Risk analysis for measles reintroduction post global certification of

Risk
analysis
for
measles
reintroduction
post
global
certification
of
eradication
Dr
Ray
Sanders.
July
2010
Summary
and
conclusions
Measles
virus
will
continue
to
exist
after
certification
of
global
eradication
as
virus
stocks
and
infectious
materials
held
in
laboratories.
Live
virus
may
also
exist
in
undetected
foci
of
transmission
and
in
persistently
and
chronically
infected
individuals.
This
analysis
attempts
to
identify
and
evaluate
the
main
risks
for
re‐introduction
of
measles
transmission
post
certification
of
eradication
in
a
world
in
which
universal
routine
measles
immunization
is
no
longer
a
feature.
Risk
of
continuing,
undetected
wild‐type
measles
transmission
in
humans
There
are,
as
yet,
no
definitive
criteria
for
certification
of
global
measles
eradication
or
agreed
requirements
for
validation
of
these
criteria.
Without
these
criteria,
and
the
detailed
requirements
for
demonstrating
they
have
been
met,
it
is
not
possible
to
accurately
estimate
the
risk
presented
by
undetected
continuing
transmission.
Mild
or
asymptomatic
measles
infections
are
probably
very
common
among
measles‐immune
persons
exposed
to
measles
cases,
but
transmission
from
asymptomatic
cases
is
likely
to
be
very
rare.
If
it
occurs
it
is
unlikely
to
be
efficient
enough
to
sustain
transmission,
especially
in
the
highly
vaccinated
populations
expected
in
the
years
immediately
following
global
certification
of
eradication.
However,
the
potential
role
of
asymptomatic
infections
in
maintaining
transmission
requires
further
investigation.
If
the
criteria
for
global
certification
of
eradication
are
firm
enough,
and
require
rigorous
validation,
then
the
risk
of
undetected
measles
transmission
after
certification
is
very
low.
If
the
certification
criteria
are
lax,
or
validation
requirements
are
inadequate,
the
risk
will
be
higher.
Risk
of
transmission
of
vaccine‐derived
virus
The
currently
licensed
live‐attenuated
measles
vaccines
are
safe
and
efficient
and
have
been
used
successfully
to
protect
many
millions
of
individuals
and
prevent
measles
transmission.
All
current
vaccine
viruses
are
closely
related
and
belong
to
genotype
A.
There
is
no
published
conclusive
evidence
for
currently
licensed
live
attenuated
vaccine
viruses
reverting
to
wild‐type
transmissibility
or
virulence.
On
the
contrary,
the
vast
majority
of
evidence
points
to
an
impressive
level
of
genetic
stability.
However,
since
they
are
live
viruses
that
replicate
within
vaccine
recipients,
the
remote
possibility
must
exist
that
they
could
revert
to
wild‐type
characteristics.
There
is
also
no
evidence
for
the
establishment
of
vaccine‐escape
mutants.
Even
if
vaccine
viruses
were
to
revert
to
wild‐type
transmissibility,
there
is
no
reason
to
suspect
that
transmission
could
not
be
controlled
using
current
vaccines.
Risk
from
persistent
infections
There
is
no
published
evidence
that
cases
of
persistent
measles
infection
are
associated
with
the
shedding
of
infectious
virus
or
play
any
part
in
measles
transmission.
As
the
number
of
acute
measles
virus
cases
declines
in
the
years
leading
to
global
eradication,
we
can
expect
a
decline
in
the
Dr
Ray
Sanders.
Measles
re‐introduction
risk
analysis
number
of
potential
SSPE
and
MIBE
cases.
Acute
measles
infection
in
HIV‐infected
individuals
tends
to
be
more
severe,
last
longer
and
result
in
a
shorter
lived
immunity
to
re‐infection,
but
there
is
no
published
evidence
to
suggest
that
co‐infection
increases
the
potential
for
establishment
of
persistent
measles
infections,
either
with
wild‐type
virus
or
with
vaccine‐derived
virus.
Risk
from
non‐human
primates
Although
non‐human
primates
can
be
experimentally
and
naturally
infected
with
measles
virus,
and
animal‐animal
transmission
occurs,
population
sizes
are
too
small
to
maintain
epizootic
transmission
or
pose
a
threat
to
human
populations.
Risk
of
laboratory‐associated
measles
infection
Although
there
is
no
direct
evidence
for
laboratory‐acquired
measles
infections
it
is
possible
that
they
have
occurred
among
immune
laboratory
staff
and
resulted
in
asymptomatic
or
very
mild
infections.
There
is
no
published
evidence
to
suggest
that
these
asymptomatic
or
mild
infections
result
in
further
transmission
of
virus.
Measles
virus
loses
infectivity
within
a
few
hours
at
ambient
temperatures,
and
infectious
materials
stored
at
temperatures
above
‐30oC
can
be
expected
to
lose
all
infectivity
over
the
course
of
one
to
two
years.
Materials
stored
at
or
below
‐70oC,
or
freeze
dried,
maintain
infectivity
for
many
years.
Despite
the
lack
of
evidence
for
laboratory‐acquired
measles
infections
or
escape
of
virus
into
the
community,
these
must
be
considered
possibilities
in
a
post‐eradication
world.
An
appropriate
systematic
laboratory
containment
strategy
for
measles,
learning
from
the
example
set
by
the
Polio
Eradication
Initiative,
should
be
developed.
Risk
of
intentional
release
of
measles
virus
Measles
is
a
highly
infectious
virus
that
has
had
devastating
effects
on
susceptible
populations
in
the
past.
Although
it
is
unlikely
that
the
high
mortalities
seen
in
these
isolated
communities
would
be
repeated,
the
threat
of
measles
release
would
probably
be
very
effective
once
a
sizable
population
of
susceptible
individuals
had
accumulated.
This
threat
could
be
countered
by
the
establishment
of
a
measles
vaccine
stockpile,
preferably
using
a
new,
easy
to
mass‐administer,
non‐replicative
measles
vaccine.
The
size
and
nature
of
any
stockpile
should
be
defined
within
a
systematic
and
comprehensive
post‐eradication
risk
management
strategy.
Risks
for
reintroduction
of
measles
can
be
summarised
as
follows:
Magnitude
Tendency
over
time
Mitigating
actions
Continuing
wild‐type
measles
transmission
in
humans
Risk
Low
but
depends
on
certification
criteria
and
validation
requirements
Decreasing
Transmission
of
vaccine‐
derived
virus
Persistent
infections
Non‐human
primates
Laboratory‐associated
infection
Very
low
Depends
on
level
of
vaccine
use
Decreasing
Decreasing
Increasing
Base
certification
criteria
and
validation
requirements
on
dynamic
and
stochastic
modelling
data
Develop
alternative,
non‐
replicating
vaccines
Maintain
surveillance
Maintain
surveillance
Develop
systematic
laboratory
containment
strategy
Develop
vaccine
stockpiles
as
part
of
a
comprehensive
risk
management
strategy
Intentional
release
Very
low
Very
low
Very
low
but
rising
post
eradication
Very
low
but
rising
post
eradication
Page
2
Increasing
Dr
Ray
Sanders.
Measles
re‐introduction
risk
analysis
Areas
requiring
further
research
and
investigation
include:
Greater
understanding
of
the
transmission
dynamics
of
measles
Developing
more
models,
particularly
dynamic
and
stochastic
models
of
measles
transmission,
persistence
and
elimination
will
be
required
for
developing
the
certification
criteria
and
validation
requirements,
particularly
for
low‐income,
high
density
populations.
Additional
detailed
epidemiological
and
molecular
analysis
is
required
on
importations
and
outbreaks,
particularly
those
occurring
in
highly
immunized
populations
and
in
populations
with
recognized
inadequately
immunized
sub‐populations.
With
the
rapid
increase
in
the
number
of
highly
immunized
populations,
opportunities
for
studying
asymptomatic
and
atypical
infections
and
their
potential
role
in
transmission
should
be
taken.
Greater
understanding
of
the
changes
brought
about
by
the
attenuation
process
More
information
on
the
nature
of
the
changes
caused
by
attenuation
and
the
potential
for
vaccine
virus
reversion
to
wild‐type
characteristics
is
required.
More
understanding
of
the
nature
of
the
complex
interaction
between
measles
virus
and
the
host
immune
system,
including
both
humoral
and
cell‐mediated
responses,
would
probably
benefit
continued
use
of
existing
vaccines
and
development
of
new
vaccines.
All
genotype
A
viruses
detected
in
association
with
acute
cases
of
measles
and
atypical
vaccine
responses
should
be
thoroughly
scrutinized.
Full
epidemiological
information
will
be
required,
and
additional
sequence
data
from
both
clinical
samples
and
corresponding
viral
isolates
will
be
necessary
to
rule
out
the
possibility
of
transmission.
Page
3
Dr
Ray
Sanders.
Measles
re‐introduction
risk
analysis
Table
of
Contents
Error!
Bookmark
not
defined.
Page
4
Dr
Ray
Sanders.
Measles
re‐introduction
risk
analysis
Introduction.
We
do
not
yet
have
an
agreed,
definitive
definition
for
measles
eradication,
but
a
reasonable
definition
may
be:
“Interruption
of
measles
virus
transmission
globally
for
a
period
greater
than
or
equal
to
36
months,
in
the
presence
of
high‐quality
surveillance”
(modified
from
current
Global
and
Regional
definitions
of
Regional
elimination).
According
to
this
definition,
measles
virus
will
continue
to
exist,
as
virus
stocks
and
infectious
materials
held
in
laboratories.
Live
virus
may
also
continue
to
exist
in
persistently
and
chronically
infected
individuals.
What
risk
do
these
viruses
and
materials
pose
in
a
post‐eradication
world?
For
the
purposes
of
this
analysis
potential
risks
have
been
divided
into
two
categories:
•
•
‘natural’
–
associated
with
circulation
of
wild‐type
virus,
virus
persistence,
and
immunization
activities;
and
‘laboratory’
–
associated
with
laboratory
work,
storage
and
intentional
release.
These
two
categories
are
not
mutually
exclusive,
but
do
permit
a
more
systematic,
structured
assessment.
‘Natural’
risks
considered
include:
a)
b)
c)
d)
continuing
wild‐type
measles
transmission
in
undetected
human
reservoirs;
transmission
of
vaccine‐derived
virus;
persistent
and
chronic
infections;
non‐human
primate
reservoirs.
‘Laboratory’
risks
considered
include:
a)
b)
c)
d)
laboratory‐acquired
infections;
stored
infectious
materials;
virus
escape
into
the
community;
intentional
release.
If
universal
or
near‐universal
coverage
with
measles
vaccine
is
continued
after
global
eradication,
particularly
if
a
more
effective,
non‐replicating
vaccine
is
used,
the
risk
of
measles
reintroduction
will
be
minimal.
It
is
likely
that
a
number
of
national
authorities
will,
for
political
as
well
as
public
health
reasons,
choose
to
continue
routine
immunization
post
eradication.
Some
authorities
may
adopt
a
modified
immunization
schedule,
such
as
a
single‐dose
policy,
or
some
form
of
campaign
strategy.
It
is
also
likely
that
a
number
of
national
authorities,
either
through
decision
or
default,
will
cease
routine
measles
immunization.
For
the
purposes
of
this
analysis
it
has
been
assumed
that
universal
immunization
against
measles
will
not
be
continued
post
eradication,
and
that
an
increasing
global
population
will
be
susceptible
to
measles
infection
in
the
years
following
certification.
Page
5
Dr
Ray
Sanders.
Measles
re‐introduction
risk
analysis
The
analysis
concludes
with
a
brief
discussion
of
actions
required
to
reduce
the
risk
of
accidental
or
deliberate
release
of
measles
in
a
post‐eradication
world
and
areas
that
could
benefit
from
further
research.
Risk
of
continuing,
undetected
wild‐type
measles
transmission
in
humans
There
are,
as
yet,
no
definitive
criteria
for
certification
of
global
measles
eradication
or
agreed
requirements
for
validation
of
these
criteria.
Without
these
criteria,
and
the
detailed
requirements
for
demonstrating
they
have
been
met,
it
is
not
possible
to
accurately
estimate
the
risk
presented
by
undetected
continuing
transmission.
However,
based
on
current
Regional
and
Global
recommendations
on
certification
of
Regional
measles
elimination,
it
is
likely
that
eradication
criteria
will
include:
1.
2.
3.
Absence
of
circulating
measles
virus
for
at
least
one
year;
Adequate
surveillance
including
genotype
data.
Adequate
surveillance
may
be
defined
by:
• Number
of
reported
suspected
measles
cases
that
are
discarded
as
non‐measles
(targets:
≥
2/100,000
population
nationally,
≥
1/100,000
in
at
least
80%
of
districts)
• Percentage
of
reported
suspected
cases
that
have
adequate
investigation
within
48
hours
of
report
(target:
≥
80%
of
reported
suspected
cases)
• Percentage
of
reported
suspected
cases
that
have
adequate
specimens
collected
(target:≥
80%
of
reported
suspected
cases)
• Percentage
of
districts
with
access
to
a
WHO‐accredited
measles
diagnostic
laboratory
(target:
100%)
• Percentage
of
specimens
with
IgM
results
within
7
days
of
receipt
in
laboratory
(target:
≥
90%)
• Percentage
of
chains
of
transmission
with
RNA
sequence
analysis
(target:
≥
95%)
• Some
use
of
measles
avidity
assays
to
distinguish
recent
from
long‐standing
immunological
responses
• Some
demonstration
of
alternative
surveillance
mechanisms,
routine
or
supplementary,
based
on
case
detection,
investigation
and
reporting;
Achievement
of
high
population
immunity.
Population
immunity
may
be
demonstrated
by:
• ≥95%
coverage
with
routine
MCV2
in
all
districts,
or
• ≥80%
coverage
with
routine
MCV1
plus
≥95%
coverage
with
SIA
follow‐up
in
all
districts,
or
• Some
use
of
extensive
serosurvey
data.
From
experience
gained
through
Regional
polio
elimination
and
certification,
specific
criteria
may
be
used
to
fulfil
the
three
general
criteria
above,
but
it
is
unlikely
that
any
single
specific
indicator
will
be
required
to
pass
or
fail
validation.
The
strictness
and
extent
of
requirements
for
providing
evidence
that
certification
criteria
have
been
met
will
largely
determine
the
magnitude
of
risk
posed
by
undetected
continuing
measles
transmission.
But
even
with
relatively
lax
criteria
and
validation
requirements,
how
likely
is
it
that
ongoing
measles
transmission
will
be
undetected
for
a
minimum
of
one
year
before
certification?
Page
6
Dr
Ray
Sanders.
Measles
re‐introduction
risk
analysis
What
is
the
smallest
population
required
to
maintain
measles
transmission?
Measles
epidemics
have
generally
been
characterised
by
explosive
cycles
with
highly
complex
pathogen‐
and
population‐level
interactions
that
influence
transmission
dynamics
(1).
Accurately
predicting
the
critical
community
size
(CCS)
required
for
maintaining
measles
virus
circulation
is
difficult
due
to
the
large
number
of
variables
involved.
Direct
observation
and
a
range
of
both
deterministic
and
stochastic
models
suggest
that
a
population
of
250,000
to
400,000
with
5,000
to
10,000
births
per
year
is
required
to
maintain
transmission
(2,3).
High
levels
of
immunization,
low
population
density,
a
low
birth‐rate
and
good
public
health
care
facilities
increase
the
CCS.
Low
vaccine
uptake,
high
population
density,
high
birth‐rates,
high
levels
of
immunodeficiency
and
poor
public
health
care
facilities
decrease
the
CCS
(1,4,5).
Although
it
may
be
difficult
to
accurately
estimate
the
CCS
in
low‐income,
low
vaccine
coverage
populations,
it
is
easy
to
identify
these
populations.
If
disease
surveillance
and
immunization
activities
are
targeted
on
them,
and
on
any
new,
at‐risk
populations
that
may
emerge
following
displacement
caused
by
conflict
or
climate
change
(6),
the
potential
to
overlook
circulation
of
virus
in
the
year
leading
up
to
global
certification
will
be
greatly
reduced.
What
role
do
asymptomatic
infections
play
in
virus
transmission?
Measles
control
strategies
assume
that
virus
transmission
occurs
through
chains
of
clinically
recognizable
measles
cases,
and
the
surveillance
system
largely
relies
on
the
identification
of
these
cases
for
detecting
and
responding
to
outbreaks.
But
asymptomatic
infections
certainly
occur
and
may
play
an
important
role
in
measles
transmission.
Serological
evidence
for
acute
measles
infection
among
people
exposed
to
measles
virus
but
failing
to
develop
classical
symptoms
has
been
well
documented
(7,8,9,10,11,12,13,14,15)
and
it
has
long
been
recognized
that
measles
virus
can
infect
previously
immune
persons,
producing
classic
symptoms
of
measles
in
some,
but
mild
or
no
symptoms
in
most
(16,17,18,19,20).
The
estimated
rates
of
mild
or
asymptomatic
measles
infections
after
exposure
to
measles
cases
are
varied,
however,
in
part
because
of
different
diagnostic
techniques
and
different
case
definitions
used,
or
because
of
the
different
types
of
exposure.
In
several
studies
the
rates
of
mild
or
asymptomatic
infection
were
determined
during
outbreaks
in
which
persons
were
likely
to
have
had
multiple
exposures
to
measles
cases
(16,21,12,8).
A
study
of
mild
or
asymptomatic
measles
infections
among
44
persons
likely
to
have
been
exposed
to
classic
measles
during
a
3‐day
bus
trip
concluded
that
in
populations
with
high
levels
of
immunity
to
measles,
non‐classic
measles
infections
can
occur
in
at
least
20%
of
previously
immune
persons
with
close
exposure
to
a
person
with
classic
measles
(10).
It
is
possible
that
mild
or
asymptomatic
measles
infections
are
common
among
measles‐immune
persons
exposed
to
measles
cases
and
may
be
the
most
common
manifestation
of
measles
during
outbreaks
in
highly
immune
populations
(10).
Although
clinically
unimportant,
asymptomatic
measles
virus
infections
could
be
epidemiologically
important
if
infected
persons
are
capable
of
transmitting
virus.
Although
at
least
one
study
has
reported
isolation
of
measles
virus
from
an
asymptomatic
individual
in
close
contact
with
an
acute
case
(11),
another
study
failed
to
find
evidence
of
virus
shedding
from
11
seropositive
acute
case
contacts
(14).
If
transmission
from
asymptomatic
cases
does
occur,
it
is
likely
to
be
very
rare,
and
is
unlikely
to
be
efficient
enough
to
sustain
transmission
(11,15),
especially
in
the
highly
vaccinated
populations
expected
in
the
years
immediately
following
global
certification
of
eradication.
Page
7
Dr
Ray
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Measles
re‐introduction
risk
analysis
Conclusion
If
the
certification
criteria
are
firm
enough,
and
require
rigorous
validation,
then
the
risk
of
undetected
measles
transmission
after
Global
Certification
is
very
low.
If
the
certification
criteria
are
lax,
or
validation
requirements
are
inadequate,
the
risk
will
higher.
Risk
assessment:
The
risk
is
intuitively
low,
but
until
the
criteria
for
global
certification
of
measles
eradication
and
the
requirements
for
validation
are
established
it
is
not
possible
to
estimate
the
risk
posed
by
continuing
wild‐type
measles
transmission
in
undetected
reservoirs.
Risk
of
transmission
of
vaccine‐derived
virus
The
development
of
live
attenuated
measles
virus
vaccines
began
soon
after
isolation
of
the
virus
by
Enders
and
Peebles
in
1954
(22).
The
first
licensed
attenuated
measles
vaccine
was
Edmonston
B,
used
between
1963
and
1975
but
frequently
associated
with
fever
and
rash
(23).
The
further
attenuated
Schwarz
and
Moraten
strains
were
derived
from
the
original
Edmonston
strain
through
additional
passages
in
chick
embryo
fibroblasts
(Figure
1).
Despite
differences
in
their
passage
history,
these
two
vaccine
strains
have
identical
genomic
sequences
(24).
The
Moraten
vaccine
is
widely
used
in
the
United
States
of
America;
the
Schwarz
vaccine
is
used
in
many
countries
throughout
the
world,
and
the
Edmonston‐Zagreb
vaccine,
similarly
derived
from
the
Edmonston
B
strain,
is
the
most
widely
used
strain
in
developing
countries.
Other
attenuated
measles
vaccines
have
been
produced
from
locally
derived
wild‐type
strains,
particularly
in
the
Russian
Federation
(Leningrad‐16),
the
People’s
Republic
of
China
(Shanghai‐191)
and
Japan
(CAM‐70,
AIK‐C)
(23).
All
of
the
current
vaccine
viruses
are
well
documented
and
well
characterised
with
regard
to
provenance,
immunogenicity,
thermal
stability
and
genomic
structure
(25,26,27,28,29,30,31,32,33).
Although
current
vaccine
viruses
and
their
wild‐type
progenitors
share
more
than
95%
sequence
homology,
they
can
easily
be
distinguished
genetically
from
currently
circulating
wild‐type
viruses.
Page
8
Dr
Ray
Sanders.
Measles
re‐introduction
risk
analysis
Figure
1.
Relationships
of
major
current
measles
vaccine
viruses
(from
Moss
&
Scott,
2009
(23)).
Measles
virus
is
considered
to
be
one
of
the
most
contagious
of
human
pathogens,
with
a
very
high
level
of
transmissibility.
Like
wild‐type
virus,
measles
vaccine
virus
replicates
effectively
within
vaccine
recipients,
inducing
both
humoral
and
cellular
immune
responses
similar
to
natural
measles
virus
infection,
although
these
responses
are
of
lower
magnitude
and
shorter
duration.
Approximately
5%
of
children
develop
fever
and
rash
after
receiving
measles
vaccine,
and
viral
RNA
can
be
detected
in
the
urine
and
respiratory
secretions
for
some
days
post‐immunization
(34).
Vaccine
virus
can
be
isolated
from
the
blood
of
recent
vaccine
recipients,
and
has
been
detected
in
samples
of
lung,
liver,
bone
marrow
or
brain
tissues
in
the
very
rare
cases
of
severe
acute
disease
following
measles
vaccination
(35).
Virus
RNA
and
antigen
can
be
detected
in
the
urine
of
vaccine
recipients
for
up
to
14‐16
days
post‐immunization
(36,37),
but
there
is
no
published
evidence
for
the
transmission
of
vaccine
virus.
Obviously
the
changes
caused
by
the
attenuation
process
effectively
block
transmissibility.
Is
it
possible
for
vaccine
virus
to
regain
the
transmissibility
characteristics
of
wild‐type
virus?
The
reasons
for
non‐transmission
of
vaccine
viruses
are
not
fully
understood,
and
are
likely
to
be
complex.
It
has
been
proposed
that
loss
of
ability
to
interact
with
epithelial
cell
receptors
is
a
key
factor
(38,39,40).
It
is
also
possible
that
modification
of
the
virus
matrix
(M)
protein,
known
to
be
important
in
virus
budding
from
infected
cells
(41),
contributes
to
loss
of
transmissibility.
The
ability
of
vaccine
viruses
to
interfere
with
the
innate
immune
response
may
also
be
a
key
factor.
Whatever
the
reason,
it
appears
that
the
block
on
transmission
of
vaccine
viruses
is
highly
effective.
Measles
virus
is
serologically
monotypic
and
is
genetically
characterized
into
eight
clades
(A–H),
divided
into
23
recognized
genotypes
(42,43,44).
All
of
the
current
vaccines,
whether
derived
from
Edmonston
or
not,
share
a
remarkable
nucleotide
sequence
similarity
and
all
are
members
of
genotype
A
(45,24).
During
the
1950s
and
1960s,
only
measles
viruses
belonging
to
genotype
A
were
Page
9
Dr
Ray
Sanders.
Measles
re‐introduction
risk
analysis
isolated
and
may
have
had
a
world‐wide
distribution
before
vaccination
started
(46,47,48).
This
is
not
the
situation
today,
when
the
identification
of
non‐vaccine
related
genotype
A
viruses
is
very
unusual.
Over
the
past
fifteen
years
a
massive
amount
of
work
has
been
put
into
characterizing
measles
viruses
associated
with
outbreaks.
Although
there
are
still
gaps,
viruses
from
most
major
outbreaks
and
from
importations
in
areas
that
have
eliminated
indigenous
measles,
are
currently
being
sequenced
and
genetically
characterized
through
the
WHO
Laboratory
Network’s
activities.
We
now
have
a
reasonably
comprehensive
understanding
of
which
viruses
are
circulating
where
(42,43,44,49,50,51,52,53).
Against
a
background
of
several
thousand
isolates
characterized,
very
few
genotype
A
viruses
have
been
identified
during
the
past
20
years.
With
the
possible
exception
of
viruses
isolated
in
the
UK
in
1993
(54),
none
has
been
associated
with
outbreaks.
When
detected
they
have
been
sporadic
cases
with
uncertain
epidemiology,
closely
associated
with
very
recent
receipt
of
vaccine,
or
queried
as
laboratory
contaminants
(43,55,56,57,58,59,60,61,62).
Table
1
summarizes
the
published
documentation
on
the
detection
of
genotype
A
measles
viruses
since
1990.
Year
of
detection
Country
State/Province/Region
Number
of
isolates
Reference
1990
Japan
Handai?
1
(62)
1991
Argentina
Buenos
Aires
1
(63)
1993
UK
Coventry,
England
5
(54)
1995
South
Africa
Johannesburg
1
(64)
1996
Russian
Federation
Novosibirsk,
Siberia
3
(56)
1996
USA
Delaware
1
(60)
1996
China
Hunan
1
(55)
1996
UK
?
2
(58)
1996
South
Africa
Johannesburg
1
(57)
1998
UK
Importation
from
Russia
1
(58)
1999
Argentina
Buenos
Aires
2
(63)
1999
China
Henan
1
(55)
2000
UK
?
1
(58)
2001
Spain
Ibiza
1
(59)
2002
Spain
Madrid/Badajos
2
(59)
2003
Spain
Almeria
3
(59)
2003
China
Xinjiang
1
(55)
2005
Taiwan
Taichung/Taipei
2
(61)
2007
Taiwan
Tainan/Taipei
2
(61)
Table
1.
Published
documentation
on
isolation
and
characterization
of
genotype
A
measles
viruses
from
1990
to
May
2010.
Table
1
includes
isolates
that
may
represent
wild‐type
lineages
that
have
survived
since
the
pre‐
vaccination
era.
It
also
includes
viruses
isolated
from
very
recent
vaccine
recipients
presenting
with
classic
measles
symptoms.
But
it
may
also
include
vaccine‐derived
isolates
that
have
been
transmitted
from
vaccine
recipients
to
unvaccinated
contacts.
Although
some
of
these
genotype
A
viruses
have
nucleotide
substitutions
that
distinguish
them
from
vaccine
viruses,
there
is
no
published
documentation
identifying
a
distinct
set
of
genetic
markers
that
consistently
differentiates
wild‐type
viruses
from
attenuated
viruses
(46).
Measles
vaccine
viruses
re‐isolated
from
Page
10
Dr
Ray
Sanders.
Measles
re‐introduction
risk
analysis
immunosuppressed
patients
with
giant
cell
pneumonia
have
nucleotide
sequences
almost
identical
to
those
of
the
vaccine
virus,
suggesting
that
vaccine
viruses
are
very
stable
even
after
prolonged
replication
in
a
human
host
(46).
Numerous
published
studies
of
several
thousands
of
isolates
from
acute
measles
cases
investigated
over
the
past
20
years
have
failed
to
detect
genotype
A
viruses
(52,53,65,66,67,68,51,50,69,70)
(71,72,73,74,75,76,77,78,79,80)
(81,82,83).
Because
of
the
increasing
intensity
of
measles
immunization
programmes,
genotype
A
viruses,
in
the
form
of
vaccine
viruses,
should
be
the
most
abundant
measles
genotype
on
Earth.
Given
that
they
are
so
infrequently
isolated
from
measles
cases,
the
molecular
epidemiological
data
appears
to
support
the
contention
that
vaccine
viruses
do
not
readily
revert
to
wild‐type
transmissibility.
What
is
the
risk
of
measles
vaccine‐escape
mutants?
There
is
no
conclusive
published
evidence
for
the
emergence
of
measles
vaccine
escape
mutants
(84).
Measles
is
a
typical
RNA
virus
in
that
intrinsic
errors
of
the
RNA
polymerase
and
lack
of
proofreading
mechanisms
results
in
a
mutation
rate
of
9x10‐5
per
base
per
replication
and
a
genomic
mutation
rate
of
1.4
per
replication
(85).
This
is
well
within
the
typical
range
of
10‐3
to
10‐6
mutations
per
site
per
replication
(86).
As
a
consequence
of
this
high
mutation
rate,
RNA
virus
populations,
even
those
initiated
by
a
single
infectious
unit,
are
not
clonal
but
consist
of
a
large
number
of
genetic
microvariants
referred
to
as
quasispecies.
Despite
the
high
mutation
rate,
and
unlike
other
RNA
viruses
such
as
influenza
and
HIV,
measles
virus
remains
remarkably
stable.
How
can
live
attenuated
vaccines
developed
from
wild
type
measles
viruses
more
than
half
a
century
ago
still
be
effective
against
circulating
viruses?
The
answer
is
probably
associated
with
use
of
the
signalling
lymphocytic
activation
molecule
(SLAM;
also
known
as
CD150)
receptor
by
the
measles
haemagglutinin
(H)
protein,
which
is
responsible
for
cell
attachment
and
is
a
major
target
for
neutralizing
antibodies
(87).
The
envelope
of
measles
virus
has
two
types
of
glycoprotein
spikes,
designated
haemagglutinin
(H)
and
fusion
(F)
proteins.
The
H
protein
binds
to
specific
molecules
(receptors)
on
target
cells,
while
the
F
protein
mediates
membrane
fusion
between
the
virus
envelope
and
the
host
cell
plasma
membrane
through
cooperation
with
the
H
protein.
In
2000,
SLAM
was
identified
as
a
cell
receptor
for
measles
virus
(88).
SLAM
is
expressed
on
cells
of
the
immune
system,
such
as
activated
lymphocytes
and
dendritic
cells
(89).
Studies
on
the
crystalline
structure
of
the
H
protein
have
shown
that
although
most
of
this
glycoprotein
is
covered
by
sugar
chains,
the
large
surface
area
that
hosts
the
SLAM
binding
site
is
free
from
sugar
chains
(90).
Mutations
in
this
region
are
not
permitted
because
they
interfere
with
receptor
binding.
This
extreme
sequence
restriction
allows
for
very
efficient
production
of
neutralizing
antibodies
that
block
binding
of
the
virus
to
its
receptor.
So
the
original
vaccine
strains,
developed
in
the
1960s,
are
still
effective
against
current
wild‐type
viruses
(91).
Analysis
of
available
sequence
data
from
approximately
500
isolates
suggests
that
despite
the
error‐prone
viral
polymerase,
the
amino
acid
sequence
of
H
is
strongly
conserved,
with
60%
of
the
residues
being
identical
or
very
similar
(92).
It
appears
that
any
mutation
that
changes
the
nature
of
these
conserved
residues
results
in
non‐viable
virus.
Conclusion
There
is
no
current
published
data
to
support
evidence
for
currently
licensed
live
attenuated
vaccine
viruses
reverting
to
wild‐type
transmissibility.
On
the
contrary,
the
vast
majority
of
evidence
points
Page
11
Dr
Ray
Sanders.
Measles
re‐introduction
risk
analysis
to
an
impressive
level
of
genetic
stability.
However,
since
they
are
live
viruses
that
replicate
within
vaccine
recipients,
the
possibility
must
exist
that
they
could
revert
to
wild‐type
transmissibility.
There
is
strong
experimental
evidence
for
the
monotypic
nature
and
genetic
stability
of
measles
virus
being
based
on
use
of
the
SLAM
receptor.
There
is
also
no
evidence
for
the
establishment
of
vaccine‐escape
mutants.
Even
if
vaccine
viruses
were
to
revert
to
wild‐type
transmissibility,
there
is
no
reason
to
suspect
that
transmission
could
not
be
controlled
using
current
vaccines.
Risk
assessment:
Available
information
suggests
that
the
risk
of
current
live‐attenuated
vaccine
viruses
reverting
to
wild‐type
transmissibility
is
very
low,
but
it
remains
a
possibility.
Risk
from
persistent
infections
How
long
does
measles
infection
usually
persist?
In
classic
measles
cases
there
is
a
10–14
day
incubation
period
between
infection
and
the
onset
of
clinical
signs
and
symptoms,
and
infected
persons
are
usually
contagious
from
2–3
days
before
and
up
to
four
days
after
onset
of
the
rash.
Host
immune
responses
to
measles
virus
are
essential
for
viral
clearance,
clinical
recovery
and
the
establishment
of
long‐term
immunity.
Early
innate
immune
responses
occur
during
the
prodromal
phase
and
include
activation
of
natural
killer
(NK)
cells
and
increased
production
of
interferons
(IFN)‐α
and
β
(23,93,94).
However,
the
mechanisms
and
timing
of
normal
measles
virus
clearance
are
poorly
understood.
Measles
virus
has
been
isolated
from
peripheral
blood
mononuclear
cells
(PBMC)
up
to
a
week,
and
from
urine
up
to
10
days,
after
appearance
of
the
rash
(95,96).
Delayed
virus
clearance
has
been
documented
in
cases
of
malnutrition
(97,98,99)
and
patients
with
cellular
immunity
deficiencies
(100,101,102).
Detection
of
measles
virus
RNA
has
been
reported
for
up
to
4
months
in
a
case
of
congenital
measles
(103),
for
1
to
4
months
after
uncomplicated
infection
in
90%
of
HIV‐1‐infected
children
and
more
than
50%
of
HIV
non‐infected
children
(104,105,106,107).
These
data
are
consistent
with
studies
of
rhesus
macaques
showing
that
virus
clearance
occurs
over
120–150
days
(108),
suggesting
that
normal
clearance
is
a
prolonged
process.
Despite
the
reported
persistence
of
viral
RNA,
there
have
been
no
reports
of
infectious
virus
shedding
more
than
3
to
4
weeks
after
appearance
of
symptoms
(98,99).
Persistent
infection
with
measles
virus
has
definitively
been
associated
with
subacute
sclerosing
panencephalitis
(SSPE),
a
progressive
fatal
neurological
disease
with
high
levels
of
neuronal
infection
by
measles
virus
in
the
central
nervous
system
(94).
In
immunocompromised
patients,
persistent
measles
virus
has
been
linked
to
another
neurological
infection,
measles
inclusion
body
encephalitis
(MIBE)
(109).
Multiple
sclerosis,
chronically
active
autoimmune
hepatitis,
Paget’s
disease,
otosclerosis,
Crohn’s
disease
and
autism,
among
many
other
diseases,
have
also
been
suggested
at
various
times
as
long‐term
sequelae
of
measles
virus
infection.
No
confirmed
evidence
has
been
presented,
however,
to
substantiate
these
associations,
let
alone
prove
a
causative
relationship.
What
is
the
risk
from
SSPE
cases?
SSPE
is
a
slow,
progressive
disease
that
is
invariably
fatal.
The
average
period
from
initial
measles
infection
to
SSPE
symptom
onset
(latency)
usually
ranges
between
4
and
10
years,
but
has
been
reported
from
2
months
to
23
years
(110).
Children
are
far
more
likely
to
develop
this
complication
than
adults.
Reported
SSPE
incidence
varies
from
approximately
0.2
to
40
cases
per
million
population
per
year.
Direct
comparison
of
data
from
different
countries
is
problematic
because
Page
12
Dr
Ray
Sanders.
Measles
re‐introduction
risk
analysis
methods
and
quality
of
diagnosis
have
been
inconsistent.
Analyses
of
data
from
the
UK
and
USA
have
calculated
the
true
incidence
of
SSPE
to
be
approximately
4–11
cases
of
SSPE
per
100
000
cases
of
measles.
A
higher
risk
is
associated
with
earlier
infection:
the
risk
following
measles
infection
under
1
year
of
age
is
18/100
000
compared
with
1.1/100
000
after
5
years
of
age
in
the
UK
(110).
Obviously,
as
the
number
of
measles
infections
declines,
so
will
the
number
of
potential
SSPE
cases.
The
disease
initially
manifests
as
subtle
cognitive
losses,
progressing
to
more
overt
cognitive
dysfunction,
followed
by
motor
loss,
seizures
and
eventual
organ
failure
in
virtually
all
affected
individuals.
Neurons
in
both
the
gray
and
white
matter
are
infected,
and
the
disease
is
histologically
characterized
by
the
presence
of
cellular
inclusion
bodies
(111).
A
serologic
hallmark
of
SSPE,
as
compared
to
the
other
central
nervous
system
complications,
is
the
elevation
of
measles
specific
antibodies
in
the
blood
and
cerebrospinal
fluid
(94).
Most
importantly,
evidence
from
brain
biopsies
of
SSPE
patients
indicates
that
infected
neurons
do
not
release
budding
virus
(112).
Based
on
sequencing
studies
of
virus
from
these
specimens
and
from
cells
persistently
infected
with
measles
virus
isolates
from
SSPE
patients,
it
has
been
proposed
that
the
failure
of
infected
neurons
to
produce
complete
extracellular
virus
may
be
due
to
defects
in
protein
expression
caused
by
extensive
point
mutations
in
the
H,
fusion
(F)
and
matrix
(M)
genes
(113,94,114,115,116).
There
is
no
evidence
for
transmission
of
measles
virus
from
SSPE
cases.
What
is
the
risk
from
MIBE
cases?
Measles
inclusion
body
encephalitis
(MIBE)
is
a
rare
central
nervous
system
complication
following
acute
MV
infection,
has
been
described
in
children
and
adults
receiving
immunosuppressive
drugs
and
therefore
is
thought
to
chiefly
affect
immunocompromised
hosts.
MIBE
has
also
been
reported
to
result
from
receipt
of
measles
vaccine
(117).
The
neurologic
disease
usually
appears
3
to
6
months
after
the
acute
measles
rash
(111),
with
a
median
time
of
4
months
(118).
Measles
antigen
is
present
in
the
brain,
and
virus
has
been
isolated
directly
from
the
brains
of
affected
individuals
(111,119).
MIBE
differs
from
SSPE
in
the
absence
of
elevated
serum
and
cerebrospinal
fluid
neutralizing
antibodies
(94).
The
disease
course
is
relatively
short,
lasting
from
days
to
weeks,
causing
seizures,
motor
deficits,
and
stupor,
often
leading
to
coma
and
death.
Although
only
a
very
small
percentage
of
acute
measles
infections
will
go
on
to
develop
persistent
complications,
a
few
studies
have
detected
measles
virus
RNA
in
various
organs,
on
autopsy,
of
elderly
individuals
who
died
of
non‐viral
causes
(120,121).
These
findings
suggest
that
measles
virus
persists
in
the
brains
(and
other
organs)
of
healthy
individuals,
and
may
manifest
itself
in
central
nervous
system
disease
under
conditions
of
immunocompromise
or
immunosuppression.
This
has
been
underlined
by
the
case
of
a
13
year‐old
boy
that
developed
MIBE
after
receiving
a
stem
cell
transplant
(119).
Neither
the
patient
nor
the
stem
cell
donor
had
apparent
recent
measles
exposure
or
vaccination,
and
neither
had
recent
travel
to
measles‐endemic
regions.
The
patient
was
born
in
Chicago
during
the
measles
epidemic
of
1989‐1991
(birth
year
1989).
An
undiagnosed
case
of
measles
in
the
period
1989‐1991
would
suggest
a
latency
period
to
MIBE
of
12
years,
which
is
not
typical.
Cases
of
MIBE
without
clear
measles
exposure
or
infection
have
been
reported.
In
a
review
of
MIBE,
18%
of
patients
had
no
documented
measles
exposure
or
infection
(118);
however,
many
of
these
cases
occurred
in
years
when
measles
was
more
prevalent.
There
are
no
published
reports
of
infectious
measles
virus
shedding
from
MIBE
cases.
Page
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Dr
Ray
Sanders.
Measles
re‐introduction
risk
analysis
Does
HIV
co‐infection
present
a
risk
for
persistent
measles
infection
and
transmission?
As
discussed
above,
measles
virus
RNA
could
be
detected
in
samples
from
90%
of
HIV‐infected
children
one
month
after
recovery
from
acute
measles
(104),
but
in
this
study
no
attempt
was
made
to
culture
virus
from
any
samples.
In
regions
of
high
HIV‐1
prevalence,
co‐infection
with
HIV‐1
more
than
doubles
the
odds
of
death
in
hospitalized
children
with
measles
(122)
and
may
slow
the
rate
of
virus
clearance
slightly,
but
there
is
no
evidence
that
HIV‐infection
leads
to
an
increased
risk
for
persistent
measles
virus
infection.
Nor
does
HIV
infection
appear
to
present
a
risk
for
persistent
infection
with
the
measles
vaccine
virus.
A
search
for
persistent
measles
mumps
and
rubella
vaccine
viruses
in
children
with
HIV‐1
infection
failed
to
detect
virus
in
peripheral
blood
mononuclear
cells,
polymorphonuclear
leukocytes,
or
plasma
(123).
Conclusion
There
is
no
published
evidence
that
cases
of
persistent
measles
infection
are
associated
with
the
shedding
of
infectious
virus
or
play
any
part
in
measles
transmission.
As
the
number
of
acute
measles
virus
cases
declines
in
the
years
leading
to
global
eradication,
we
can
expect
a
decline
in
the
number
of
potential
SSPE
and
MIBE
cases.
Acute
measles
infection
in
HIV‐infected
individuals
tends
to
be
more
severe,
last
longer
and
result
in
a
shorter
lived
immunity
to
re‐infection,
but
there
is
no
published
evidence
to
suggest
that
co‐
infection
increases
the
potential
for
establishment
of
persistent
measles
infections,
either
with
wild‐
type
virus
or
with
vaccine‐derived
virus.
Risk
assessment:
Available
information
suggests
that
the
relatively
small
number
of
persistent
measles
virus
cases,
including
those
that
may
result
from
co‐infection
with
HIV,
pose
a
very
low
risk
for
reintroduction
of
measles.
Risk
from
non‐human
primates
A
large
proportion
of
our
current
knowledge
of
measles
and
measles
infection
mechanisms
have
come
from
experimental
infection
of
non‐human
primates.
In
1911,
Goldberger
and
Anderson
demonstrated
that
macaques
inoculated
with
filtered
secretions
from
measles
patients
developed
measles,
proving
the
causative
agent
was
a
virus
(124).
A
wide
range
of
non‐human
primate
species
are
susceptible
to
experimental
infection
with
measles
virus.
These
include
Macaca
mulatta,
M.
fascicularis,
M.
radiata,
M.
cyclopis,
Papio
cristatus,
Cercopithecus
aethiops,
Saimiri
sciureus,
Colobus
quereza,
Pan
troglodytes,
Callithrix
jacchus,
Saguinus
oedipus,
S.
fuscicollis,
and
Aotus
trivirgatus
and
Ateles
species
(125,126,127).
As
would
be
expected
from
an
effective
animal
model,
many
species
respond
to
infection
in
a
manner
very
similar
to
humans
(128,129,130).
Inadvertent
transmission
of
either
measles
(from
humans)
or
the
closely
related
canine
distemper
virus
(from
dogs)
to
captive
non‐human
primates
has
caused
numerous
outbreaks
with
significant
morbidity
and
mortality
(131,127,132,133,134).
Non‐human
primates
in
the
wild
appear
to
be
free
from
measles,
only
contracting
infection
when
they
come
into
contact
with
infected
humans
(125).
Human‐to‐
primate
disease
transmission
can
potentially
cause
significant
morbidity
and
mortality
among
wild
primate
populations.
Serological
evidence
of
measles
infection
in
free‐ranging
populations
of
non‐
human
primates
has
been
well
documented
(135,136,137).
Evidence
exists
of
measles
infection
in
non‐human
primate
populations
with
frequent
contact
with
human
populations,
as
well
as
in
wild
Page
14
Dr
Ray
Sanders.
Measles
re‐introduction
risk
analysis
populations
with
minimal
human
contact
(127).
A
cross‐sectional
study
of
wild
macaques
(Macaca
tonkeana)
in
Sulawesi,
Indonesia,
found
serological
evidence
of
measles
evidence
in
5
of
15
animals
surveyed
(136).
Because
human
populations
represent
the
largest
reservoir
of
the
measles
virus,
it
is
most
likely
that
measles
epizootics
in
non‐human
primate
populations
are
initiated
by
human
to
non‐human
primate
transmission
and
subsequently
spread
by
animal
to
animal
transmission.
Due
to
their
relatively
small
numbers,
it
is
unlikely
that
natural
populations
of
non‐human
primates
are
significant
or
sustainable
reservoirs
of
measles
virus
(127).
Conclusion
Although
non‐human
primates
can
be
experimentally
and
naturally
infected
with
measles
virus,
and
animal
to
animal
transmission
occurs,
population
sizes
are
too
small
to
maintain
epizootic
transmission.
Risk
assessment:
Available
information
suggests
that
infections
in
non‐human
primates
pose
a
very
low
risk
for
reintroduction
of
measles.
Risk
of
laboratory‐associated
measles
infection
Risks
posed
by
laboratory‐maintained
measles
viruses,
through
accidental
or
intentional
release,
are
largely
dependent
on
whether
universal
immunization
against
measles
is
continued
or
if
it
is
stopped
on,
or
soon
after,
global
certification.
If
the
decision
is
made
to
continue
universal
immunization,
possibly
with
non‐replicating
vaccines,
the
risk
posed
by
laboratory‐maintained
virus
will
be
very
low,
since
there
will
be
almost
universal
immunity.
If,
however,
universal
immunization
stops
after
global
certification,
the
risks
posed
by
laboratory‐maintained
measles‐infectious
materials
will
progressively
increase,
as
the
number
of
measles‐susceptibles
in
the
population
increases.
The
risks
include
not
only
accidental
release
of
live
measles
virus
from
laboratories
and
attenuated
virus
vaccine
production
facilities,
but
threat
of
deliberate
release.
What
is
the
evidence
for
laboratory‐acquired
measles
infection?
A
series
of
surveys
for
laboratory‐acquired
infections
conducted
in
the
UK
(138,139,140,141,142,143,144),
the
USA
(145,146,147,148,149)
and
Japan
(150)
failed
to
include
measles
among
the
listed
infections.
A
recent
review
of
principles
for
prevention
of
laboratory‐
associated
infections
also
failed
to
make
mention
of
measles
(151).
An
extensive
literature
search
failed
to
find
documented
evidence
of
laboratory‐acquired
measles
infection.
This
leaves
three
possibilities:
laboratory‐acquired
measles
infections
have
not
occurred;
the
infections
that
have
occurred
have
been
below
the
threshold
of
sensitivity
of
the
surveillance
systems;
or,
measles
has
been
considered
a
trivial
disease
and
infections
have
not
been
reported
(152,153).
Prior
to
the
1970s
it
is
to
be
expected
that
almost
all
staff
working
in
clinical
microbiology
and
research
laboratories
would
have
been
exposed
to
measles
infection
during
childhood.
From
the
1970s
onwards
it
is
to
be
expected
that
all
new
staff
coming
to
work
in
these
laboratories
would
have
received
at
least
one
dose
of
measles
vaccine.
It
is
unlikely
therefore,
that
exposed
laboratory
staff
would
develop
acute
measles
symptoms
from
laboratory‐acquired
infections.
But
given
the
very
high
transmissibility
of
measles
virus,
it
is
possible
that
exposure
to
infectious
virus,
and
Page
15
Dr
Ray
Sanders.
Measles
re‐introduction
risk
analysis
resulting
asymptomatic
infections,
or
very
mild,
atypical
infections
have
occurred.
If
they
have
occurred,
it
is
probable
that
these
infections
have
gone
undetected,
or
simply
overlooked
as
unimportant.
How
stable
is
measles
virus
in
the
environment
and
in
laboratory
materials?
Measles
is
not
a
physically
robust
virus.
It
is
viable
for
less
than
2
hours
at
ambient
temperatures
on
surfaces
and
objects,
while
the
aerosolized
virus
typically
remains
infective
for
only
30
minutes
to
2
hours,
depending
on
environmental
conditions
(154,155).
It
is
very
sensitive
to
heat
and
is
inactivated
after
less
than
40
minutes
at
56°C,
even
in
medium
containing
a
protein
stabilizer
such
as
5%
calf
serum
(156).
Virus
in
maintenance
medium
loses
at
least
2
logs
of
titre
when
stored
at
+6oC
for
14‐20
weeks
and
loses
all
infectivity
after
1
year
at
this
temperature.
Addition
of
a
protein
stabilizer
improves
virus
longevity,
with
a
loss
of
approximately
2
logs
of
titre
after
1
year
at
+6oC.
Interestingly,
storage
at
‐30oC
offers
little
advantage
over
storage
at
+6oC,
with
a
1‐2
log
loss
of
titre
over
1
year.
Storage
at
‐72oC
or
below
results
in
very
little
loss
of
virus
infectivity,
and
infectious
materials
maintained
at
this
temperature
should
retain
infectivity
for
many
years
(156).
The
virus
survives
freeze‐drying
relatively
well
and,
when
freeze‐dried
with
a
protein
stabilizer,
can
survive
storage
for
decades
at
‐70oC
(156,155).
In
common
with
many
other
enveloped
viruses
it
is
inactivated
by
solvents,
such
as
ether
and
chloroform,
by
acids
(pH<5),
alkalis
(pH>10),
and
by
UV
and
visible
light.
It
is
also
susceptible
to
many
disinfectants,
including
1%
sodium
hypochlorite,
70%
alcohol
and
formalin.
Which
laboratory
materials
present
a
risk?
Measles
virus
infectious
materials
include
autopsy
or
clinical
samples
(e.g.
pharyngeal
secretions,
urine,
blood)
from
measles‐infected
persons
or
recent
live‐attenuated
vaccine
recipients,
and
laboratory
derived
materials
(e.g.
virus
isolates
and
reference
stocks,
materials
derived
from
inoculated
cell
cultures,
laboratory
animals).
Measles
virus
potential
infectious
materials,
those
that
are
suspected
to
contain
infectious
measles
viruses,
include
pharyngeal
secretions
and
blood
samples
collected
for
any
purpose
at
a
time
and
in
a
place
where
measles
viruses
were
circulating,
and
stored
under
conditions
that
would
preserve
virus
infectivity.
They
also
include
products
of
these
materials
in
measles
virus
permissive
cells
or
animals
(157).
What
types
of
risk
do
laboratories
present?
Risks
post
measles
eradication
will
exist
at
two
levels:
• occupational
risk
of
exposure
among
laboratory
staff,
• community
risk
of
laboratory‐associated
measles
exposure.
The
three
most
common
routes
of
exposure
to
infectious
agents
in
the
laboratory
are
ingestion,
inhalation,
and
injection
(153).
Measles
virus
can
remain
infectious
on
surfaces,
such
as
work
benches
and
door
handles,
for
up
to
two
hours.
If
transferred
from
the
hand
to
the
mouth,
nose
or
conjunctiva,
they
can
initiate
infection
of
epithelial
cells
(158).
Although
there
are
no
recorded
incidents
of
laboratory‐acquired
measles
virus
infections,
several
surveys
document
the
frequent
occurrence
of
ingesting
more
readily
recognized
pathogens,
such
as
Shigella
and
Salmonella
(139,140,141,142,143,147,153).
The
most
common
route
for
natural
transmission
of
measles
is
believed
to
be
by
inhalation
of
aerosolized
virus;
infectious
droplets
being
produced
by
talking,
coughing
and
sneezing
by
infected
individuals
(158).
Small
particles
(<5‐μ
droplet
nuclei)
of
suspended
evaporated
residues
can
move
about
rooms
and
buildings
on
air
currents
and
when
Page
16
Dr
Ray
Sanders.
Measles
re‐introduction
risk
analysis
inhaled
deposit
primarily
in
the
lower
respiratory
tract
(159).
Laboratory
activities
that
expose
staff
to
aerosols
generated
from
infectious
material
(e.g.
centrifugation,
blending,
vigorous
pipetting,
etc.),
and
exposure
to
infected
laboratory
animals,
present
a
risk
for
infection.
The
most
common
route
for
delivery
of
current
measles
vaccines
is
by
injection.
So,
injection
and
needle‐stick
injuries
involving
measles
virus
infectious
materials
obviously
present
a
risk
for
infection.
Community
members
may
be
exposed
to
infectious
measles
virus
from:
• contaminated
laboratory
workers,
• infected
laboratory
workers,
• contaminated
air
effluents,
• transport
of
infectious
material,
• escaped
infectious
animals.
Again,
no
published
evidence
exists
for
the
escape
of
infectious
measles
virus
from
the
laboratory
into
the
community.
Given
the
rapid
inactivation
of
measles
virus
under
normal
environmental
conditions,
the
length
of
time
available
for
infectious
virus
to
be
carried
out
of
the
laboratory
and
into
the
community,
either
on
the
body
or
clothes
of
a
contaminated
worker,
or
in
contaminated
air
effluents,
is
probably
limited
to
2
hours.
This
reduces
the
risk
to
a
very
low
level.
As
discussed
above,
available
evidence
suggests
that
immunized
individuals,
who
develop
asymptomatic
or
mild
infections,
are
unlikely
to
transmit
the
virus
(10),
reducing
the
community
risk.
We
can
assume
that
laboratories
implementing
good
laboratory
practices
(GLP)
or
good
management
practices
(GMP)
will
minimize
the
risks
of
release
to
the
environment
by
properly
packaging
and
transporting
infectious
materials
in
accordance
with
current
international
laws
and
regulations.
Given
the
security
concerns
that
surround
laboratory
animal
houses
and
research
facilities,
the
likelihood
that
measles‐
infected
animals
would
escape
into
the
community
must
be
extremely
small.
Conclusion
Although
there
is
no
direct
evidence
for
laboratory‐acquired
measles
infections
it
is
possible
that
they
have
occurred
among
immune
laboratory
staff
and
resulted
in
asymptomatic
or
very
mild
infections.
There
is
no
published
evidence
to
suggest
that
these
possible
asymptomatic
or
mild
infections
result
in
further
transmission
of
virus.
Measles
virus
loses
infectivity
within
a
couple
of
hours
at
ambient
temperatures
in
the
environment,
and
infectious
materials
stored
at
temperatures
above
‐30oC
can
be
expected
to
lose
all
infectivity
over
the
course
of
one
to
two
years.
Despite
the
lack
of
evidence
for
laboratory‐acquired
measles
infections
or
escape
of
virus
into
the
community,
in
a
post‐eradication
world
these
must
be
considered
possibilities
due
to
the
highly
infectious
nature
of
measles.
Risk
assessment:
In
a
measles
post‐eradication
world
without
routine
universal
immunization,
measles
laboratories
(and
measles
live
vaccine
production
facilities)
will
pose
a
very
low
but
increasing
risk
for
reintroduction
of
measles.
Risk
of
intentional
release
of
measles
virus
Bioterrorist
threats
do
not
work
against
populations
that
have
been
fully
immunized.
However,
in
a
post‐eradication
world
in
which
universal
routine
immunization
has
ceased,
a
growing
population
Page
17
Dr
Ray
Sanders.
Measles
re‐introduction
risk
analysis
will
be
susceptible
to
measles,
and
measles
will,
eventually,
become
a
credible
agent
for
bioterrorism.
The
devastating
effect
of
measles
on
susceptible
populations
in
the
pre‐vaccination
era
has
been
well
documented
(158).
This
is
particularly
true
for
the
islands
of
the
Pacific.
In
1848
in
Hawaii,
10,000
natives,
about
10
percent
of
the
population,
died
during
an
epidemic
(160,161,162).
In
1861
on
Aneityum
in
the
New
Hebrides,
the
population
was
reduced
by
about
60
per
cent
in
a
measles
epidemic
(163).
In
1875
in
Fiji,
20,000
natives,
20
to
25
per
cent
of
the
population,
died
of
measles
(164).
In
1907,
again
in
Fiji,
6
per
cent
of
30,000
cases
died,
and
in
1911
on
Rotuma
16
per
cent
of
the
population
died
of
measles
(165).
In
1936
measles
caused
100
deaths
and
14,282
cases
in
the
Gilbert
Islands
(166),
and
in
1937
in
Hawaii,
there
were
205
deaths
for
13,680
cases
of
measles
(167).
In
1946
in
the
British
Islands
of
the
South
Pacific,
there
were
1,000
deaths
for
15,000
to
20,000
cases
of
measles
(168).
There
are
many
other
accounts
of
similar
devastating
measles
epidemics
in
isolated
communities
around
the
world.
With
advances
in
modern
medical
treatment
it
is
unlikely
that
similar
mortality
rates
would
be
inflicted
one
or
two
generations
post
measles
eradication,
but
deliberate
release
would
cause
extensive
disruption
to
medical,
public
health
and
social
services,
and
probably
incur
enormous
containment
costs.
The
threat
of
release,
with
the
knowledge
of
the
potential
disruption
and
financial
expense
it
could
cause,
would
make
measles
an
effective
agent
for
bioterrorists
once
a
large
enough
population
of
measles‐susceptibles
had
accumulated.
Measles
is
not
currently
included
in
the
CDC
Bioterrorism
Agent
Categories
(169,170),
but
this
situation
will
need
to
be
reviewed
in
the
years
following
eradication.
Conclusion
Measles
is
a
highly
infectious
virus
that
has
had
devastating
effects
on
susceptible
populations
in
the
past.
Although
it
is
unlikely
that
the
high
mortalities
seen
in
these
isolated
communities
would
be
repeated,
the
threat
of
intentional
release
would
probably
be
very
effective
once
a
sizable
population
of
susceptible
individuals
had
accumulated.
Risk
assessment:
The
risk
of
deliberate
release
of
measles
will
be
very
low
at
the
time
of
global
eradication,
but
will
rise
rapidly
with
accumulation
of
unvaccinated
measles
susceptibles.
Actions
required
to
reduce
the
risk
of
accidental
or
deliberate
release
of
measles
One
approach
to
reducing
the
risk
of
measles
re‐introduction
would
be
adoption
of
a
strategy
to
minimize
availability
of
measles
virus,
through
removal
of
live
viruses
from
laboratories
and
securely
containing
all
infectious
material
that
remains,
and
establishing
an
insurance
policy
in
the
form
of
a
vaccine
stockpile.
Reducing
the
risk
of
accidental
release:
a
laboratory
containment
strategy
A
systematic
laboratory
containment
strategy
for
measles,
learning
from
the
example
set
by
the
Polio
Eradication
Initiative
(171),
starting
now
and
continuing
into
the
post‐eradication
era,
would
minimise
the
risk
of
accidental
re‐introduction
of
measles
virus.
The
strategy
established
for
polio
outlines
three
distinct
phases.
Phase
1
would
last
from
the
present,
when
measles
continues
to
circulate,
to
the
time
when
measles
transmission
ceases.
Phase
2
would
cover
the
certification
Page
18
Dr
Ray
Sanders.
Measles
re‐introduction
risk
analysis
period,
and
Phase
3
would
take
place
in
the
post
eradication,
post
global
certification
period.
These
three
Phases
for
polio
have
been
clearly
described
in
a
series
of
published
Global
Action
Plans
(172,173,157).
The
laboratory‐associated
risks
posed
by
measles
are
considerably
lower
than
those
posed
by
polio,
and
strategies
for
reducing
the
risk
even
further
should
not
simply
duplicate
the
activities
developed
for
polio,
but
be
proportionate
and
appropriate
for
measles.
The
general
approach
taken
by
the
Polio
Eradication
Initiative,
and
lessons
learned
from
implementing
the
polio
containment
strategy,
should
provide
a
sound
starting
point
for
measles.
Strategies
for
reducing
the
risk
in
the
pre‐
eradication
phase
should
be
based
on
the
following
principles:
•
•
•
•
minimizing
the
number
of
laboratories
retaining
measles
virus
infectious
and
potential
infectious
materials;
minimizing
the
risks
of
operations
in
laboratory
and
measles
live
vaccine
production
facilities;
minimizing
the
susceptibility
of
workers
to
measles
virus
infection
and
shedding;
minimizing
susceptibility
of
community
to
measles
virus
spread.
The
highest
risks
are
presented
by
those
laboratory
operations
involving
measles
virus
replication,
including
the
growth
of
vaccine
strains
for
live
vaccine
production.
The
lowest
risks
are
non‐
replicative,
biosafety‐appropriate
operations
performed
with
potentially
infectious
clinical
materials.
In
the
years
leading
up
to
global
eradication
all
work
with
wild
measles
viruses
should
require
biosafety
level‐2
(174),
with
additional
requirements
for
restricting
laboratory
access,
and
maintenance
of
accurate
records
of
measles
virus
materials.
Establishing
national
measles
inventories,
and
calls
to
safely
dispose
of
all
unwanted
measles
infectious
and
potential
infectious
materials,
as
has
been
accomplished
for
polio,
would
also
be
required.
The
second
phase
of
risk
reduction
would
consist
essentially
of
validating
the
containment
activities
at
national,
regional
and
global
levels
as
a
requirement
for
Global
Certification.
Stopping
universal
measles
immunization
post
certification
(third
phase)
will
alter
the
relative
weights
of
the
principles
on
which
minimizing
the
risk
from
the
laboratory
is
based
(157):
•
•
•
minimizing
susceptibility
of
communities
to
measles
virus
spread
will
no
longer
apply
in
those
countries
that
elect
to
stop
measles
immunization;
minimizing
the
susceptibility
of
workers
to
measles
virus
infection
and
shedding,
in
the
absence
of
a
non‐infectious
vaccine,
will
rely
solely
on
prevention
of
infection;
minimizing
the
number
of
laboratories
retaining
measles
virus
materials
and
minimizing
the
risks
of
operations
in
those
laboratories
becomes
much
more
important.
We
are
currently
considering
the
prospect
of
global
cessation
of
measles
transmission
approximately
a
decade
from
now,
allowing
reasonable
time
to
develop
an
appropriate
measles
laboratory
containment
strategy
and
for
laboratory
research
on
measles
viruses
to
continue
under
current,
biosafety
level‐2,
conditions.
It
also
allows
time
for
continued
development
of
alternative
measles
vaccines
and
specific
antivirals.
Page
19
Dr
Ray
Sanders.
Measles
re‐introduction
risk
analysis
Developing
a
vaccine
stockpile
Live
attenuated
measles
vaccines
have
been
highly
successful
in
protecting
populations
against
measles
and
stopping
measles
transmission.
As
discussed
above,
these
vaccines
are
very
safe,
and
pose
only
a
small
potential
risk
for
establishing
transmission
of
vaccine‐derived
viruses
in
a
post
eradication
world.
To
remove
this
risk
a
new
vaccine
that
has
no
capacity
for
replication
or
transmission
is
required
(175).
The
ideal
measles
vaccine
would
be
inexpensive,
safe,
heat‐stable,
immunogenic
in
neonates
or
very
young
infants,
and
administered
as
a
single
dose
without
the
need
to
use
a
needle
or
syringe
(93),
be
100%
effective
and
100%
incapable
of
transmission.
While
such
a
vaccine
would
have
clear
benefits
for
the
eradication
of
measles,
it
would
be
as
a
vaccine
for
stockpiling
post
eradication
that
it
would
come
into
its
own.
Several
vaccine
candidates
with
some
of
these
characteristics
are
undergoing
development
and
testing.
Features
of
these
new,
potential
measles
vaccines
have
been
extensively
reviewed
(175,176).
How
large
a
measles
vaccine
stockpile
would
be
required
is
very
difficult
to
predict
without
modelling.
Requirements
would
obviously
be
dynamic,
depending
on
some
fairly
complex
variables,
including
the
number
of
susceptibles
accumulating
in
the
community,
the
effectiveness
of
the
vaccine,
transmission
dynamics
of
the
virus
and
the
effectiveness
with
which
any
event
requiring
an
immunization
response
was
detected,
reported
and
responded
to.
Decisions
on
such
big,
expensive
items
as
establishing
a
measles
vaccine
stockpile
should
not
be
taken
in
isolation,
but
considered
systematically
and
included
in
a
consensus
risk
management
strategy,
as
has
been
achieved
for
polio
(177,178,179,180,181,182).
Development
of
a
post
measles
eradication
risk
management
strategy
should
begin
as
soon
as
possible.
Areas
requiring
further
research
The
risks
of
re‐introduction
of
measles
post
global
eradication
may
be
reduced
by
applying
knowledge
acquired
through
key
areas
of
research
conducted
in
the
years
leading
up
to
eradication.
These
key
areas
include
the
following:
Greater
understanding
of
the
transmission
dynamics
of
measles
In
drawing
up
the
certification
criteria
and
validation
requirements
it
will
be
necessary
to
engage
experts
familiar
with
the
development
of
dynamic
and
stochastic
models
of
measles
transmission,
persistence
and
elimination.
This
will
be
particularly
important
for
determining
the
certification
and
validation
requirements
for
low‐income,
high
density
populations.
Based
on
the
experience
gained
in
polio
eradication,
this
will
be
most
relevant
for
selected
populations
in
Africa,
the
Indian
sub‐
continent
and
large
refugee/migrant
population
camps.
Important
information
can
also
probably
be
gained
from
detailed
epidemiological
and
molecular
analysis
of
outbreaks,
particularly
those
occurring
in
highly
immunized
populations,
high‐density
populations,
and
in
generally
highly‐immunized
populations
with
inadequately
immunized
sub‐
populations.
With
the
rapid
increase
in
the
number
of
highly
immunized
populations,
opportunities
for
studying
asymptomatic
and
atypical
infections
and
their
potential
role
in
transmission
should
be
taken.
Greater
understanding
of
the
changes
brought
about
by
the
attenuation
process
Page
20
Dr
Ray
Sanders.
Measles
re‐introduction
risk
analysis
If
currently
licensed
attenuated
measles
vaccines
are
to
be
used
in
a
post‐eradication
world,
more
information
on
the
nature
of
the
changes
caused
by
attenuation
and
the
potential
for
reversion
to
wild‐type
characteristics
will
be
required.
An
alternative
would
be
to
speed
up
development,
testing
and
introduction
of
new
measles
vaccines
that
are
not
dependent
on
live
attenuated
virus.
More
understanding
of
the
nature
of
the
complex
interaction
between
measles
virus
and
the
host
immune
system,
including
both
humoral
and
cell‐mediated
responses,
would
probably
benefit
continued
use
of
existing
vaccines
and
development
of
new
vaccines.
In
the
years
leading
up
to
global
eradication,
all
genotype
A
viruses
detected
in
association
with
acute
cases
of
measles
should
be
thoroughly
scrutinized.
Full
epidemiological
information
will
be
required,
and
additional
sequence
data
from
both
clinical
samples
and
corresponding
viral
isolates
will
be
necessary
to
rule
out
the
possibility
of
transmission
of
vaccine‐derived
virus.
Thorough
genetic
analyses,
including
full
genomic
sequencing,
should
be
performed
on
selected
vaccine
viruses
that
are
associated
with
common
vaccine
reactions
as
well
as
those
detected
in
the
very
rare
sever
reactions
to
vaccination.
Page
21
Dr
Ray
Sanders.
Measles
re‐introduction
risk
analysis
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