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Dengue - A Virus Without Borders
Department of Pathology
Center for Biodefense and Emerging Infectious Diseases
Institute for Human Infections and Immunity
Center for Tropical Diseases
Nikos Vasilakis, PhD
Rural settlement near Ngari, Senegal
Brazil - UTMB : A Long Relationship
Adapted from: Morens, Folkers & Fauci. Nature 2004
H1N1
influenza
Global Pathogen Emergence
Global Aviation Network
Hufnagel L et al. PNAS 2004;101:15124-15129
©2004 by National Academy of Sciences
Dengue Emergence
Spillover in sylvatic habitats
e.g. eastern Senegal
Urban dengue
Ae. aegypti
Ae. albopictus
Throughout
the tropics
and
subtropics
Malaysia,
West Africa
Arboreal Aedes spp.
Dengue Emergence
Urban dengue
Ae. aegypti
Ae. albopictus
Throughout
the tropics
and
subtropics
Spillover in sylvatic habitats
e.g. eastern Senegal,
Nigeria, peninsular Malaysia
Malaysia,
West Africa
Arboreal Aedes spp.
DomRep1981 Thai/734/00
Th0/348/91 Thai/0485/01
Thai/87/77 Thai/476/97 Thai/179/97
Mal/P75-215/75 BFaso/1349/82
Austral/TSV01/93 China/FJ11/99 Thai/1974 Thai/38/1974
Thai/NH73/93 Thai/NH36/93
Thai/NH55/93 Thai/17/98 Thai/78/01 Thai/C0167/96
Thai/263/95 Thai/K10/94 Thai/55/99
Thai/26/88 Thai/433/85
Thai/NHp14/93 Thai/168/79 Thai/498/84
Thai/16681/64 NGuinea/NGC/44
Braz/64022/98 Ven/Mara4/90 Mart/1998
Jam/N1409/83 Chin/04/85
Thai/284/90 Peru/1950/95 Peru/291396
Peru/1797/95 Ven/131/92
Ven/2/87 PRico/1328/77
Bfaso/2039/80 ICoast/A1247/80 Bfaso/A2022/80 ICoast/A510/80 ICoast/578/80 Guin/PM33974/81
Sen/319/99 Sen/320/99
Sen/5505/91 Nig/1208/66 Nig/11664//66 Nig/11234/66 Sen/20761/74 Sen/A10674/70
Mal/P81407/70
Mal/P72-1244/72 Thai/0673/80 Thai/0442/80
FrGuiana/89 Braz/90
Braz/111/97 Braz/233/97 Braz/MR/01 Parag/259/00
Argen/297/00 Argen/293/00
ICoast/Abidjan/98 Thai/0488/94 Thai/0097/94
Sing/S275/90 Thai/0102/91 Thai0049/01
Thai/0336/91 Thai/0323/91
Djibouti/98 Chin/Guangzhou/80 Thai/0081/82 Thai/0008/81
Jap/Mochizuki/43 Indon/A88/88
Thai/1687/98 Thai/1283/98
Thai/0104/93 Thai/0055/93
Thai/0007/87 Thai/0010/87
Martin/99
Phil/H87/56
DENV-1
Sylvatic
Human
Sylvatic
Human DENV-3
Sylvatic
Human
DENV-2
Sylvatic
Human DENV-4
5% nucleotide
Sequence divergence
MRCA≤1000
years ago
MRCA≤600
years ago
MRCA≤200
years ago
SriL/00
94
100
97
97
97
94
94
90
Ancestral
Sylvatic DENV
in Asia
Chen & Vasilakis (2011) Viruses 3:1562-1608
Global Dengue Virus Distribution - 1960
DENV-1 DENV-2 DENV-3 DENV-4
DENV-1 DENV-2
DENV-1 DENV-2
Global Dengue Virus Distribution - 2010
DENV-1 DENV-2 DENV-3 DENV-4
DENV-1 DENV-2 DENV-3 DENV-4
DENV-1 DENV-2 DENV-3 DENV-4
DENV-1 DENV-2 DENV-3 DENV-4
DENV-1 DENV-2 DENV-3 DENV-4
DENV-1 DENV-2 DENV-3
Dengue in Brazil : 1986 -2010
Range of Dengue Disease DENV inoculation
asymptomatic infection symptomatic infection
fever, myalgia, arthralgia, nausea,
vomiting, headache, rash
hemorrhagic manifestations
skin hemorrhages, gingival bleeding and epistaxis,
gastrointestinal bleeding, menorrhagia
dengue fever
without hemorrhage
DF
undifferentiated fever
dengue fever with hemorrhage
DF severe hemorrhagic disease
plasma leakage, liver enlargement, circulatory failure
dengue hemorrhagic fever
DHF
grades I and II
Shock
dengue shock syndrome
circulatory failure, shock
DSS
grades III and IV
Dengue in Brazil : Epidemic of 2008
Ernesto Marques, MD/PhD, FIOCRUZ, Recife
Ernesto Marques, MD/PhD, FIOCRUZ, Recife
Dengue Incidence Rate in Brazil
Dengue Transmission Cycle
Vasilakis etal. (2011), Nature Reviews Microbiology 9:532-541
Was human dengue emergence
mediated by adaptation to the
peridomestic mosquito vectors,
Aedes aegypti and Ae. albopictus,
and/or human reservoir host ?
Dengue Emergence in Peridomestic
Mosquitoes
Sylvatic versus Endemic: t-test; P > 0.5
% m
osq
uit
oes w
ith
dete
cta
ble
vir
us i
n s
ali
va
Hanley et al. PLoS Negl. Trop. Dis. (in peer review)
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a Groups of SCID-Huh-7 mice were inoculated into the tumor with 4.0 – 4.2 log10 ffu of the indicated virus. Serum was collected on day 7 and virus titer was determined on C6/36 cells b Indicates the country and year that virus strain was isolated c ‘Endemic’ denotes human or Ae. aegypti isolates or strains that are associated with peridomestic transmission d Virus titer in serum was determined by focus forming immunoassay (FFA) in C6/36 cells e The limit of detection of the assay is 0.5 ffu/ml f Mean peak titers were assigned to statistical groups using one-way ANOVA, df = 5; F=25.6; P<0.0001 and the Tukey-Kramer post hoc test (P < 0.05). Groups with the same letter designation
are not significantly different; all means not sharing a letter are significantly different.
Vasilakis et al. (2007). Virology 358:402-412
n = 7
n =
7 n = 6
n = 6
n = 6
n = 6
A
B, C
D
C, E
A, B
D, E
Dengue Emergence in Vertebrate Hosts :
in vivo
a moDCs (2.5 x 105 per sample) from two healthy human volunteers were infected with an MOI = 2 of the indicated virus. Supernatants were collected 48 hrs p.i. and viral output was
determined on C6/36 cells b Indicates the country and year that virus strain was isolated c ‘Endemic’ denotes human or Ae. aegypti isolates or strains that are associated with peridomestic transmission d Virus titer in serum was determined by focus forming immunoassay (FFA) in C6/36 cells e The limit of detection of the assay is 0.5 log10 ffu/ml f Mean peak titers were assigned to statistical groups using the Tukey-Kramer post hoc test (P < 0.05). Groups with the same letter designation arenot significantly different; all means not
sharing a letter aresignificantly different. Unpaired t-test endemic versus sylvatic using mean values from 4 endemic and 6 sylvatic: df = 8; t = 1.35; P = 0.21
Vasilakis et al. (2007). Virology 358:402-412
A A
B
B
B
B B
B
C C
Dengue Emergence in Vertebrate Host :
ex vivo
Human dengue emergence was
NOT mediated by adaptation to
the peridomestic mosquito vectors,
Aedes aegypti and Ae. albopictus,
or human reservoir host !!
Do Evolutionary Processes among
Sylvatic DENV-2 Facilitate Emergence?
Adapted from: Vasilakis et al. (2007). J. Virol. 81:9591-9595
Can Sylvatic Dengue Re-emerge ??
Sylvatic Dengue in West Africa
Only DENV-2 has a sylvatic focus in West Africa Cornet, etal. (1979, 1984). Saluzzo etal. (1986)
Oscillating periodicity of sylvatic amplification cycles
(1974, 1980-1982, 1989-1990, 1999-2000) Diallo etal (2003)
Unlike other arboviruses, rainfall amount and distribution have no correlation
with sylvatic DENV emergence Davies et al. (1985). Linthicum et al. (1999). Diallo et al. (2003)
Virus circulates in peridomestic habitats, but no recorded clinical cases:
- virus is confined to the forest, or
- if human/mosq/human transmission occurs, its levels are low and
asymptomatic
Do unrecognized,
spillover epidemics are caused by sylvatic DENV-2 strains in
West Africa??
Vasilakis, Tesh and Weaver (2008). EID 14:502-504
DENGUE VIRUSES FROM FEBRILE PATIENTS IN NIGERIA,
1964-1968 D.E. CAREY, O.R. CAUSEY, S. REDDY AND A.R. COOKE LANCET 1971 1(7690);105-106
Can Sylvatic Dengue Re-emerge ??
Documented Human Sylvatic Cases in Africa
1970: 6 yr old girl living in Bandia prefecture, Senegal. (Robin etal. ‘Isolement du virus dela dengue au Senegal’. Ann. Virol. 1980 131:149-154)
1983: Caucasian scientist while investigating the 1983 amplification
cycle in SE Senegal. Severe clinical presentation.
1983: Caucasian tourist returning from Casamance. Classic DF clinical
presentation. (Saluzzo etal. ‘Isolation of dengue 2 and dengue 4 viruses from patients in Senegal’. TRSTMH 1986 80:5)
1990: 31 yr old Caucasian returning from military manoeuvres in
eastern Senegal. (Monlun etal. ‘Caracteres cliniques et epidemiologiques de la dengue 2 au Senegal’. Med. Mal.
Infect. 1992 22:718-721)
1990: 15 yr old Senegalese boy living in the vicinity of Kedougou presented with malaria-like disease & arthralgia lasting one month (Monlun etal. ‘Caracteres cliniques et epidemiologiques de la dengue 2 au Senegal’. Med. Mal. Infect. 1992 22:718-721)
2009: 27 yr old Guinea Bissau native returning to Spain via Dakar. First documented DHF case in Africa due to sylvatic DENV infection. (Franco etal. ‘First report of sylvatic DENV-2 associated with dengue hemorrhagic fever in West Africa’. PLoS NTD 2011 accepted for publication)
Can Sylvatic Dengue Re-emerge in Africa??
Human Prevalence
Vasilakis, Hanley, and Weaver (2010) In: Frontiers in Dengue Virus Research. Caister Academic Press (Hanley & Weaver, Eds).
Can Sylvatic Dengue Re-emerge in Africa??
Geographic Range of Vector and NHP
Vasilakis etal. (2011), Nature Reviews Microbiology 9:532-541
Can Sylvatic Dengue Re-emerge in Asia??
Human Exposure
Vasilakis, Hanley, and Weaver (2010). In: Frontiers in Dengue Virus Research. Caister Academic Press (Hanley & Weaver, Eds).
Can Sylvatic Dengue Re-emerge in Asia??
Geographic Range of Vector and NHP
Vasilakis etal. (2011), Nature Reviews Microbiology 9:532-541
Does the presence of pre-existing
antibodies to endemic DENV in the
human population could influence
the re-emergence of sylvatic DENV ??
Homotypic and Heterotypic Sylvatic Neutralization
of DENV-2 Sera at Day 42 Post Vaccination
Vasilakis et al. (2008). Am. J. Trop. Med. Hyg. 79:128 - 132
Homotypic and Heterotypic Sylvatic DENV-4
Neutralization of Convalescent Patient Sera
Durbin etal. In peer review, EID
Strong homotypic neutralization of sylvatic strains
Strong homotypic neutralization could explain the periodicity of sylvatic
amplification cycles and absence of epidemics in the human population
Should a licensed vaccine lead to the eradication of the endemic
transmission cycle in the future, re-emergence of sylvatic strains into
the endemic cycle would be limited by sterilizing homotypic immunity
Role of Pre-existing DENV Abs in Emergence
of DENV
Re-emergence Potential and Implications
for Public Health
Re-emergence of current sylvatic DENV can pose a major public health
problem
Success of programs to reduce or eradicate dengue from human
populations utilizing vector control programs or vaccination may be
short-lived
Success of such programs would hinge on sustainable vaccination AND
vector control programs to reduce the endemic vector mosquitoes
If endemic transmission cycle is eradicated, cessation of anti-dengue
measures for a sufficiently long time could lead to the rise of susceptible
human populations, as well as, the establishment of adequate
populations of endemic vector mosquitoes
Sylvatic DENV in the Americas?
Vasilakis etal. (2011), Nature Reviews Microbiology 9:532-541
Hemagogous janthinomys (S. America?)
Aedes mediovittatus (S. America?)
Assess the risk that they pose to contemporary human
populations
Ecological studies of the identity of the vertebrate hosts
of sylvatic DENV, their role in the maintenance and
amplification of these viruses
Better diagnostic assays
And Now What?
Acknowledgements
Financial Support:
Department of Pathology
DARPA PROPHECY - DARPA-BAA-10-93 NIAID/CPCIDB - HHSN272200800048C
CDC Fellowship Training Program in Vector-Borne Infectious Diseases, T01/CCT622892
Institut Pasteur de Dakar
Senegal Mawlouth Diallo, PhD
Amadou A. Sall, PhD
University of Buea
Cameroon Eric B. Fokam
CDC, PR Jorge Munoz-Jordan, PhD
NIH Brian Murphy, MD
Steve Whitehead, PhD
NMSU Kathryn A. Hanley, PhD
JHSPH Anna Durbin, MD
Duke/NUS Eng Eung Ooi, MD
Instituto Nacional de Salud
Publica, Mexico Jose Ramos-Castaneda, PhD
UNIMAS, Malaysia Mary Jane Cardosa, PhD
Weaver Lab Eleanor Deardorff, PhD
Shannan Rossi, PhD
Joan Kenney, MPH
Wenli Kang
Anonymous Blood Donors
World Reference
Center for
Emerging Viruses
and Arboviruses Bob Tesh, PhD
Hilda Guzman
PSU Eddie Holmes, PhD
Vasilakis Lab Evgeniya Volkova, MSc
Sandra Mayer, DVM
FIOCRUZ, Recife E.T. Marques, MD/PhD
Marli Tenorio, PhD
Laura Gil, PhD
FAMERP, São Jose do Rio
Preto Mauricio L. Nogueira, MD/PhD