Hippolyte Darré1, Simon Arsène1, Anne Vaslin Chessex2, Lorenz Lehr2, Baulier Edouard2, Caterina Sansone2, Cristhyne Leon1
1Nova In Silico, 2OM Pharma
OBJECTIVES OM-85 is a bacterial lysate used to prevent recurrent respiratory tract infections (RTIs) in children [1]. To support OM-85 development in children in the challenging landscape for respiratory clinical trials during and after the COVID-19 pandemic, we developed a computational mechanistic model of RTIs and OM-85 mechanism of action, overlaid with an epidemiological model of common respiratory viruses [2]. This model reproduces epidemiological data in children, as well as the placebo-controlled and interventional arms of multiple OM-85 studies in the same population. OM-85 has also shown potential to protect other populations at risk of recurrent RTIs, such as elderly adults and patients with chronic obstructive pulmonary disease (COPD) [3, 4]. Therefore, we aimed to expand the model’s context of use to these populations, to support the OM-85 clinical studies for these groups. METHODS The mechanistic model of RTIs describes the key immunological pathways involved in responding to a viral infection. The model was initially calibrated to reproduce the reaction to a viral challenge in healthy adults. This was then scaled to children and coupled with an epidemiological model. The result was a model which reproduces epidemiological data in this age group, as well as both the placebo-controlled arm and the interventional arm of multiple OM-85 studies in children. To extend the model’s context of use to the elderly and COPD populations, we calibrated the model on data from viral challenges and epidemiological data in the corresponding groups. For this, we introduced changes to the immunological reactions to viral infections based on the evidence present in the literature for these populations [5, 6]. For the elderly population, we hypothesized that immunosenescence would lead to: – Increased viral load needed to activate the immune response, reflecting lower immune system reactivity, particularly of dendritic cells. – Decreased T cell activation due to lower T cell receptor diversity, and increased natural death rate of T cells. – Decreased IgG and IgA efficacy, due to weakened B cell activity. For the COPD population, we made the evidence-based hypotheses that increased inflammation of the airways would lead to: – Reduced T cell efficacy due to cell exhaustion and increased natural decay. – Increased viral load required to activate the immune response due to weakened immune system. – Reduced efficacy of IgA, due to failure in the transcytosis system leading to decreased concentration of IgA in the airway epithelium surface. – Reduced clearance rate of the virus due to weakened mucociliary functions. RESULTS After expansion of its context of use, the model is able to reproduce epidemiological data in both the elderly and COPD populations. The model also captures the number of RTIs in the placebo-controlled and the interventional arms of multiple OM-85 clinical trials in these populations. The simulations also predict that, while OM-85 retains efficacy for all age groups, it does decline with age, consistent with a similar age-related decline in efficacy observed for vaccines [5]. CONCLUSIONS We developed a mechanistic model able to account for changes in the immune responses to viral infections due to age-related immunosenescence and to chronic inflammation and changes in the airway epithelium in COPD. The model reproduces epidemiological data as well as clinical trial data. Such a model could be used to inform potential efficacy of OM-85 in these special populations and support the design of more efficient clinical trials.
[1] Yin et al. Broncho-vaxom in pediatric recurrent respiratory tract infections: A systematic review and meta-analysis. Int. Immunopharmacol. (2018). [2] Arsène et al. Modeling the disruption of respiratory disease clinical trials by non-pharmaceutical COVID-19 interventions. Nat Commun. (2022). [3] Gareri et al. Efficacy of OM-85 in Recurrent Respiratory Tract Infections. Rev Recent Clin Trials. (2023). [4] Troiano et al. Bacterial lysates (OM-85 BV): a cost-effective proposal in order to contrast antibiotic resistance. J Prev Med Hyg. (2021). [5] Hou et al. Insights into vaccines for elderly individuals: from the impacts of immunosenescence to delivery strategies. npj Vaccines (2024). [6] de Fays C et al. Secretory Immunoglobulin A Immunity in Chronic Obstructive Respiratory Diseases. Cells. (2022).
Reference: PAGE 33 (2025) Abstr 11532 [www.page-meeting.org/?abstract=11532]
Poster: Drug/Disease Modelling - Infection