Zika Virus Vectors and
Reservoirs
Scott C. Weaver
Institute for Human Infections and Immunity
and Department of Microbiology and
Immunology,
University of Texas Medical Branch,
Galveston
Discovery of enzootic Zika virus
transmission focus, 1947-48
Discovery Timeline of Zika Virus and
Human Disease
•
1937-1947: Rockefeller Foundation efforts to identify the
sylvatic or enzootic vector in Uganda, Yellow Fever
Research Institute, Entebbe, Uganda
•
1947: Caged sentinel Rhesus monkeys placed on platforms
in the Zika Forest canopy. One animal developed a 39.7°F
fever and Zika virus was isolated from the serum on the
third day of fever via intracerebral inoculation of infant mice
•
1948: Zika virus was isolated from Aedes africanus
mosquitoes collected in the same forest
•
1954: ZIKV was isolated from the serum of a febrile girl in
Nigeria, and infection was confirmed in 2 other persons by
seroconversion
•
1956: Experimental human (yellow-fever vaccinated)
infection confirmed flu-like illness with headache, fever,
malaise, nausea
•
1966: ZIKV isolated from A. aegypti mosquitoes in Malaysia
•
1977: First human infections in Asia described in Indonesia
Serologic Evidence of ZIKV
Distribution until 2007
Serologic evidence
Virus detection or confirmed human case
Quartet of arboviruses in West Africa with history
of urban emergence: yellow fever, dengue,
chikungunya, Zika
Amplification
periodicity: 7-8
years except Zika
A. furcifer
A. taylori
A. luteocephalus
A. furcifer
Patas, African
green monkeys,
Guinea baboon
A. aegypti
A. albopictus
Emergence into the urban transmission cycle:
Comparisons with DENV, CHIKV, YFV
1. Yellow fever virus: Originated in Africa, emerged into human
cycles following the domestication of A. aegypti; transport of A.
aegypti and infected persons aboard sailing ships, especially
during to the slave trade, resulted in regular introductions into the
Americas and establishment of spillback enzootic circulation (but
why not in Asia?)
2. Dengue viruses: Originated in Southeast Asia, diversified into 4-5
serotypes while still in the enzootic cycle (possibly selected by
immune enhancement). Enzootic spillover and emergence into
the human cycles followed by transport to the Americas centuries
ago; spillback of DENV-2 into an enzootic cycle in West Africa
(but why not in the Americas?)
3. Chikungunya virus: Originated in Africa and emerged repeatedly
into the urban cycle following the domestication of A. aegypti;
transport along with infected persons aboard sailing ships
resulted in regular introductions into Asia and the Americas but no
documented establishment of enzootic circulation outside of
Africa.
J. E. Bryant, et a., PLoS Pathog 3, e75 (2007); E. Wang et al., J. Virol. 74, 3227-3234 (2000); S. M. Volk et al., J. Virology 84, 6497-6504 (2010). S. B.
Halstead, Emerg Infect Dis 21, (2015).
Risks for ZIKV Spillback into
Permanent Enzootic Cycles
Enzootic yellow fever
Physical Map of the World, April 2008
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St.Lawrence
Lake
Huron
Ottawa
FINLAND
Gulf
of
Bothnia
Stockholm
Lake
Winnipeg
Tijuana
ISLAS
REVILLAGIGEDO
(MEXICO)
White Sea
SWEDEN
(DEN.)
Oslo
Labrador
Sea
Lake
Superior
(U.S.)
F r e n c h
Tórshavn
Rockall
R
IF
T
D
e
a
t
h
V
a
lle
y
(
lo
w
e
s
tp
o
in
tin
N
o
r
t
h
A
m
e
ric
a
,8
6
m
)
180
ARCTICOCEAN
NEW SIBERIAN ISLANDS
LaptevSea
A
r
c
tic
C
ir
c
le
(
6
6
°
3
3
')
NORWAY
Faroe
Islands
Reykjavík
Edmonton
T
r
o
p
ic
o
fC
a
n
c
e
r(
2
3
°
2
7
')
Papeete
(NORWAY)
ICELAND
Denmark
Strait
Nuuk (Godthåb)
(U.K.)
Los Angeles
Honolulu
(Fr. Poly.)
150
120
SEVERNAYA
ZEMLYA
Norwegian
Sea
Jan Mayen
Davis
Strait
Hudson
Bay
CANADA
S
IN
A
T
N
U
O
M
San Francisco
HAWAIIAN
ISLANDS
SOCIETY
ISLANDS
90
KaraSea
NOVAYA
ZEMLYA
(NORWAY)
G
R
E
A
T
Y
K
C
O
R
NORTH
Johnston Atoll
60
FRANZ JOSEF
LAND
Svalbard
BarentsSea
Baffin
Island
Great
SlaveLake
30
(N.Z.)
(DENMARK)
Vancouver
Seattle
(U.S.)
30
Longyearbyen
Greenland
Bay
Great
Bear Lake
Whitehor se
Gulf of Alaska
PACI FI C
Niue
(N.Z.)
0
ARCTIC OCEAN
Greenland Sea
Baffin
A
r
c
tic
C
ir
c
le
(
6
6
°
3
3
')
U. S.
M
t
.M
c
K
in
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y
(
h
ig
h
e
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in
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N
o
rt
h
A
m
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ric
a
,6
1
9
4
m
)
Anchor age
OCEAN
Kiritimati
(Christmas Island)
(KIRIBATI)
30
ISLANDS
Banks
Island
Victoria
Island
LANDS
N IS
ALEUTIA
K I R I B A T I
60
Ellesmere
Island
QUEEN ELIZABETH
Beaufort Sea
Barrow
60
0
90
120
ARCTICOCEAN
Scale 1:35,000,000
Robinson Projection
standard parallels 38°N and 38°S
R
B
e
r
m
u
d
a
M
ID
-A
TL
A
N
T
IC
AUSTRALIA
Sicily / AZORES
O
N
A
L
IP
T
L
A
• Yellow fever virus: ½ (Americas but not
Asia)
• Dengue viruses: ½ (Africa for DENV-2,
none detected in the Americas)
• CHIKV: 0/2 (none detected in Asia or the
Americas)
• Zika virus? No direct evidence in Asia
but virtually surveillance
But independent enzootic circulation is
difficult to distinguish from temporary
spillback unless sufficient genetic
divergence between enzootic and
human strains is detected, or
epizootics in nonhuman primates
0
30
60
90
120
150
180
(N.Z
Phylogenetic Tree of Zika Virus Strains
BR/ZIKV/BeH815744/2015
Zika Virus probably
originated in Africa
BR/ZIKV/BeH818995/2015
BR/ZIKV/BeH819966/2015
SR/ZIKV/Z1106033/2015
BR/ZIKV/BeH819015/2015
PR/ZIKV/PRVABC59/2015
GT/ZIKV/103344/2015
Americas,
2015
GT/ZIKV/8375/2015
BR/ZIKV/Natal_RGN/2015
HT/ZIKV/1225/2014
Asian/Am
erican
lineage
BR/ZIKV/SPH2015/2015
French Polynesia, 2013
Cambodia, 2010
FM/ZIKV/MICRONESIA/2007 Yap, 2007
MY/ZIKV/P6_740/1966
Malaysia, 1966
PF/ZIKV/HPF/2013
KH/ZIKV/FSS13025/2009
SN/ZIKV/DakArD7117/1968
SN/ZIKV/DakAr41519/1984
SN/DakAr41671/1984
SN/ZIKV/DakAr41525/1984
SN/ZIKV/DakAr41662/1984
SN/ZIKV/DakAr41666/1984
SN/ZIKV/DakArD128000/1997
NG/ZIKV/IBH30656/1968
African
lineage
CF/ZIKV/DakArB13565/1976
CF/ZIKV/DakArB7701/?
CF/ZIKV/DaKArB15076/?
SN/ZIKV/DakArD157995/2001
UG/ZIKV/MR766/1947
NG/SPOV/CHUKU/1952
ZA/SPOV/SM6_V1/?
SN/KEDV/DakArD14701/1972
0.2
African
sister
flaviviruses
Historic and Recent History of
Zika Virus Spread and Epidemics
2015
2007
2013
2015
2015
2007
2014
Outbreaks
Serologic evidence
Virus detection or confirmed human case
2013
2014
Hypotheses For the Recent
ZIKV Emergence
1. ZIKV underwent adaptive evolution to enhance infectivity of urban
Aedes (Stegomyia) spp. vectors (like chikungunya virus, in which
the Indian Ocean lineage underwent a series of A. albopictus-adaptive
mutations from 2005-2009.
2. ZIKV underwent adaptive evolution to enhance human viremia
(which would not only enhance transmission efficiency, but could
increase the risk of transplacental fetal transmission).
3. The stochastic introduction of ZIKV into naïve populations in the South
Pacific allowed for sufficient levels of amplification to facilitate the
introduction into Brazil (assisted by increased global travel, expansion
of tropical cities and A. aegypti populations; i.e. no change or
difference among ZIKV strains in epidemic potential or
virulence). The Cape Verde epidemic, with A. aegypti transmission, if
confirmed to be caused by an African ZIKV lineage strain, would
support hypothesis 3.
K. A. Tsetsarkin et al., Nature Comm 5, 4084 (2014).
Why have major outbreaks of ZIKV infection
never been detected in Africa or Asia?
1. Epidemics occur in Africa and Asia but remain
undetected due to difficulty in clinical diagnosis and lack
of specific diagnostics for flaviviruses
2. Relatively constant levels of enzootic spillover and/or
endemic human-mosquito-human transmission result in
relatively constant levels of infection that remain
undetected due to lack of surveillance and ZIKV
diagnostics; microcephaly could also be overlooked
under these circumstances or be rare due to immunity in
women of child-bearing age
3. ZIKV strains in Africa and Asia that did not undergo
vector- or human-adaptive evolution have lower
efficiency of transmission and epidemic potential
(<R0)
Acknowledgements
Rubing Chen, Robert Tesh, Nikos Vasilakis
Kathy Hanley
Derek Cummings
Ben Althouse
Amadou Sall
Doug Watts
Mawlouth Diallo
Funding: NIH-NIAID R01-AI069145, R01-AI071192, R01-AI48807