3rd September 2010 INSERM, Lyon The Centre for Emergency Preparedness and Response Translational Research Miles Carroll Director of Research CEPR Miles.carroll@hpa.org.uk

Health Protection Agency NIBSC CEPR HPA CfI CRCE RMN/LaRs

Developing Interventions: UK & Global Public Health CEPR: Translational Research Activities Developing Interventions: UK & Global Public Health Safe containment, diagnosis and study of dangerous pathogens Applied research capability including animal facilities Development and production of highly specialised biological products Emergency response capability Working in Partnership with Industry and academia

Translational Research Vaccines Therapeutics Antibiotics/antivirals Immunotherapy Immune modulation Diagnostics Decontamination Developing Interventions for UK Public Health: In Partnership with Industry and Academia

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, Menningitis, Anthrax, Plague, Dysport (cerebral Palsy), Erwinase (childhood leukaemia treatment, Decontamination products

Translational Research Model Industry Vaccine Ags Chlamydia Vaccine Discovery Product CEPR(HPA) US Govt MCM Academia/Govt/NforP HPA plays a pivotal role in development of future health care interventions

Key Research Activities TB Correlates of Protection Vaccines Antibiotics Toxins Botulinum Clostridium Immunotherapy Diagnostics Biosafety Detection Decontam HCAI/vCJD Training Diagnostics Technology Bio/Molecular Mening & Pertussis Correlates Vaccines Animal Models Efficacy studies Aerosol Path/ Imaging SIV Research Immune Assay NVEC Clinical Trials Assay Validation Immune Modulation Inflammation Adjuvants Emerging Diseases Virology Bacteriology SPRU Support Medical Counter Measures NIAID Anthrax Research Aligned with HPA Strategy and Programmes

Developing Interventions for Emerging Diseases & Bio-threat Agents Tradition route is in vitro, then human Phase 1, 2 and then Phase 3 trials Discovery Development Licensure Pure research Translational research Traditional clinical efficacy trials not possible with diseases like Anthrax, Plague, Meliodosis, Glanders and Ebola The FDAs “Animals Rule” provides an alternative where Efficacy in 2 animal models may be accepted for licensure

The NIAID Programme at HPA CEPR Anthrax in mice and NHPs (C1, D1) Plague in mice (C18) Q fever in mice (C19) Melioidosis in mice (C19) Filoviruses (C20) Anthrax in NHPs (D1) Melioidosis in NHPs (D19) Glanders in NHPs (D19) Flu (E10) Multiple agents in NHPs (D8, Dstl) Monkeypox in NHPs (D4/D7, D18, E07) GLP Antibiotics, small molecules & therapies (A1, B1) Vaccines Discovery Development Licensure Pure research Translational research

Animal Models: Development of New Interventions for Infectious Diseases Development & evaluation of vaccines, therapeutics and diagnostics

High consequence pathogens - Surveillance and development of interventions Easily Transmitted High mortality Limited / no treatment Approximate mortality rates Viral Hemorrhagic Fevers: Ebola Dengue (HF) Lassa fever CCHF 50 - 95% <20% 30 - 80% Bacterial infections: 1% / 20% ~40% Cutaneous Anthrax Inhalation Anthrax 5% / 90% 1% / 60% Pneumonic plague Bubonic plague Viral infections: Orthopox 30 - 60%

High Consequence Pathogen Studies Remit: Responsible for maintaining research and development programmes concerned with viral haemorrhagic fevers and arboviruses in line with the department’s capacity as a HPA reference centre and WHO collaborating centre for virus research and reference. Reduce the impact of new and re-emerging health threats and help manage UK health protection emergencies through effective early detection and response.

Special Pathogens Reference Unit Virus Reference service: Flaviviridae Bunyaviridae Togaviridae Reoviridae Arboviruses “To reduce the impact of new and re-emerging threats and manage UK health protection emergencies through effective early detection and response” Virus research programme provides ready to action relevant skills and knowledge capacity to rapidly respond to new virus threats (c.f. expertise of virology staff to pandemic flu activities) Haemorrhagic Fever viruses Filoviridae Arenaviridae Others “Work on high consequence pathogens through WHO international collaborations to build preparedness to infectious disease threats” Orthopoxvirus Hantavirus Henipaviruses

Understanding viruses Current virology projects Outputs: Programme built around GIA Assay development / validation Direct patient monitoring Assay roll out to global partners Underpinning Knowledge Training & Knowledge transfer Work at high containment (CL4) Scientific reputation Travel advice GIA Arbo / VHF Georgia SC DTRA / UK NIAID Filovirus reagents DTRA Ebola model Euro-P4 FP7 Epidemiology Kazakhstan Japan-P4 Kyrgyzstan UK - CPAC ArboZ-net Surveillance Understanding viruses Infrastructure “To reduce the impact of new and re-emerging threats and manage UK health protection emergencies through effective early detection and response” “Strengthening public health capacity re better diagnostics and response” “Building similar capacities in partner / collaborating countries leading to better preparedness to new and re-emerging threats”

Translational Research Activities Product Research Development Clinical C.difficile TB Therapeutics Sepsis MCM Chlamydia Meningitis Pertussis Vaccines MCM TB Emerging Dis Influenza MCM Pathogens HCAI Diagnostics Diagnostics vCJD Blood Emerging Dis Radiation

The Centre for Emergency Preparedness and Response Miles Carroll Deputy Director Head of Research

Understanding Pathogenesis and Disease Kinetics: H1N1 This is a really nice slide. Points to make: Kinetics of viral load correlate with dose as expected Nasal wash is a good method to analyse upper respiratory involvement Peak rises quickly and reduces quickly in an earlier time frame than the progression of clinical disease Nasal wash - viral load TCID50 Developed for Evaluation of swine flu vaccines

Influenza Animal Models: How Realistic Are They? Natural infection - dose ≈ 0.6 – 3.0 pfu Ferret model – dose = 106 pfu I start with the animal dose here and then move to the human situation with an obviously much reduced dose. – One of the questions I had in London last week was asking about natural routes of transmission in humans and whether it was direct via droplets or fomites. Continue by posing the hypothesis that a lower dose would still give rise to similar infection in the model Human disease kinetics:incubation period 2-7 days for H1N1. Would lower dose effect disease kinetics and pathogenesis? Increased sensitivity for evaluation of vaccines and therapeutics 18