Zika virus emergence in the A potential threat to Europe? · BNITM and altona Diagnostics (2016)...
Transcript of Zika virus emergence in the A potential threat to Europe? · BNITM and altona Diagnostics (2016)...
WHO Collaborating Centre for Arbovirus and Haemorrhagic Fever Reference and Research, Hamburg, GermanyNational Reference Centre for Tropical Diseases
Jonas Schmidt‐ChanasitRome 19.04.2016
Zika virus emergence in the Americas –A potential threat to Europe?
WHO statement, 1 February 2016
“The Committee advised that the recent cluster of microcephaly cases and other neurological disorders reported in Brazil, following a similar cluster in French Polynesia in 2014, constitutes a Public Health Emergency of International Concern (PHEIC).“
I. Surveillance for Zika virus infectionshould be enhanced
II. The development of new diagnosticsfor Zika virus infection should beprioritized
III. Vector control measures andappropriate personal protectivemeasures should be aggressivelypromoted and implemented
The number of suspected microcephaly cases in Brazil relied on a screening test that had very low specificity and
therefore overestimated the actual number of cases by including mostly normal children with small heads.
Victoria et al. (2016) Lancet
907 confirmed cases of microcephaly or other nervous system malformation among newborns have been reported
in Brazil since 22 October 2015.
PAHO (March 2016)
The increases of microcephaly cases in Pernambuco state, Brazil were registered 7‐8 months after the
first detection of Zika virus cases.
PAHO (March 2016)
1874
1924
2001
PYF
COK2013
NCL
2010
BRA
COL
GTM MTQ
2013
HTIMEX
2014
SUR
PRI
2014
2013
UGA
CAF
GAB
CIV
BFASEN THA
KHM
MYS
PHL
FSN
Cadar, BNITM (2016)
Spatiotemporal spread pattern of Zika virus based on analysis of NS5, envelope, and complete genome sequences
demonstrates recent introduction into Brazil.
DQ859059_1947_Uganda
KF383115_1968_Central African Republic
HQ234501_1984_Senegal
KF268949_1980_Central African Republic
KF383119_2001_Senegal
Brazil Central African RepublicCambodia Guatemala Haiti Malaysia Martinique MicronesiaFrench PolynesiaPuerto RicoSenegal Suriname Thailand Uganda
KF268950_1976_Central African Republic
KF268948_1976_Central African Republic
HQ234499_1966_Malaysia
EU545988_2007_Micronesia
JN860885_2010_Cambodia
KF993678_2013_Thailand
KJ776791_2013_French_Polynesia
KU647676_2015_Martinique
KU527068_2015_Brazil
KU321639_2015_Brazil
KU509998_2014_Haiti
KU501217_2015_Guatemala
KU501216_2015_Guatemala
KU365779_2015_Brazil
KU365777_2015_Brazil
KU365780_2015_Brazil
KU312312_2015_Suriname
KU501215_2015_Puerto Rico
KU365778_2015_Brazil
African lineage
Asian lineage
1501251007550250
Ongoing outbreakin Americas
Years Cadar, BNITM (2016)
So far, two genetic lineages are described : the African and the Asian lineage of Zika virus.
Congenital Zika virus infection and microcephaly
Mlakar et al. (2016) NEJM
enital Zika virus infection and fetal brain damage
risk of microcephaly increases to about 1% when mothers are ected with Zika virus during the first trimester of pregnancy.
e incidence of Guillain‐Barré syndrome cases during the French Polynesian outbreak was mated to be 0.24 per 1000 Zika virus infections.
e geographic distribution of GBS cases in alvador indicates that there is a spatial and mporal association with Zika virus cases.
HPs, African lineage of Zika virus achieved peak plasma at least one order of magnitude lower those observed in nimals infected with the Asian lineage of Zika virus.
Twenty‐two pregnant NHPs with and without pre‐existing anti‐dengue immunity will be inoculated with low passage
Asian and African lineage of Zika virus 15 days after insemination and monitored for birth defects.
BNITM and FIOCRUZ (2016)
0 14 21 30 54 140
ZIKV s.c. 106 and10515 days after insemination
Euthanasia and necropsy mother and offspring
Baseline valuesPregnancy confirmation Artificial Insemination
Delivery
108947 64 74 162dpi40 120 200dpi
⅓ amniocentesis ⅓ ⅓amniocentesis amniocentesis
sampling of blood, urine and sonography
‐ Does the observed association of Zika virus infection withmicrocephaly and GBS simply reflect an increasedincidence of infection or is it the result from a change invirulence or is it caused by co‐factors?
‐ Will Zika virus become endemic and an enzootictransmission cycle develop in the Americas ?
Urgent questions / tasks
‐4 0 7 14 21 28 60 120 240 480
symptoms
days after onset of symptoms
antib
ody titer
IgG
IgM
Course of Zika virus diagnostic parameters in flavivirus‐naive individuals.
ZIKV RNA
ZIKV RNA
urine
blood
BNITM (2016)
Dudley et al. (2016) bioRxiv
In NHPs, prolonged detection of viral RNA in urine and salivaafter clearance from the blood was demonstrated.
There is growing evidence of sexual transmission of Zika virus.
Ortenzio et al. (2016) NEJM
BNITM and altona Diagnostics (2016)
Development and evaluation of specific and sensitive CE‐IVD marked real‐time PCR test kits for Zika virus detection:
The limit of detection for Zika virus using the RealStar® Zika Virus RT‐PCR Kit1.0 is 0.61 copies/μl (95% confidence interval 0.39 to 1.27 copies/μl).
Viruses tested to demonstrate the analyticalspecificity of the RealStar® Zika Virus RT‐PCR Kit 1.0
Corman et al. (2016)
Most of the in‐house assays showed comparably high analytical sensitivity with around 5 copies per reaction.
Corman et al. (2016)
We projected the estimated risk of false‐negative test results for Zika virus RNA to 20% upon usage of highly sensitive assays with a detection threshold of 5 copies per reaction.
Development and evaluation of specific and sensitive CE‐IVD marked Zika virus ELISA:
BNITM and EUROIMMUN (2016)
IgM
IgG
Seroconversion panels confirmed the high sensitivity of the Zika virus ELISA:
BNITM and EUROIMMUN (2016)
Sample GenderAge in
years
Days after onset of
symptoms
PCR EUROIMMUN ELISA
Material Results
IgG (Ratio) IgG IgM (Ratio) IgM
pos: > 1,1 Results pos: > 1,1 Resultsbl: 0,8-1,0 bl: 0,8-1,0
patient 1 f 273 Serum pos.
17 2,2 pos. 4,8 pos.56 3,0 pos. 0,8 bl.
patient 2 7 1,3 pos. 4,0 pos.25 2,2 pos. 1,1 pos.
patient 3 m 45
3 Urine pos.4 0,1 neg. 0,2 neg.11 0,8 bl. 1,7 pos.26 2,1 pos. 1,6 pos.
patient 4 m 4 3 Urine pos. 0,1 neg. 0,4 neg.
patient 5 f 28 11 Urine pos. 2,6 pos. 7,5 pos.22 4,8 pos. 5,6 pos.
ka virus diagnostic algorithm in Germany
a virus diagnostic algorithm of the CDC
and laboratory findings of imported Zika virus infections diagnosed at e WHO CC until the beginning of the epidemics in the Americas.
y year clinical findings Zika virusdiagnostics reference
d November 2013
52‐year‐old woman,fever, polyarthralgia, rash
IgG+, IgM+, VNT+, RT‐PCR‐
Tappe et al. (2013) Eurosurveillance
December2013
31‐year‐old woman, fever, polyarthralgia, myalgia, rash,
Lymphopena, neutropenia
IgG+, IgM+, RT‐PCR+
Wæhre et al. (2014) Emerg Infect Dis
January2014
31 Jahre, weiblich, fever, polyarthralgia, rash, conjunctivitis, lymphadenopathy, Zahnfleischblutungen
IgG+, IgM+, qRT‐PCR+
Zammarchi et al. (2015) J Clin Virol
January2014
33‐year‐old man, fever, polyarthralgia, rash, conjunctivitis,
lymphadenopathy, leukopenia, thrombozytopenia
IgG+, IgM+, RT‐PCR‐
Zammarchi et al. (2015) J Clin Virol
a August 2014
45‐year‐old woman, fever, polyarthralgia, rash, conjunctivitis, IgG+, IgM+,
VNT+ PCR‐Tappe et al. (2015) Emerg Infect Dis
functional T cell activation was seen during the acute phase of virus disease (ZVD) characterized by respective cytokine level ses, followed by a decrease in the reconvalescent phase of ZVD.
IL-2
ormal Acute Recovery
*
IFN-g
Normal Acute Recovery0
100
200
300
400
500
pg/m
l
*IL-4
Normal Acute Recovery0
2
4
6
8
pg/m
l
*
IL-6
**
IL-13
20
40
60
80
pg/m
l
* *IL-17
50
100
150
pg/m
l
**
very from ZIKV infection is associated with restoration rmal numbers of immune cells in the periphery as well s with normal function of antigen‐presenting cells.
cells
T cells
CD4TCD8T
Naive C
D4Mem
ory C
D4Naiv
e CD8
Memory
CD8
ControlsZika
MFI 37/4 Bead uptake
Controls Zika0
10000
20000
30000
40000
MFI
FIT
C
Simple point‐of‐care diagnostics (Ag, Ab or RNA) will be needed.
Harmonization of VNTs (reference ZIKV strains?, PRNT50 or PRNT90, FRNTs, endpoint titration?)
Urgent questions / tasks
Aedes aegypti populations with widespread resistance to insecticides
ore than 19 mosquito species were und to be infected with Zika virus
portant intraspecies differences for the vector petence of Aedes aegypti and Aedes albopictus
14 days after oral exposure to ZIKV
uropean Aedes aegypti and Aedes albopictus pulations are competent vectors for Zika virus.
Aedes albopictus is an invasive mosquito species in Europe:
2010 2016
ECDC (2010 and 2016)
Luehken, BNITM (2016)
Modeling of suitable areas for Zika virus in Europe
Luehken, BNITM (2016)
The conservative model (28°C), demonstrates that costal areas of France, Italy, Greece, and
Turkey are suitable for Zika virus.
ZIKV + Ae.albopictus
ZIKV
Luehken, BNITM (2016)
The generous model (25°C), demonstrates that most parts of the Mediterranean countries are
suitable for Zika virus.
ZIKV + Ae.albopictus
ZIKV
- May
Infection of Aedes aegypti (lab strain) and Culex pipiens (lab strain)
Infection18, 21, 23, 25°C
Collection of Culex torrentium, Aedes
vexans, Aedes albopictus, and Aedes japonicus
eggs
Breeding
sampling 0,4,7,14,21 dpi
RNA isolation of all samples & qPCR analysis
TCID50
April June - August September - December 2017
Publishing results
Indigenous and invasive mosquito species from Germany will be infected with low passage Asian and African lineage of Zika
virus and tested for virus replication and transmission.
Heitmann and Jansen (2016) BNITM
Returning viremic travellers may ignite autochthonous infections in European countries. Therefore, it will be important to enhance vigilance towards the early detection of imported cases of ZIKV infection in Europe,
in order to reduce the risk of autochthonous transmission.
„Mit der Meldepflicht für Arbovirensorgen wir außerdem dafür, dassetwa eine Zika‐Infektion beiReiserückkehrern in Deutschlandbesser überwacht werden kann.Damit gewinnen dieGesundheitsämter vor Ort wertvolleZeit zum schnellen Handeln."
Hermann Gröhe ‐ Minister of Health, Germany
Targeted and sustainable vector control measures
Is Zika virus able to infect and be transmitted by other mosquito genera (e.g. Culex, Mansonia, Anopheles) ?
Urgent questions / tasks