Pre-clinical testing & development of gut microbiome modulators

Objectives:

Pre-clinical studies to optimize two interventions for prevention of post-weaning diarrhoea based on gut microbiome modulation: a symbiotic product developed by BIOMIN and an in-farm faecal transplantation technique developed by UCPH. The following objectives will be pursued:

  • Optimise formulation and dosage of feed additives
  • Optimise the bioprocesses for feed additive production on industrial scale
  • Standardise the procedures for faecal donor selection and screening
  • Test the faecal transplantation technique under field conditions
  • Determine the mechanisms by which microbiota modulation prevents post-weaning diarrhoea

BIOMIN and the University of Copenhagen have expertise and facilities for developing and producing probiotics and faecal transplants, respectively. Schothorst Feed Research provides an E. coli mild infection model and animal facilities for testing feed additivies in vivo. Pathogen screening and metagenomics/transcriptomics profiling by DNA/RNA sequencing are performed at UCPH. Metabolomics and inflammatory serum protein and cytokine profiling are done at WR. SEGES will provide access to a commercial pig farm.

WP Leader: University of Copenhagen

Involved Partners: DSM-firmenich, Schothorst Feed Research, SEGES Innovation, Wageningen Research

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Pre-clinical testing & development of anti-ETEC veterinary medicinal products

Objectives:

Focus on development of safe, efficient and pathogen-targeted polymer- and phage-based veterinary medicinal products (VCPs) to replace colistin and other HP-CIAs that are currently used for treatment of ETEC infections in pigs. Both products have the potential to improve tolerability, efficacy and selective pathogen targeting, using low-cost and scalable tools. The main outcome is comprehensive data and information in a pre-clinical development package, with assessments of microbiological effects, toxicity in vitro and in vivo, efficacy and tolerability in vivo and information about manufacturing options for the field trials. More specifically, the following objectives will be pursued to further develop the two anti-ETEC products:

  • Determine potency and spectrum of activity
  • Develop the in vitro safety information package
  • Assess clinical efficacy and safety in piglets
  • Assess target specificity in vivo

EA provides the initial phage formulation developed in collaboration with UCPH. The polymer and phage formulations are mainly tested and developed at RVC and UCPH, respectively. SFR and UCPH provide porcine E. coli infection models and animal facilities for in vivo testing of the two products. ETEC screening and metataxonomics/metagenomics profiling by 16S rDNA and shotgun sequencing are performed at UCPH, which also provides clinical strains for susceptibility testing.

WP Leader: The Royal Veterinary College

Involved Partners: University of Copenhagen, Easy AgriCare, Schothorst Feed Research, SEGES Innovation

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Pre-clinical testing & development of injectable and oral immunostimulants

The objective is to generate the data package necessary to comply with the regulatory requirements to run the clinical trials with two different products: A supplementary feed based on bacterial extracts from Ochrobactrum intermedium (Oi) and an injectable VMP containing purified LPS from Oi. The two products will be further developed using in experimental infection models reproducing ETEC and respiratory infections. The specific objectives are to:

  • Determine the withdrawal period, tolerance and efficacy of the injectable immunostimulant
  • Optimise the dosage regimen of the oral immunostimulant
  • Measure the impact of the injectable immunostimulant on the immune system of sows and weaners
  • Assess the impact of the oral immunostimulant on gut health

UCM is responsible for the performance of all tasks. UCPH will collaborate to establish the ETEC infection model at UCM. Inflammatory serum protein and cytokine profiling is performed at WR.

WP Leader: Universidad Complutense de Madrid

Involved Partners: University of Copenhagen, SEGES Innovation, Wageningen Research

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Pre-clinical testing & development of feeding strategies at farrowing and weaning

The overall aim is to conduct small scale pre-clinical trials to validate the use of pre-weaning dietary interventions applied to lactating sows (feeding strategy 1) and post-weaning dietary interventions applied to the piglets (feeding strategy 2) for prevention of neonatal and post-weaning diarrhoea, respectively. The specific objectives are to:

  • Validate an effective feeding strategy for piglets to prevent post-weaning diarrhoea.
  • Validate an effective feeding strategy for lactating sows to prevent neonatal and post-weaning diarrhoea.

SFR performs pig experiments at their animal facilities. Bacteriological analysis of faecal samples and metataxonomics/ metagenomics profiling by 16S rDNA and shotgun sequencing are performed at UCPH. Metabolomics and inflammatory serum protein and cytokine profiling are performed at Wageningen Research.

WP Leader: Schothorst Feed Research

Involved Partners: University of Copenhagen, SEGES Innovation, Wageningen Research

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Intervention assessment on clinical efficacy under field conditions

The overall objective is to assess clinical efficacy of selected AVANT interventions under field conditions. The most promising interventions against enteric and respiratory diseases will be selected based on the efficacy and safety outcomes generated by pre-clinical testing, regulatory assessment and market considerations. Farm trials will be designed and conducted to measure the effects of each selected intervention on pig disease and productivity. The specific objectives are to:

  • Select the interventions with the highest market potential
  • Design clinical trials and select farms to obtain statistically meaningful results on efficacy of interventions
  • Confirm efficacy of interventions in clinical trials on commercial pig herds

SEGES coordinates the activities and performs the farm trial in Denmark. Cooperl and Schothorst Feed Research perform the farm trials in France, Spain and Netherlands, respectively. University of Copenhagen perform bacteriological analysis of the samples collected during the trials. All partners participate in the selection of the interventions to be tested under field conditions, and in the design and dimensioning of the field trials via the Executive Board.

WP Leader: SEGES Innovation

Involved Partners: University of Copenhagen, Schothorst Feed Research, The Royal Veterinary College, Easy AgriCare, Universidad Complutense de Madrid, Cooperl, DSM-firmenich, University of Bern, University of Liverpool

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Intervention assessment on reduction of antimicrobial use at farm and EU levels

The overall objective is to quantify the potential benefits on antimicrobial consumption at farm and EU levels derived from large-scale adoption of the AVANT interventions. This objective will be achieved by combining of a long field trial and statistical approaches. More specifically, the objectives are to:

  • Conduct a field trial to estimate the relative efficacy of each selected intervention to reduce antimicrobial use
  • Map the reduction of antimicrobial use in Europe attributable to the selected interventions
  • Project the reduction in antimicrobial use that could be obtained in Europe by 2030
  • Assess the cost-effectiveness of the gut microbiome-related interventions

WP Leader: Cooperl

Involved Partners: SEGES Innovation, University of Bern, University of Liverpool

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Regulatory affairs

Provides regulatory support to other plans for the duration of the project. The main objective is to assure that regulatory requirements are considered so that the data produced for the interventions (the respective candidates) are relevant for a later dossier application/compliance with regulatory requirements for marketing authorisation. Specifically, this plan will:

  • Advise WP1-4 on claims and pre-clinical study set up
  • Support clarification with the respective regulatory authorities where necessary
  • Support the selection of most promising interventions by providing a tabulated regulatory GAP analysis
  • Regulatory guidance for the selected interventions on field study outlines and protocols (WP5)
  • Regulatory input on antimicrobial resistance monitoring (WP6)

All the work in this plan is conducted by KLIFOVET, the partner specialized in regulatory affairs. Results are periodically reported to the Executive Board and individual partners via the Coordinator University of Copenhagen.

WP Leader: KLIFOVET

Involved Partners: University of Copenhagen

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