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The History of Dengue Research before 1950 A Forgotten History ?. Early Dengue Investigation in the Shadow of Yellow Fever Research. Reminder “Dengue”=dengue or dengue-like illness Period covered: 1890-1950. Important Events: 1897-98. 1. “Filterable agent” [=virus]

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The History of Dengue Research before 1950 A Forgotten History ?

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The History of Dengue Research before 1950A Forgotten History ?

Early Dengue Investigationin the Shadow of Yellow Fever Research

Reminder“Dengue”=dengue or dengue-like illnessPeriod 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)


Henry Rose Carter

(Source: Am. J. Publ. Hlth. 15:994; 1926)

Etiologic Investigation:Transmission Mechanism

Experimental Design for Dengue Transmission Studies

Source of

“infectious agent”

2. Location for human


Special Considerations for Human Experiment

  • Informed Consent

  • Monetary Reward

Dengue Transmission Mechanism:Early Researchers

Harris Graham

(Source: American University of Beirut, Lebanon)

Dengue Studies in Cubaby 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


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 right-van 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 DengueViruses

Year Location Serotype

  • Nagasaki, Japan DENV-1

    1943-44 Hawaii DENV-1

  • New Guinea DENV-1 and


Serologically-identified Viruses

1924-25 Philippines DENV-4

1925-26 QLD, Australia DENV-1

  • South Africa DENV-1

    1929-30 Philippines DENV-1

  • QLD, Australia DENV-2/DENV-1

  • Singapore DENV-1

    1944-45 Guam DENV-2(DENV-1?)

  • Calcutta, India DENV-1

    1942-44 Japan DENV-1(DENV-2?)

Clinical Definition of “Dengue”- a Source of Constant Controversy

  • 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


Rumpell-Leede test (=Tourniquet test)

Borbely’s vascular resistance test


Correlations among increased vascular permeability, thrombocytopenia, and hemorrhage


Selected Records of Fatal Cases

1895-1926 Australia 816

QLD, Australia 97

1904-05 Australia 201

Australia 93

1907-09 Vietnam 4

Okinawa, Japan 508

Taiwan 26

1943-44 Philippines 7

Taiwan 5



[A] 1897 - 1902

[B] 1926 - 1931

[C] 1940 - 1944

Other “Unusual” Syndromes1. CNS syndrome2. Pulmonary syndrome

3. Ophthalmologic Dysfunctions(Source:Yuguchi, Kai-Gun-Ikai-Shi 32:627;1943)

Medical Care


Salicylates (Aspirin-contraindicant)


Blood transfusion

Pandemic Pattern of Dengue Spread and Human Movement

The Importance of Human Movement by Ships andthe 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

Western Australia—1912

International Sanitary


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


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


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:

Predatory mosquitoes

(Toxorhynchites spp.)

2. Fishes

Toxorhynchites Larva(Source: New South Wales Arbovirus Surveillance and Vector Monitoring Programme, Australia)

Kill fish (Oryzias latipes)


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 Loss in wage (pound/ % Sick Workers

Category shilling/d)

1 438/4/8 65.6

2 569/2/7 23.8

3 213/17/4 17.0

4 200/0/0 20.0

5 220/0/0 20.0

6 303/0/0 26.0

7 500/0/0 35.0

8 130/0/0 24.0

9 1451/0/0 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)


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

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