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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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Early dengue investigation in the shadow of yellow fever research l.jpg
Early Dengue Investigationin the Shadow of Yellow Fever Research

Reminder dengue dengue or dengue like illness period covered 1890 1950 l.jpg
Reminder“Dengue”=dengue or dengue-like illnessPeriod covered: 1890-1950

Important events 1897 98 l.jpg
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

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George Miller Sternberg(Source: U.S. Army Archive)

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Walter Reed

(Source: U.S. Army Archive)

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Farewell Clara….Clara was buried in Havana, Cuba and later reburied in New Jersey at Fairmount Cemetery


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Charles Franklin Craig

(Source: Am. J. Trop. Med., 1951)

Vector borne transmission of human diseases historical events before dengue research l.jpg
Vector-Borne Transmission of Human Diseases:Historical Events before Dengue Research

Patrick manson source u s army archives l.jpg
Patrick Manson(Source: U.S. Army Archives)

Ronald ross source u s army archive l.jpg
Ronald Ross(Source: U.S. Army Archive)

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Carlos Juan Finlay

(Source: Univ. Virginia Claude Moore Health Science Library)

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Henry Rose Carter

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

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Etiologic Investigation:Transmission Mechanism

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Experimental Design for Dengue Transmission Studies

Source of

“infectious agent”

2. Location for human


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Special Considerations for Human Experiment

  • Informed Consent

  • Monetary Reward

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Harris Graham

(Source: American University of Beirut, Lebanon)

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Dengue Studies in Cubaby the Former Members of the Walter Reed Commission: Left—Aristides Agramonte; Right– Juan Guiteras (Source of photos: Wikipedia Commons)

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T.L. Bancroft

(Source: Courtesy of Australian Nat. Univ.)

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Percy M. Ashburn(Source: U.S. Army Archive)

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Makoto Koizumi(Source: The 50-year history (1929-79) of parasitologic research in Japan. Japanese Society of Parasitologists, 1981)

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J. Burton Cleland

(Source: Courtesy: Australian National


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Joseph Franklin Siler(Source: U.S. Army Archive)

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James S. Simmons

(Source: U.S. Army Archive)

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Emilius Paulus Snijders

(Source: Academic Medical Centre, University of Amsterdam, The Netherlands)

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Dutch group portrait by Lizzy Ansingh (1933): From left to right-van Loghem, Kuenen, Schueffner, Swellengrebel, Snijders (Source: Univ. Museum Amsterdam)

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Etiologic Investigation: right-van Loghem, Kuenen, Schueffner, Swellengrebel, Snijders (Source: Univ. Museum Amsterdam)

Virus Isolation

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Susumu Hotta right-van Loghem, Kuenen, Schueffner, Swellengrebel, Snijders (Source: Univ. Museum Amsterdam)

(Source: Kobe University School of Medicine,

Kobe, Japan)

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Mrs. Mochizuki right-van Loghem, Kuenen, Schueffner, Swellengrebel, Snijders (Source: Univ. Museum Amsterdam)

(Source: S. Hotta-- Uirusu, 51:106; 2001)

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Albert B. Sabin right-van Loghem, Kuenen, Schueffner, Swellengrebel, Snijders (Source: Univ. Museum Amsterdam)

(Courtesy: U.S. Army )

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Sabin visiting Hotta at Kobe University, 1961

(Source: Kobe University, Kobe, Japan)

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Cornelius Becker Philip 1961

(Source: J. Parasitol. 73:678)

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Laboratory-identified Dengue 1961 Viruses

Year Location Serotype

  • Nagasaki, Japan DENV-1

    1943-44 Hawaii DENV-1

  • New Guinea DENV-1 and


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Serologically-identified Viruses 1961

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?)

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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

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Atypical Clinical Symptoms or Syndromes: ControversyExtensive Hemorrhage and/or Shock with Fatal Outcome

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F. E. Hare Controversy

(Source: J. Aaskov, Austr. Defense Force Health 4:66;2003)

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Hemorrhagic Manifestations and Fatality Controversy


Rumpell-Leede test (=Tourniquet test)

Borbely’s vascular resistance test


Correlations among increased vascular permeability, thrombocytopenia, and hemorrhage

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Selected Records of Fatal Cases Controversy

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

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Fatal Controversy


[A] 1897 - 1902

[B] 1926 - 1931

[C] 1940 - 1944

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Other “Unusual” Syndromes Controversy1. CNS syndrome2. Pulmonary syndrome

3 ophthalmologic dysfunctions source yuguchi kai gun ikai shi 32 627 1943 l.jpg
3. Ophthalmologic Dysfunctions Controversy(Source:Yuguchi, Kai-Gun-Ikai-Shi 32:627;1943)

Medical care l.jpg

Medical Care Controversy


Salicylates (Aspirin-contraindicant)


Blood transfusion

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The Importance of Human Movement by Ships Controversyandthe Critical Roles played by the Physicians on board for unraveling Dengue Transmission

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Mapping New Cases in Chronologic Order Controversy

(Source: Miyao,T. Kaigun-Gun-Ikai-Zasshi 20:564;1931)

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Recognition of dengue as an urban disease Controversy

(Source: Barraud, P.J. Indian J. Med. Res. 16:377; 1928)

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Transmission in a Military Barrack Quarter

(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 l.jpg
Dengue Attack Difference—Indoor vs Outdoor Quarter (Source: Clayton,F.H.A. J. Roy. Army Med. Corps 14:171;1910)

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Epidemiologic Reporting Quarter

Dengue as a reportable disease

Western Australia—1912

International Sanitary


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Seasonality in Endemic Area Quarter (Source: Simmons, J.S., et al. Philippine J. Sci. 44:1;1931)

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Multiple Dengue Infection Quarter

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

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Antibody Responses to Dengue Infection: Quarter Primary vs Secondary Infection

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Antibody response profiles—primary (lower curve) vs re-infection (upper curve)

(Source: Hotta, S & Kimura, R. Nisshin Igaku 36:470;1949)

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Development of Serologic Tests re-infection (upper curve)

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 l.jpg
Animal Model re-infection (upper curve)

Vertebrates other than primates

Unique breed of Swiss (albino) mouse

“dba” =dilute brown non-agouti

Subhuman primates

Macaca fasciatus

Macaca philippinensis

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Vector Identification and Biology re-infection (upper curve)


Aedes aegypti -- T. Bancroft

Ae. albopictus– M. Koizumi

Ae. scutellaris – R.H. Daggy

Breeding technique:

Ae. aegypti – J. Siler

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Geographic Distribution of Vectors re-infection (upper curve)

Aedes aegypti and Ae. albopictus

H. Kumm – 1931

Clara Ludlow

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Clara S. Ludlow re-infection (upper curve)

(Source: George Washington University Photographic Collection)

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Venereal and Vertical Transmission in Mosquitoes re-infection (upper curve)

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)

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Jean-Paul Simond re-infection (upper curve)

(Courtesy: Thomas P. Monath)

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Emile Marchoux re-infection (upper curve)

(Courtesy: Thomas P. Monath)

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Vector Competence re-infection (upper curve)

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Vector Control: re-infection (upper curve) Biological Control:

Predatory mosquitoes

(Toxorhynchites spp.)

2. Fishes

Slide74 l.jpg
Toxorhynchites Larva re-infection (upper curve) (Source: New South Wales Arbovirus Surveillance and Vector Monitoring Programme, Australia)

Slide75 l.jpg

Kill fish re-infection (upper curve) (Oryzias latipes)


Vector control l.jpg

Vector Control re-infection (upper curve)

Applications of Insecticides

Including Indoor Residual Spray of DDT

Vector control77 l.jpg
Vector Control re-infection (upper curve)

  • Source reduction

  • Community participation

  • Public education and organized campaign

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Dengue Prevention other than Vector Control re-infection (upper curve)

Unusual people’s reaction to fear

International Convention

League of Nations

Legislation of Law

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Vaccine Development- attenuation or inactivation methods re-infection (upper curve)

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

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Economic Cost re-infection (upper curve)

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Economic Cost Estimate re-infection (upper curve) [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

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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 l.jpg
Acknowledgments Interaction: Grave Sites of Walter Reed and Albert Sabin

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