fondation mérieux: healthy and unhealthy health markets st … · iha sponsorship of antivenom:...

Fondation Mérieux:

Healthy and unhealthy health markets

21st January 2015

Rob Harrison

Alistair Reid Venom Research Unit

Liverpool School of Tropical Medicine

The global neglect of snakebite victims

and their treatment: an overview

Rob Harrison



Antivenom is an effective treatment

Elapids (cobras)Neurotoxic

Haemotoxic Vipers

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/

http://www.google.co.uk/url?sa=i&rct=j&q=World+Poverty+Map&source=images&cd=&cad=rja&docid=yRpu_UkKCiHlzM&tbnid=V607vw4O91CUTM:&ved=0CAUQjRw&url=http%3A%2F%2F2012books.lardbucket.org%2Fbooks%2Fsociology-understanding-and-changing-the-social-world-brief-edition-v1.1%2Fsection_09_05.html&ei=9xl1UeCsLYT60gWntIGYCA&bvm=bv.45512109,d.d2k&psig=AFQjCNFcP87lJeeaKwSTUM4P_u3zLqJnuw&ust=1366715152245864


Global Poverty

Snakebite Mortality


Yet snakebite mortality is high



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


How many victims die from snakebite?



Envenomings Deaths

Europe 10,000 128


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



Envenomings Deaths

Europe 10,000 128


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


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

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


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


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


Snakebite – a disease of rural poverty

causing high mortality and permanent disability

Snakebite Mortality

Snakebite is an another Neglected Tropical Disease (WHO, 20010)

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



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



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

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?

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%

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%

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

Vipers Haemotoxic

Elapids Neurotoxic



• Affordability

• Safety


- Research to revise current antivenom manufacture protocols





• Affordability

• Safety


- Research to revise current antivenom manufacture protocols



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


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


% anti-E.ocellatusIgG bound to venom column

E. ocellatus venom immobilised on sepharose

10.2%


is very poor


0.5 ml

IgG specific to pathogenic toxins

Anti

venom

IgG

10 ml

1ml

Many venom proteins are weakly

or non-pathogenic


Only about 5% of antivenom IgG targets pathogenic venom proteins

Efficacy of current antivenom is restricted

to the snake whose venom was used in its

manufacture


0.5 ml


Anti

venom

IgG

10 ml

1ml

Antivenom efficacy is snake species and therefore geographically restricted


0.5 ml1ml


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

Efficacy of current antivenom is further compromised by

adding additional venoms to increase species cover because:

0.5 ml


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

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


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

Molecular construction of a toxin-specific snake antivenom• Isolate all genes from snake venom glands

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

(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

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

A: E ocellatus

B: E p leakeyi

C: E leucogaster

D: E coloratus

E: E c sochureki

F: C cerastes




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


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



A: E ocellatus

B: E p leakeyi

C: E leucogaster

D: E coloratus

E: E c sochureki

F: C cerastes




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


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





• Affordability

• Safety

AND• Develop treatment of venom-induced tissue destruction – no medicinal treatment


• Permanent disability in ~100,000 victims pa

• 8,000 amputations in sub-Saharan Africa

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.


- by exploiting the unique VHH domain of heavy-chain only camelid IgG

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



CH3

CH2 CH2

VHH VHH

CH3

CH2 CH2

VHH VHH

CH3

CH2 CH2

CH1

VH

CL

VL

CH1

VH

CL

VL



CH3

CH2 CH2

VHH VHH

CH3

CH2 CH2

VHH VHH

CH3

CH2 CH2

CH1

VH

CL

VL

CH1

VH

CL

VL



CH3

CH2 CH2

VHH VHH

CH3

CH2 CH2

VHH VHH

CH3

CH2 CH2

CH1

VH

CL

VL

CH1

VH

CL

VL




- preclinical efficacy of anti-venom camelid IgG VHH

Vipers Haemotoxic

Elapids Neurotoxic



• Affordability

• Safety


Research to resolve the African antivenom market failure: feasible

but requires more support from research-funding agencies

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



MRC, Wellcome Trust,

Leverhulme Trust, BBSRC, CVRL

Photographs:

Warrell, Wuster

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