Immunomodulating effects of the single bacterial strain therapy EDP1815 on innate and adaptive immune challenge responses - a randomized, placebo-controlled clinical trial

Abstract

The gut microbiome can modulate systemic inflammation and is therefore target for immunomodulation. Immunomodulating effects of EDP1815, a bacterial commensal strain of Prevotella histicola, were studied in healthy participants. Effects on adaptive immunity were evaluated by a neo-antigen challenge with keyhole limpet haemocyanin (KLH), while effects on innate immunity were evaluated by topical toll-like receptor 7 (TLR7) agonist imiquimod. Capsules with two enteric coating levels (EC1, EC2) were compared. Thirty-six healthy participants were included and received a daily dose of 8 × 10¹⁰ cells EDP1815-EC1, EDP1815-EC2 or placebo (randomization 1:1:1) for 60 days. They received KLH vaccinations at days 8, 24 and 36, with intradermal skin challenge at day 57. KLH challenge outcomes were antibody levels, and skin blood flow and erythema after skin challenge, measured by imaging techniques. Imiquimod administration started at day 57, for 72 h. Outcomes consisted of imaging measurements similar to the KLH challenge, and the influx of inflammatory cells and cytokines in blister fluid. There was no effect of EDP1815 treatment on the KLH challenge, neither on the imaging outcomes of the imiquimod challenge. There was a consistently lower influx of inflammatory cells in the blister fluid of EDP1815-treated participants (neutrophils, p = 0.016; granulocytes, p = 0.024), more pronounced in EC1. There was a lower influx of interleukin [IL]-1β, IL-6, IL-8, IL-10, interferon [IFN]-γ and tumour necrosis factor in blister fluid of EDP1815-treated participants. EDP1815 had immunomodulatory effects on the innate immune response driven by imiquimod, but no effect on the KLH challenge was observed. Trial registration number: NCT05682222; date: 22 July 2022.

Keywords: Autoimmune diseases; Imiquimod Immunodermatology; Immune challenges; Keyhole limpet haemocyanin; Microbiome.

Fig. 1

Schematic study overview. KLH, keyhole limpet haemocyanin; LSCI, laser speckle contrast imaging

Fig. 2

Treatment effect on keyhole limpet haemocyanin (KLH) challenge responses. Basal flow (AU) (a), flare (AU) (b) and erythema (AU) (c) of the skin over time after intradermal KLH skin challenge, measured by laser speckle contrast imaging (LSCI) and multispectral imaging. KLH-specific IgG antibodies (d) and KLH-specific IgM antibodies (e) over time during KLH immunizations, expressed as % compared to baseline. Participants were immunized at day 8, 22 and 36. Mean (standard deviation). AU arbitrary unit. p-values refer to the following contrasts: upper p-value EDP1815 overall vs placebo; EC1 EDP1815-EC1 vs placebo; EC2 EDP1815-EC2 vs placebo

Fig. 3

Treatment effect on imaging outcomes of imiquimod challenge. Basal flow (AU) (a), flare (AU) (b) and erythema (AU) (c) of imiquimod-treated skin during the imiquimod challenge, measured by laser speckle contrast imaging (LSCI) and multispectral imaging. Mean (standard deviation). AU arbitrary unit. p-values refer to the following contrasts: upper p-value EDP1815 overall vs placebo; EC1 EDP1815-EC1 vs placebo; EC2 EDP1815-EC2 vs placebo

Fig. 4

Treatment effect on influx of inflammatory cells in blister fluid during imiquimod challenge. a–m Absolute numbers of inflammatory cells in blister fluid of blisters induced on imiquimod-treated skin during the imiquimod challenge. Mean (standard deviation). p-values could not be calculated for intermediate monocytes, non-classical monocytes and plasmacytoid dendritic cells due to a non-normal distribution of measurements. p-values refer to the following contrasts: upper p-value EDP1815 overall vs placebo; EC1 EDP1815-EC1 vs placebo; EC2 EDP1815-EC2 vs placebo. *p < 0.05

Fig. 5

Treatment effect on cytokine influx in blister fluid during imiquimod challenge. a–k Cytokine concentrations in blister fluid of blisters induced on imiquimod-treated skin during the imiquimod challenge. CXCL-10, CXC-motif chemokine ligand 10; IFN, interferon; IL, interleukin; TNF, tumour necrosis factor. Mean (standard deviation). p-values refer to the following contrasts: upper p-value EDP1815 overall vs placebo; EC1 EDP1815-EC1 vs placebo; EC2 EDP1815-EC2 vs placebo