA). Overall, these results indicate that this innovative vaccine formulation confers protection against L. infantum infection, supporting the advancement of the vaccine formulation into process development and manufacturing and the conduction of toxicity studies towards future phase I human clinical trialsEuropean Community’s Seventh Framework Programme, grant number 603181 (Clinical Studies on a Multivalent Vaccine for Human Visceral Leishmaniasis [MuLeVaClin]), and by the RD16CIII/0003/0002 and RD16/0027/0008 Red de Investigación Cooperativa de Enfermedades Tropicales, Subprograma RETICS del Plan Estatal de I+D+I 2013–2016, co-funded by ERD

Protective Efficacy in a Hamster Model of a Multivalent Vaccine for Human Visceral Leishmaniasis (MuLeVaClin) Consisting of the KMP11, LEISH-F3+, and LJL143 Antigens in Virosomes, Plus GLA-SE Adjuvant

Visceral leishmaniasis (VL) is the most severe clinical form of leishmaniasis, fatal if untreated. Vaccination is the most cost-effective approach to disease control; however, to date, no vaccines against human VL have been made available. This work examines the efficacy of a novel vaccine consisting of the Leishmania membrane protein KMP11, LEISH-F3+ (a recombinant fusion protein, composed of epitopes of the parasite proteins nucleoside hydrolase, sterol-24-c-methyltransferase, and cysteine protease B), and the sand fly salivary protein LJL143, in two dose ratios. The inclusion of the TLR4 agonist GLA-SE as an adjuvant, and the use of virosomes (VS) as a delivery system, are also examined. In a hamster model of VL, the vaccine elicited antigen-specific immune responses prior to infection with Leishmania infantum. Of note, the responses were greater when higher doses of KMP11 and LEISH-F3+ proteins were administered along with the GLA-SE adjuvant and/or when delivered within VS. Remarkably, hamsters immunized with the complete combination (i.e., all antigens in VS + GLA-SE) showed significantly lower parasite burdens in the spleen compared to those in control animals. This protection was underpinned by a more intense, specific humoral response against the KMP11, LEISH-F3+, and LJL143 antigens in vaccinated animals, but a significantly less intense antibody response to the pool of soluble Leishmania antigens (SLA). Overall, these results indicate that this innovative vaccine formulation confers protection against L. infantum infection, supporting the advancement of the vaccine formulation into process development and manufacturing and the conduction of toxicity studies towards future phase I human clinical trials.This research was funded by the European Community’s Seventh Framework Programme, grant number 603181 (Clinical Studies on a Multivalent Vaccine for Human Visceral Leishmaniasis [MuLeVaClin]), and by the RD16CIII/0003/0002 and RD16/0027/0008 Red de Investigación Cooperativa de Enfermedades Tropicales, Subprograma RETICS del Plan Estatal de I+D+I 2013–2016, co-funded by ERDF “Una manera de hacer Europa” funds.S

An agent based modeling approach for the analysis of tuberculosis - Immune system dynamics

Tuberculosis is one of the world's deadliest diseases that infects one third of the world's population, mostly in developing countries. However, tuberculosis is becoming again very dangerous also for developed countries, due to the increased mobility of the world population, and the appearance of several new bacterial strains that are multi-drug resistant. With the aim to help in finding new therapeutic interventions against tuberculosis, we present the application of a computational modeling infrastructure named UISS (Universal Immune System Simulator) able to simulate the main features and dynamics of the immune system activities. We show a further development of UISS to consider the underlying tuberculosis pathogenesis and its interaction with the host immune system. Even though the model can be further personalized employing immunological parameters and genetic information, based on the available data, we obtained simulation scenarios able to reproduce persistent latent infection or the development of active disease. In particular, UISS is able to simulate those mechanisms in which M. tuberculosis is involved in the early influx of alveolar macrophages and recruited neutrophils until the formation of the tuberculous granuloma, at both cellular and molecular levels

Predicting the artificial immunity induced by RUTI® vaccine against tuberculosis using universal immune system simulator (UISS)

Tuberculosis (TB) represents a worldwide cause of mortality (it infects one third of the world's population) affecting mostly developing countries, including India, and recently also developed ones due to the increased mobility of the world population and the evolution of different new bacterial strains capable to provoke multi-drug resistance phenomena. Currently, antitubercular drugs are unable to eradicate subpopulations of Mycobacterium tuberculosis (MTB) bacilli and therapeutic vaccinations have been postulated to overcome some of the critical issues related to the increase of drug-resistant forms and the difficult clinical and public health management of tuberculosis patients. The Horizon 2020 EC funded project "In Silico Trial for Tuberculosis Vaccine Development" (STriTuVaD) to support the identification of new therapeutic interventions against tuberculosis through novel in silico modelling of human immune responses to disease and vaccines, thereby drastically reduce the cost of clinical trials in this critical sector of public healthcare

Pre-clinical antigenicity studies of an innovative multivalent vaccine for human visceral leishmaniasis

<div><p>The notion that previous infection by <i>Leishmania</i> spp. in endemic areas leads to robust anti-<i>Leishmania</i> immunity, supports vaccination as a potentially effective approach to prevent disease development. Nevertheless, to date there is no vaccine available for human leishmaniasis. We optimized and assessed <i>in vivo</i> the safety and immunogenicity of an innovative vaccine candidate against human visceral leishmaniasis (VL), consisting of Virus-Like Particles (VLP) loaded with three different recombinant proteins (LJL143 from <i>Lutzomyia longipalpis</i> saliva as the vector-derived (VD) component, and KMP11 and LeishF3+, as parasite-derived (PD) antigens) and adjuvanted with GLA-SE, a TLR4 agonist. No apparent adverse reactions were observed during the experimental time-frame, which together with the normal hematological parameters detected seems to point to the safety of the formulation. Furthermore, measurements of antigen-specific cellular and humoral responses, generally higher in immunized <i>versus</i> control groups, confirmed the immunogenicity of the vaccine formulation. Interestingly, the immune responses against the VD protein were reproducibly more robust than those elicited against leishmanial antigens, and were apparently not caused by immunodominance of the VD antigen. Remarkably, priming with the VD protein alone and boosting with the complete vaccine candidate contributed towards an increase of the immune responses to the PD antigens, assessed in the form of increased <i>ex vivo</i> CD4⁺ and CD8⁺ T cell proliferation against both the PD antigens and total <i>Leishmania</i> antigen (TLA). Overall, our immunogenicity data indicate that this innovative vaccine formulation represents a promising anti-<i>Leishmania</i> vaccine whose efficacy deserves to be tested in the context of the “natural infection”.</p></div