LT Tyler M. Sharp, Ph.D.

USPHS Scientific and Training SymposiumJune 21, 2011

A Dengue Epidemic in Puerto Rico, 2010

National Center for Emerging and Zoonotic Infectious DiseasesDivision of Vector-Borne Diseases — Dengue Branch

Dengue Most important vector-borne

viral disease worldwide ~100 million infections/year ~500,000 hospitalizations/year ~25,000 deaths/year

Four dengue viruses (DENV1–4) cause an acute febrile illness Common symptoms: fever,

headache, myalgia, retro-orbital and joint pain, rash

Severe symptoms: hemorrhage, shock, death

Photos credits: “Train-the-Trainer” course material, CDC 2010

Adapted from Vaccine 2002; 3043-3046

Dengue Virus Infections

Survive95-99.5%

Death0.5 - 5%

Infection Incidence ~ 5% / year

Asymptomatic 75%

Symptomatic 25%

Dengue Fever95-99%

Severe dengue1-5%

The Vicious Cycle of DENV InfectionsMosquito acquires virus during

feeding, virus replicates in mosquito

Mosquito acquires virus during feeding, virus replicates in

mosquito

Mosquito bites

susceptible human,

transfers DENV

Mosquito bites

susceptible human,

transfers DENV

Prevention and Control of Dengue Surveillance

Disease Vector

Primary prevention Vector control Vaccination

Secondary prevention Clinical care Anti-viral drugs

Image: http://www.lafayettela.gov/eos/dpt122mosquitocontrol.asp

Puerto Rico and Dengue 3.7 million individuals

Endemic

Seasonal

7,000 – 24,000 cases/year

Passive surveillance Image: http://www.caribbeanplanning.com/caribbean-map.htm

PuertoRico

1 2 3 4 5 6 7 8 9 10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

36

37

38

39

40

41

42

43

44

45

46

47

48

49

50

51

52

0

200

400

600

800

1000

Week of Illness Onset

Susp

ecte

d C

ases

Recent Dengue Epidemics in Puerto Rico

Mean

1 2 3 4 5 6 7 8 9 10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

36

37

38

39

40

41

42

43

44

45

46

47

48

49

50

51

52

0

200

400

600

800

1000

Week of Illness Onset

Susp

ecte

d C

ases

Recent Dengue Epidemics in Puerto Rico

1994

Mean

1 2 3 4 5 6 7 8 9 10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

36

37

38

39

40

41

42

43

44

45

46

47

48

49

50

51

52

0

200

400

600

800

1000

Week of Illness Onset

Susp

ecte

d C

ases

Recent Dengue Epidemics in Puerto Rico

19981994

Mean

1 2 3 4 5 6 7 8 9 10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

36

37

38

39

40

41

42

43

44

45

46

47

48

49

50

51

52

0

200

400

600

800

1000

Week of Illness Onset

Susp

ecte

d C

ases

Recent Dengue Epidemics in Puerto Rico

19982007

1994

Mean

1 2 3 4 5 6 7 8 9 10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

36

37

38

39

40

41

42

43

44

45

46

47

48

49

50

51

52

0

200

400

600

800

1000

Week of Illness Onset

Susp

ecte

d C

ases

Recent Dengue Epidemics in Puerto Rico

19982007

1994

2010

Mean

1 2 3 4 5 6 7 8 9 10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

36

37

38

39

40

41

42

43

44

45

46

47

48

49

50

51

52

0

200

400

600

800

1000

Week of Illness Onset

Susp

ecte

d C

ases

Recent Dengue Epidemics in Puerto Rico

2010

Mean

Diagnostics

Positive: RT-PCR or IgM ELISA positive

Negative: RT-PCR and IgM ELISA negative

Indeterminate: negative RT-PCR, no convalescent specimen

0 5Day Post-Onset of Symptoms

IgG

IgM

Virus

10 90

RT-PCR IgM ELISAAcute Convalesce

nt

Negative11.0%

Positive46.6%

Diagnostic Results, 2010

Indeterminate42.2%

Suspected Cases (n = 23,622)

IgM32.3%

RT-PCR67.7%

Positive Cases (n = 10,947)

Viral Serotypes, 2010

DENV-169.0%DENV-2

7.4%

DENV-423.6%

RT-PCR Positive Cases(n = 7,416)

Dengue incidence per 10,000 pop

1.16 - 16.33

16.34 - 27.41

27.42 - 42.97

42.98 - 161.33

Rates of Lab Positive Cases by Municipality, 2010

Dengue incidence per 10,000 pop

1.16 - 16.33

16.34 - 27.41

27.42 - 42.97

42.98 - 161.33

Lab positive cases per 1,000 persons

0.1-1.61.7-2.72.8-4.34.4-16.1

Overall incidence: 2.9 lab positive cases per 1,000 persons

<1 1-4 5-9 10-14

15-19

20-29

30-39

40-49

50-59

60-69

70 +0

500

1000

1500

2000

2500

0

1

2

3

4

5

6

7

8

Age Group

Case

sAge Distribution of Lab Positive Cases,

201047% of cases were in

adults Cases per 1,000 Individuals

<1 1-4 5-9 10-14 15-19 20-29 30-39 40-49 50-59 60-69 70+0

200

400

600

800

1000

1200

1400

1600DENV-1

Age Group

Case

sAge distribution of serotypes, 2010

<1 1-4 5-9 10-14 15-19 20-29 30-39 40-49 50-59 60-69 70+0

200

400

600

800

1000

1200

1400

1600

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%DENV-1

Age Group

Case

sAge distribution of serotypes, 2010

Percent Serotype

Jan Feb Mar Apr May Jun Jul Aug Sep Oct Nov Dec0

500

1000

1500

2000

2500

0

2

4

6

8

10

Month of Illness Onset

Case

sLab Positive Cases and Lab

Positive Deaths by Month, 2010D

eaths

Suspected deaths: 123Lab positive deaths: 38

Age Distribution of Lab Positive Deaths, 2010

89% of deaths were in adults

<1 1-4 5-9 10-14

15-19

20-29

30-39

40-49

50-59

60-69

70 +0

2

4

6

8

10

12

Age Group

Dea

ths

<1 1-4 5-9 10-14 15-19 20-29 30-39 40-49 50-59 60-69 70 +0

1

2

3

4

5

6

7 DENV-1DENV-4DENV-2

Age Group

Dea

ths

Deaths by Serotype*, 2010(n = 17)

*32 of 38 deaths have a confirmed serotype.

(n = 10)(n = 5)

History of Dengue in the United States

First documented outbreak in Philadelphia in 1780

Dengue disappeared in the US following vector elimination due to concerns of yellow fever

Travel-associated dengue has re-introduced the virus into the US

Re-emergence of Dengue in the United States

Dengue more common than malaria in some travelers

Mosquito vector exists in US

Imported outbreaks in TX, FL, HI

In 2010, 702 cases reported from 38 states

18X under-reporting

Distribution of Aedes mosquitoes

Mosquito surveillance data courtesy of Chester G. Moore, Colorado State University

Travel-associated Dengue in US, 2010

Source: ArboNET

Lead StatesNY 178FL 133CA 36NJ 29IL 23PA 22TX 19WA 19IN 19OH 16

702 cases reported from 38 states

>3011-303-101-20

Travel-associated Dengue in US, 2010

Source: ArboNET

1 5 9 13 17 21 25 29 33 37 41 45 490

102030405060 US Travel Cases

Puerto Rico, Dominican Republic, Haiti and other Caribbean Islands made up nearly half of all cases

Travel Destination Cases Percent

PUERTO RICO 93 16

DOMINICAN REPUBLIC 82 14

OTHER CARIBBEAN ISLANDS

50 8

INDIA 50 8HAITI 38 6NICARAGUA 26 4

PHILIPPINES 22 4

VENEZUELA 22 4

COLOMBIA 21 4

HONDURAS 21 4

Cas

es

Week of Report

Travel-associated Dengue in US, 2010

Source: ArboNET

Puerto Rico, Dominican Republic, Haiti and other Caribbean Islands made up nearly half of all cases

Travel Destination Cases Percent

PUERTO RICO 93 16

DOMINICAN REPUBLIC 82 14

OTHER CARIBBEAN ISLANDS

50 8

INDIA 50 8HAITI 38 6NICARAGUA 26 4

PHILIPPINES 22 4

VENEZUELA 22 4

COLOMBIA 21 4

HONDURAS 21 41 5 9 13 17 21 25 29 33 37 41 45 49

0100200300400500600

0102030405060US Travel

CasesPuerto Rico

Puer

to R

ico

Cas

es

Week of Report

Conclusions Dengue is re-emerging Large epidemic in PR in 2010

2.9 lab positive cases/1,000 individuals Most lab positive deaths ever (n = 38)

3.5 lab positive deaths/1,000 lab positive cases 10–19 year olds most affected

6.5 lab positive cases per 1,000 persons Most deaths in adults

Median age: 44 years Epidemics in PR overflow into the

continental U.S.

Future Steps Examine dengue deaths for:

Risk factors Under-reporting and -recognition

Emphasize personal protection Avoid mosquito bites

Educate physicians in clinical case management 8,300 physicians and 2,500 nurses trained

Evaluation of clinical case management

For more information please contact Centers for Disease Control and Prevention1600 Clifton Road NE, Atlanta, GA 30333Telephone, 1-800-CDC-INFO (232-4636)/TTY: 1-888-232-6348E-mail: cdcinfo@cdc.gov Web: www.cdc.govThe findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention.

AcknowledgementsAidsa Rivera, M.S. –Fatal case findings and PDSS oversight

Rosa Rodriguez, Ph.D. – EDSS oversightJorge L. Muñoz-Jordan, Ph.D. – Lab Chief, Molecular diagnostics and research

Elizabeth Hunsperger, Ph.D. – Lab Chief, Serology diagnostics and researchLuis Santiago, MPH – Statistical analysis and data processing

LCDR Fermín Argüello, M.D., MPH – Study design and analysisHal Margolis, M.D. – Dengue Branch Chief

CAPT Kay Tomashek, M.D., MPH – Epidemiology Chief

National Center for Emerging and Zoonotic Infectious DiseasesDivision of Vector-Borne Diseases — Dengue Branch

Deaths per Population, 2010

<1 1-4 5-9 10-14

15-19

20-29

30-39

40-49

50-59

60-69

70 +0

1

2

3

4

5

6

7

8

9

10

0.00

0.50

1.00

1.50

2.00

2.50

Age Group

Dea

ths

Deaths per 100,000 Individuals

Overall : 0.9 lab positive deaths per 100,000 individuals

Consecutive Infections, 2010

Age SexFirst Onset

Date Dx-1Second

Onset Date Dx-2

Interval between

events (days)

11 Male 12/10/2010 DENV-1 12/10/2010 DENV-4 0

12 Male 12/8/2010 DENV-1 12/8/2010 DENV-4 0

5 Male 8/9/2010 DENV-1 9/15/2010 IgM(+) 3766 Male 7/28/2010 DENV-2 9/22/2010 IgM(+) 56

22 Male 4/27/2010 IgM(+) 6/28/2010DENV-1, IgM(+) 62

34 Male 9/3/2010 DENV-2 12/6/2010 IgM(+) 9473 Male 8/16/2010 DENV-4 11/27/2010 IgM(+) 103

0.83 Male 7/10/2010 DENV-1 11/7/2010 DENV-4 120

16 Male 3/6/2010 DENV-1 8/14/2010 DENV-4 161

41 Male 12/30/2009 DENV-1 10/27/2010 DENV-4 301

Distribution of Aedes aegypti, 2007

Source: Chester G. Moore, Dept. of Microbiology, Immunology & Pathology, Colorado State

University

Distribution of Aedes albopictus, 2007

Source: Chester G. Moore, Dept. of Microbiology, Immunology & Pathology, Colorado State

University

Dengue incidence per 10,000 pop

1.16 - 16.33

16.34 - 27.41

27.42 - 42.97

42.98 - 161.33

Rates of Lab Positive Cases by Municipality, 2010

Dengue Incidence 10,000 pop

39.74 - 153.83

24.55 - 39.73

15.24 - 24.54

1.13 - 15.23123

Fatalities

Under-reporting of Dengue in Puerto Rico

Lack of reporting 10-27 symptomatic cases for every reported case in

1990’s• Failure of patients to present• Lack of clinical supicion• Failure of clinicians to report

Alternative methods of reporting Category-1 form Specimens sent off island for diagnostics (3 major

companies)• Company A: ~2,000 from June-December, 2010

Asymptomatic cases ≤ 90% of all infections

In total, we estimate that 5-10% of Puerto Ricans were infected in 2010 ~350,000 individuals

Accuracy of Enhanced Fatal Dengue Surveillance, 2010

Jan Feb Mar Apr May Jun Jul Aug Sep Oct Nov Dec0

2

4

6

8

10

12

14

16

0

500

1000

1500

2000

2500PendingNeg or IndetPositiveCases

Month, 2010

Dea

ths Cases

<1 1-4 5-9 10-14 15-19 20-29 30-39 40-49 50-59 60-69 70+0

5

10

15

20

25

30

35

DENV-1DENV-4DENV-2

Age Group

DHFC

ases

DHF Cases by Serotype, 2010

(n = 57)(n = 70)(n = 17)

DHF Cases by Serotype, 2010

DENV-1 DENV-2 DENV-40%

10%

20%

30%

40%

50%

60%Kids

Adults

Serotype

DH

F Ca

ses

(%)

(n = 92)

(n = 52)

DHF Cases per PopulationD

HF Cases per 1,000 Individuals<1 1-4 5-9 10-

1415-19

20-29

30-39

40-49

50-59

60-69

70 +0

10

20

30

40

50

60

0.00

0.05

0.10

0.15

0.20

0.25

0.30

0.35

Age Group

Coun

t DH

F Ca

ses

Overall : 6.7 lab positive DHF casesper 100,000 individuals

DHF Cases per DF CasesD

HF Cases per 1,000 D

F Cases<1 1-4 5-9 10-14

15-19

20-29

30-39

40-49

50-59

60-69

70 +0

10

20

30

40

50

60

010

20304050

6070

8090100

Age Group

Coun

t DH

F Ca

ses

Overall : 21.4 lab positive DHF cases per 1,000 lab positive cases

1 2 3 4 5 6 7 89 10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

36

37

38

39

40

41

42

43

44

45

46

47

48

49

50

51

52

0

200

400

600

800

1000

1200

Sus-pectedCon-firmed

Week of Onset

Sus

pect

ed C

ases

Suspected and Confirmed Cases by Week, 2010

Outbreak declaredFeb. 27, 2010

-2 0 2 4 6 8 10 12 Day of Illness

Critical Phase

Clinical Course of Dengue Infection

Mosquitobite

Acute Febrile Phase

Viremia

Convalescent Phase

Usually 3 to 5 days

1 to 3 days; usually <48 hrs

Range: 2 to 7 days; usually 3 to 5 days

* Typically uncomplicated DHF/DSS lasts for 10 to 12 days

Range: 3 to 14 d; usually 4 to 7 days

Incubation

WHO Dengue Case Definitions (1997)• Dengue fever (DF)

– Fever plus 2 of: headache, retro-orbital pain, myalgia, joint pain, bone pain, rash, bleeding, low WBC count

• Dengue hemorrhagic fever (DHF): – Fever, hemorrhagic manifestation(s),

thrombocytopenia (≤100,000 cells per mm³), plasma leakage

• Dengue shock syndrome (DSS):– DHF plus rapid, weak pulse and narrow pulse

pressure, OR DHF plus hypotension and cold, clammy skin and restlessness

Characteristics of the 2010 EpidemicSuspected

casesn = 23,622

Laboratory positive cases

n = 10,956

Laboratory negative cases

n = 2,588

Indeterminate cases

n = 9,999

Median age, years 18 18 18 18

Age range 5 days – 102 years

1 month – 102 years

17 days – 90 years

5 days – 100 years

Male, # (%) 12,720 (53.8) 6,061 (55.3) 1,313 (50.7) 5,298 (53.0)

Dengue fever, # (%) 17,035 (72.1) 8,844 (80.7) 1,756 (67.9) 6,401 (61.0)

Hospitalized*, # (%) 8,004 (58.7) 4,173 (66.0) 887 (57.4) 2,911 (54.5)

Hemorrhage, # (%) 6,989 (29.6) 3,773 (34.4) 753 (29.1) 2,394 (23.9)

DHF/DSS, # (%) 408 (1.7) 254 (2.3) 57 (2.2) 93 (0.9)

Deaths, # (%) 118 (0.5) 38 (0.3) 36 (1.4) 44 (0.4)

* denominator varies due to data availability

<1 1-4 5-9 10-14

15-19

20-29

30-39

40-49

50-59

60-69

70+0

100

200

300

400

500

600

700

800

900

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%DENV-1

Age Group

Hos

pita

lized

Cas

esAge Distribution of Hospitalized Cases,

2010Percent Serotype

<1 1-4 5-9 10-14

15-19

20-29

30-39

40-49

50-59

60-69

70+0

10

20

30

40

50

60

70

80

90

100Rates of Hospitalization by

Serotype, 2010 DENV-1DENV-4

Age Group

Hos

pita

lizat

ions

per

100

Infe

ctio

ns

Infecting Serotypes in Non-Hospitalized and Hospitalized Individuals, 2010

<1 1-4 5-9 10-14

15-19

20-29

30-39

40-49

50-59

60-69

70+0.0%5.0%

10.0%15.0%20.0%25.0%

Hospitalized

DENV-1DENV-4

Age GroupTota

l Inf

ectio

ns p

er

Sero

type

<1 1-4 5-9 10-14

15-19

20-29

30-39

40-49

50-59

60-69

70+0.0%5.0%

10.0%15.0%20.0%25.0%

Non-Hospitalized

DENV-1DENV-4

Tota

l Inf

ectio

ns

per

Sero

type

Hospitalization something or other, 2010

<1 1-4 5-9 10-14 15-19 20-29 30-39 40-49 50-59 60-69 70+0.0%10.0%20.0%30.0%40.0%50.0%60.0%70.0%80.0%90.0%

100.0%

Non-Hospitalized Cumulative

DENV-1DENV-2DENV-4

Age Group

Cum

ulat

ive

% H

ospi

taliz

ed

<1 1-4 5-9 10-14 15-19 20-29 30-39 40-49 50-59 60-69 70+0.0%10.0%20.0%30.0%40.0%50.0%60.0%70.0%80.0%90.0%

100.0%

Hospitalized Cumulative

DENV-1DENV-2DENV-4

Age Group

Cum

ulat

ive

% H

ospi

taliz

ed

DENV-1 74.1%

DENV-2

5.4%

DENV-420.5%

Infecting Serotype in Hos-pitalized Individuals, 2010

Acute specimens Are Representative of Hospitalization Rates of the Entire

Population

<1 1-4 5-9 10-14

15-19

20-29

30-39

40-49

50-59

60-69

70+0.0%

5.0%

10.0%

15.0%

20.0%

25.0%

RT-PCRIgMTotal

Age Group

Hos

pita

lized

*

*

* *

*

*^

*

* = sig diff of IgM from RT-PCR^ = sig diff of Total from RT-PCR

Dengue in Puerto Rico

• First major epidemics reported in 1915 and 1945

• In 1963, DENV first isolated in Puerto Rico

• There were six large, island-wide outbreaks between 1969 – 1986

• Two large outbreaks in 1990s (1994, 1998)

• In 2000s, one large outbreak in 2007 (all 4 serotypes) with 10,508 suspected cases or 3 cases per 1,000 − Over 50% hospitalized; 1/3 reported hemorrhage,

2% had DHF, and 44 died

Dengue in Puerto Rico

• Dengue is endemic in PR with seasonal pattern − Low transmission: March—June− Peak transmission: August—November

• Dengue is reportable by law in Puerto Rico• Suspected dengue cases are reported every

week to the Puerto Rico Department of Health; free diagnostic testing is done at CDC Dengue Branch in San Juan – Passive surveillance since 1969– Purpose of surveillance is to use data to guide vector

control and prevention efforts

1987

1989

1991

1993

1995

1997

1999

2001

2003

2005

2007

2009

0

1000

1500

2000

5000

6000

Denv-1Denv-2Denv-3Denv-4Marker

Number of dengue viral isolates by year in Puerto Rico, 1986-2006

RT-P

CR P

osit

ive

Case

s

Year

Sex Distribution of Lab Positive Cases and Deaths, 2010

Male55.3%

Female44.7%

Sex of Positive Cases(n = 10,936)

Male39%

Female61%

Sex of Positive Fatal Cases(n = 33)

Dengue Virus (DENV)• Single stranded RNA virus• Member of Flavivirus family

Selected Flaviruses

Tick-borne encephalitis virus

West Nile VirusMurray Valley Encephalitis VirusJapanese Encephalitis Virus

St. Louis Encephalitis Virus

DENV 1DENV 3

DENV 2DENV 4

Yellow Fever Virus

0 5 90yearsTime Post-Onset of Symptoms

IgGIgM

Virus

5Time Post-Onset of Symptoms

IgG

IgM

0 90years

Virus

Primary Dengue Infection Secondary Dengue Infection

Current Diagnostic Methods

IgM is not detectable ~20% of acute 2° cases

days days

Atypical Routes of Dengue Transmission

• Evidence of transmission of dengue through receipt of donor organs or tissue1

− Bone marrow, renal transplant• Transmission of dengue documented via receipt

of blood products (RBC transfusion)2,3

– Screening of PR blood bank donors found virus in 1 per 1,000 donors during a non-outbreak year4

• Seven reports of transmission after occupational exposure in a healthcare setting1

1 Wilder-Smith A, et al. ,Threat of Dengue to Blood Safety in Dengue-Endemic Countries. EID 2009; 15(1):8-11. 2 Chuang et al., Review of dengue fever cases in Hong Kong during 1998 to 2005. Hong Kong Med J 2008;14:170-177.3 Tambyah et al., Dengue hemorrhagic fever transmitted by blood transfusion. N Engl J Med 2008;359:1526-1527.4 Mohammed, H. et al. , Dengue Virus in Blood Donations, Puerto Rico, 2005. Transfusion 2008; 48:1348-1354.

Vertical Transmission of Dengue4

• Infrequent, but can occur in utero or during parturition – Rates may depend on severity of maternal infection

• Symptomatic congenital DENV infections had symptomatic mother with infection late in pregnancy or at delivery

• Average time between mom and newborn onset is 7 days

• Most congenital cases described had fever, thrombocytopenia and hepatomegaly– Hemorrhagic manifestation in half– Pleural effusion and/or rash in one quarter– Clinical presentation not associated with maternal immune

status or mode of delivery4Pouliot S.H., et al., Maternal dengue and pregnancy outcomes: a systematic review. Obstetr Gynecol Survey 2010.

Risk factors for Severe Dengue• Host factors

• Obesity1

• Chronic disease (diabetes, asthma)2

• Previous dengue infection1 • Age (infant)1

• Co-circulation of multiple serotypes in the same geographic region

• Level of neutralizing antibody• Timing of infection key as protective immunity wanes2

1 Scott Halstead (2008). Dengue. Tropical Medicine: Science and Practice. London: Imperial College Press.2Figueiredo MAA, et al. (2010) Allergies and Diabetes as Risk Factors for DHF. PLoS Negl Trop Dis 4(6): e699.

0100200300400500600700800900

1000

Rep

orte

d C

ases

(Tho

usan

ds)

Reported Cases of Dengue in the Americas, 1980 – 2008*

*Note: Reported cases as of January 27,2009 from Pan American Health Organization (PAHO)

Evaluation

Developer Producer Vaccine Type Phase 1Phase

2Phase

2b

Sanofi Pateur Sanofi PateurTetravalent

live-attenuatedchimera (YF17d)

2010(underway)

WRAIR GlaxoSmithKline

Tetravalentlive Attenuated ? 2010

NIH Buntantan

DENV-DENV (1,2,3)

Chimera + DENV-4

with gene deletion

2009(completed

in USA)2010

(Brazil)

CDC InViragen/SingVax

DENV-DENV (1,3,4)

Chimera + DENV-2 live attenuated

2010?

HawaiiBiotech

HawaiiBiotech

MonovalentRecombinant

Envelope subunit2009

(underway)

Current dengue vaccine candidates

Differential Diagnosis of Dengue

• Leptospirosis• Influenza• Malaria• Typhoid fever• Measles• Rubella• Rickettsial

infections (typhus, scrub typhus)

• Enterovirus• Meningococcemia• Bacterial sepsis• Chikungunya• West Nile Virus• Other viral

hemorrhagic fevers

Dengue Case Investigation Report

Life Cycle of Aedes aegypti

Eggs

Larva

Pupa

Adult

Female lays on average 100-120 eggs on inside of containers (above water) five times in her lifetime.

Eggs survive for up to 6 months and hatch when submerged in water (takes ~24 hours).

Approximately 6 days

2 days

Note: Fecundability dependent on environmental conditions such as rain, humidity and temperature. The total time for development is dependent upon water temperature and food supply, and typically ranges from 4 to 10 days. Larvae die at temperatures below 10 degrees and above 44 degrees Celsius.

Recent US Dengue Outbreaks 1980 – Texas 63 cases (23 no travel) 1986 – Texas-Mexico border 17 cases from

passive surveillance (9 no travel) 1995 – Texas 29 cases from active

surveillance (7 no travel) 1999 – Laredo, Texas 11 cases from active

surveillance (2 no travel) 2001 – Hawaii 165 cases via active

surveillance 122 no travel, 7 cases in visitors to Hawaii

2005 – Cameron County, Texas Active surveillance (24 cases, 2 no travel) Retrospective medical review (16 cases)

Leptospirosis Potentially fatal acute

febrile illnesses Clinical presentation similar to

dengue

Infection via exposure to animal urine Rats, dogs most common

Caused by Leptospira bacteria >200 serovars

Endemic in Puerto Rico Passive surveillance

Images: khmersong.info (top); (bottom).

Lepto Deaths and Dengue Cases by Month, 2010

Lepto Deaths

Jan Feb Mar Apr May Jun Jul Aug Sep Oct Nov Dec0

500

1000

1500

2000

2500

0

2

4

6

8

10Suspected lepto deaths*

Week of Illness Onset

Confi

mre

d De

ngue

Cas

es

Geographic Distribution of Leptospirosis Deaths, 2010

= 1 confirmed fatal case= 2 confirmed fatal cases

= 1 suspected fatal case

= 2 suspected fatal cases