MS Porton Down Microbiology & Translational Research Mission - PowerPoint PPT Presentation

MS Porton Down Microbiology & Translational Research Mission – Public Health England “To protect and improve the nation’s health and to address inequalities, working with national and local government, the NHS, industry, academia, the public and the voluntary and community sector .” Phil Marsh on behalf of Miles Carroll

PHE - Porton  emergency response capability  high containment of pathogenic agents [CL2-CL4]  diagnostic capabilities [RIPL]  culture collection (CC of PHE)  developmental production  biopharmaceutical manufacture  translational research

An Integrated Capability for the Development of Interventions Development route is in vitro , in vivo , product development and clinical studies NVEC Discovery Development Licensure Applied research Translational research Working with Partners to develop interventions. Past successes: Whooping cough, Meningitis, Anthrax, Plague, Dysport (cerebral Palsy ), Erwinase (childhood leukaemia treatment, Decontamination products

Infectious Disease Programmes TB Toxins Biosafety Mening & Vaccines Botulinum Detection Pertussis Antibiotics Clostridium Decontam Correlates Diagnostics Immunotherapy HCAI/vCJD Vaccines Diagnostics Training Preclinical Diagnostics Efficacy studies Technology Aerosol Research Diagnostics Pathol/ Imaging Bio/Molecular Immunology Medical GxP Emerging Immune Immune Assay Counter Modulation Clinical Trials Diseases Measures Assay Validation Inflammation Virology/Influenza Product release NIAID Adjuvants Bacteriology assays Anthrax Developing Interventions with academia, Govt and industry

Pure culture: Capabilities - Chemostat  Neisseria gonorrhoeae  Continuous culture device  Legionella pneumophila O 2  Controlled and defined environment  C  Salmonella enteritidis pH  Select a “growth - limiting” nutrient  oral opportunitic pathogens  Mycobacterium tuberculosis / M. bovis  Constant growth rate for prolonged periods - steady state Conditions:  Defined, physiological state • Carbon limitation rpm  Vary individual parameters • Nitrogen limitation • Iron limitation  Direct cause-and-effect relationships • Growth temperature Medium Biomass  Expression profiles are reproducible • Growth rate

Application of chemostats to drug evaluation Development of a rapid assay Definition of live, dead, and drug tolerant (persisting) bacteria Fluorescence stains and flow cytometry Defined O 2 pH populations : • 96 well plate • Drug combinations • Live • Fluorescent stain • Dead • Fix • Persistent • Flow cytometry INH TVCs A INH B DAY 0 - No drug 1.00E+08 0 ug/ml R2 R3 1.00E+07 Host-like conditions 0.25 ug/ml 1.00E+06 FL1 log 0.5 ug/ml 1.00E+05 1 ug/ml cfu/ml 1.00E+04 R4 R5 2 ug/ml 1.00E+03 4 ug/ml Slow growth FL6 log 1.00E+02 8 ug/ml DAY 04 1.00E+01 16 ug/ml No drug 0.5 µg/ml INH 1.00E+00 32 ug/ml R3 R2 R2 R3 Day 0 Day 1 Day 2 Day 3 Day 4 Stationary phase FL1 log FL1 log s INH C 100 0 ug/ml 90 R4 R5 R4 R5 % of events in gate R5 (CV + SG - ) 0.25 ug/ml 80 FL6 log FL6 log 70 0.5 ug/ml 8 µg/ml INH 16 µg/ml INH Biofilm 60 1 ug/ml R2 R3 R2 R3 50 2 ug/ml 40 FL1 log FL1 log 4 ug/ml 30 Reproducible 8 ug/ml 20 10 16 ug/ml R4 R5 R4 R5 0 models 32 ug/ml Day 0 Day 1 Day 2 Day 3 Day 4 FL6 log FL6 log source of cells CL3 cell sorting: - defined bacterial populations for further analyses

Preclinical testing at Porton Down • Range of models. • Immunogenicity and challenge studies. • ACDP3 containment facilities: in vitro , in vivo , ex vivo studies. • Large capability (largest TB vaccine evaluator in Europe – small animal models).

Aerobiology expertise Aerosol Generation • Nebulisers generate particles in respirable range <5 µm. • Henderson Apparatus controlled by Aero-MP (relative humidity, flow rates, exposure times, suspending fluid). • Directional flow systems - (bespoke ‘sow’ system or individual mask). • Plethysmography equipment. • Reproducible, low dose (5-10 cfu), even distribution.

National & International Reference Centre • Haemorrhagic Fever viruses Filoviridae Arenaviridae • Arboviruses Flaviviridae Bunyaviridae Togaviridae WHO Collaborative Centre for Viruses Reoviridae (Arboviruses & VHFs) Porton Down 1976 • Orthopoxviruses • Hantaviruses • Henipaviruses Flexible film isolator with computer controlled exposure system 9 In vitro and in vivo R&D at high containment; PHE Porton

PHE Porton: Unique Translational Research Capability New antigens: Correlates of protection: - meningitis - meningitis - TB - pertussis - anthrax - TB - C. difficile Translational R&D Evaluation in preclinical models: Evaluation [clinical trials]: [drugs, vaccines, etc] - NVEC - medical counter-measures - grants - TB - commercial - ‘flu - ......& many others....

Translational Research Model Industry Discovery Product PHE Academia/Govt/NforP PHE plays a pivotal role in translating Research into future health care interventions