mers-cov, the story - sciensano · mers-cov (hcov-emc, ncov) summary geographic situation human...
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MERS-CoV, the story
Chantal Reusken, [email protected]
Case report (sept 2012)
Zaki et al NEJM 2012
Van Boheemen et al., mBio 2012
60 year-old Saudi male
Fever, cough, expectoration, shortness of
breath
Body temperature 38,3 oC
Pneumonia
Impairment of renal function
Co-morbidities including bacterial
infections
Identification novel ß-coronavirus
MERS-CoV (hCoV-EMC, nCoV)
Summary geographic situation human MERS.
autochtonous
travel-related
Status as of May 16, 2016: 1733 confirmed with 628 deaths
27 countries
travel-related,
limited local transmission
travel-related outbreak
Cluster UK
nCoV-EMC
Retrospective
Jordan cluster
Cluster Jeddah / Abu Dabi
Current rise ?
Cluster Korea
Weekly distribution MERS cases.
Period March 2012 – 13 May 2015
Cluster Riyadh
Peak spring 2014?
increased surveillance? Change case definition
increased nosocomial transmission?
increased virus transmissibility?
diagnostic lab artifact?
increased zoonotic transmission (increase primary cases)?
Jeddah
Riyadh
WHO mission 2014: severe lack/breach IPC measures
Drosten et al., CID 2015.
No evidence for contamination in Jeddah laboratory.
Phylogenetic and phenotypic analysis Jeddah and Riyadh circulating strains
biologically unchanged viruses
Jeddah: vast majority nosocomial transmission
Riyadh: multiple independent sources (zoonotic, human import other regions, nosocomial)
Median age 45 yrs
Male 68.2%
Asymptomatic 25.1%
Symptomatic:
Mortality 36.5%
HCW 20.9%
Non-HCW 97.3% contact
clinic/conf./resp. ill
2.7% no contact
N = 255
Oboho et al., NEJM 2015
H2H transmission, amplification in health care facilities
No evidence for sudden increase in primary cases; exposure to animals was not assessed in this study!
Cluster Korea
Weekly distribution MERS cases.
Period March 2012 – 13 May 2015
Korea
increased surveillance?
increased nosocomial transmission?
increased virus transmissibility?
diagnostic lab artifact?
increased zoonotic transmission (increase primary cases)?
Lee and Wong, Int. J. Infec. Dis. 2015
20 May 2015
Korea
30 June 2015
186 cases
Index case
Korea
increased surveillance?
increased nosocomial transmission?
increased virus transmissibility?
diagnostic lab artifact?
increased zoonotic transmission (increase primary cases)?
- No evidence for changed properties virus
- After onset of illness: 9 days before diagnosis
- Tradition: Doctor shopping
- Overcrowed ER, hospital rooms
- Risk procedures in crowded rooms
- Tradition: Family and friends
Weekly distribution MERS cases.
Period March 2012 – 13 May 2015
Cluster Riyadh
Cluster Riyadh
Source: ECDC
WHO mission: “overcrowded
conditions, movement of patients who
were infected but did not yet have a
diagnosis, and some breakdowns in
the application of infection prevention
and control (IPC) meaures””.
3 sept 2015, IHR emergency committee on MERS-CoV:
“insufficient awareness about the urgent dangers posed by this virus,
insufficient engagement by all relevant sectors,
insufficient implementation of scalable infection control measures,
especially in health care settings such as emergency departments””
“progress is not yet sufficient to control this threat ”
“The Committee further noted that its advice has not been completely
followed. Asymptomatic cases that have tested positive for the virus are not
always being reported as required. Timely sharing of detailed information of
public health importance…………remains limited and has fallen short of
expectations.
Inadequate progress has been made…………….
The Committee was disappointed at the lack of information from the animal
sector. ”
MERS-CoV zoonotic transmission from bats?
MERS-CoV is phylogenetically related to bat CoVs (A)
and replicates in a range of bat cell lines (B), in contrast to
SARS-CoV (Van Boheemen et al., mBio 2012; Muller et al., MBio 2014)
A
Source: _ Memish et al., Middle East respiratory syndrome coronavirus in bats, Saudi Arabia. Emerg. Infect. Dis. November 2013
* 181 nt fragment in conserved RdRp
* Only 1 bat
* Sequence identical to strain provided as control.
• No other fragments generated incl with WHO advised tests.
Bats: possible primary reservoir
for MERS - CoV
Intermediate hosts of MERS- CoV
Deeper virus origins
Unlikely that bats are the immediate contact for the human cases as
human contacts with bats occurs with relatively low frequency.
Plausible a spillover from bats to humans through intermediated species
(e.g. domesticated or agricultural animals).
MERS-CoV binding region of DPP4
susceptible hosts ?
non susceptible hosts ?
Raj et al., Nature 2013
Raj et al., JV 2014
Eckerle et al., EID, 2014
v. Doremalen et al., J. Virol 2014
Haagmans et al., JV 2015
Haagmans et al., Science 2016
Phylogenetic analysis of the virus binding region of DPP4 indicated that small
animals including ferret and mice are more divergent in the DPP4 virus binding
region and these animals not susceptible for MERS-CoV infection
Livestock
Reusken et al., Eurosurveillance 2013
Hemida et al., Eurosurveillance 2013
Perera et al., Eurosurveillance 2013
Alexandersen et al., Transbound Emerg. Dis, 2014
Alagaili et al., Mbio, 2014
Meyer et al., EID, 2015
N = 346; Egypt, Jordan, KSA, UAE
N = 244; Egypt, Jordan, KSA
N = 84; Egypt, Jordan, KSA
N = 8; Egypt
N = 240; KSA
N = 192; UAE
No evidence for MERS-CoV
Case-control study (Alradaddie et al, 2015) :
no significant more risk when in contact with goat, sheep, horses
Peak spring 2014?
Reusken et al.,2013, the Lancet ID
Raj et al., EID, 2014 Haagmans et al., LID, 2014
MERS-CoV outbreak human and camels same barn Qatar
MERS-CoV isolate camel Qatar
molecular and serology evidence
serology evidence
primary/secondary cases
import/secondary cases
SAU
ARE
QAT
ETH
EGY
NGA
KEN
JOR
KWT
ESP
TUN
SDN
OMN YEM
IRN
LBN
DZA
SOM
ISR
Dromedaries as source for MERS-CoV
TUR
a.o. :
Reusken, 2013, 2014
Perera 2013
Hemida 2013, 2014
Haagmans 2014
Alexandersen 2014
Alagialli, 2014
Nowotny 2014
Meyer 2014
Memish 2014
Corman 2014
Chu 2014
Azhar 2014
Wernery, 2015
Farag, 2015
PKN
Evidence: since at least 3 decades
More virus less antibody pos in young
Overall > 80% seropos
Evidence for time-limited infection, re-infection
population serology
Mackay and Arden, Virus Research, 2015
Butchering/
Do people with daily exposure to camels/ camel
products have a higher risk for MERS-CoV infection
than people without camel contact?
Camel Human ?
HCoV-OC43 S1 array
B C E F G1 G2 H I J0
20000
40000
60000
80000
human cohorts
RF
U
SARS-CoV S1 array
A B C D E F G1 G2 H I J0
20000
40000
60000
80000
human cohorts
RF
U
NL / GER QAT non-camel
QAT camel NL / GER QAT camel
QAT non-camel
MERS-CoV S1 array
A B C D E F G1 G2 H I J0
20000
40000
60000
80000
human cohorts
RF
U
N=20 (20/294)
Confirmation 17/18 by
PRNT and/or IFA
NL / GER
QAT non-camel
QAT camel
Camel slaughterers 4/5
Sheep slaughterers 3/104
6.8% camel workers seropositive
all healthy!
Reusken et al., EID 2015
MERS-CoV shedding camels at slaughterhouse
High shedding rates slaughterhouse camels Qatar, n=105
Farag et al., IEE, 2015
97% seropositivity
A
B
C
59% shedding
Cross sectional studie KSA
Müller et al., LID, 2015
Reusken et al., Eurosurveillance 2014
PCR* Serology
Barn #
Animal #
Age Dam
(years)
Age Calf
(months)
Nasal swab
Rectal swab
Whole Milk
Milk fat Skim milk
cell pellet
Milk totala
Serumb Milkb Serumc Milkc
1 1 8 3 ─ ─ ─ ─ ─ ─ ─ + + ≥1280 80
2 7 4 + ─ + ─ ─ ─ + + + 640 Eq.
3 10 4 ─ + ─ ─ ─ ─ ─ + + ≥1280 80
4 8 5 + ─ ─ ─ ─ ─ ─ + + ≥1280 Eq.
5 7 6 + + + ─ + + + + + ≥1280 40
6 9 7 + ─ + ─ + + + + + ≥1280 40
7 9 7 + ─ + ─ + + + + + ≥1280 40
2 8 10 5 ─ + + ─ + + + + + ≥1280 40
9 8 3 ─ ─ ─ ─ ─ ─ ─ + + ≥1280 40
3 10 15 8 ─ ─ ─ ─ ─ ─ ─ + + ≥1280 nt
11 12 5 ─ ─ ─ ─ ─ ─ ─ + + ≥1280 20
12 10 7 ─ ─ ─ ─ ─ ─ ─ + + ≥1280 80
Totald 5 (41.7) 3 (25) 5 (41.6) 1 (8.3) 4 (33.3) 4 (33.3) 5 (41.6) 12(100) 12(100) 12(100) 9 (82)
Transmission routes - milking/ consumption raw milk
MERS-CoV stable in camel milk 72 h at 4 C
48 h at 22 C
v. Doremalen et al., Eurosurveillance 2013
MERS-CoV RNA in traditional milk
Adney et al., EID 2014
Haagmans et al., Science 2016
Experimental inoculation dromedary
Tissue culture PCR
Shedding and replication in URT
Mild resp disease
MVA-MERS S vaccination reduces replication
of MERS-CoV upon challenge (day 4 p.i.)
Antibodies directed against the spike protein of MERS-
CoV can be induced by vectored vaccines correlating
with the induction of protective immunity in dromedary
camels Haagmans et al., Science 2016
B
A
N=10
N=15
MERS-CoV in Alpaca herd in Qatar?
micro-array titers MERS-CoV
alpaca dromedary10
20
40
80
160
320
640
1280
2560
<
Tit
er
PRNT90 MERS-CoV
alpaca dromedary10
20
40
80
160
320
640
1280
2560
<
Tit
er
Reusken et al., EID 2016
Alpacas are New World camelids and
their worldwide population is estimated
at three million animals with 94% living
in the high Andean regions of South-
America (Peru, Bolivia, Chili and
Argentina) of which a vast majority in
Peru (88% of the world population).
Alpacas are increasingly being kept
outside South-America mainly for their
fleece with numbers accumulating in
2014 to 230,000 in the USA, 35,000 in
the UK and 150,000 in Australia.
Wide circulation in dromedary camels
Multiple zoonotic events since 2012
sporadic primary transmission camel -> human
Seasonality in primary cases, camel weaning period??
Occasional amplification through human-2-human transmisson
nosocomial transmission, household setting
inefficient, low transmission rate in humans seems not self-
sustaining (R < 1)
Cauchemez et al., 2013
Poletto et al., Eurosurveillance 2014
Large potential for international dissimenation
Haji: 9-14 sept 2016
Source: ECDC
2010
1,000 Haji permits per 1,000,000 muslims per country
Thank you
Bart Haagmans
Stalin Raj
Saskia Smits
Suzan Pas
Erwin De Bruin
Anne vd Linde
Robert Kohl
Annemiek van der Eijk
Theo Bestebroer
Ron Fouchier
Ab Osterhaus
Marion Koopmans
12 known human cases since september 2012
Latest case January 2015
10/2014: 2 new cases
> 95% of the camels tested seropositive (n ~200 camels)
Construction workers, n= 56
Sheep handler, n=10
Camel handler, n=22, n=155
Slaughterhouse workers
camels n=5
sheep n=104
Central animal market workers,
n=8
Population NL sera, n= 72
Recent common CoV infection NL /GER, n=68
MERS-CoV GER contact study, n=44
Diagnostic sera returning NL travelers, n=46
3
6
WHO working group on MERS-CoV. Plos path, in press.
Other studies occupational exposure
Aburizaiza et al., JID 2014
226 workers abattoir Jeddah/Makkah (KSA), 2012
Memish et al., Influenza and Other Resp Viruses 2014
51 camel workers Jazan (KSA), 2012
Chu et al., EID 2014
114 workers abattoir with MERS-CoV pos camels, Egypt 2013
Hemida et al., EID 2015
3 workers abattoir
4 workers daily intensive contact, known pos camels
8 workers regular contact, known pos camels
Source: ECDC
Travel period Haji 2014
Cluster in the UK – Jan/Feb 2013 -> H2H transmission
3 confirmed cases
Primary case: 60Y male, travelling from Pakistan/Saudi Arabia
Onset on 24 January, 5 days after arriving in KSA (Makah/Medina)
Traveled to UK 4 days later, died 19 March
Secondary cases: household contacts (West Midlands area, UK)
38y.o. son, immunosuppressed, onset 6 Feb, died on 17 Feb
30y.o. niece, onset 5 Feb
Lessons learned:
Human-to-human transmission confirmed
co-infections happen (flu).
Zambon et al unpublished