Luis Barreto, MBBS, MD, MHSc Christopher J. Rutty, Ph.D. Rob Van

Aventis Pasteur
Luis Barreto, MBBS, MD, MHSc
Vice President Public Affairs and
Director of International Public Health Affairs,
Corporate Public Policy, Aventis Pasteur
Christopher J. Rutty, Ph.D.
Historical consultant, Health Heritage Research Services
Rob Van Exan, Ph.D.
Director Immunization Policy, Aventis Pasteur Limited
Presented at the Canadian Conference on Counter-Terrorism & Public Health, Toronto, Oct 30, 2003
Aventis Pasteur
The History of Vaccine Development
Man’s First
Vaccine
Chinese
inoculator with
9Efficacy?
his patient.
9Safety?
Immunization against
smallpox was
9Delivery?
popularized in
eleventh century
9Research
Cost?
China by the
Buddhists
who practiced
immunization byCost?
9Development
blowing powdered
smallpox scabs into
9Manufacturing?
the patients nose.
L. Barreto, Canada & the Smallpox Vaccine Story, 1916-2003, Canad ian Conference on Counter-Terrorism, & Public Health, Toronto, Oct 30, 2003
Aventis Pasteur
The History of Vaccine Development
Smallpox in Canada
Epidemics in Canada
9Introduced by French Settlers 1635
9Massive epidemics killed many
settlers, but decimated native
populations
1750 Biological Warfare
9British deliberately spread
smallpox to natives by giving
them infected blankets as “a
token of good fortune”
3
Images: CBC-TV series Canada: A People s H istory
L. Barreto, Canada & the Smallpox Vaccine Story, 1916-2003, Canad ian Conference on Counter-Terrorism, & Public Health, Toronto, Oct 30, 2003
Aventis Pasteur
The History of Vaccine Development:
Canada’s Role in Smallpox Eradication
Smallpox Vaccine in Canada
9Smallpox vaccine introduced to Canada in
late 1800’s
9Connaught Laboratories plays leadership
role in development of Smallpox Vaccine
9Connaught Laboratories plays leadership
role in WHO eradication of smallpox in 1980
9Smallpox declared bio-terrorist threat,
9/11/01
9Aventis Pasteur manufactures smallpox for
Canada 2003
4
Image: Aventis Pasteur Limited; WHO
L. Barreto, Canada & the Smallpox Vaccine Story, 1916-2003, Canad ian Conference on Counter-Terrorism, & Public Health, Toronto, Oct 30, 2003
Aventis Pasteur
The Best Smallpox Vaccine in the
Galaxy…
…Made in Canada!
"Directly and indirectly, the ammunition
for the the production of y our
I have just completed
[smallpox eradication] campaign bore the indelible
order. I guess that you will shortly have on hand
stamp —made in Canada . To a once-Canadian, it
10 million doses of the best smallpox
was always a personal sourceabout
of pride.
vaccine ever made in our galaxy.
Dr D. A. Henderson, Chief, WHO Smallpox Eradication Unit,to Dr. Robert J.
Wilson, Connaught Laboratories Limited, June
18, 1979
Dr. Paul
Fenje, Connaught Medical Research Laboratories, to
Dr. Donald A. Henderson, Chief, WHO Smallpox Eradication
Unit., Feb. 16, 1971
Dr. Paul Fenje
Dr. Donald A. Henderson
Images: Dr. P. Fenje; John s Hopkins School o f Public Health website
L. Barreto, Canada & the Smallpox Vaccine Story, 1916-2003, Canad ian Conference on Counter-Terrorism, & Public Health, Toronto, Oct 30, 2003
5
Aventis Pasteur
1916-21: Canada Gets Serious About
Smallpox Vaccine
1916
1917
Connaught Antitoxin Laboratories
9“Connaught” buys cattle & equipment
from Ontario Vaccine Farm in Palmerston
9Smallpox virus seed and bulk vaccine
supplied to Connaught from New York City
Health Department Laboratories
9Smallpox vaccine production begins with
harvest of vaccinia pulp from Calf #1.
9First lot of vaccine released in Dec 1917.
1918
1919
1920
1921
9Connaught supplies more than 600,000
doses of vaccine to Canadian military by
end of WWI
Connaught s smallpox vaccine was produced
in front left corner rooms of this building from
1917 to 1950.
9Connaught supplies 1 million doses of
vaccine to control serious smallpox
outbreaks in Ontario
6
Images: Aventis Pasteur Limited
L. Barreto, Canada & the Smallpox Vaccine Story, 1916-2003, Canad ian Conference on Counter-Terrorism, & Public Health, Toronto, Oct 30, 2003
Aventis Pasteur
1921-32: Canadian Science Making the Best
Smallpox Vaccine Possible
Connaught Research
1920s – Scientific papers begin
tradition of comprehensive research
into smallpox vaccine improvement.
1924 - Effectiveness of
Connaught’s smallpox vaccine
dramatically demonstrated during
serious smallpox outbreak in
Windsor
1927-32 – Process improvements
further reduce bacterial
contamination of vaccine and
improve potency and stability.
7
Image: Aventis Pasteur Limited
L. Barreto, Canada & the Smallpox Vaccine Story, 1916-2003, Canad ian Conference on Counter-Terrorism, & Public Health, Toronto, Oct 30, 2003
Aventis Pasteur
1930-40s: “Elementary Bodies” and
Freeze-Dried Smallpox Vaccine
1930s – Connaught scientist, Dr. James
Craigie, conducts key research into
isolating “elementary bodies” of vaccinia
virus
World War II - Persistent smallpox
incidence in tropical countries underscored
limits of liquid (glycerinated) vaccine
1948 - World Health Organization
established and seeks dried smallpox
vaccine to better control disease
Elementary Bodies of Vaccinia Virus
1948 - Dr. L.H. Collier of the Lister Institute begins work on freeze-dried smallpox
vaccine based work of Dr. Craigie and Dr. C.R. Amies at Lister, but who soon joined
Connaught
8
Image: Aventis Pasteur Limited
L. Barreto, Canada & the Smallpox Vaccine Story, 1916-2003, Canad ian Conference on Counter-Terrorism, & Public Health, Toronto, Oct 30, 2003
Aventis Pasteur
1958-62 – Forging a Freeze-Dried
Smallpox Vaccine at Connaught
Towards a Dried Vaccine
1957-58 - Major smallpox epidemic strikes
Bangladesh, causing 100,000 cases. Red Cross
and WHO seek emergency supplies of vaccine
1958 - Connaught quickly supplies 1.5 million
doses of liquid vaccine.
Emergency also prompts intense work to
develop a freeze-dried smallpox vaccine
1958 - Dr. Cleve Russell Amies arrives at
Connaught and leads dried smallpox vaccine
development work
Dr. Cleve Russell Amies
9
Image: Aventis Pasteur Limited
L. Barreto, Canada & the Smallpox Vaccine Story, 1916-2003, Canad ian Conference on Counter-Terrorism, & Public Health, Toronto, Oct 30, 2003
Aventis Pasteur
1958-62 – Forging a Freeze-Dried
Smallpox Vaccine at Connaught
Dried Vaccine Progress
1960 - Amies prepares small batches
of freeze-dried vaccine.
1960-61 - Larger batches of dried
vaccine tested in several field trials,
primarily with the Canadian Armed
Services
1962 - Amies leaves Connaught
10
Image: Aventis Pasteur Limited
L. Barreto, Canada & the Smallpox Vaccine Story, 1916-2003, Canad ian Conference on Counter-Terrorism, & Public Health, Toronto, Oct 30, 2003
Aventis Pasteur
Dr. Paul Fenje:
Connaught’s
Vaccine Visionary
1915 - Born in Novi Sad, Yugoslavia
1940 - MD, University of Zagreb
1945-46 - District Medical Officer, Macedonia
1946-48 - Bacteriologist, Institute of Public
Health, Novi Sad
1949 - Diploma in Public Health, Institute of
Hygiene, Belgrade
1950-55 - Head, Public Health Laboratory,
Sremska Mitrovica
1955 - Head, Dept. Medical Virology, Pasteur
1958
- Joined
Connaught Medical Research
Institute,
Novi Sad
Dr Fenje
Connaught
Dr. PaulatFenje
Image: Aventis Pasteur Limited
Laboratories, specializing in rabies vaccine
1958 - Joined Connaught Medical Research
1962
- Assumed
responsibility
for vaccine
Connaught’s
Laboratories,
specializing
in rabies
smallpox vaccine development and production
1962 - Assumed responsibility for Connaught’s
1979
- Retired
smallpox
vaccine development and production
1979 Retired
L. Barreto, Canada & the Smallpox Vaccine Story, 1916-2003, Canad ian Conference on Counter-Terrorism, & Public Health, Toronto, Oct 30, 2003
11
Aventis Pasteur
1962 – Refreshing Freeze-Dried Smallpox
Vaccine Development
New Smallpox Vaccine Priorities
9New research priorities established for the
further development of smallpox vaccines at
Connaught under direction of Dr. Fenje.
9Top priority given to further development of
a dried smallpox vaccine.
9Initial WHO eradication program stalled in
1955 after vaccine donated by the Soviet
Union found to be contaminated with certain
extraneous viruses.
9Connaught’s smallpox vaccines tested
free of all known viruses.
12
Images: Aventis Pasteur Limited
L. Barreto, Canada & the Smallpox Vaccine Story, 1916-2003, Canad ian Conference on Counter-Terrorism, & Public Health, Toronto, Oct 30, 2003
Aventis Pasteur
1962 – Refreshing Freeze-Dried Smallpox
Vaccine Development
The Drive for Eradication
9The WHO thus focused on developing
new vaccine standards
9new epidemics in developing countries
9several alarming outbreaks in Europe
9cases imported from endemic areas.
13
Image: WHO
L. Barreto, Canada & the Smallpox Vaccine Story, 1916-2003, Canad ian Conference on Counter-Terrorism, & Public Health, Toronto, Oct 30, 2003
Aventis Pasteur
August 1962 - Toronto Smallpox
Alarm
Connaught recommended that the Canadian
The importance of global smallpox control
government
preparing
a stockpile
North
Americanconsider
vulnerability
to smallpox
exposed
was reinforced
of dried smallpox vaccine.
Fears of Imported Smallpox
914 year-old boy returning home to Toronto from Brazil via
New York developed smallpox en route
9international emergency declared.
9mass vaccination campaigns on both sides of the border
rapidly deployed.
Canada s last smallpox case
Images: Toronto Star, Aug 20, 1962; Aventis
Pasteur Limited
9Connaught supplied 150,000 doses of glycerinated vaccine
during the emergency.
9Fortunately it was a mild case with no secondary spread.
L. Barreto, Canada & the Smallpox Vaccine Story, 1916-2003, Canad ian Conference on Counter-Terrorism, & Public Health, Toronto, Oct 30, 2003
14
Aventis Pasteur
1962-66 – Setting and Meeting
Smallpox Vaccine Standards
Global Standards for Smallpox Vaccine
1962 - Fenje intensifies dried vaccine development to meet new WHO standards
1963-64 - Routine production of freeze-dried vaccine established at Connaught
1964-65
Potency
test becomes
standard
Aug 1964– -CAM
Canadian
licensing
of
Connaught’s freeze-dried smallpox vaccine
Dec 1964 - Connaught’s freeze-dried
smallpox vaccine meets WHO standards
1965 - U.S. agrees to sponsor a more
sophisticated WHO global smallpox
eradication program
15
Images: Aventis Pasteur Limited
L. Barreto, Canada & the Smallpox Vaccine Story, 1916-2003, Canad ian Conference on Counter-Terrorism, & Public Health, Toronto, Oct 30, 2003
Aventis Pasteur
1962-66 – Setting and Meeting
Smallpox Vaccine Standards
Meeting Rising Global Standards for Smallpox Vaccine
1965-66 - Fenje further upgrades freeze-dried vaccine to meet stricter Canadian,
WHO and U.S. standards
1966 - New building at Connaught enables large-scale freeze-dried smallpox
vaccine production
16
Images: Aventis Pasteur Limited
L. Barreto, Canada & the Smallpox Vaccine Story, 1916-2003, Canad ian Conference on Counter-Terrorism, & Public Health, Toronto, Oct 30, 2003
Aventis Pasteur
1967-68 – Energizing Smallpox
Eradication
1966
1967 – Connaught:
named one of two WHO
International Smallpox
Vaccine Reference
Centers
Connaught
Toronto
RIJKS
Bilthoven
1967-68 – Drs. Paul Fenje and R.J. Wilson begin consulting work in South America
to improve the quality of local smallpox vaccine producers, especially in Brazil.
17
Image: WHO
L. Barreto, Canada & the Smallpox Vaccine Story, 1916-2003, Canad ian Conference on Counter-Terrorism, & Public Health, Toronto, Oct 30, 2003
Aventis Pasteur
1967-68: Smallpox Vaccine for Jet Injector
Jet
Injector
9Fenje next worked to prepare a sterile
dried vaccine for jet injection that met
strict WHO standards.
9Jet injector speeds up mass
immunization programs
18
Image: Aventis Pasteur Limited
L. Barreto, Canada & the Smallpox Vaccine Story, 1916-2003, Canad ian Conference on Counter-Terrorism, & Public Health, Toronto, Oct 30, 2003
Aventis Pasteur
Dr. Robert J. Wilson: Smallpox Vaccine
Supervisor
Dr Robert J. Wilson
1967 –- Born
Consultant,
Pan A merican Health Organization,
1915
in Edmonton
improving local smallpox vaccine production in South
America
1935-37 – Research Assistant, Connaught Medical
Research Laboratories, Western Division, University of
June
– Director, Connaught Medical Research
British 1972
Columbia
Laboratories
1942 – MD, University of Toronto
July 1972 – Scientific Director, Connaught
1942-45
– Royal
Canadian Navy
Laboratories
Limited
1980
1946 – Retired
Diploma of Public Health, School of Hygiene,
University of Toronto
March 30, 1989 – Died
1946 – Research A ssociate, Connaught Medical
Research Laboratories, University of Toronto
Dr. Robert J. Wilson (1915-89)
19
Images: Aventis Pasteur Limited
L. Barreto, Canada & the Smallpox Vaccine Story, 1916-2003, Canad ian Conference on Counter-Terrorism, & Public Health, Toronto, Oct 30, 2003
Aventis Pasteur
D.A. Henderson – R.J. Wilson – P. Fenje:
Smallpox Eradication Engineers
Dr D A Henderson
"I appreciate only too well how many of the concepts in the execution of the smallpox program
saw the first light of day over a glass of beer with Bob [Wilson] and Paul [Fenje].
What I don t recall is whether the ideas stemmed from Wilson or Fenje,
so perhaps they are better attributed to Wilje (or should it be Fenson?).
D.A. Henderson to P. Fenje, June 18, 1979
Dr Paul Fenje
Dr R. J Wilson
Image: Smallpox & its
Eradication (WHO, 1980)
L. Barreto, Canada & the Smallpox Vaccine Story, 1916-2003, Canad ian Conference on Counter-Terrorism, & Public Health, Toronto, Oct 30, 2003
20
Aventis Pasteur
1970-74 – Using the “Best Smallpox
Vaccine in this Galaxy”
1970-74
rts
o
p
e
ny r
a
n
ee
her
9Canadian government donates a total of
t
b
a
e
r
v
ha
e is
e
h
r
35,000,000 doses of Connaught’s freezee
k
thin
er th
I
hat
h
t
t
.
e
dried smallpox vaccine to the WHO
s
y
t
h
x
ew
oub
ala
d
g
m
s
w
g
i
e
n th
ve f
i
9for the jet injector and regular edried
askin
a
e
h
n
n
it.
hI
be
cci
f
g
a
y
o
l
u
v
t
vaccine that could be administered
with
o
d
x
n
lpo
alth
ecte
l
rece
p
a
g
s
x
n
m
e
a
i
the bifurcated needle.
rm
t is
je h
est s
o
a
f
n
b
r
h
e
1971
e
,
s
w
F
p
i
0
l
1
o
h
s
t
i
it used
ll d
on vaccine
i
9Connaught’s
smallpox
ugus
"Pau
w
d
w
A
l
o
,
t
e
i
w hAsia. plied
e fi Africa
erson
oand
hEast
d
t
n
n
primarily
in
e
k
p
m
fro
.A. H
ly a
s to
r
D
u
e
o
o
t
p
i
o
anx
if pr R . J . W i l s o n
21
Image: Aventis Pasteur Limited
L. Barreto, Canada & the Smallpox Vaccine Story, 1916-2003, Canad ian Conference on Counter-Terrorism, & Public Health, Toronto, Oct 30, 2003
Aventis Pasteur
1971-72 – Raising the Smallpox Stakes
1971
1967
April 1972 – Major smallpox
outbreak in Bangladesh
prompts emergency at and
expedites delivery of 5 million
doses of Connaught’s dried
vaccine to be used with the
bifurcated needle.
Your vaccine, incidentally, is perfor ming magnificently both in the Congo and Ethiopia.
The good packaging and ease of reconstitution have both been commented upon. Take
rates in primaries have been in the range of 98% to 100%.
D.A. Henderson to P. Fenje, Aug. 27, 1971
Images: WHO, Aventis Pasteur Limited
L. Barreto, Canada & the Smallpox Vaccine Story, 1916-2003, Canad ian Conference on Counter-Terrorism, & Public Health, Toronto, Oct 30, 2003
22
Aventis Pasteur
1972-74 – Securing a Canadian Smallpox
Vaccine Stockpile
March-April 1972
9serious smallpox outbreak in Yugoslavia
9caused by pilgrim returning from Mecca,
9resulted in 170 cases and 40 deaths
9prompts planning for smallpox vaccine
emergency stockpiles:
‰at the WHO
‰in smallpox-free countries like Canada.
March 1974
9Connaught prepares and holds 1,000,000 doses
of freeze-dried smallpox vaccine as emergency
stockpile for Canadian government
Image: WHO
L. Barreto, Canada & the Smallpox Vaccine Story, 1916-2003, Canad ian Conference on Counter-Terrorism, & Public Health, Toronto, Oct 30, 2003
23
Aventis Pasteur
1977-78 : Smallpox’s Last
Stand
August 1978
Oct. 26, 1977
9A major smallpox scare resulted when smallpox virus
Last natural
case in the
world
occurred
in
escaped
in asmallpox
British laboratory
and
infected
a medical
Somalia.
photographer.
9Incident raised alarms around the world about the
secure storage of the smallpox virus.
9It also highlighted the potential threat of an intentional
release of the smallpox virus as a biological weapon.
24
Images: WHO; Toronto Star, Sept. 2, 1978
L. Barreto, Canada & the Smallpox Vaccine Story, 1916-2003, Canad ian Conference on Counter-Terrorism, & Public Health, Toronto, Oct 30, 2003
Aventis Pasteur
1979 - Ensuring
Eradication
Preparing for New Stockpiles
January 1979 - New Canadian smallpox
vaccine stockpile needed
February 1979 - WHO proposal for 25
million dose smallpox vaccine stockpile at
Connaught for emergency use in Latin
America.
March-April 1979 - Fenje prepares 17
vaccinia pulps for proposed new vaccine
stockpiles.
September 1979 – Dr. Fenje retires from
Connaught
November 1979 - Smallpox vaccine
distribution in Canada discontinued.
Images: Dr. P. Fenje
L. Barreto, Canada & the Smallpox Vaccine Story, 1916-2003, Canad ian Conference on Counter-Terrorism, & Public Health, Toronto, Oct 30, 2003
25
Aventis Pasteur
1980 - Connaught Concludes Smallpox Vaccine Pr
December 9, 1979 - WHO officially declares
smallpox eradicated from the globe.
s
virJuly 1980ething
d
e
e
smallpox vaccine production
by
s
e
som
e
ep th
v
e
a
k
h
o
t
t
h
em
migof
bl1980
o
e
t.”smallpox
r
w
c
p
u
y
t
March
Production
freeze-dried
d
a
a
e
o
w
r
r
s
t hi Canadianlistockpile.
e a g vaccine
sed p Remaining
n
b
n
i
t
e
t
o
c
s
n
a
for
new
e
l
l
r
l
i
t
u
w
, 1980
a
o
2
y
d
e
1
l
r
.
n
e
t
a
r
p
a
p
e
u
,S
vaccine eproduction
materials i–m15
seed virus
“It s
come
itedpulps,
o pre
t
o
t
l
L
e
b
s
e
a
i
m
be samples -- put
ator freeze
e ti
in
toand
bordeep
a
s
L
a
t
o
h
s
g
for som
on
onnau
k
c
C
a
,
r
b
o
t
l
c
l
l Dire
to fa
pulp of
February 1980 - Connaught plans
phase-out
d
n
a
s
u
Dr. E.W
n, Me
. Pearso
dica August 1980 - Suggestion made that
Connaught’s remaining 15 vaccinia pulps be
destroyed.
Not everyone agrees…
26
Image: WHO
L. Barreto, Canada & the Smallpox Vaccine Story, 1916-2003, Canad ian Conference on Counter-Terrorism, & Public Health, Toronto, Oct 30, 2003
Aventis Pasteur
Through the Cold War to the War on
Terrorism
Only
two official freezers contain the
last smallpox virus samples (in the U.S.
and Russia)
27
Image (Book cover): Richard Preston, The Demon in the Freezer (2002)
L. Barreto, Canada & the Smallpox Vaccine Story, 1916-2003, Canad ian Conference on Counter-Terrorism, & Public Health, Toronto, Oct 30, 2003
Aventis Pasteur
2001-2003 – “9/11” and
Renewing Smallpox Security
Sept. 11, 2001 - Twenty-two years after
smallpox was officially declared eradicated from
the Earth…..
…..the spectre of smallpox has re-emerged from
history as a potentially devastating bio-terrorist
weapon.
2002-2003 - Uncertainties about the potential
use of smallpox virus as a terrorist weapon
prompted efforts in many countries to prepare
new supplies of smallpox vaccine, including in
Canada.
28
Image: Toronto Sun, Nov 4, 2001
L. Barreto, Canada & the Smallpox Vaccine Story, 1916-2003, Canad ian Conference on Counter-Terrorism, & Public Health, Toronto, Oct 30, 2003
Aventis Pasteur
2002-03 - Stockpile From the Freezer
2002 - 15 vaccinia pulps and other smallpox
vaccine materials, originally prepared in
1979, retrieved from the deep freeze at
Aventis Pasteur’s Connaught Campus in
Toronto.
After passing rigorous tests, these
vaccinia pulps now being processed
into 15 million doses of smallpox
vaccine for a new Canadian stockpile.
29
Images: Aventis Pasteur Limited
L. Barreto, Canada & the Smallpox Vaccine Story, 1916-2003, Canad ian Conference on Counter-Terrorism, & Public Health, Toronto, Oct 30, 2003
Aventis Pasteur
Smallpox Vaccine in Canada:
Legacies & Lessons
Aventis Pasteur
Lyon
Toronto
Connaught
– Aventis
Pasteur
Aventis
Pasteur
Global
Supply
9Long history of experience
2003 with the
development and production of effective
smallpox
9
Canada vaccines.
Played key role in the eradication of
9US
smallpox.
9France
9Preserved smallpox vaccine production
capabilities.
Swiftwater
30
Image: WHO
L. Barreto, Canada & the Smallpox Vaccine Story, 1916-2003, Canad ian Conference on Counter-Terrorism, & Public Health, Toronto, Oct 30, 2003
Aventis Pasteur
Vaccine industry is global
• National plans-national coordination-national authority
• Integration with global or continental planning
Industry – government collaboration
• Planning
• Investment
• Prioritization
Vaccine stockpiles
31
Aventis Pasteur
Acknowledgements
Palma Mancuso and her Smallpox Team Aventis Pasteur
Health Canada
¥
Dr. Ron St. John
¥
Mr. Scott Broughton
32