innate response targets for therapy cde themed competition launch

Centre Defence Enterprise

for

Themed Competition Briefings

CDE themed competition

Innate response targets for therapy

Themed competition

Requirements

Bounded

Specific

Innovation Network events

Advice

Opportunity

Networking

Innate response session scope

Programme Overview

Military context

Technical challenges

Military Context

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Scope

• Mission • Future Force 2020 • CBRN protection requirement

– Threat – Policy

• CBRN programme – Policy – CBR protection – Current capabilities and challenges

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Defence in a changing world

Defence’s mission:

To protect our country and guarantee its security and independence

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Source: Defence Transformation

FF 2020 • Significant Defence reform

– Post Afghanistan Contingency – ‘Carter’s circles’ – FF 2020 structure – Budget c.£36Bn pa – Manpower: c.175k

• Navy c.30k • Army c.82k + 30k • RAF c.33k

Homeland Defence

Force Projection

Defence Engagement

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Source: Defence Transformation

CBR(N) Protection requirement

Threat

Policy Finance ££££ SDSR15

Defence Strategic Direction13

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CBRN protection

plan

Source: BBC.co.uk

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CBR Protection Requirement (Threat)

State Threat

Lone Wolf Threat Industrial Threat

Terrorist Threat

Source: Open source

CBR Protection Requirement (Threat - 2)

Nervous system• Nerve agents• Toxins

Lung• Sulphur mustard• Phosgene• Toxic industrial

chemicals

Skin• Sulphur mustard• Nitrogen mustard• Toxic industrial

chemicals

Multiple targets• Ionising

radiation

• Biological

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• Hazard area • ‘Detect to treat’

CBR Protection Requirement (Threat - 3)

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Source: Open source

CBRN Protection Requirement (Policy)

Prevention of Supply

Protection Elimination

Arms Control Disablement

Deterrence

Cooperative Non-Cooperative UK CBRN Protection Policy: Armed Forces should be able to “Survive and

Operate” in all CBRN environments

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CBRN Protection Requirement (Capability)

Decision Makers

Inform

Medical CM

Environmental Sense

Medical Sense

Non-CBR Surveillance

Protective Measures

Physical Protection

Hazard Manage-

ment

Sense

Knowledge Manage-

ment

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CBRN Protection Requirement (Capability - 2)

Deposited Hazard

Vapour Aerosol

Airborne Hazard

Liquid/solid

Sense

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Knowledge Manage-

ment

Networked BRACIS (IOC Oct 13)

CBRN Protection Requirement (Capability - 3)

RFI

Advice

CBRN Reachback (IOC Jan 14)

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Medical CM

CBRN Protection Requirement (Capability - 4)

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Physical Protection

CBRN Protection Requirement (Capability - 5)

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Hazard Management

CBRN Protection Requirement (Capability - 6)

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• Way forward? – A variety of projects are underway to improve our capability – There is a plan – Some funding has been allocated

CBRN Protection Requirement (Capability - 7)

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Summary

• Defence Reform – FF 2020 • Evolving threat – State and non-state • Policy challenges

– Bio: ‘Detect to treat’ – ‘Survive and operate in all CBRN environments’ is difficult

• CBRN Protection capabilities are beginning to get the investment they need

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Medical Countermeasures to Biological Agents

Defence Science and Technology Laboratory

UNCLASSIFIED

Biological Agents

• Very low infectious dose – Highly toxic

• Infectious via the inhalational route • Cause endemic disease • Usually zoonotic diseases • Lethal or incapacitating • BTWC has no schedules and no verification regime

UNCLASSIFIED

Microbiology capabilities

• Containment of highly dangerous microbiological organisms

• Aerosolisation of dangerous pathogens

• Modelling of diseases in animal models

UNCLASSIFIED

Microbiology high containment

UNCLASSIFIED

UNCLASSIFIED

Regulations and Best Practise

• Dangerous Pathogens work conducted in accordance with Health and Safety Executive (ACDP/ACGM/COSHH) and DEFRA guidelines

• Animal studies conducted under licence by the Home Office

UNCLASSIFIED

Vaccination • Name derived from use of cowpox (Vaccinia) to protect against

smallpox – Jenner 1796 – Pasteur 1881

• Suspension of dead, attenuated or otherwise modified micro-organisms USED TO INDUCE IMMUNITY TO A DISEASE – Stimulates immune system (e.g. antibodies) – Induces memory – Eradicates disease

The most cost effect way to treat infectious disease

UNCLASSIFIED

Time (days)

Perc

ent s

urvi

val

0 7 14 21 280

20

40

60

80

100ConjugateLPSTetHc + LPSPBSTetHc

Bac

teria

(cfu

/ sp

leen

)

Conjugate LPS

TetHc + LPSPBS

TetHc

10

100

1000

10000

100000

1000000

P<0.001

Exp.

1Ex

p.2

Exp.

1Ex

p.2

Exp.

1Ex

p.2

Exp.

1Ex

p.2

Exp.

1Ex

p.2

ConjugateLPSTetHc + LPSPBSTetHc

Burkholderia and Francisella vaccines

UNCLASSIFIED

Antibiotics

• Not active against some bacteria – Natural resistance

• Different antibiotics required for different agents • Relapsing infection • Trigger to treat required • Compliance/Side effects

– 44% completed 60 day course during BA letter attacks BUT • Broad spectrum of activity • No predefined threat spectrum

UNCLASSIFIED

CFI is a broad spectrum antibiotic effective against multiple BW agents

• Treatment with encapsulated

ciprofloxacin effectively treats three BW agents: F. tularensis, Y. pestis and C. burnetii

• In collaboration with Health Protection Agency, Defence Research and Development Canada and Aradigm Corporation

UNCLASSIFIED

Humanised Antibody for the Treatment of Venezuelan Equine Encephalitis Virus (VEEV)

• No available licensed vaccines or antivirals for treatment of VEEV

• A mouse monoclonal antibody is effective for the treatment of VEEV in a mouse model of disease

• Humanised antibody produced to reduce potential adverse reactions in humans

– biologically active

– protects mice against lethal VEEV challenge

0 5 25 50 75 100 0

20

40

60

80

100

Antibody (μg) Administered

Perc

ent S

urvi

val

Survival of BALB/c mice pre-treated with humanised antibody before challenge with 100LD50 of VEEV

O'Brien LM et al, Virology. 2012, Goodchild SA, et al, Antiviral Res. 2011

UNCLASSIFIED

Summary

• A flexible response is essential

• Vaccines provide excellent protection for those immunised before exposure

• Post-exposure therapies provide a rapid response capability against some agents

• Following a BW attack, and for some agents, it will be necessary to use both post-exposure therapies and vaccines

Innate response targets for therapy

CDE themed competition March 25 - June 5 2014

31 March 2014

Key dates

• Competition launches today • Presentation to follow • Opportunity for Q&A • Webinar Tuesday 1 April • Deadline for applications Thursday 5 June 2014 at 17:00 hrs via Centre for Defence Enterprise Portal • Funding decisions to be made July 2014 • Notifications end July

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Background: biothreat agents

• Pathogenic for man or animals

• Very low infectious dose

• Infectious via the inhalational route

• Cause endemic disease around world

• Usually are zoonotic diseases

• Lethal or incapacitating

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Defence against biothreats

• Many potential biothreat agents • How to defend against them? • Impossible to make a vaccine/therapy for every potential agent • Require generic therapy

Generic approach to therapy • By influencing the host response

• Requires an understanding of the host response to pathogen & safe ways to influence it

• Requires identification of relevant targets or pathways in the host

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Innate (host) response targets for therapy

• Objective of this competition is to look broadly across research and development to identify host cell targets and pathways

• Using data derived from diverse infection models

• Respondents to competition do not need to work directly with biothreat agents

• Ultimate aim is to apply the most innovative approaches to biothreat agents

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CDE themed competition specifics • Seeking innovative proposals for short projects (<1year); £30-

80k guide; (£500k total budget)

• Show proof-of-concept for your proposal; there is funding allocated for follow-on work for successful projects

• Competition divided into 3 challenges

• Respondents need to address 1 of the challenges, may address >1, do not have to address all 3

• Challenges described fully in the competition document

• Bids must be ethical and compliant with UK government legislation

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Challenge 1

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Identification of new cellular or host pathway targets

Identification of new cellular or host pathway targets • In host-pathogen model of your choice

– Does not need to be a biodefence pathogen – Does not need to be in vivo

• Conditioning of cells ex vivo eg to profile responses or prior to adoptive transfer

• Targeting cells in situ eg – to refocus them – to activate them – to induce them to traffic – to redirect them

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Identification of new cellular or host pathway targets May involve the identification of eg • immuno stimulants • modulators • transfection factors • chemokines, cytokines or the induction (or blockade) of these • cytokine/chemokine/growth factor receptors and application of these to modulate host responses

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Identification of new cellular or host pathway targets

• Some of these may be

exogenous and some endogenous factors

• Some endogenous natural

regulators /regulatory pathways may be exploited

• to reduce inflammation and to restore homeostasis

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Normal

Overactive Underactive

Possible outcomes Proposals for

– identification of new cellular targets /pathways – new applications of manipulating known cellular targets/pathways – demonstration that targets may be influenced beneficially, for

example to: • prevent cytotoxicity • prevent/reduce microbial invasion • reduce microbial load • restore normal cell function

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Challenge 2

Identification of new candidate therapies

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Identification of new candidate therapies Exploit appropriate cellular targets and pathways to identify new therapies by, for example:

• enhancing cell-mediated immunity • investigating novel combinations • identification and manipulation of significant

transcription factors • micro RNA-directed therapies or antagonists

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Possible outcomes • Candidate therapies should be druggable and generic • Proposals should show proof-of-concept

• Does not exclude the re-purposing or augmentation of existing

therapies

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Challenge 3

Identification of new platform technologies

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Identification of new platform technologies

For assessing therapeutic benefit • Novel technologies such as:

• non-invasive methods of in-vivo/ex-vivo analysis eg bio-imaging or tracking

• Transcriptomics including micro RNA analysis

• In-silico modelling of host responses

• Novel assays to monitor the host immune response

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Possible outcomes

• New technologies which may facilitate the identification and development of candidate therapies

• Proposals should demonstrate the impact of the technology on therapeutic development

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What we want • Highly innovative approaches that are significantly different from

existing technologies

• Generally technology readiness level (TRL) ≤ 3

• Generic approaches (not pathogen specific)

• Approaches applicable to intracellular pathogens where

appropriate

• Approaches that will lead to a feasible clinical product

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What we don’t want Proposals that concern: • high technology readiness level (TRL) capability • serological targets only (rather than cellular) • antibody-based therapies (but antibodies as a targeting

mechanism are acceptable) • existing solutions or technology already tested and found to

have limited utility • a paper study or review or similar • pre-exposure therapies or therapeutics • topical therapies for wounds

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Successful proposals

• Each will be assigned a Technical Partner

– Provides interface between project and defence community

– If project successful, potential routes to exploitation developed

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Summary

• Competition launches today • Webinar Tuesday 1 April • Closes on Thursday 5 June 2014 at 17:00 hrs • Short proof-of-concept proposals • If successful, potential for follow-on funding • May include additional research to develop technology for MOD • Competition information available on CDE website

www.science.mod.uk

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31 March 2014