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
UNCLASSIFIED© Crown copyright 2014 Dstl
31 March 2014

Scope
• Mission
• Future Force 2020
• CBRN protection requirement
– Threat
– Policy
• CBRN programme
– Policy
– CBR protection
– Current capabilities and challenges
31 March 2014

Defence in a changing world
Defence’s mission:
To protect our country and
guarantee its security and independence
31 March 2014
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
31 March 2014
Source: Defence Transformation

CBR(N) Protection requirement
Threat
Policy Finance
££££
SDSR15
Defence Strategic
Direction13
31 March 2014
CBRN
protection
plan
Source: BBC.co.uk

31 March 2014
CBR Protection Requirement
(Threat)
State Threat
Lone Wolf Threat Industrial Threat
Terrorist Threat
Source: Open source

(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
31 March 2014

• Hazard area
• ‘Detect to treat’
(Threat - 3)
31 March 2014
Source: Open source

CBRN Protection Requirement
(Policy)
Prevention of
Supply
ProtectionElimination
Arms
Control
Disablement
Deterrence
Cooperative Non-Cooperative
UK CBRN Protection Policy: Armed Forces should be able to “Survive and
Operate” in all CBRN environments
31 March 2014

(Capability)
Decision
Makers
Inform
Medical
CM
Environmental
Sense
Medical Sense
Non-CBR
Surveillance
Protective Measures
Physical
Protection
Hazard
Manage-
ment
Sense
Knowledge
Manage-
ment
31 March 2014

(Capability - 2)
Deposited
Hazard
Vapour Aerosol
Airborne
Hazard
Liquid/solid
Sense
31 March 2014

Knowledge
Manage-
ment
Networked BRACIS (IOC Oct 13)
(Capability - 3)
RFI
Advice
CBRN Reachback (IOC Jan 14)
31 March 2014

Medical
CM
(Capability - 4)
31 March 2014

Physical
Protection
(Capability - 5)
31 March 2014

Hazard
Management
(Capability - 6)
31 March 2014

• Way forward?
– A variety of projects are underway to improve our capability
– There is a plan
– Some funding has been allocated
(Capability - 7)
31 March 2014

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
31 March 2014

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
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)
Percentsurvival
0 7 14 21 28
0
20
40
60
80
100
Conjugate
LPS
TetHc + LPS
PBS
TetHc
Bacteria(cfu/spleen)
Conjugate
LPS
TetHc + LPS
PBS
TetHc
10
100
1000
10000
100000
1000000
P<0.001
Exp.1
Exp.2
Exp.1
Exp.2
Exp.1
Exp.2
Exp.1
Exp.2
Exp.1
Exp.2
Conjugate
LPS
TetHc + LPS
PBS
TetHc
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
PercentSurvival
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
© Crown copyright 2014 Dstl
31 March 2014

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
31 March 2014

31 March 2014
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
31 March 2014

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
31 March 2014

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
31 March 2014

Challenge 1
31 March 2014
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
31 March 2014

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
31 March 2014

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
31 March 2014
Normal
OveractiveUnderactive

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
31 March 2014

Challenge 2
Identification of new candidate therapies
31 March 2014

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
31 March 2014

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
31 March 2014

Challenge 3
Identification of new platform technologies
31 March 2014

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
31 March 2014

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
31 March 2014

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
31 March 2014

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
31 March 2014

Successful proposals
• Each will be assigned a Technical Partner
– Provides interface between project and defence community
– If project successful, potential routes to exploitation
developed
31 March 2014

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
31 March 2014

Innate response targets for therapy CDE themed competition launch

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