MERS-CoV, the story

Chantal Reusken, c.reusken@erasmusmc.nl

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