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Fondation Mérieux:
Healthy and unhealthy health markets
21st January 2015
Rob Harrison
Alistair Reid Venom Research Unit
Liverpool School of Tropical Medicine
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The global neglect of snakebite victims
and their treatment: an overview
Rob Harrison
Alistair Reid Venom Research Unit
Liverpool School of Tropical Medicine
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Antivenom is an effective treatment
Elapids (cobras)Neurotoxic
Haemotoxic Vipers
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Antivenom is an effective treatment
Elapids (cobras)Neurotoxic
Haemotoxic Vipers
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Global Poverty
45 antivenom manufacturers globally
India
5 manufacturers
Asia
Manufacturers in:
Thailand
Japan
China
Indonesia
Phillipines
Korea
Myanmar
Pakistan
Australia
CSL
Europe
Manufacturers in:
France
Poland
UK
Russia
Serbia
Middle East/N Africa
Manufacturers in:
Iran
Saudi Arabia
Israel
Egypt
Tunisia
AlgeriaN America
Manufacturers in:
USA
Mexico
C America
Manufacturers in:
Costa Rica
S America
Manufacturers in:
Brazil
Colombia
Argentina
Peru
Venezuela
Uruguay
Ecuador
Sub-Saharan Africa
Manufacturer in:
South Africa
http://apps.who.int/bloodproducts/snakeantivenoms/database/
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Global Poverty
Snakebite Mortality
45 antivenom manufacturers globally
Yet snakebite mortality is high
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Global mortality from snakebite is estimated at 95,000 deaths per year
Kasturiratne et al, PLoS Med, 2009
Envenomings Deaths
Europe 10,000 128
Middle East 3,000 78
USA 2,500 7
C & S America 129,000 2,300
Africa 420,000 32,000
Asia 2,000,000 57,500
Australasia 1,250 4
Snakebite Mortality
45 antivenom manufacturers globally
How many victims die from snakebite?
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Global mortality from snakebite is estimated at 95,000 deaths per year
Kasturiratne et al, PLoS Med, 2009
Envenomings Deaths
Europe 10,000 128
Middle East 3,000 78
USA 2,500 7
C & S America 129,000 2,300
Africa 420,000 32,000
Asia 2,000,000 57,500
Australasia 1,250 4
45,000 deaths pa
The need for more accurate snakebite disease-burden data
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Global mortality from snakebite is estimated at 95,000 deaths per year
Kasturiratne et al, PLoS Med, 2009
Envenomings Deaths
Europe 10,000 128
Middle East 3,000 78
USA 2,500 7
C & S America 129,000 2,300
Africa 420,000 32,000
Asia 2,000,000 57,500
Australasia 1,250 4
45,000 deaths pa
Recommendation:
Region-wide surveys of
• Incidence, Mortality, Morbidity
• Socioeconomic impact
• Availability of effective AV
Sponsored by Gov’ts & IHAs
The need for more accurate snakebite disease-burden data
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45 antivenom manufacturers globally
Who is dying from snakebite, and why?
Envenomings Deaths %
Europe 10,000 128 1.3
Middle East 3,000 78 2.6
USA 2,500 7 0.3
C & S America 129,000 2,300 1.7
Africa 420,000 32,000 7.6
Asia 2,000,000 57,500 4.8
Australasia 1,250 4 0.3
Most snakebite deaths occur in Asia and Africa
Case fatality is highest in African snakebite victims
Total: 95,000
Snakebite Mortality
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Those countries than can least afford antivenom have the highest snakebite deaths
Government Per Capita Expenditure on Health (US$)
Snakebit
e M
ort
ality
(lo
g)
Snakebite mortality and gov’t expenditure on health
Harrison et al, PLoS NTD, 2009
Snakebite Mortality
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Harrison et al, PLoS NTD, 2009
Snakebite mortality: low quality of life and poverty
Countries with lowest HDI ranking have highest snakebite mortality rates
Human Development Index – an index of quality of life
educationliteracyincomelife expectancy
Snakebite Mortality
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Harrison et al, PLoS NTD, 2009
Snakebite mortality: low quality of life and poverty
Countries with lowest HDI ranking have highest snakebite mortality rates
Human Development Index – an index of quality of life
educationliteracyincomelife expectancy
Snakebite Mortality
Recommendation:
IHA sponsorship of antivenom:
• that is effective
• and affordable
IHA support for regional AV
manufacture in Africa
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Harrison et al, PLoS NTD, 2009
Snakebite – a disease of rural poverty
causing high mortality and permanent disability
Snakebite Mortality
Snakebite is an another Neglected Tropical Disease (WHO, 20010)
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In some areas of W Africa, snakebite is in the top 10 causes of hospital admission
(N. Ghana) and over 70% beds (NE Nigeria) can be occupied by snakebite victims
Snakebite – a disease of rural poverty
causing high mortality and permanent disability
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In some areas of W Africa, snakebite is in the top 10 causes of hospital admission
(N. Ghana) and over 70% beds (NE Nigeria) can be occupied by snakebite victims.
This situation exacerbated by cessation of antivenom supply by European
manufacturers in 2000
Snakebite – a disease of rural poverty
causing high mortality and permanent disability
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Antivenom is lifesaving – so why what caused
antivenom supply crisis to Africa?Vipers Haemotoxic
Partly because:
• AV is expensive (>$200/treatment)
• AV is ineffective against local effects
• AV causes adverse effects (50% patients)
• AV dose-efficacy is poor (2-20 vials)
Elapids Neurotoxic
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Vipers Haemotoxic
Partly because:
• AV is expensive (>$200/treatment)
• AV is ineffective against local effects
• AV causes adverse effects (50% patients)
• AV dose-efficacy is poor (2-20 vials)
Elapids Neurotoxic
Also - compounding economic factors:
• In Africa – AVs are manufactured
only by commercial companies
• AV is expensive to manufacture
• Demand poor
• Very poor commercial profits
• AV Manufacture (Europe) ceased
• AV Supply to W Africa near to nil
Antivenom is lifesaving – so what caused
cessation in antivenom supply to Africa?
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The antivenom market failure in Africa resulted in a dangerous
therapeutic vacuum
Antivenom manufactured
with venom from Indian
snakes was 1/10th price of
FAV-Afrique but ineffective
– increasing case fatality
from 1.8% to 12.1%
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Recommendation:
• Improve regional recognition of snakebite disease burden – advocacy
• Improve regional antivenom regulatory control
• Establish regional pre-clinical testing labs
• Establish regional clinical snakebite-treatment training centres
• Support pharmaceutical companies to develop effective & affordable antivenoms
• Gov’t & IHA support for aggressive advocacy/marketing of effective, cheap antivenoms
• Establish funding for research to develop next-generation snakebite therapies
The African antivenom market failure can be reversed – with support
from governments, international health agencies and pharmaceutical
companies
Antivenom manufactured
with venom from Indian
snakes was 1/10th price of
FAV-Afrique but ineffective
– increasing case fatality
from 1.8% to 12.1%
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Vipers Haemotoxic
Elapids Neurotoxic
Research priorities to improve antivenom:• Dose efficacy
• Cross-species clinical efficacy
• Affordability
• Safety
AND• Develop treatment of venom-induced tissue destruction
The African antivenom market failure can be sustainably reversed –
with research to develop next-generation snakebite therapies
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Vipers Haemotoxic
Elapids Neurotoxic
Research priorities to improve antivenom:• Dose efficacy
• Cross-species clinical efficacy
• Affordability
• Safety
AND• Develop treatment of venom-induced tissue destruction
- Research to revise current antivenom manufacture protocols
The African antivenom market failure can be sustainably reversed –
with research to develop next-generation snakebite therapies
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Research priorities to improve antivenom:• Dose efficacy
• Cross-species clinical efficacy
• Affordability
• Safety
AND• Develop treatment of venom-induced tissue destruction
- Research to revise current antivenom manufacture protocols
The African antivenom market failure can be sustainably reversed –
with research to develop next-generation snakebite therapies
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Dose Efficacy of current antivenom
Anti
venom
IgG
10 ml
Most vials of antivenom are 10 ml
Research to resolve the African antivenom market failure
Treatment of victim with
1 vial of EchiTabG antivenom
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Dose Efficacy of current antivenom
is poor
Only 10% of antivenom IgG is specific to venom proteins – 90% is redundant
Anti
venom
IgG
10 ml
1ml
IgG specific to venom proteins
Research to resolve the African antivenom market failure
% anti-E.ocellatusIgG bound to venom column
E. ocellatus venom immobilised on sepharose
10.2%
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Dose Efficacy of current antivenom
is very poor
IgG specific to venom proteins
0.5 ml
IgG specific to pathogenic toxins
Anti
venom
IgG
10 ml
1ml
Many venom proteins are weakly
or non-pathogenic
Research to resolve the African antivenom market failure
Only about 5% of antivenom IgG targets pathogenic venom proteins
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Efficacy of current antivenom is restricted
to the snake whose venom was used in its
manufacture
IgG specific to venom proteins
0.5 ml
IgG specific to pathogenic toxins
Anti
venom
IgG
10 ml
1ml
Antivenom efficacy is snake species and therefore geographically restricted
Research to resolve the African antivenom market failure
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0.5 ml1ml
Research to resolve the African antivenom market failure
The Egyptian cobra
The boomslang
The saw-scaled viper
The puff adder The spitting cobra
The green mamba
The need for polyspecific
antivenom in Africa
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Efficacy of current antivenom is further compromised by
adding additional venoms to increase species cover because:
0.5 ml
IgG specific to pathogenic toxins
Anti
venom
IgG
10 ml
Research to resolve the African antivenom market failureThe spitting cobra
The puff adder
The more venoms used in manufacture:
– the more immunogens
- the more distinct IgGs generated
- the less IgG to each snake venom
- the more vials required for cure
- the greater the adverse effects
- the greater the cost
Research needed to increase amount of
effective IgG in a vial of antivenom
Antivenom efficacy is snake species and therefore geographically restricted
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Antivenom that is toxin-specific
• Immunisation with few, rationally selected immunogens
Improve dose efficacy - reduce adverse effects
- increase affordability
Patient
MoH
Increase demand
Increase commercial manufacturing incentives
Improve delivery of antivenom to rural poor communities
We are pursuing a gene-based approach to developing toxin-specific antivenom
Research to resolve the African antivenom market failure
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Casewell et al, PLoS NTD 2010
Molecular construction of a toxin-specific snake antivenom
for all African Echis saw-scaled vipers
Echis coloratus
Echis pyramidum leakeyi
Echis ocellatus
0.921.00
1.00 E. ocellatus. E. jogeri
E. pyramidum, E. leucogaster, E. khosatzkiiE. coloratus and E. omanensis
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Molecular construction of a toxin-specific snake antivenom• Isolate all genes from snake venom glands
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Molecular construction of a toxin-specific snake antivenom• Isolate all genes from snake venom glands
• Transcriptomics to define and distinguish toxins from non-toxic proteins
Construct an epitope-string – a synthetic protein/DNA sequence used for immunisation to generate toxin-specific antibodies
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(PBS) (pVS) (MP)
(DC) (MP+DC) (Eo string)
Wagstaff et al, 2006 PLOS Medicine, e184
MHD assay
E ocellatus venom
Molecular construction of a toxin-specific snake antivenom• Neutralisation of venom-induced haemorrhage by anti-SVMP epitope string IgG
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A: E ocellatus
B: E p leakeyi
C: E leucogaster
D: E coloratus
E: E c sochureki
F: C cerastes
G: B arietans (Ghana)
H: B arietans (Zimbabwe)
I: B gabonica (West Africa)
7 mg/lane
10#
15#
35#
50#
75#
100#150#225#
A# B# C# D# E# F# G# H# I#
10#
15#
35#
50#
75#
100#150#225#
A# B# C# D# E# F# G# H# I#
10#
15#
25#
35#
50#
75#100#
A# B# C# D# E# F# G# H# I#
10#
15#
25#
35#
50#
75#
100#
A# B# C# D# E# F# G# H# I#
10#
15#
25#
35#
50#
75#
100#150#225#
A# B# C# D# E# F# G# H# I#
HIS-Tag SUMO-Tag
Pre-immune Mixedmonospecific An venom-EchitabG
10#
15#
25#
35#
50#75#100#
A# B# C# D# E# F# G# H# I#
MBP-Tag
EchiTAbG antivenom
>200 venom protein immunogens
Serological responses of antivenom vs mice immunised with
recombinant Echis toxin-specific epitope-strings: African viper venoms
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A: E ocellatus
B: E p leakeyi
C: E leucogaster
D: E coloratus
E: E c sochureki
F: C cerastes
G: B arietans (Ghana)
H: B arietans (Zimbabwe)
I: B gabonica (West Africa)
7 mg/lane
10#
15#
35#
50#
75#
100#150#225#
A# B# C# D# E# F# G# H# I#
10#
15#
35#
50#
75#
100#150#225#
A# B# C# D# E# F# G# H# I#
10#
15#
25#
35#
50#
75#100#
A# B# C# D# E# F# G# H# I#
10#
15#
25#
35#
50#
75#
100#
A# B# C# D# E# F# G# H# I#
10#
15#
25#
35#
50#
75#
100#150#225#
A# B# C# D# E# F# G# H# I#
HIS-Tag SUMO-Tag
Pre-immune Mixedmonospecific An venom-EchitabG
10#
15#
25#
35#
50#75#100#
A# B# C# D# E# F# G# H# I#
MBP-Tag
Mixed toxin-specific IgGs EchiTAbG antivenom
13 epitope-string immunogens >200 venom protein immunogens
Serological responses of antivenom vs mice immunised with
recombinant Echis toxin-specific epitope-strings: African viper venoms
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A: E ocellatus
B: E p leakeyi
C: E leucogaster
D: E coloratus
E: E c sochureki
F: C cerastes
G: B arietans (Ghana)
H: B arietans (Zimbabwe)
I: B gabonica (West Africa)
7 mg/lane
10#
15#
35#
50#
75#
100#150#225#
A# B# C# D# E# F# G# H# I#
10#
15#
35#
50#
75#
100#150#225#
A# B# C# D# E# F# G# H# I#
10#
15#
25#
35#
50#
75#100#
A# B# C# D# E# F# G# H# I#
10#
15#
25#
35#
50#
75#
100#
A# B# C# D# E# F# G# H# I#
10#
15#
25#
35#
50#
75#
100#150#225#
A# B# C# D# E# F# G# H# I#
HIS-Tag SUMO-Tag
Pre-immune Mixedmonospecific An venom-EchitabG
10#
15#
25#
35#
50#75#100#
A# B# C# D# E# F# G# H# I#
MBP-Tag
Mixed toxin-specific IgGs EchiTAbG antivenom
13 epitope-string immunogens >200 venom protein immunogens
Next:
- Expand this approach to all medically-important African snakes – continent wide efficacy
- Convert to toxin-specific Mcabs - to increase dose efficacy by 90% and reduce costs
Serological responses of antivenom vs mice immunised with
recombinant Echis toxin-specific epitope-strings: African viper venoms
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Research priorities to improve antivenom:• Dose efficacy
• Cross-species clinical efficacy
• Affordability
• Safety
AND• Develop treatment of venom-induced tissue destruction – no medicinal treatment
Research to resolve the African antivenom market failure
• Permanent disability in ~100,000 victims pa
• 8,000 amputations in sub-Saharan Africa
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CH3
CH2 CH2
VHH VHH
CH3
CH2 CH2
VHH VHH
CH3
CH2 CH2
CH1
VH
CL
VL
CH1
VH
CL
VL
Conventional IgG1 IgG2 IgG3
Heavy-chain only IgG
150 kDa
15 kDa
The papain-cleaved 15 kDa VHH has same tissue distribution dynamics as venom toxins – therefore
anti-venom VHH is a promising candidate to reduce venom-induced tissue necrosis.
Research to resolve the African antivenom market failure
- by exploiting the unique VHH domain of heavy-chain only camelid IgG
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Neutralisation of venom induced:
Camel
IgG type: Lethality (µg) Haemorrhage (µg) Coagulation (µg)
Total IgG 1250 600 200
IgG2 (HcIgG) ND 150 50
VHH 250 75 100
Horse
SAVP - F(ab')2 720 300 480
CH3
CH2 CH2
VHH VHH
CH3
CH2 CH2
VHH VHH
CH3
CH2 CH2
CH1
VH
CL
VL
CH1
VH
CL
VL
Conventional IgG1 IgG2 IgG3
Heavy-chain only IgG
CH3
CH2 CH2
VHH VHH
CH3
CH2 CH2
VHH VHH
CH3
CH2 CH2
CH1
VH
CL
VL
CH1
VH
CL
VL
Conventional IgG1 IgG2 IgG3
Heavy-chain only IgG
CH3
CH2 CH2
VHH VHH
CH3
CH2 CH2
VHH VHH
CH3
CH2 CH2
CH1
VH
CL
VL
CH1
VH
CL
VL
Conventional IgG1 IgG2 IgG3
Heavy-chain only IgG
CH3
CH2 CH2
VHH VHH
CH3
CH2 CH2
VHH VHH
CH3
CH2 CH2
CH1
VH
CL
VL
CH1
VH
CL
VL
Conventional IgG1 IgG2 IgG3
Heavy-chain only IgG
Research to resolve the African antivenom market failure
- preclinical efficacy of anti-venom camelid IgG VHH
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Vipers Haemotoxic
Elapids Neurotoxic
Research priorities to improve antivenom:• Dose efficacy
• Cross-species clinical efficacy
• Affordability
• Safety
AND• Develop treatment of venom-induced tissue destruction
Research to resolve the African antivenom market failure: feasible
but requires more support from research-funding agencies
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Topic 1
References
Key Points:
• Snakebite is an important, neglected disease of the rural poor in Africa and Asia
• more accurate data is needed on mortality, morbidity and socioeconomic impact – raise awareness
• need Gov’ts and IHAs to recognise and act to reduce snakebite deaths and morbidity
• Current antivenom therapy can be effective but requires urgent improvement
• better regulatory control needed
• need to establish regional training on clinical management of snakebite
• need Gov’ts and IHAs to support development and delivery of effective, affordable antivenom
• Need for funding agencies to support science devising more effective, affordable snakebite therapy
• Gov’ts and IHAs to liaise with Pharma to support delivery of these new effective, affordable therapies
Rob Harrison
Alistair Reid Venom Research Unit
Liverpool School of Tropical Medicine
MRC, Wellcome Trust,
Leverhulme Trust, BBSRC, CVRL
Photographs:
Warrell, Wuster