The History of Dengue Research
before 1950
A Forgotten History ?
Early Dengue Investigation
in the Shadow of Yellow
Fever Research
Reminder
“Dengue”=dengue or denguelike illness
Period covered: 1890-1950
Important Events: 1897-98
1. “Filterable agent” [=virus]
2. Vector-borne transmission
3. Extrinsic incubation period
4. Controversy on etiology of YF
5. Dengue outbreaks in Texas
6. Spanish-American War
George Miller Sternberg
(Source: U.S. Army Archive)
Walter Reed
(Source: U.S. Army Archive)
Farewell Clara….
Clara was buried in Havana, Cuba and later reburied in
New Jersey at Fairmount Cemetery
.
Charles Franklin Craig
(Source: Am. J. Trop. Med., 1951)
Vector-Borne
Transmission of
Human Diseases:
Historical Events before
Dengue Research
Patrick Manson
(Source: U.S. Army Archives)
Ronald Ross
(Source: U.S. Army Archive)
Carlos Juan Finlay
(Source: Univ. Virginia Claude Moore Health Science
Library)
Photo
Henry Rose Carter
(Source: Am. J. Publ. Hlth. 15:994; 1926)
Etiologic Investigation:
Transmission Mechanism
Experimental Design for
Dengue Transmission
Studies
1. Source of
“infectious agent”
2. Location for human
experiment
Special Considerations for
Human Experiment
1. Informed Consent
2. Monetary Reward
Dengue Transmission
Mechanism:
Early Researchers
Harris Graham
(Source: American University of Beirut, Lebanon)
Dengue Studies in Cuba
by the Former Members of the Walter Reed
Commission: Left—Aristides Agramonte; Right– Juan
Guiteras (Source of photos: Wikipedia Commons)
T.L. Bancroft
(Source: Courtesy of Australian Nat. Univ.)
Percy M. Ashburn
(Source: U.S. Army Archive)
Makoto Koizumi
(Source: The 50-year history (1929-79) of parasitologic research in
Japan. Japanese Society of Parasitologists, 1981)
J. Burton Cleland
(Source: Courtesy: Australian National
University)
Joseph Franklin Siler
(Source: U.S. Army Archive)
James S. Simmons
(Source: U.S. Army Archive)
Emilius Paulus Snijders
(Source: Academic Medical Centre, University of
Amsterdam, The Netherlands)
Dutch group portrait by Lizzy Ansingh (1933): From left to rightvan Loghem, Kuenen, Schueffner, Swellengrebel, Snijders
(Source: Univ. Museum Amsterdam)
Etiologic
Investigation:
Virus Isolation
Susumu Hotta
(Source: Kobe University School of Medicine,
Kobe, Japan)
Mrs. Mochizuki
(Source: S. Hotta-- Uirusu, 51:106; 2001)
Albert B. Sabin
(Courtesy: U.S.
Army )
Sabin visiting Hotta at Kobe University, 1961
(Source: Kobe University, Kobe, Japan)
Cornelius Becker Philip
(Source: J. Parasitol. 73:678)
Laboratory-identified Dengue
Viruses
Year
1943
1943-44
1944
Location
Serotype
Nagasaki, Japan
DENV-1
Hawaii
DENV-1
New Guinea
DENV-1 and
DENV-2
Serologically-identified Viruses
1924-25
1925-26
1927
1929-30
1942
1943
1944-45
1945
1942-44
Philippines
QLD, Australia
South Africa
Philippines
QLD, Australia
Singapore
Guam
Calcutta, India
Japan
DENV-4
DENV-1
DENV-1
DENV-1
DENV-2/DENV-1
DENV-1
DENV-2(DENV-1?)
DENV-1
DENV-1(DENV-2?)
Clinical Definition of “Dengue”- a
Source of Constant Controversy
1. Variation depending on
physicians, year, location, and
unknown human conditions
2. “Typical” vs “atypical” symptoms
3. Syndrome in human experiment
as ‘standard”
4. Confusion with other etiologies
Atypical Clinical
Symptoms or
Syndromes:
Extensive Hemorrhage
and/or Shock with Fatal
Outcome
F. E. Hare
(Source: J. Aaskov, Austr. Defense Force Health 4:66;2003)
Hemorrhagic Manifestations and
Fatality
Diagnosis:
Rumpell-Leede test (=Tourniquet test)
Borbely’s vascular resistance test
Study:
Correlations among increased vascular
permeability, thrombocytopenia, and
hemorrhage
(Source: www.historyplace.com)
Selected Records of Fatal Cases
1895-1926
1897
1904-05
1926
1907-09
1931
1932
1943-44
1944
Australia
QLD, Australia
Australia
Australia
Vietnam
Okinawa, Japan
Taiwan
Philippines
Taiwan
816
97
201
93
4
508
26
7
5
[A] 1897 - 1902
[B] 1926 - 1931
[C] 1940 - 1944
Fatal
Non-Fatal
Other “Unusual” Syndromes
1. CNS syndrome
2. Pulmonary syndrome
3. Ophthalmologic Dysfunctions
(Source:Yuguchi, Kai-Gun-Ikai-Shi 32:627;1943)
Medical Care
1. Antipyretics
2. Salicylates (Aspirincontraindicant)
3. Immunotherapy
4. Blood transfusion
Pandemic Pattern of
Dengue Spread and Human
Movement
The Importance of Human
Movement by Ships
and
the Critical Roles played by
the Physicians on board for
unraveling Dengue
Transmission
Investigating the
Patterns of Dengue
Spread in Urban
Areas
Mapping New Cases in Chronologic Order
(Source: Miyao,T. Kaigun-Gun-Ikai-Zasshi 20:564;1931)
Recognition of dengue as an urban disease
(Source: Barraud, P.J. Indian J. Med. Res. 16:377; 1928)
Investigating the
Mechanism of
Transmission in
Living Quarter
Transmission in a Military Barrack
(Source: Kennedy, R.S. Indian Med. Gaz. 46:436; 1912)
Dengue Attack Difference—Indoor vs Outdoor
(Source: Clayton,F.H.A. J. Roy. Army Med. Corps 14:171;1910)
Epidemiologic Reporting
Dengue as a reportable
disease
1. Western Australia—1912
2. International Sanitary
Convention--1934
Cyclic Pattern of
Epidemic in Dengue
Endemic Area
(Seasonality)
Seasonality in Endemic Area
(Source: Simmons, J.S., et al. Philippine J. Sci. 44:1;1931)
Multiple Dengue Infection
1. Occurrence
2. Interpretation
a. Dengue-multiple etiologies
b. Opposition to vaccine development
3. Emergence of the concept of “multiple
immunotype”
4. Existence of 4 serotypes
Antibody Responses
to Dengue Infection:
Primary vs Secondary
Infection
Antibody response profiles—primary (lower
curve) vs re-infection (upper curve)
(Source: Hotta, S & Kimura, R. Nisshin Igaku 36:470;1949)
Development of Serologic Tests
A. Complement Fixation Test (CF)
Earlier application for YF since 1929
Application to dengue by Sabin- 1948
B. Neutralization (in vivo) Test (NT)
Development for YF since 1929
Sawyer and Lloyd—1931
Application to dengue in the 1940s
Animal Model
Vertebrates other than primates
Unique breed of Swiss (albino) mouse
“dba” =dilute brown non-agouti
Subhuman primates
Macaca fasciatus
Macaca philippinensis
Vector Identification and
Biology
Vectors:
Aedes aegypti -- T. Bancroft
Ae. albopictus– M. Koizumi
Ae. scutellaris – R.H. Daggy
Breeding technique:
Ae. aegypti – J. Siler
Geographic Distribution of Vectors
Aedes aegypti and Ae. albopictus
H. Kumm – 1931
Clara Ludlow
Clara S. Ludlow
(Source: George Washington University Photographic Collection)
Venereal and Vertical Transmission
in Mosquitoes
Venereal Transmission
Simmons, et al. (1931)
Vertical Transmission
Impacts of earlier YF studies by
Simond and Marchoux
For dengue
Legendre (1911) and Siler, et al. (1925)
Jean-Paul Simond
(Courtesy: Thomas P. Monath)
Emile Marchoux
(Courtesy: Thomas P. Monath)
Vector Competence
Vector Control:
Biological Control:
1. Predatory mosquitoes
(Toxorhynchites spp.)
2. Fishes
Toxorhynchites Larva
(Source: New South Wales Arbovirus Surveillance and
Vector Monitoring Programme, Australia)
Kill fish (Oryzias latipes)
(Source: http://biol1.bio.nagoyau.ac.jp:8000/9808/8.html)
Vector Control
Applications of
Insecticides
Including Indoor Residual
Spray of DDT
Vector Control
• Source reduction
• Community participation
• Public education and
organized campaign
Dengue Prevention other than
Vector Control
Unusual people’s reaction to fear
International Convention
League of Nations
Legislation of Law
Vaccine Development- attenuation or
inactivation methods
Cleland (1917-19) – human passage
Blanc & Caminopetros (1931)– bovine bile
St. John & Holt (1931) – killed vaccine
Holt, et al. (1931) – X-ray irradiation
Simmons, et al. (1929-31) – mosquito passage
+ antiserum + desiccation
Hotta & Kimura (1943-49) – formalin
Sabin & Schlesinger (1944-49) –attenuation in
suckling mice
Economic Cost
Economic Cost Estimate
[reproduced with minor modifications]
(Source: Hamlyn-Smith, R. Ann. Trop. Med. Parasitol.
25:21;1931)
Occupation
Category
1
2
3
4
5
6
7
8
9
Loss in wage (pound/
shilling/d)
438/4/8
569/2/7
213/17/4
200/0/0
220/0/0
303/0/0
500/0/0
130/0/0
1451/0/0
% Sick Workers
65.6
23.8
17.0
20.0
20.0
26.0
35.0
24.0
15.3
Completing the full Circle of YF and
Dengue Research History Interaction:
Grave Sites of Walter Reed and Albert
Sabin
(Arlington National Cemetery, Virginia)
(Source: U.S. National Archives)
Acknowledgments
Yuki Eshita- Oita University School of Medicine, Oita,
Japan
David Hill – U.S. Army, Silver Spring, Maryland, USA
Eva Lee – Australian National University, Canberra,
ACT, Australia
Jennifer Lehman – CDC, Fort Collins, Colorado, USA
Mathieu Mazarin – CDC, Fort Collins, Colorado, USA
Thomas P. Monath – Kleisner Perkins Caufield & Byers,
Menlo Park, California, USA
J.F. Wendte – Medical Centre, University of
Amsterdam, the Netherlands