Modelling of potential

pandemics
Christophe Fraser
MRC Centre for Outbreak Analysis and Modelling
WHO Collaborating Centre for Infectious Disease Modelling

NAS Symposium on Gain of Function Research

Session 4: Potential Benefits of GOF Research I: Surveillance, Detection and Prediction

% from the
sed on con, or 0.03 to
ng the alternce/absence
% based on
nd 0.08 to
one. These
ewhat as a
but we debecause it
d by WHO

erations of local transmission

seen
in those
Disease
Epidemiology,
Imperial
Glozter,
A. Hyman,
M. Koell
further sensitivity
analysis
and methods.]
[Table 1 and (8)]. Using the date of 15 February
Gabriel M. Leung,2 Lai-Ming Ho,2 Tai-Hing Lam,283, 743 (1995).
andepidemics
V. Simanis for has
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The extent
College
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UKnum16.case-fatality
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D. T. Stinchcomb,
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viacase
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95% CI 4991) Thuan
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2 detection bias;
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as the
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ber of cases one case generates
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number
estimates
of between
4(2001).
4
5
ratio
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secondary
cases
was 20%
(742). Detection of milder
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Thomas
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to
single
indithe course of their infectiousProf
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is a PhD,
key mea- 1.31 and 1.42, depending on which variant of
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Extending
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sophisticated
Bayesian
estima4.
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D.
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The
rate
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spread
of
an
epidemicand
infection
control
was
implemented,
but
that
R
in
the
absence
of
controls
was
in
the
range
0813.
Three
independent
Prof CA Donnelly ScD,
(D.P.S.).
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K.
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growth,
the
method (11) that allows for stochastic variapresent
analysis
of the bound
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whether such spread is self-sustaining
S Riley PhD, datation
sources
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1, an
with
upper
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syndrome
(SARS)
epidemic
in
Hong
Kong.
The
epidemic
to
date
has
been
depends
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the magnitude
of a key epidemi21.
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two
large
clustersinitiated
by
two
separate
super-spread
ological
parameter,
the
basic
reproduction
Materials
and
Methods
Institute
of Evolutionary
of infections (Yf) and
mates for R0 with wider
estimated
start date and size
ranges:
posterior
median
=of age (3),
J. Kimple
et al., J. Biol. Chem.
276, (R
29275
(2001). asFigs.
7. by
F. Yu,
X. Morin,
Y. Cai, in
X. Yang,
W. Chia, Cell
100,By
399fitting
those
over
60
years
and this could
to S4 number
Interpretation
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that
a slowly
growing
epidemic
is underway
either
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beings
or 22.
inaR.an
animal
), defined
theS1average
events (SSEs)and
ongoing
community
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stochastic
number
0
Biology,
Ashworth
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(Fig. in
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References
an underestimate of overall morbidity.
by one primary
model estimates,
to data on
1512
cases,
including
these
we show
that
the
cation
ofcensoring
uncertainty
in transmissibility
and
provision
of the
firstclusters,
estimates
of the
scale
of (2001).of secondary cases generated
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of on
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we online material.
24. SeeSSEs,
supporting
353 (2000).
T hifeone
o
f
the
generation
time
distribution
informed
by
prefrom the exponential
growth
rate
Edinburgh,
Edinburgh,
UK also
when
additional
deaths
subsequently
arise
among
the epidemic and extent of case detection biases, we provide
valuableM.information
forwere
more
informed
risk25.
assessment.
Schaefer,infections
M. Petronczki,
D. Dorner,
M. Forte,
J. A.case
peak
(#SEM at of
thean
0.95
February
2003; accepted
introduction
agent28into
a population,
a 8M
estimate that 2.7 9.secondary
generated
per
on Average
average
at velocities in "m/s
thealready
Bayesian
coa- in surveillance data, can
assumes that the (Prof
generation
time distribution
cases
included
A Rambaut
PhD); and for vious estimates of influenza,
Knoblich, Cell 107, 183 (2001).
confidence interval) were as follows (A, anterior spinPublished online 15 May 2003;

Experience from past

and current epidemics

demic Potential of a Strain of

e w e ng l a n d
uenza
A (H1N1): Early nFindings
on severity

j o u r na l

m e dic i n e

original
Introduction

Downloaded from www.sciencemag.org on October 5, 2009

1
1
the start of the epidemic,
substantial
hospital
transalso bias estimates of the true case fatality ratio
iratory
dis- 1* Christl A. Donnelly,
tophe Fraser,
* Simon
Cauchemez,
William P. Hanage,1
10. Y. Cai, F.with
Yu, S.a Lin,
W. Chia, X. contribution
Yang, Cell 112, from
51
dle pole;
P, posterior spindle pole): gpr-1/2(RNAi), A:
10.1126/science.1084146
Institut
Pasteur,
Unit of
1
1
1
1
1
(4). Finally,
suspected Bill
deaths&
may
not all have
mission.
Transmission
rates
fellFP7,
during
the National
epidemic, primarily
as 0.20
a result
of P: 0.18 # 0.04,
unity
La
(2003).
# 0.03,
n $ 15; goa-1/gpaIncludeEpidemiology,
this information
when c
Department
of Infectious Disease
Fac. VanofKerkhove,
T. Dirdre Hollingsworth,
Jamie
Griffin,
Rebecca
F.
Baggaley,
Funding
Medical
Research
Council,
Melinda
Gates
Foundation,
EU
and
Institute
of
General
Molecular
Genetics
of
RNA
1
A J. Lyons,1 Thibaut Jombart,1 Wes R. Hinsley,1 Nicholas C. Grassly,1 been caused by infection with the novel virus.
ulty of Medicine, Imperial College London, Exhibition
eJenkins,
of which
Emily
reductions
in
population
contact
rates
and
improved
hospital
infection
Medical Sciences.
Viruses,
UMR3569
1
These uncertainties necessarily affect any estimate
Road, London SW7 2AZ, UK. 2Department of ComC. Ghani,
NeilCNRS,
M. Ferguson1;
used by theFrancois Balloux,1 Azra
control, but also because of more rapid hospital attendance by symptomatic
munity Medicine, University of Hong Kong, 21 SasUniversit
Paris
Diderot
of
the
case
fatality
ratio
(CFR).
at other viindividuals. As a result, the epidemic is now in decline, although continued
in the
Guando
2
soon Road, Pokfulam, Hong November
Kong. 3Research
Office,
On the basis of international travel patterns,
Andrew Rambaut,
Oliver
G. Pybus
Sorbonne
Paris Cit,
Paris,3;
7
ime as the
rmedfor
cases
had
died; thisRestrictions
death tollonislonger
expected
vigilance confi
is necessary
this to
be maintained.
range to
Peoples
Republic
of Chi
Health, Welfare and Food Bureau,
Government
of the
we
would
expect
a
proportion
of
cases
of
any
France (V Enouf PhD,
is substan9
4
5
4
4
Hong
Kong
Special
Administrative
Region,
19th
Floor,
rapidly
throughout
the w
population
movement
are
shown
to
be
a
potentially
useful
additional
coninfection spreading
widelywith
in Mexico
to be exez-Gatell,
Bojorquez
Chapela,
Palacios known
Zavala ; human
TheEthel
earliest
infections
Middle
East rise since some patients are still in hospital.
4
for a sea- Celia M. Alpuche-Aranda,
Prof SIetza
van der
Werf PhD)
Murray Building, Garden Road,
Hong
Kong.
Departported by travelers (5). Owing to intense surveilAs
of
21
May
2003,
795
trol
measure
in
some
contexts.
We
estimate
that
most
currently
infected
among 616
ment of Health, Government of the Hong Kong Sperespiratory syndromelance
coronavirus
(MERS-CoV)
occurred
Although
progress
has
been made
in characterising
the
for influenza-like
illness in those returning
Correspondence
Dulce Ma. Espejo
Guevara6; to:
reported
to
WHO
from
persons
are
now
hospitalized,
which
highlights
the
importance
of
control
of
during the
cial Administrative Region, Wu Chung House, 213 28
from1Mexico,
ascertainmentand
of early
cases in cation
newin
Jordan
in
March,
2012,
epidemiology
of
MERS-CoV,
many
uncertainties
with
isolation
identifi
5
recorded.
The e
Prof
Neil
M
Ferguson,
MRC
nosocomial
transmission.
Queens Road East, Wanchai,deaths
Hong Kong.
Hong Kong
break (Fig.
7
7
ly affected countries was almost certainly more
Francesco Checchi,7 Erika
Garcia,
Stephane
Hugonnet,
Cathy Roth7
10
Hospital Authority, 147B Argyle
Kowloon,
Kong, Street,
mainland
China,
Centre
for Outbreak
Analysis
and of
remain.
the virus from a complete
patientandinrapid
Saudi
Arabia
occurring
Little
is
known
about
the
extent
of
human
al (CI) of 0
than local surveillance of mild
1
1 optimal treat1 6Department ofand
Hong Kong.
Community
and(Canada)
Family h
B
Toronto
Theout
evolution
and spread of the Steven
etiological
diagnostic
tests, and Fraser,
formulate
Modelling,
Department
of
Riley,
*
Christophe
* Christl
A. Donnelly,
Mexico.
flow
of
The WHO Rapid Pandemic
Assessment
Collaboration
some months later.2 cases
infection or the
degree
of
detection
bias
towards
more
By inAug
8, Airline
2013,passenger
94 virologically
Medicine,
Chinese University of Hong Kong, School of
1
1
2
ular
concern
because
of
nt outbreak
agent
of
severe
acute
respiratory
syndrome
ment
protocols
to
reduce
morbidity
and
morInfectious Disease Epidemiology,
Mexico shows a significant correlation with
Azra C. Ghani, Laith J. Abu-Raddad, Anthony J. Hedley,
1,35 the
Public Health, Prince of Wales Hospital, Shatin, N.T.,
severe
cases.
If
the
severe
cases
currently
being
detected
confi
rmed
human
cases
and
17
probable
cases
had
A (H1N1) virus has
spread
rapidly
across
the
globe.
Judging
its
pandemic
efluenza
the transerations
of
local
transmi
frequency
of
detected
confirmed
cases
worldwide
(SARS),
a
novel
coronavirus
(1),
has
resulted
tality
(2
4).
Great
progress
has
been
made
2
2
2
Imperial College London, Norfolk
Hong Kong.
Gabriel M. Leung, Lai-Ming Ho, Tai-Hing Lam,
s difficult
nevertheless essential to inform
appropriate health
date
of thewith limited data, butPlace,
(Spearman
correlation coefficient:
0.56, in
P =an
0.004)
areas. The extent of th
international
effort
coordiwith, 2forminority
example, of
the2afull
sequence
of the
only
a
small
sentinel
much
larger
exposure
is suspected
asunparalleled
the represent
London W2 1PG, UK been reported. Zoonotic
2
3
*TheseLo,
authors
contributed equally to this work.
Thuan Q. Thach, Patsy Chau, King-Pan Chan, Su-Vui
By analyzing
outbreak in Mexico, early data on international spread, and viral
(Fig. 1, A and B). We thus use data on cases
among
ted.
Epide- the
been
byE-the o
nated
by
the
World
Health
Organization
RNA
virus
reported
on
13
April
2003
(5,
6).
Articles
C
neil.ferguson@imperial.ac.uk
To whom correspondence
should worsened
be addressed.
4
4
5
milder cases
(as
occurred
early
in the Ho,
2009
ofestimates
human infection,
in view methods
of theto estimate
initially number of Pak-Yin
versity,
severity. Our
travelers and backcalculation
Leung,The
Thomas
Tsang,
William
Koon-Hung
Lee,5
ergencewe
of make an early assessment of transmissibility andsource
clusters
of
infection
link
mail:
s.riley@imperial.ac.uk
(WHO)
to
characterize
the
virus,
develop
epidemic
apparently
originated
in
early
11
23,000
in Mexicooccurrence
by late April, the
6 case-fatality ratio
number
of peoplewith
infectedthe
in Mexico.
eatLa
Gloria(range 6000 to 32,000) individuals had been infected
in Mexico
sporadic
of total
cases
together
genetic H1N1 pandemicEdith
), the
might
M. C. Lau,
Neil M. Ferguson,1 Roy
M. Anderson1
viduals
and/or
spatial
lo
estimated
case
fatality
ratio
(CFR)
of
0.4%
(range:
0.3
to
1.8%)
based
on
confirmed
and
Key underlying assumptions in this 6analysis are
outbreak is
The rate of spread
of
similarity
of
MERS-CoV
to
bat
coronaviruses.
be
substantially
lower
than
what
current
surveillance
However,
deaths
reported
to
that
time.
In
a
community
outbreak
in
the
small
community
of
La
that
population
mixing
in
Mexico
is
equally
likewww.sciencemag.org
SCIENCE
VOL
300
20
JUNE
2003
1961
bruary 2009

article

Transmission Dynamics of the Etiological

Agent of SARS in Hong Kong: Impact of
Public Health Interventions

Downloaded from www.sciencemag.org on October 5, 2009

Ebola Virus Disease in West Africa

The First 9 Months of the Epidemic
and Forward Projections

racruz, no deaths were attributed to infection, giving an upper

95% bound on CFR of
We Conversely,
present an analysis
of the
first 10
weeks
of the severe acute respiratory
whether such spread is
ly between Mexican
residentsdid
and tourists,
for the
severe
acute
respiratory
epidemiological
investigations
of cases
not fiand
nd a data suggest.
s, although substantial uncertainty remains, clinical severity appears less than that seen tourists and Mexican residents are at equal risk
syndrome
(SARS)
epidemic
in
Hong
Kong.
The
epidemic
to
date
has
been
depends on the magnitud
ng the start
(SARS) epidemic
of clustersinitiated
2003, little evidence
of
of
exposure
to animals
ordif-the syndrome characterized
18 influenza pandemic but comparable with that seen in theconsistent
1957 pandemic. pattern
Clinical
of infection
(despite demographic
and other
by
two
large
by
two
separate
super-spread
ological parameter, the
diversity
in in La Gloria were twice that in adults (<15 years of age: 61%; 15
7 years:
12
s in children
ferences).
If infections
are concentrated
away
fromnot
undetected
mild
or
subclinical
infections
existed,
environment,
and,
as
of
Aug
8,
2013,
the
virus
had
even
events
(SSEs)and
by ongoing
community
transmission.
By fitting a stochastic
number (R0), defined as t
seecollected
different epidemiological analyses gave basic reproduction number (R0) estimates in traveler destinations (Fig. 1E presents the spatial
13
of secondary cases genera
model serological
to data on 1512
cases, including
these
clusters,
we show that the
t diversity
beenofisolated
fromof anydistribution,
animal by
species.
Recently,
however,
after
detailed
follow-up
studies.
In
the
of
1.4 to 1.6, whereas a genetic analysis gave a central estimate
1.2. This range
state, of cases within Mexico by
D to 73 generations of human-to-human transmission
E having occurred in 5 May), the number of people infected in Mexico
case in a susceptible popu
etiological agent of SARS is moderately transmissible. Excluding SSEs, we
ock model.
onsistent
with 14
camels
from
Oman
and
the
Spanish
Canary Islands were absence ofestimate
robust that
community-based
serological surveys
ble
introduction of an agent
2.7 secondary infections were generated per case on average at
latehemagApril. Transmissibility is therefore substantially higher than that of seasonal flu, and will be underestimated, and conversely will be
not estimates of R0 obtained from previous influenza
discovered
previously
infected
MERS- for MERS-CoV,
assessment
of with
the aextent
of undetected
pandemics. to have been
ecases
with lower
the start
of the epidemic,
substantial
contribution from hospital transoverestimated
if the
epidemic by
hasthe
dispropore analyzed
8
1
tionately
affected
geographical
zones visited caseby
rates fell during the epidemic,
primarily as a result of
Department of Infectious Dise
CoV or a closely related
virus.
infection mission.
must Transmission
rely on epidemiological
inference.
The
high apparent
at April
assumes
29
2009, the World Health Orga- travels from that country. There are uncertainties travelers. Under the assumption that reporting of
ulty of Medicine, Imperial Col
reductions in population contact rates and improved hospital infection
aspect of risk assessment is the by symptomatic
ratio
in reported
cases
is cause
for concern:
as of Another essential
ulation
(7). announced that the rapid about all aspects of fatality
this outbreak,
including
the infections
zation (WHO)
in travelers
was complete,
we estimated
Road, London SW7 2AZ, UK.
control, but also because of more rapid hospital attendance
14 e dic i n e
munity Medicine, University o
and
origin
of
the
virus,
obalofspread
the
number
of
infections
that
occurred
in
Mexico
me
most of a strain of influenza A virulence, transmissibility,
T
h
e
n
w
e ng
lKerkhove,
aepidemic
n dChristl
j oand
u
r na
o f Riley,
m
of e
transmissibility,
ain l
study
Aug 8, 2013, WHO reported that 46 of the 94 virologicallySimoncharacterisation
Cauchemez*, Christophe
Fraser*,
Maria
D Vanthe
A now
Donnelly,
Steven
Andrew Rambaut,
Vincent Enouf, soon Road, Pokfulam, Hong K
individuals.
As
a
result,
is
decline,
although
continued
rus
A) detected
of 12 in the previous week war- and this in turn results in uncertainty in judging by late April from a model of the interval-censored
Sylvie van der Werf, Neil
M Ferguson
vigilance
is necessary for this to be maintained. Restrictions on longer range
Health, Welfare and Food Bure
ving
the global
pandemic alert level to the pandemic potential of the virus and when re- country case counts, which varied between 18,000
al (CrI):
3
Hong Kong Special Administra
population
movement are shown to be a potentially useful additional conactive
public
health
responses,
such
as
recommen(www.who.int/csr/disease/swineflu/).
and
32,000
(Table
1),
depending
on
the
mean
The genetic
Murray Building, Garden Road
dations
to
stay
at
home
or
to
close
schools,
should
dicates
sustained
human-to-human
transduration
of
stay
of
tourists
assumed,
with
perhaps
trol
measure
in
some
contexts.
We
estimate
that
most
currently
infected
Address
reprint
requests
to
Dr.
Christl
Summary
50
www.thelancet.com/infection
Vol
14
January
2014
REPORTS
e doubling
ment of Health, Government
be
implemented
in
individual
countries.
Here
we
a
novel
influenza
strain
of
animal
origin
the
most
credible
single
value
(based
on
journey
are now
hospitalized,
highlights
the importance
of control
Lancet Infect Dis 2014; Background The persons
% CrI: 4.5
novel Middle
East
respiratory which
syndrome
coronavirus
(MERS-CoV)
had, asof
of Aug 8, 2013,
caused
cial Administrative
Region, W
Donnelly
at
c.donnelly@imperial.ac.uk
Fig.world,
1. (A).and
Theexported
number of report
passengers
flying
outearly
of Mexico
by actualinto
destination
and the
number
findings
of key
investigations
the duration
HO
region of the
data)
beingof
23,000. An
alternative
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those
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14:
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nosocomial
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xponential
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confi
rmed
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cases
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infection
worldwide.
We
analysed
epidemiological
and
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confirmed
cases
as reported
on 30that
April
2009.
number
of cases exported
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j asone caseresult
outbreak
could
aid (B)
suchThe
policy
decisions.
cted in other regions.
In this
outbreak,
that assumed
at least
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confirmed
inPublished
an underestimate
of overall morbidity.
Dr. Christopher
Dye
dyec@who.int.
Authority,
147B Ar
e estimate
Online data
to assess the extent of human or
infection,
the performance
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detection, and the transmission Hospital
potential
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a function
estimated
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travelers
in by late
presenceofofthe
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plus ofinforeign
affected countryreported
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been
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gave lower
Right
censoring
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occurs
Hong Kong. 6Department of C
November
13, of
2013
h it is for- Mexico from country j on any given day in March or April. Black circles: minimal number based on
The
evolution
and
spread
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the
etiological
diagnostic
tests,
and
formulate
optimal
treatMERS-CoVarise
with and without control measures.
cases in other nations associated with 88 suspected deaths in Mexico as of 4 May 2009 estimates of the number infected
in Mexico,
in deaths
the subsequently
Medicine, Chinese University o
when
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http://dx.doi.org/10.1016/
plete sam- one exposure per epidemiological
agentamong
of severe acute respiratory syndrome
ment protocols to reduce morbidity and morcluster; in
filled
red circles,
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Public Health, Prince of Wales
S1473-3099(13)70304-9
cases
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*The
authors
(members
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ects
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the
(SARS),
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(1), has
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(2
4). Great
progresscases
has been
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Mean
assumed
generation2009
time(2)]distribution
(red)1 indicative
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or Outbreak Analysis
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Department
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viewed
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1
Methods
We
assembled
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database
confi
rmed
and
probable
from
public
sources
and
also
bias
estimates
of
the
true
case
fatality
ratio
See
Christophe
* Christl
A.
Donnelly,
Simon
William
P. Hanage,
These findDisease
Epidemiology,
Imperial
College
ative
stochastic
model
of estimates),
distribution,
and London,
(D) Fraser,
corresponding
posterior
distribution
of1 RCauchemez,
lence
of the
infection.
The *interpretation
of thesefor
of resulting
CFR
andComment
it fittedpage
the 6
in
an
unparalleled
international
effort
coordiwith,
for
example,
the
full
sequence
of
the
0 estimates
Health
Organization
[WHO]
Ebola
Re1
1
1
*These authors
(4).
Finally,
suspected
deaths
may
not
all
have
edicine,
Norfolk Place, London
W2
1PG, Kerkhove,
UK.
estimated
the
incubation
period
and
generation
time
from
case
cluster
data.
Using
data
of
numbers
of
visitors
to
the contributed eq
Maria
D.
Van
T.
Dirdre
Hollingsworth,
Jamie
Griffin,
Rebecca
F.
Baggaley,
is are conCopyright
Cauchemez
et al.
an epidemic within Mexico statistics
with travelers
infected
a ratenumber
proportional
to theobserved
estimated
densityofofexported
depends
on theat total
of infecnumber
casesin
key counnated virus.
by the World Health Organization
RNA virus reported on 13 April 2003 (5, 6).
1
1
1
1
Evolutionary Biology, University of Edinburgh,1
To whom
correspondence sh
been
caused
bysubinfection
with the
novel
sponse
team
who
contributed
to
this
arHelen
E.
Jenkins,
Emily
J.
Lyons,
Thibaut
Jombart,
Wes
R.
Hinsley,
Nicholas
C.
Grassly,
stigation
of
Middle
East
and
their
duration
of
stay,
we
estimated
the
number
of
symptomatic
cases
in
the
Middle
East.
We
did
3
Open
Access
article
distributed
travelers
per
local
resident.
The
two
bar
charts
correspond
to
a
7-day
delay
between
infection
and
tions,
including
those
with
mild
infection
or
who
tries
(such
as
the
United
States
and
Canada)
oratories, Edinburgh EH9 3JT, UK. Department
mail: s.riley@imperial.ac.uk
(WHO)
to
characterize
the
virus,
develop
The
epidemic
apparently
originated
in
early
1
1
1
These
uncertainties
necessarily
affect
any
estimate
Francois
Balloux, inAzra
C.among
Ghani,
Neilunknown,
M.(E)Ferguson
; acuteworse
under
the terms
CC BY independent analyses, looking at the growth in incident clusters, the growth in viral population, the reproduction
current
confirmation
(blue)Oxford
and no
delay
(orange)
cases
travelers.
Number
of
respiratory
are
asymptomatic,
which
is currently
stantially
than did the first
model.
Weofused
Universityepiof Oxford,
South Parks Road,
ticle) are listed in the Appendix.
4
of date
theauthors
case
Directorate
of Epidemiology,
FCO.
K.
ows
a pre- General
given
the absence
of aasspecific
serological
for(1), 30
infection
cases per 100,000
inhabitants
by state
reported
on 5 Maytest
2009
demonstrating
April 2009 spatial
as the cut-off
for fatality
the
dataratio (CFR).
*These
contributed
number of cluster index cases, and cluster sizes to characterise the dynamical properties of the epidemic and the
2
3
a, 177 5th Floor, Mexico City, 01480, Mexico.
On
the
basis
of
international
travel
patterns,
Oliver
G. associated
Pybus ;
theMexico.
newAndrew
H1N1 Rambaut,
influenza strain
and
analyzed, but the case data analyzed
aretosubject
on the first distribution of disease within
www.sciencemag.org SCIENCE VOL 300 20 JUNE 2003
equally
this study
itute of Epidemiological Diagnosis and Reference,
transmission
we and
would
expectofa proportion
of casesscenario.
of any
population-level screening. As of 4 May 2009, to delays (clinical onset, testing,
reporting)
Carpio No. 470 (3 piso), Col Santo Toms,
MRC
Centre
for
Outbreak
This article was published on September
4 11,356 suspected and 822
4
infection
laboratory-confirmed
to 1 Palacios
week, so Zavala
these estimates
may bespreading
more rep- widely in Mexico to be exSecretara
de Salud - Celia
C.P. 11340, Mexico. 6Hugo
Lopez-Gatell,
M. Alpuche-Aranda,5 Ietza
Bojorquez Chapela,4up
Ethel
;
Analysis and Modelling,
Salud
Veracruz2009
Soconusco
No. 36,
Colonia
19deJUNE
VOL
324
SCIENCE
www.sciencemag.org
Findings
The
estimated
number
of
symptomatic
cases
up to Aug 8, 2013, is 940 (95% CI 2902200), indicating that at
cases
have
been
reported
in
Mexico
(1),
but
these
ported
by
travelers
(5).
Owing
to
intense
surveilresentative
of
infections
up
to
23
April.
The
epi23, 2014, at
NEJM.org.
Department of Infectious
P. 910 Xalapa, Veracruz, Mxico State. 7World
6
may representDulce
an underestimate
of true case
num- demic has subsequentlyDisease
spread
further,
although
lance
for
influenza-like
illness
in
those
returning
least
62%
of
human
symptomatic
cases
have
not
been
detected. We find that the case-fatality ratio of primary cases
Ma.
Espejo
Guevara
;
Epidemiology,
Imperial
nization.
bers as surveillance has understandably focused on the impact of the nonpharmaceutical
intervenfromLondon,
Mexico,
ascertainment
of earlyvia
cases
in new-surveillance (74%; 95% CI 4991) is biased upwards because of detection bias; the case-fatality
College
London,
UK
detected
routine
rs contributed equally to this work.
7 Furthermore,
7
cases.
severe cases
in older7 Cathy
DOI: 10.1056/NEJMoa1411100
tionsRoth
introduced
in Mexico islynot
yet
known.
affected
countries
almost
certainly more
(S Cauchemez
PhD, was
Francescosevere
Checchi,
Erika Garcia,7 Stephane
Hugonnet,
orrespondence should be addressed. E-mail:
ratio
of secondary
cases was 20% (742). Detection of milder cases (or clinical management) seemed to have improved
individuals will be more difficult to identify beOn the basis of the 9 confirmed
and
92
susProf
C Fraser
PhD,
@imperial.ac.uk
complete
and
rapid
than local surveillance of mild
Copyright
2014 Massachusetts
Society.were not self-sustaining when
in recent months. Analysis of human
clustersindicated
that chains ofMedical
transmission
cause of the higher rate of respiratory illness in pected deaths that were reported
by 30
April
2009
are members of this collaboration.
MD
Van
Kerkhove
PhD,
cases
in Mexico.
Airline passenger flow out of

WHO Ebola Response Team*

A bs tr ac t

Background

Middle East respiratory syndrome coronavirus:

quantification of the extent of the epidemic, surveillance
biases, and transmissibility

On March 23, 2014, the World Health Organization (WHO) was notified of an outbreak of Ebola virus disease (EVD) in Guinea. On August 8, the WHO declared the
Pandemic Potential of a Strain of
epidemic to be a public health emergency of international concern.

original article

Influenza A (H1N1): Early Findings

Ebola Virus Disease in West Africa

The
First 9 Months of the Epidemic
By September 14, 2014, a total of 4507 probable and confirmed cases,
including
2296 deaths from EVD (Zaire species) had been reported from five countries
in Forward Projections
and
Methods

The WHO Rapid Pandemic Assessment Collaboration

A novel influenza
A (H1N1) virus has spread rapidly across the globe. Judging its pandemic
Results
www.sciencemag.org SCIENCE VOL 324 19 JUNE 2009

potential is difficult with limited data, but nevertheless essential to inform appropriate health

5, 2009

West Africa Guinea, Liberia, Nigeria, Senegal, and Sierra Leone. We analyzed a
detailed subset of data on 3343 confirmed and 667 probable Ebola cases collected
in Guinea, Liberia, Nigeria, and Sierra Leone as of September 14.

WHO Ebola Response Team*

A bs t r ac t

control
Prof CA
Donnelly
ScD, infection
Mexico
shows
a significant
correlation
withwas
the implemented, but that R in the absence of controls was in the range 0813. Three independent
S
Riley
PhD,
data
sources
provide
frequency of detected1557
confirmed cases worldwide evidence that R cannot be much above 1, with an upper bound of 1215.
Prof N M Ferguson DPhil);
(Spearman
correlation coefficient: 0.56, P = 0.004)

Lessons learnt

Epidemic response needs well-organised classical public health.

Timeliness is most important.

Diagnostics, prompt isolation, social distancing, risk communication.

Require data systems, multidisciplinary cross-validation, sharing of

data and samples.

To date:

Vaccines have arrived too late for outbreaks.

Treatment as prevention is haphazard.

Huge role for basic virological science, but why GOF with PPP?

Predicting pandemics

H5N1, H7N9, MERS, Ebola clearly identified as threats prior to

any GOF-PPP experiments.

2009 H1N1pdm, SARS - less so.

Cause: surveillance gaps, not lack of understanding.

LETTER RESEARCH
Segment

Test antigens

Ferret antisera

12345678

4167/
1999

1304/
2003

1110/
2006

Cal/4/
2009

NS29/
2009

1559/
2008

CS H1N1 CS H1N2 TRIG H1N2 H1N1/09 EA H1N1 EA* H1N1

Sw/HK/4167/1999

CS H1N1

1:20,480

1:320

1:10,240

1:2,560

1:2,560

<1:10

Sw/HK/1304/2003

CS H1N2

1:1,280

1:2,560

1:640

1:80

1:40

<1:10

Sw/HK/1110/2006

TRIG H1N2 1:40,960 1:1,280

1:10,240

1:640

1:5,120

<1:10

Cal/04/2009

H1N1/2009

1:2,560

1:1,280

160

<1:10

Sw/HK/8512/2001

EA H1N1

1:10,240 1:1,280

1:5,120

1:2,560 1:10,240

1:320

Sw/HK/1669/2002

1:160

1:640

EA H1N1

1:5,120

1:1,280

1:2,560

1:1,280 1:10,240

Sw/HK/NS129/2003 EA H1N1

1:5,120

1:1,280

1:2,560

1:1,280 1:10,240

Sw/HK/1716/2006

1:2,560

1:640

1:1,280

1:640

EA H1N1

Sw/HK/NS952/2008 EA H1N1

1:160

1:2,560

<1:10

H1N1pdm emerged
from out of
a surveillance gap
1:2,560

1:640

1:640

1:320

1:2,560

<1:10

1:640

1:160

1:1,280

1:80

1:10,240

<1:10

EA* H1N1

<1:10

<1:10

<1:10

<1:10

1:40

<1:10

Sw/HK/1559/2008

EA* H1N1

<1:10

<1:10

<1:10

<1:10

1:40

1:5,120

Sw/HK/247/2009

Sw/HK/NS29/2009

EA H1N1

Sw/HK/72/2007

EA* H1N1

<1:10

<1:10

<1:10

<1:10

1:40

1:2,560

Sw/HK/NS613/2009 EA* H1N1

<1:10

<1:10

<1:10

<1:10

1:10

1:2,560

Sw/HK/2481/2009

EA* H1N1

<1:10

<1:10

<1:10

<1:10

1:20

1:2,560

Sw/HK/NS186/2009 EA* H1N1

<1:10

<1:10

<1:10

<1:10

1:40

1:2,560

Figure 4 | Antigenic characterization of SwIV measured by haemagglutinin

inhibition assays. Titres are shaded according to their respective major SwIV
HA lineages (see Figs 13); low (1:20, 1:40) and non-reactive titres (,1:10) are
shaded in lighter colours. Underlined values represent homologous antibody
titres. EA-reassortant viruses (indicated by asterisks) showed poor
crossreactivity against antisera raised towards CS, TRIG, H1N1/2009 and late
(20062009) pure EA viruses. Excepting the earliest EA-reassortant virus (Sw/
HK/72/2007), all remaining EA-reassortants reacted well against antisera
raised towards the EA-reassortant virus Sw/HK/1559/2009, indicating
progressive antigenic change of this novel reassortant.

CS
EA
TRIG
H1N1/2009
Avian
Human H3N2

1974

1:640

1978

1982

1986

1990

1994

1998

2002

2006

2010

Year

Figure 3 | Phylogenies and divergence times of the haemagglutinin genes of

classical swine and European avian-like SwIV. a, CS; b, EA. Coloured boxes
adjacent to tips show the lineage classification of each gene segment of SwIV
isolated in this study. Arrows indicate the long branches that lead to newly

motifs observed in several hosts. By 1999, most viruses sampled had the
GPKV motif previously described from pigs16. CS and TRIG viruses
that contributed the NS gene to H1N1/2009 have a truncated NS gene,
as do the antigenically variant Sw/HK/72/2007-like viruses. The role of
the truncated NS gene in inter-species transmission clearly merits
further study. Furthermore, a modest but significant (P , 0.01) change
in selection pressure was observed between European EA viruses isolated shortly after cross-species transmission (non-synonymous to
synonymous (dN/dS) substitution rate ratio of 0.24; 95% confidence
interval 5 0.220.27) and those isolated later (dN/dS 5 0.17; 95% confidence interval 5 0.140.20), consistent with the hypothesis that hostspecific selection increased viral adaptation after the introduction of
EA viruses into swine (Supplementary Table 6).
Our unique longitudinal study reveals a genetically and antigenically
dynamic SwIV population within a single region and provides a baseline
for future studies of the virus elsewhere. The epidemiology and evolu-

Vijaykrishna et al Nature 2011

MERS

MERS emerged and remains in a surveillance gap.

Rambaut, epidemic.bio.ed.ac.uk

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potentially serious threat. These results highlight critical areas in which more data are needed for
15
6ster
(2006).
et al., Science 325, 481 (2009).
assessing, and potentially averting, this threat.
3et (2005).
al., Vet. Res. 43, 28 (2012).
J. A. Doudna, Proc.
Acad. Sci. 1,2,3
U.S.A.Judith
106, M. Fonville,1,2 Andr E. X. Brown,4 David F. Burke,1,2 David L. Smith,3,5,6
ColinNatl.
A. Russell,
and the A/Vietnam/
ecent studies have shown that the amino acid substitutions (1), 20
009).
1,2
7
7
7
7
uchier,
Sarah
L.
James,
Sander
Herfst,
Sander
van
Boheemen,
Martin
Linster,
Eefje
J.
Schrauwen,
A/Indonesia/5/2005 avian A/H5N1 influ- 1203/2004 A/H5N1 influenza virus requires four
A. C. Lowen, S. Mubareka, P. Palese, 1,2
PLoS
7
9
9
Leah Katzelnick, Ana Mostern,1,2,8
Thijs
Kuiken,
Eileen Maher,
substitutions and reassortment (2), to become
enza
virus
may require
as few Gabriele
as five Neumann,
5,
, 6e1000252
(2011). (2009).

. 103,

Perez,
).
2011).

t 222, 66

entary

2004).

.S.A. 106,

PLoS

the probability are random mutation, positive selection, long infection, alternate functionally equivalent substitutions, and transmission of partially
adapted viruses as a proportion of the withinhost diversity both in the avian-mammal and the
mammal-mammal transmission events (10, 1418).
The factors we considered that can decrease
the probability are an effective immune response,
deleterious substitutions, and order-dependence
in the acquisition of substitutions. We considered
these factors for starting viruses differing in
the number of mutations that separates them
from a respiratory droplettransmissible A/H5N1
virusviruses that require five, four, three, two,
or one mutations at specific positions in the virus HA, reflecting that zero, one, two, three, or
four of the mutations are already present in the
avian population and thus are present at the start
of the infection in mammals. We treat each amino
acid substitution as if it can be acquired by a
single-nucleotide mutation, as is the case for

Albert D. M. E. Osterhaus,7 Yoshihiro Kawaoka,9,10,11,12 Ron A. M. Fouchier,7 Derek J. Smith1,2,3,7*

25
0

hill-climb
all-or-nothing
neutral
3

Time (days)

hill-climb
hill-climb + intra-host diversity
hill-climb + functionally equiv. mutations
5

Time (days)

hill-climb
hill-climb + deleterious
hill-climb + order
5

Time (days)

www.sciencemag.org
SCIENCE
JUNE
1541
Avian A/H5N1 influenza
viruses pose a pandemic
threat. AsVOL
few 336
as five 22
amino
acid2012
substitutions,
or four with reassortment, might be sufficient for mammal-to-mammal transmission through respiratory Fig. 3. Factors that increase or decrease the proportion of respiratory sites for a virus requiring four mutations (green), eight sites for a virus
droplettransmissible A/H5N1 virus based on starting viruses that require five requiring three mutations (orange), seven sites for a virus requiring two
droplets. From surveillance data, we found that two of these substitutions are common in A/H5N1
(blue), four (green), three (orange), two (red), or one (purple) mutation (or mutations (red), and six sites for a virus requiring one mutation (purple),
viruses, and thus, some viruses might require only three additional substitutions to become
mutations) to become respiratory droplettransmissible. (A) The effect of hill- both with hill-climb selection, compared with hill-climb selection alone. (C)
transmissible via respiratory droplets between mammals. We used a mathematical model of within-host climb and all-or-nothing positive selection compared with random mutation The effect of two of the required substitutions being individually deleterious
alone. (B) The effect of avianmammal transmission of partially adapted virus (for these two specific substitutions, either substitution alone reduces the
virus evolution to study factors that could increase and decrease the probability of the remaining
a result of intra-host diversity (100 viruses start the infection, one of replicative fitness of the virus to zero) and the effect of complete order
substitutions evolving after the virus has infected a mammalian host. These factors, combined with the as
which has a mutation) and the effect of alternate substitutions with 10 dependence of acquiring substitutions, both with hill-climb selection as
presence of some of these substitutions in circulating strains, make a virus evolving in nature a
functionally equivalent sites for a virus requiring five mutations (blue), nine compared with hill-climb selection alone.
potentially serious threat. These results highlight critical areas in which more data are needed for
assessing, and potentially averting, this threat.
22 JUNE 2012 VOL 336 SCIENCE www.sciencemag.org
1544

It is not possible
to calculate
amino acid substitutions
(1), and the A/Vietnam/ the level of risk precisely because of
1203/2004 A/H5N1 influenza virus requires four
substitutions and reassortment (2),
uncertainties
into become
some aspects of the biology.

ecent studies have shown that the

A/Indonesia/5/2005 avian A/H5N1 influenza virus may require as few as five

www.sciencemag.org

SCIENCE

VOL 336

22 JUNE 2012

1541

Aim: basic science, not risk assessment.

cf.: experience with HIV, Bonhoeffer et al Science 2014, Kouyos et al PLOS Genetics 2012, Carlson et al Science 2014, Fraser et al Science 2014

.............................................................................................................................................................................
t
Competing
interestswhere
statement
The how
authorsnovel
declare that
they have nosuch
competing
l to quantify
Sex
It is unclear
when,
and
pathogens
as financial
interests.
415, genetic
ditive
human immunodeficiency virus (HIV), monkeypox and severe
and non-

acute respiratory
syndrome (SARS) will cross the barriers that
Correspondence and requests for materials should be addressed to D.W.C.
letters
separate(d.coltman@sheffield.ac.uk).
their natural reservoirs from human populations and
components:
n ) andignite
the epidemic spread of novel infectious diseases. New
(V
the
e
2
d as h pathogens
V a/
are believed to emerge from animal reservoirs when
on
s and ratios.
ecological changes increase the pathogens opportunities to enter
ed by using
the human population1 and to generate subsequent human-totistical
tests
297,
human ..............................................................
transmission2. Effective human-to-human transmission
requires that the pathogens basic reproductive number, R 0,
1790
should exceed one, where R 0 is the average number of secondary
mt 55, 243249
infections arising from one infected individual in a completely
Ecol.
susceptible population3. However, an increase in R 0, even when
do we know and
insufficient to generate an epidemic, nonetheless increases the
1
2
Antia1, Roland
R. Regoes
, JacobHere
C. Koella
& Carl
T. Bergstrom3
&
numberRustom
of subsequently
infected
individuals.
we show
that,

es

humans. Genetic changes of the new host might be more likely for
domesticated or endangered species than for humans.
Here we show that factors, such as ecological changes, that
increase the R 0 value of the potential pathogen to a level not
sufficient to cause an epidemic (that is, R 0 remains less than one)
can greatly increase the length of the stochastic chains of disease
transmission. These long transmission chains provide an opportunity for the pathogen to adapt to human hosts, and thus for the
disease to emerge.
Our model is illustrated in Fig. 1. Introductions occur stochastically from the natural reservoir of the pathogen, and each primary
case is followed by stochastic transmission that generates a variable
number of subsequent infections in the human population. We

to nature

General theory

ventional view is
conventional view
one, whereas in th
and evolution dur
R 0 to increase ab
as HIV1,11,12, SAR
prevalence studies
the reservoir woul
usually dead ends
associated with a
diseases emerging
virus, which mov
1
Figure 2 One-step evolution. A single change i
| VOLEmory
426 | 11 DECEMBER
| www.nature.com/nature
oture
hornPublishing
and body
DepartmentNATURE
of Biology,
University,2003
Atlanta,
Georgia 30322, USA
Group
R . 1. a,conduct
The probability thatadditiona
an introduction le
2
of the pathogen (filled circle in Fig. 1) is highly
Laboratoire de Parasitologie Evolutive, Universite Pierre et Marie Curie,
tionson the
tomutation
estimate
linearly dependent
rate m. Linest
Figure 1 Schematic for the emergence of an infectious disease. Introductions from the
xual selection in
75252 Paris, France
branching process
model
(see
Supplementary
reservoir are followed by chains of transmission in the human population. Infections with
and to determineIn
3
Monte-Carlo simulations following 10 introducti
the introduced strain (open circles) have a basic reproductive number R , 1. Pathogen
Department
of
Biology,
University
of
Washington,
Seattle,
Washington
98195,
the withintroduced
In the
ventional evolution
viewgenerates
is the
Rstrain
0 of
ms. Nature 422,
an evolved
(filled circles)
R . 1. The infections pathogen.
introductiontransmission.
depends
on the R value ofSuch
caused
the int
USA
by
the
evolved
strain
can
go
on
to
cause
an
epidemic.
Daggers
indicate
no
further
pathogen.
The
solid,
dashed
and
dotted
lines
co
than
conventional
view the R 0 of these infections must be angreater
gens
that have an
transmission.
R of 1,000, 1.5 and 1.2 respectively.
.............................................................................................................................................................................
one, whereas
in the mechanism described here it is less than
one, for emer
potential
NATURE | VOL 426 | 11 DECEMBER 2003 | www.nature.com/nature
2003 Nature Publishing Group
ong, H. M. Sex
It is unclear when, where and how novel pathogens such as
and evolution during the stochastic chains of transmission allows
The framework
ons. Nature 415,
human immunodeficiency virus (HIV), monkeypox and severe
gens
that have bee
such
R 0 to increase above one. In the case of human infections
1,11,12
1317
1821
smallpox there
, SARS
and (potentially) monkeypox of
, seroas HIV
acute respiratory syndrome (SARS) will cross the barriers that
s in ungulates
as, from
but not restric
prevalence studies among groups at high risk of infection
separate their natural reservoirs from human populations and
have are
originated. A
the reservoir would allow evaluation of whether crossover events
d population
ignite the epidemic spread of novel infectious diseases. New
population
is clea
9).
usually dead ends, as we expect in our model, or whether they
are
pathogens are believed to emerge from animal reservoirs when
harvesting on
in th
associated with a large number of secondary cases. In the transmission
case of
ecological changes increase the pathogens opportunities to enter
diseases emerging into non-human populations, such as theimmunity
Nipah to sma
123 (2003).
the human population1 and to generate subsequent human-to2224
nation,
, it may be possible
towe expect
virus, which moved from bats to pigs
2
les. Science 297,
human transmission . Effective human-to-human transmission
to a level st
conduct additional tests involving controlled experimentalalbeit
infecrequires that the pathogens basic reproductive number, R 0,
in pigs)85% cross
tions to estimate the R 0 (in this case of the bat Nipah virus about
293, 17861790
suggest
should exceed one, where R 0 is the average number of secondary
and to determine whether it evolves during the course of chains
of that this i
human
000).
infections arising from one infected individual in a completely
transmission.
Such
may additionally
to identify
patho- populatio
Figure 3 Multiple-step
evolution.
Herestudies
multiple evolutionary
changes arehelp
required
for
end. Afr. J. Ecol.
that have
to evolve rapidly and thus haveevolution
a high of mon
susceptible population3. However, an increase in R 0, even when
evolution of gens
the pathogen
to havean
an Rability
0 . 1. a, Jackpot model with m 0.1 and n
human pathogen (
forwith
emergence.
insufficient to generate an epidemic, nonetheless increases the
intermediatepotential
changes each
R 0 equal to that of the introduced pathogen: increasing
on horn
followed, may be
The(n)framework
presented
hereof has
special
relevance
the number of steps
greatly decreases
the probability
evolution,
and makes
it more for pathonumber of subsequently infected individuals. Here we show that,
The present stu
beenpathogen.
driven b,
toAlternative
extinction
by vaccination.
sensitive to gens
the R 0that
of thehave
introduced
multi-step
models for the In the case
These include ex
NATURE | VOL 426 | 11 DECEMBER 2003 | www.nature.com/nature
of smallpox
there
probably
reservoirs
of model
related
zoonoses (such
one-intermediate
(n 1) case.
The are
jackpot
model (solid
line), additive
(dashed
2003 Nature Publishing Group
interactions such
as, valley
but not
monkeypox)
line) and fitness
modelrestricted
(dotted line) to,
are shown
(see text for from
details).which smallpox may
areas and subpopu
have originated. Although the R 0 of monkeypox in the human
of the pathogen in
population is clearly less than one, there are occasional chains
canBbeof
applied to
See also, Lloyd-Smith et al isEpidemics
2014
and
Park
et
al
Proc
R
Soc
2013
1821
close totransmission
1. We find thatinthethe
probability
of emergence depends
most
. As the
level of herd
human population
28,29

The role of evolution in the

emergence of infectious diseases
letters to nature

Natural selection: infection begets transmission,

transmission begets epidemics

Predicting pandemics:
empiricism meets theory

Infection predicts transmission.

Transmission predicts epidemic emergence.

Focus on infections that cause human cases and clusters

Surveillance

POLICY FORUM
Public Health Risk from the
Surveillance
response
Avian H5N1 &
Influenza
Epidemic
R0

n to humans and subsequent reas- collected in the participating countries. It from outbreaks causing high morbidity and
nt of avian and human influenza also serves as a mechanism for alerting mortality. Furthermore, outside of the deviruses in coinfect- countries to the emergence of strains with veloped world, few countries have the veted individuals (2). pandemic potential or unusual pathogenic- erinary services infrastructure to undertake
online at
ncemag.org/cgi/ Reassortment could
ity. A survey of the network inP2002
U B resultL I C H Eeffective
A L T H surveillance. As the current H5N1
ll/304/5673/968 link the high transed in the development of a WHO action avian epidemic highlights, the zoonotic orimissibility associat- plan for the next 5 years to improve on cur- gin of pandemic influenza strains means
h human-adapted viruses with the rent surveillance weaknesses (6). Issues that improved surveillance and control of
tes of mortality observed in the cur- highlighted were the current wide variabil- animal (particularly avian) influenza needs
man cases and thus trigger a poten- ity in the number of viral isolates submit- to be a priorityas much to safeguard pubevastating pandemic.
lic health as to promote animal welfare.
0.8
d pandemic planning (3) and worldThe demands of annual vaccine prepa0.6
urveillance is central in mounting an
ration
inevitably mean that greatest empha0.4
0.2
e global response to combat such
sis is placedNeil
on monitoring
antigenic
variM. Ferguson,*
Christophe
Fraser,
0
However, surveillance must be linked
ation
and
understanding
its
molecular
ba0
10
20
30
40
Christl A. Donnelly, Azra C. Ghani, Roy M. Anderson
opriate analysis for the stuttering besis. However, improving pandemic surveilCumulative number
s of a threatening epidemic to be delance additionally requires more research
of avian to human cases
rapidly and reliably. Currently the
(in H5N1
secure laboratory
to measure
he ongoing
influenza settings)
epidemic
influenza centers in 83 countries. The maHealth Organization (WHO) tracks
frequency
of viralposes
reassortment
hosts
16
in Asian the
bird
populations
risks in jor
focus of the network is on compiling in25% (R0 ~ 0.33)
14
mber of avian-to-human and possible
exposed
to
multiple
different
viral
strains
to public as well as animal health (1), formation for influenza vaccine formula12
to-human transmission events reportand to define the detailed genetic basis of
due
to
the
potential
for cross-species trans- tion, based on the analysis of viral isolates
10
15% (R0 ~ 0.2)
ection of even a single case of humanhost specificity, pathogenicity, and trans8
mission to humans
and(7).subsequent reas- collected in the participating countries. It
an transmission of an avian virus can
missibility
6
sortment of avian
also
n increase in pandemic alert levels
Howand
do wehuman
quantifyinfluenza
the possible risks
of serves as a mechanism for alerting
4
5% (R0 ~ 0.05)
viruses
coinfectto the emergence of strains with
ntially high cost to affected countries
a pandemic
strains in
emerging,
and howcountries
can
2
ularly if travel advisories are issued).
we
rapidly
but
reliably
detect
the
emer0
ed
individuals
(2).
pandemic
potential or unusual pathogenicEnhanced online at
20 40 60 80 100 120 140 160 180 200
we argue that observation of low-level
gence
of
such
a
strain?
Simple
mathematiwww.sciencemag.org/cgi/ Reassortment could
ity. A survey of the network in 2002 resultCumulative number
to-human transmission is not a key
cal
analysis
can
provide
some
insights.
link the high trans- edAtin the development of a WHO action
of avian to humancontent/full/304/5673/968
cases
ld, but rather the primary focus should
any time point, the risk of a reassortment
missibilityto associatAnalyzing avian influenza surveillance data. event is proportional
etecting increases in viral transmissithe number ofplan
peo- for the next 5 years to improve on curhuman-adapted
viruses
rent surveillance weaknesses (6). Issues
(Top) Illustration of the reliabilityed
of Rwith
0 estimat a stage where containment might be
ple coinfected
with with
humanthe
and avian
R
estimates
(the
shading
delintion
methods.
high rates of mortality
observed
in the curhighlighted were the current wide variabil0
. To help ongoing consultation (4), we
strains. Making
the reasonable
assumptions
eates
the
95%
confidence
intervals)
are
shown
a method to detect increases in viral
rent human cases
and of
thus
trigger a potenthat 10%
the population
are infectedity
within the number of viral isolates submitderived from data on the number of avian-to- human influenza over the 12 weeks of a
ssibility based on examination of
tially
devastating
pandemic.
human cases seen, the number of human-hu- typical influenza season (8), and that there
of human cases.
0.8
Good
pandemic planning (3) and worldman clusters, and the size of the largest
cluster.
0.6
WHO Global Influenza Network
is
a
1-day
window
in
early
infection
where
surveillance
is central in mounting an
The surveillance data used was wide
generated
by
s established in 1948, and today
coinfection with an avian strain is possible,0.4
0.2
simulating an avian influenza epidemic
with Rglobal
effective
0
ses 4 collaborating centers and 112
thenresponse
0.12% of to
the combat
populationsuch
are suscepti- 0
= 0.2 in humans. (Bottom) Threshold
size
of
the
threats. However,
beanby
linked
10 limited
20
30
40
P UWHO
B L I C national
H E A LT H
ted
different
countries,
ions recognized as
ble surveillance
to coinfectionmust
with
avian
strain
at 0 and the
largest cluster expected by chance for a range of
to appropriate analysis for the stuttering
fractionbeof isolates that undergoCumulative
detailed
number
levels of human-to-human transmission, as any one time. Hence, even if reassortment
analysis
and
sequencing.
is
certain
following
coinfection,
the
probaginnings of a threatening epidemic to be deof avian to human cases
quantified by the proportion of avian-to-human
hors are in the Department of Infectious
Surveillance
of
avian
and
livestock
(parbility
of
a
reassortment
event
having
octected
rapidly
and
reliably.
Currently
the
cases generating secondary cases (approximate
Epidemiology, Faculty of Medicine, Imperial
ticularly
porcine)
influenza
is
less
satisfacafter n cases
of avian
influenza in 16
London, St. Marys campus, Norfolk Place,
R0 values are also shown). Anomalous
behavior
World
Health curred
Organization
(WHO)
tracks
nGovernment
tory.
veterinary services are re;
so
600 human
humans
is
1

(1

0.0012)
W2 1PG, UK.
might be suspected if a clusterthe
exceeds
this of avian-to-human and possible
25% (R0 ~ 0.33)
14
number
sponsible
for
surveillance,
with the Food
infections
would
be
required
for
a
50%
threshold
size.
Note
how
the
expected
maxifor correspondence. E-mail: neil.ferguson@
12
human-to-human
transmission
events
reportand
Agriculture
(FAO) and the
chance
of reassortment,
and
around 45Organization
for a 10
mum
size increases
cases accumulate.
ac.uk
Neilcluster
M. Ferguson,*
Christophe
Fraser,
World
Organization
for
Animal
Health
15% (R0 ~ 0.2)
Detection
of5%even
a single
case of humanchance.
If reassortment
is a rare out- 8
uthors contributed equally.
See A.
supporting
online
fored.
methods.
Christl
Donnelly,
Azramaterial
C. Ghani,
Roy
M. Anderson
(OIE)
collating
data
from
those
countries
to-human transmission of an avian virus can
6 on disease outsubmitting information
cause
an
increase
in
pandemic
alert
levels
4
he ongoing
H5N12004
influenza
influenza
centers in 83 countries. The ma- breaks. There is no systematic
surveillance
14 MAY
VOLepidemic
304 SCIENCE
www.sciencemag.org
5% (R0 ~ 0.05)
at
potentially
high
cost
to
affected
countries
2 or wild birds based
in Asian bird populations poses risks jor focus of the network is on compiling in- for influenza in livestock
(particularly
if travel
to public as well as animal health (1), formation
for influenza
vaccineadvisories
formula- are
on issued).
random sampling or0 other well-defined
80 100 120 140 160 180 200
due to the potential for cross-species trans- tion, based
onwe
the argue
analysis
of viral
isolates ofsampling
Here,
that
observation
low-levelschemes. Most20data40are60collated
Cumulative
mission to humans and subsequent reas- collected
in the participating
countries. It is not
fromaoutbreaks
human-to-human
transmission
key causing high morbidity and number
of of
avian
to human cases
sortment of avian and human influenza also serves as a mechanism for alerting mortality. Furthermore, outside
the dethreshold, but rather the primary focus should
viruses in coinfect- countries to the emergence of strains with veloped world, few countries have the vetavian
influenza surveillance data.
be on
detecting
increases
in viral transmissied individuals (2). pandemic
potential
or unusual
pathogenicerinary services Analyzing
infrastructure
to undertake
Enhanced online at
(Top)As
Illustration
the reliability of R0 estimability of
at the
a stage
where
containment
might be
www.sciencemag.org/cgi/ Reassortment could
ity. A survey
network
in 2002
result- effective
surveillance.
the currentofH5N1

ted by different countries, and

fraction of isolates that unde
analysis and sequencing.
Surveillance of avian and liv
ticularly porcine) influenza is
tory. Government veterinary ser
sponsible for surveillance, wi
and Agriculture Organization (F
World Organization for Ani
(OIE) collating data from tho
submitting information on d
breaks. There is no systematic
for influenza in livestock or wild
on random sampling or other
sampling schemes. Most data
from outbreaks causing high m
mortality. Furthermore, outsid
veloped world, few countries h
erinary services infrastructure
effective surveillance. As the c
avian epidemic highlights, the
gin of pandemic influenza st
that improved surveillance an
animal (particularly avian) infl
to be a priorityas much to sa
lic health as to promote animal
The demands of annual va
ration inevitably mean that gre
sis is placed on monitoring an
ation and understanding its m
sis. However, improving pande
lance additionally requires m
(in secure laboratory settings)
the frequency of viral reassortm
exposed to multiple different
and to define the detailed gen
host specificity, pathogenicity
missibility (7).
How do we quantify the pos
a pandemic strains emerging,
we rapidly but reliably detec
gence of such a strain? Simple
cal analysis can provide some
any time point, the risk of a
event is proportional to the num
ple coinfected with human

Human infections & clusters are alone cause for enhanced

response.

Most timely response would be based on timely reporting of cases.

Public Health Risk from the

Avian H5N1 Influenza Epidemic

Threshold

POLICY FORUM

R0

Surveillance must be prompt.

Threshold

Pre-pandemic vaccine strain

selection

Timely development of vaccines could be transformative.

Vaccine seed stocks can speed this up, but also focus on other rate
limiting steps, esp. international agreements on regulation and conduct
of human trials.

Shouldnt aims be:

to prioritise strains with evidence of infection and transmission?

to cover antigen space, and monitor antigenic drift?

to plug gaps in surveillance?

to make more / faster seed stocks (Dormitzer et al. STM 2013)?

Conclusions

Direct benefits for enhanced surveillance and modelbased prediction of GOF experiment with PPP should not
be overstated.

Indirect benefits of basic science are likely huge, but

rationale for work dangerous pathogens requires benefits
that outweigh risks and opportunity costs.

Benefits of GOF with PPP for pre-pandemic vaccine

production should be probed in depth.

Risks are real and present (Lipsitch & Inglesby mBio

2014).