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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:
 

Risk

Continuing
wild‐type
 measles
transmission
in
 humans

 Transmission
of
vaccine‐ derived
virus
 Persistent
infections
 Non‐human
primates
 Laboratory‐associated
 infection
 Intentional
release


Magnitude

Low
but
depends
on
 certification
criteria
and
 validation
requirements
 Very
low
 Very
low
 Very
low
 Very
low
but
rising
post
 eradication
 Very
low
but
rising
post
 eradication


Tendency
over
time

Decreasing


Mitigating
actions

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


Depends
on
level
of
vaccine
 use
 Decreasing
 Decreasing
 Increasing


Increasing



 


Page
2



 


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



 



Measles
re‐introduction
risk
analysis
 
 Table
of
Contents
 Error!
Bookmark
not
defined.
 
 
 Page
4
 
 
 .Dr
Ray
Sanders.


 ‘Natural’
risks
considered
include:
 a) b) c) d) continuing
wild‐type
measles
transmission
in
undetected
human
reservoirs.
 We
do
not
yet
have
an
agreed.
as
virus
stocks
and
infectious
 materials
held
in
laboratories.
structured
 assessment.Dr
Ray
Sanders.
and
that
an
increasing
global
 population
will
be
susceptible
to
measles
infection
in
the
years
following
certification.
such
as
a
single‐dose
policy.
and
 ‘laboratory’
–
associated
with
laboratory
work.
choose
to
continue
routine
immunization
post
eradication.
but
a
reasonable
 definition
may
be:
 
“Interruption
of
measles
virus
transmission
globally
for
a
period
greater
than
or
equal
to
36
 months.
either
through
decision
or
default.
or
some
form
of
campaign
strategy.
 If
universal
or
near‐universal
coverage
with
measles
vaccine
is
continued
after
global
eradication.
and
immunization
 activities.
for
political
as
well
as
public
health
 reasons.
 transmission
of
vaccine‐derived
virus.
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.
 According
to
this
definition.
Live
virus
may
also
continue
to
exist
in
persistently
and
chronically
 infected
individuals.
It
 is
also
likely
that
a
number
of
national
authorities.
storage
and
intentional
release.
in
the
presence
of
high‐quality
surveillance”
(modified
from
current
Global
and
Regional
 definitions
of
Regional
elimination).
 persistent
and
chronic
infections.
but
do
permit
a
more
systematic.

It
is
likely
that
a
number
of
national
authorities
will.
 These
two
categories
are
not
mutually
exclusive.
 stored
infectious
materials.
 particularly
if
a
more
effective.
 ‘Laboratory’
risks
considered
include:
 a) b) c) d) laboratory‐acquired
infections.
the
risk
of
measles
reintroduction
will
 be
minimal.
will
cease
 routine
measles
immunization.
measles
virus
will
continue
to
exist.
virus
persistence.
 
 
 Page
5
 
 
 .
non‐replicating
vaccine
is
used.
definitive
definition
for
measles
eradication.

Some
authorities
may
adopt
a
 modified
immunization
schedule.
For
the
purposes
of
this
analysis
it
has
been
assumed
that
universal
 immunization
against
measles
will
not
be
continued
post
eradication.
 virus
escape
into
the
community.
 non‐human
primate
reservoirs.
 intentional
release.
Measles
re‐introduction
risk
analysis
 
 Introduction.


how
likely
is
it
that
ongoing
measles
transmission
will
be
undetected
for
a
minimum
 of
one
year
before
certification?

 
 
 Page
6
 
 
 .
 Adequate
surveillance
including
genotype
data.
or
 • ≥80%
coverage
with
routine
MCV1
plus
≥95%
coverage
with
SIA
follow‐up
in
all
 districts.
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.
undetected
wild‐type
measles
transmission
in
humans
 There
are.
Adequate
surveillance
may
be
defined
by:

 • Number
of
reported
suspected
measles
cases
that
are
discarded
as
non‐measles

 (targets:
≥
2/100.
specific
criteria
may
be
 used
to
fulfil
the
three
general
criteria
above.

 Achievement
of
high
population
immunity.
based
on
current
Regional
and
Global
 recommendations
on
certification
of
Regional
measles
elimination. Absence
of
circulating
measles
virus
for
at
least
one
year.Dr
Ray
Sanders.
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.
investigation
and
reporting.000
population
nationally.
≥
1/100.
but
it
is
unlikely
that
any
single
specific
indicator
will
 be
required
to
pass
or
fail
validation.
Population
immunity
may
be
demonstrated
by:
 • ≥95%
coverage
with
routine
MCV2
in
all
districts. 2.
But
even
with
relatively
lax
criteria
and
validation
 requirements.
or
 • Some
use
of
extensive
serosurvey
data. 
 From
experience
gained
through
Regional
polio
elimination
and
certification.
 Risk
of
continuing.

Without
these
criteria.
it
is
likely
that
eradication
criteria
 will
include:
 1.
it
is
not
possible
to
accurately
estimate
the
risk
presented
by
 undetected
continuing
transmission.
based
on
case
detection.
no
definitive
criteria
for
certification
of
global
measles
eradication
or
agreed
 requirements
for
validation
of
these
criteria.

However.
routine
or
 supplementary.
 
 3.
as
yet.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.
and
the
detailed
requirements
 for
demonstrating
they
have
been
met.

8.
High
levels
of
immunization.
or
because
of
the
different
types
of
exposure.
Although
at
least
one
study
has
 reported
isolation
of
measles
virus
from
an
asymptomatic
individual
in
close
contact
with
an
acute
 case
(11).
but
mild
or
no
 symptoms
in
most
(16.000
to
400.
 What
role
do
asymptomatic
infections
play
in
virus
transmission?
 Measles
control
strategies
assume
that
virus
transmission
occurs
through
chains
of
clinically
 recognizable
measles
cases.
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.12.20).Dr
Ray
Sanders.5).
at‐risk
populations
that
may
emerge
following
 displacement
caused
by
conflict
or
climate
change
(6).
Serological
evidence
for
acute
measles
infection
 among
people
exposed
to
measles
virus
but
failing
to
develop
classical
symptoms
has
been
well
 documented
(7.
 
 
 Page
7
 
 
 .
the
potential
to
overlook
circulation
of
virus
 in
the
year
leading
up
to
global
certification
will
be
greatly
reduced.3).
producing
classic
symptoms
of
measles
in
some.10.000
with
5.13.
a
low
birth‐rate
and
good
public
health
care
facilities
increase
the
CCS.15)
and
it
has
long
been
recognized
that
measles
virus
can
infect
 previously
immune
persons.12.000
to
 10.
it
is
likely
to
be
very
rare.

 Although
it
may
be
difficult
to
accurately
estimate
the
CCS
in
low‐income.

If
disease
surveillance
and
immunization
 activities
are
targeted
on
them.19.
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).17.15).
high
birth‐rates.
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).
high
levels
of
immunodeficiency
and
poor
 public
health
care
facilities
decrease
the
CCS
(1.11.
it
is
easy
to
identify
these
populations.4.000
births
per
year
is
required
to
maintain
transmission
(2.21.
low
vaccine
coverage
 populations.
The
estimated
rates
of
mild
or
asymptomatic
measles
infections
 after
exposure
to
measles
cases
are
varied.
 Although
clinically
unimportant.8).

But
asymptomatic
infections
certainly
occur
and
 may
play
an
important
role
in
measles
transmission.
in
part
because
of
different
diagnostic
 techniques
and
different
case
definitions
used.
and
the
surveillance
system
largely
relies
on
the
identification
of
these
 cases
for
detecting
and
responding
to
outbreaks.
Accurately
 predicting
the
critical
community
size
(CCS)
required
for
maintaining
measles
virus
circulation
is
 difficult
due
to
the
large
number
of
variables
involved.
If
transmission
from
asymptomatic
cases
does
occur.
Low
 vaccine
uptake.9.18.
low
 population
density.
another
study
failed
to
find
evidence
of
virus
shedding
from
11
seropositive
acute
case
 contacts
(14).
and
is
 unlikely
to
be
efficient
enough
to
sustain
transmission
(11.
high
population
density.
especially
in
the
highly
vaccinated
 populations
expected
in
the
years
immediately
following
global
certification
of
eradication.
asymptomatic
measles
virus
infections
could
be
epidemiologically
 important
if
infected
persons
are
capable
of
transmitting
virus.
Direct
observation
and
a
range
of
both
 deterministic
and
stochastic
models
suggest
that
a
population
of
250.
however.
and
on
any
new.
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
(16.14.


the
risk
will
higher.31.
particularly
in
the
Russian
Federation
 (Leningrad‐16).
All
of
 the
current
vaccine
viruses
are
well
documented
and
well
characterised
with
regard
to
provenance.

 Risk
assessment:
The
risk
is
intuitively
low.27.
the
People’s
Republic
of
China
(Shanghai‐191)
and
Japan
(CAM‐70.
then
the
risk
of
 undetected
measles
transmission
after
Global
Certification
is
very
low.
Measles
re‐introduction
risk
analysis
 Conclusion
 If
the
certification
criteria
are
firm
enough.
the
Schwarz
vaccine
is
used
in
many
countries
 throughout
the
world.
or
validation
requirements
are
inadequate.
and
require
rigorous
validation.
 immunogenicity.
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.
and
the
Edmonston‐Zagreb
vaccine.29.
is
the
most
widely
used
strain
in
developing
countries.30.
 they
can
easily
be
distinguished
genetically
from
currently
circulating
wild‐type
viruses.
 
 
 Page
8
 
 
 .33).
The
further
 attenuated
Schwarz
and
Moraten
strains
were
derived
from
the
original
Edmonston
strain
through
 additional
passages
in
chick
embryo
fibroblasts
(Figure
1).
 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).
these
two
vaccine
strains
have
identical
genomic
sequences
(24).
Other
attenuated
measles
vaccines
 have
been
produced
from
locally
derived
wild‐type
strains.
 used
between
1963
and
1975
but
frequently
associated
with
fever
and
rash
(23).Dr
Ray
Sanders.
The
Moraten
vaccine
is
 widely
used
in
the
United
States
of
America.
Despite
differences
in
their
passage
 history.

If
the
certification
criteria
are
 lax.
The
first
licensed
attenuated
measles
vaccine
was
Edmonston
B.
thermal
stability
and
genomic
structure
(25.
AIK‐C)
(23).28.
Although
 current
vaccine
viruses
and
their
wild‐type
progenitors
share
more
than
95%
sequence
homology.32.26.
similarly
derived
from
the
Edmonston
B
 strain.


and
are
likely
to
be
 complex.
share
a
remarkable
nucleotide
sequence
similarity
and
all
are
members
of
 genotype
A
(45.

Relationships
of
major
current
measles
vaccine
viruses
(from
Moss
&
Scott.
 Approximately
5%
of
children
develop
fever
and
rash
after
receiving
measles
vaccine.
 Measles
virus
is
considered
to
be
one
of
the
most
contagious
of
human
pathogens.
 Vaccine
virus
can
be
isolated
from
the
blood
of
recent
vaccine
recipients.43.
It
is
also
possible
that
modification
of
the
virus
matrix
(M)
protein.44).
but
there
is
no
published
evidence
for
the
 transmission
of
vaccine
virus.
contributes
to
loss
of
transmissibility.
Like
wild‐type
virus.
known
to
be
 important
in
virus
budding
from
infected
cells
(41).
Obviously
the
changes
caused
by
the
attenuation
process
effectively
 block
transmissibility.
bone
marrow
or
brain
tissues
in
the
very
rare
cases
of
severe
acute
disease
 following
measles
vaccination
(35).Dr
Ray
Sanders.
with
a
very
high
 level
of
transmissibility.
and
viral
RNA
 can
be
detected
in
the
urine
and
respiratory
secretions
for
some
days
post‐immunization
(34).39.

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.
All
of
the
current
vaccines.37).
it
appears
that
the
block
on
transmission
of
vaccine
viruses
is
highly
effective.
2009
(23)).
Whatever
 the
reason.
whether
derived
from
 Edmonston
or
not.40).
 divided
into
23
recognized
genotypes
(42.
During
the
1950s
and
1960s.24).
Measles
re‐introduction
risk
analysis
 
 Figure
1.
Virus
RNA
and
antigen
can
be
detected
in
the
urine
of
vaccine
 recipients
for
up
to
14‐16
days
post‐immunization
(36.
inducing
both
humoral
and
cellular
immune
responses
similar
to
natural
measles
 virus
infection.
and
has
been
detected
in
 samples
of
lung.
only
measles
viruses
belonging
to
genotype
A
were
 
 
 Page
9
 
 
 .
liver.
The
ability
 of
vaccine
viruses
to
interfere
with
the
innate
immune
response
may
also
be
a
key
factor.
It
has
been
proposed
that
loss
of
ability
to
interact
with
epithelial
cell
receptors
is
a
key
 factor
(38.
 Measles
virus
is
serologically
monotypic
and
is
genetically
characterized
into
eight
clades
(A–H).
although
these
responses
are
of
lower
magnitude
and
shorter
duration.
measles
vaccine
virus
replicates
effectively
within
 vaccine
recipients.


 Table
1
includes
isolates
that
may
represent
wild‐type
lineages
that
have
survived
since
the
pre‐ vaccination
era.
This
is
 not
the
situation
today.50.

Although
there
are
still
gaps.
 We
now
have
a
reasonably
comprehensive
understanding
of
which
viruses
are
circulating
where
 (42.62).58.
very
few
genotype
A
viruses
have
 been
identified
during
the
past
20
years.
But
it
may
also
include
vaccine‐derived
isolates
that
have
been
 transmitted
from
vaccine
recipients
to
unvaccinated
contacts.
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
1.48).51.60.53).
viruses
from
most
major
 outbreaks
and
from
importations
in
areas
that
have
eliminated
indigenous
measles.61.
Measles
re‐introduction
risk
analysis
 isolated
and
may
have
had
a
world‐wide
distribution
before
vaccination
started
(46.
closely
associated
with
very
recent
receipt
of
vaccine.
With
the
possible
exception
of
viruses
isolated
in
the
UK
in
 1993
(54).
 Table
1
summarizes
the
published
documentation
on
the
detection
of
genotype
A
measles
viruses
 since
1990.
Measles
vaccine
viruses
re‐isolated
from
 
 
 Page
10
 
 
 .44.
 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.49.
It
also
includes
viruses
isolated
from
very
recent
vaccine
recipients
presenting
with
 classic
measles
symptoms.43.Dr
Ray
Sanders.
Published
documentation
on
isolation
and
characterization
of
genotype
A
measles
viruses
from
1990
 to
May
2010.

 Against
a
background
of
several
thousand
isolates
characterized.
Over
the
past
fifteen
years
a
massive
amount
of
work
has
been
put
into
characterizing
 measles
viruses
associated
with
outbreaks.
Although
some
of
these
genotype
A
 viruses
have
nucleotide
substitutions
that
distinguish
them
from
vaccine
viruses.

When
detected
they
have
been
sporadic
cases
 with
uncertain
epidemiology.
or
queried
as
 laboratory
contaminants
(43.56.47.
England
 5
 (54)
 1995
 South
Africa
 Johannesburg
 1
 (64)
 1996
 Russian
Federation
 Novosibirsk.57.
there
is
no
 published
documentation
identifying
a
distinct
set
of
genetic
markers
that
consistently
differentiates
 wild‐type
viruses
from
attenuated
viruses
(46).59.52.55.
are
currently
 being
sequenced
and
genetically
characterized
through
the
WHO
Laboratory
Network’s
activities.
none
has
been
associated
with
outbreaks.
when
the
identification
of
non‐vaccine
related
genotype
A
viruses
is
very
 unusual.


SLAM
is
expressed
on
cells
of
the
immune
system.
So
the
original
vaccine
strains.

On
the
contrary.79.

 What
is
the
risk
of
measles
vaccine‐escape
mutants?
 There
is
no
conclusive
published
evidence
for
the
emergence
of
measles
vaccine
escape
mutants
 (84).53.
RNA
virus
populations.78.80)
(81.50.Dr
Ray
Sanders.83).67.
Mutations
in
this
region
are
not
permitted
because
they
interfere
with
 receptor
binding.4
per
replication
(85).

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.72.68.
while
the
F
protein
mediates
 membrane
fusion
between
the
virus
envelope
and
the
host
cell
plasma
membrane
through
 cooperation
with
the
H
protein.
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
1.74.
Measles
re‐introduction
risk
analysis
 immunosuppressed
patients
with
giant
cell
pneumonia
have
nucleotide
sequences
almost
identical
 to
those
of
the
vaccine
virus.
This
is
well
within
the
typical
range
of
10‐3
to
10‐6
mutations
 per
site
per
replication
(86).
genotype
A
viruses.
The
envelope
of
measles
virus
 has
two
types
of
glycoprotein
spikes.
Analysis
of
available
 sequence
data
from
approximately
500
isolates
suggests
that
despite
the
error‐prone
viral
 polymerase.
 even
those
initiated
by
a
single
infectious
unit.75.51.

 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.
The
H
 protein
binds
to
specific
molecules
(receptors)
on
target
cells.77.76.
which
is
responsible
for
 cell
attachment
and
is
a
major
target
for
neutralizing
antibodies
(87).
It
appears
that
any
mutation
that
changes
the
nature
of
these
 conserved
residues
results
in
non‐viable
virus.73.70)
 (71.
This
extreme
sequence
restriction
allows
for
very
efficient
production
of
 neutralizing
antibodies
that
block
binding
of
the
virus
to
its
receptor.
such
as
activated
lymphocytes
and
dendritic
 cells
(89).
 Conclusion
 There
is
no
current
published
data
to
support
evidence
for
currently
licensed
live
attenuated
vaccine
 viruses
reverting
to
wild‐type
transmissibility.
should
be
the
most
 abundant
measles
genotype
on
Earth.
designated
haemagglutinin
(H)
and
fusion
(F)
proteins.
Despite
the
high
mutation
rate.
the
large
surface
area
that
hosts
the
SLAM
binding
site
is
 free
from
sugar
chains
(90).
the
molecular
epidemiological
data
appears
to
support
the
contention
that
vaccine
viruses
do
 not
readily
revert
to
wild‐type
transmissibility.65.66.
measles
virus
remains
remarkably
stable.
SLAM
was
identified
as
a
cell
receptor
for
measles
virus
 (88).
Studies
on
the
crystalline
structure
of
the
H
protein
have
shown
that
although
most
of
this
 glycoprotein
is
covered
by
sugar
chains.
with
60%
of
the
residues
being
 identical
or
very
similar
(92).

Given
that
they
are
so
infrequently
isolated
from
measles
 cases.
 also
known
as
CD150)
receptor
by
the
measles
haemagglutinin
(H)
protein.
in
the
form
of
vaccine
viruses.
and
unlike
other
 RNA
viruses
such
as
influenza
and
HIV.
suggesting
that
vaccine
viruses
are
very
stable
even
after
prolonged
 replication
in
a
human
host
(46).
the
vast
majority
of
evidence
points
 
 
 Page
11
 
 
 .
are
not
clonal
but
consist
of
a
large
number
of
 genetic
microvariants
referred
to
as
quasispecies.
In
2000.82.
are
still
effective
against
current
wild‐type
viruses
(91).
As
a
consequence
of
this
high
mutation
rate.
 developed
in
the
1960s.69.
Because
of
the
increasing
intensity
of
measles
 immunization
programmes.
the
amino
acid
sequence
of
H
is
strongly
conserved.


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.Dr
Ray
Sanders.
 Risk
assessment:
Available
information
suggests
that
the
risk
of
current
live‐attenuated
 vaccine
viruses
reverting
to
wild‐type
transmissibility
is
very
low.
persistent
 measles
virus
has
been
linked
to
another
neurological
infection.
but
it
remains
a
possibility.
have
also
been
suggested
at
 various
times
as
long‐term
sequelae
of
measles
virus
infection.
Host
immune
responses
to
measles
virus
are
essential
for
 viral
clearance.
Children
are
far
more
likely
to
develop
this
complication
 than
adults.
Paget’s
disease.106.
measles
inclusion
body
encephalitis
 (MIBE)
(109).
Reported
SSPE
incidence
varies
from
approximately
0.
Despite
the
reported
persistence
of
viral
RNA.
No
confirmed
evidence
has
been
 presented.96).
Measles
virus
has
been
isolated
from
 peripheral
blood
mononuclear
cells
(PBMC)
up
to
a
week.98.
let
alone
prove
a
causative
relationship.

Even
if
vaccine
viruses
were
to
revert
to
wild‐type
transmissibility.
Delayed
virus
clearance
has
been
documented
in
cases
of
 malnutrition
(97.
 Persistent
infection
with
measles
virus
has
definitively
been
associated
with
subacute
sclerosing
 panencephalitis
(SSPE).
Crohn’s
disease
and
autism.
and
infected
persons
are
usually
contagious
from
2–3
days
before
and
 up
to
four
days
after
onset
of
the
rash.102).
chronically
active
autoimmune
hepatitis.94).101.
progressive
disease
that
is
invariably
fatal.
and
from
urine
up
to
10
days.
However.
 otosclerosis.
the
possibility
must
exist
that
they
could
revert
to
wild‐type
transmissibility.
there
have
been
no
 reports
of
infectious
virus
shedding
more
than
3
to
4
weeks
after
appearance
of
symptoms
(98.
to
substantiate
these
associations.99).
 There
is
strong
experimental
evidence
for
the
monotypic
nature
and
genetic
stability
of
measles
 virus
being
based
on
use
of
the
SLAM
receptor.
after
 appearance
of
the
rash
(95.
Multiple
sclerosis.
In
immunocompromised
patients.

 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.
but
has
been
 reported
from
2
months
to
23
years
(110).
Direct
comparison
of
data
from
different
countries
is
problematic
because
 
 
 Page
12
 
 
 .
suggesting
that
normal
 clearance
is
a
prolonged
process.
a
progressive
fatal
neurological
disease
with
high
levels
of
neuronal
infection
 by
measles
virus
in
the
central
nervous
system
(94).
Measles
re‐introduction
risk
analysis
 to
an
impressive
level
of
genetic
stability.
the
mechanisms
and
timing
 of
normal
measles
virus
clearance
are
poorly
understood.
among
many
other
diseases.99)
and
patients
with
cellular
immunity
deficiencies
(100.
 What
is
the
risk
from
SSPE
cases?
 SSPE
is
a
slow.107).
there
is
 no
reason
to
suspect
that
transmission
could
not
be
controlled
using
current
vaccines.
however.
since
they
are
live
viruses
that
replicate
within
 vaccine
recipients.105.
However.
The
average
period
from
initial
measles
 infection
to
SSPE
symptom
onset
(latency)
usually
ranges
between
4
and
10
years.
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.
Detection
of
 measles
virus
RNA
has
been
reported
for
up
to
4
months
in
a
case
of
congenital
measles
(103).2
to
40
cases
per
million
 population
per
year.
These
data
are
consistent
with
studies
of
rhesus
 macaques
showing
that
virus
clearance
occurs
over
120–150
days
(108).
There
is
also
no
evidence
for
the
establishment
of
 vaccine‐escape
mutants.
clinical
recovery
and
the
establishment
of
long‐term
immunity.


 causing
seizures.
however.
and
may
manifest
itself
in
central
 nervous
system
disease
under
conditions
of
immunocompromise
or
immunosuppression.
lasting
from
days
to
weeks.
MIBE
has
also
been
reported
 to
result
from
receipt
of
measles
vaccine
(117).1/100
000
after
5
years
of
age
in
the
UK
(110).
Neither
the
patient
nor
the
stem
cell
donor
had
apparent
recent
measles
exposure
 or
vaccination.
is
the
elevation
of
measles
specific
 antibodies
in
the
blood
and
cerebrospinal
fluid
(94).
progressing
to
more
overt
cognitive
 dysfunction.Dr
Ray
Sanders.
There
are
no
published
reports
 of
infectious
measles
virus
shedding
from
MIBE
cases.121).
a
few
studies
have
detected
measles
virus
RNA
in
various
organs.
and
virus
has
been
isolated
directly
from
the
brains
of
affected
individuals
 (111.115.
Based
on
 sequencing
studies
of
virus
from
these
specimens
and
from
cells
persistently
infected
with
measles
 virus
isolates
from
SSPE
patients.
motor
deficits.
on
autopsy.
followed
by
motor
loss.
 What
is
the
risk
from
MIBE
cases?
 Measles
inclusion
body
encephalitis
(MIBE)
is
a
rare
central
nervous
system
complication
following
 acute
MV
infection.
seizures
and
eventual
organ
failure
in
virtually
all
affected
 individuals.
The
patient
was
born
in
 Chicago
during
the
measles
epidemic
of
1989‐1991
(birth
year
1989).
and
neither
had
recent
travel
to
measles‐endemic
regions.
which
is
not
 typical.
so
will
the
number
of
potential
SSPE
cases.
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.
Measles
antigen
is
 present
in
the
brain.
evidence
from
brain
biopsies
 of
SSPE
patients
indicates
that
infected
neurons
do
not
release
budding
virus
(112).
 Obviously.
many
 of
these
cases
occurred
in
years
when
measles
was
more
prevalent.94.
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.
Neurons
in
both
the
gray
and
white
matter
are
infected.
An
undiagnosed
case
of
 measles
in
the
period
1989‐1991
would
suggest
a
latency
period
to
MIBE
of
12
years.
A
serologic
hallmark
of
SSPE.116).
and
the
disease
is
histologically
 characterized
by
the
presence
of
cellular
inclusion
bodies
(111).
These
findings
suggest
that
measles
virus
 persists
in
the
brains
(and
other
organs)
of
healthy
individuals.
The
disease
course
is
relatively
short.
often
leading
to
coma
and
death.
 
 The
disease
initially
manifests
as
subtle
cognitive
losses.
has
been
described
in
children
and
adults
receiving
immunosuppressive
drugs
 and
therefore
is
thought
to
chiefly
affect
immunocompromised
hosts.
Measles
re‐introduction
risk
analysis
 methods
and
quality
of
diagnosis
have
been
inconsistent.
Cases
of
MIBE
without
clear
measles
exposure
or
infection
have
been
reported.114.
of
 elderly
individuals
who
died
of
non‐viral
causes
(120.
This
has
 been
underlined
by
the
case
of
a
13
year‐old
boy
that
developed
MIBE
after
receiving
a
stem
cell
 transplant
(119).
 
 Although
only
a
very
small
percentage
of
acute
measles
infections
will
go
on
to
develop
persistent
 complications.
with
a
median
time
of
4
months
(118).
fusion
(F)
and
matrix
(M)
genes
(113.
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.
MIBE
differs
from
SSPE
in
the
absence
of
elevated
serum
and
cerebrospinal
fluid
 neutralizing
antibodies
(94).
as
the
number
of
measles
infections
declines.
18%
of
patients
had
no
documented
measles
exposure
or
infection
(118).
The
neurologic
disease
usually
appears
3
to
6
 months
after
the
acute
measles
rash
(111).119).
and
stupor.
In
a
review
 of
MIBE.
as
 compared
to
the
other
central
nervous
system
complications.
Most
importantly.
 
 
 Page
13
 
 
 .
There
is
 no
evidence
for
transmission
of
measles
virus
from
SSPE
cases.


Papio
cristatus.
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).
 pose
a
very
low
risk
for
reintroduction
of
measles.
 fascicularis.
Pan
troglodytes.
These
include
Macaca
mulatta.
or
plasma
(123).
last
longer
and
result
in
 a
shorter
lived
immunity
to
re‐infection.
cyclopis.
Colobus
 quereza.
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.
Saguinus
oedipus.
 polymorphonuclear
leukocytes.
radiata.130).132.
In
1911.127).
but
there
is
no
published
evidence
to
suggest
that
co‐ infection
increases
the
potential
for
establishment
of
persistent
measles
infections.
Callithrix
jacchus.
proving
the
causative
agent
was
a
virus
(124).
 
 Acute
measles
infection
in
HIV‐infected
individuals
tends
to
be
more
severe.
M.
Goldberger
and
Anderson
 demonstrated
that
macaques
inoculated
with
filtered
secretions
from
measles
patients
developed
 measles.
Evidence
exists
of
measles
infection
in
 non‐human
primate
populations
with
frequent
contact
with
human
populations.136.

 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.
but
in
this
study
no
attempt
was
made
 to
culture
virus
from
any
samples.
Non‐human
primates
in
the
wild
appear
to
be
free
from
measles.
As
the
number
of
acute
 measles
virus
cases
declines
in
the
years
leading
to
global
eradication.
fuscicollis.
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.
A
wide
range
of
non‐human
primate
species
 are
susceptible
to
experimental
infection
with
measles
virus.
M.
but
there
is
no
evidence
that
HIV‐infection
leads
to
an
increased
risk
for
 persistent
measles
virus
infection.
 
 Risk
assessment:
Available
information
suggests
that
the
relatively
small
number
of
 persistent
measles
virus
cases.
either
with
wild‐ type
virus
or
with
vaccine‐derived
virus.Dr
Ray
Sanders.
Nor
does
HIV
infection
appear
to
present
a
risk
for
persistent
 infection
with
the
measles
vaccine
virus.
including
those
that
may
result
from
co‐infection
with
HIV.126.
As
would
be
expected
from
an
effective
animal
model.
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.
In
regions
of
high
HIV‐1
prevalence.129.
we
can
expect
a
decline
in
the
 number
of
potential
SSPE
and
MIBE
cases.
as
well
as
in
wild
 
 
 Page
14
 
 
 .133.
Cercopithecus
aethiops.127.
 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.
many
 species
respond
to
infection
in
a
manner
very
similar
to
humans
(128.
Human‐to‐ primate
disease
transmission
can
potentially
cause
significant
morbidity
and
mortality
among
wild
 primate
populations.137).
 only
contracting
infection
when
they
come
into
contact
with
infected
humans
(125).
Saimiri
sciureus.134).
S.
and
Aotus
trivirgatus

 and
Ateles
species
(125.
M.
Serological
evidence
of
measles
infection
in
free‐ranging
populations
of
non‐ human
primates
has
been
well
documented
(135.


through
accidental
or
intentional
release.
the
risks
posed
by
laboratory‐maintained
measles‐infectious
materials
will
 progressively
increase.
 
 Risk
assessment:
Available
information
suggests
that
infections
in
non‐human
primates
pose
 a
very
low
risk
for
reintroduction
of
measles.
it
is
possible
that
exposure
to
infectious
virus.
the
infections
that
have
 occurred
have
been
below
the
threshold
of
sensitivity
of
the
surveillance
systems.139.
A
recent
review
of
principles
for
prevention
of
laboratory‐ associated
infections
also
failed
to
make
mention
of
measles
(151).
or
soon
after.
the
USA
(145.
The
risks
 include
not
only
accidental
release
of
live
measles
virus
from
laboratories
and
attenuated
virus
 vaccine
production
facilities.
but
threat
of
deliberate
release.153).
If
the
decision
is
made
to
continue
universal
immunization.

It
is
unlikely
therefore.141.
and
 
 
 Page
15
 
 
 .
measles
has
 been
considered
a
trivial
disease
and
infections
have
not
been
reported
(152.149)
and
Japan
(150)
failed
to
include
 measles
among
the
listed
infections.143.144).
global
certification.
or.
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.
found
serological
evidence
of
measles
evidence
in
5
of
15
animals
 surveyed
(136).148.
are
 largely
dependent
on
whether
universal
immunization
against
measles
is
continued
or
if
it
is
stopped
 on.140.
the
risk
posed
by
laboratory‐maintained
virus
will
be
very
 low.
A
cross‐sectional
study
of
wild
macaques
(Macaca
 tonkeana)
in
Sulawesi.
that
exposed
laboratory
 staff
would
develop
acute
measles
symptoms
from
laboratory‐acquired
infections.
Indonesia.142.
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.
 What
is
the
evidence
for
laboratory‐acquired
measles
infection?
 A
series
of
surveys
for
laboratory‐acquired
infections
conducted
in
the
UK
 (138.146.
 possibly
with
non‐replicating
vaccines.
 Risk
of
laboratory‐associated
measles
infection
 Risks
posed
by
laboratory‐maintained
measles
viruses.Dr
Ray
Sanders.
however.
But
given
the
 very
high
transmissibility
of
measles
virus.
An
extensive
literature
search
 failed
to
find
documented
evidence
of
laboratory‐acquired
measles
infection.
 Conclusion
 Although
non‐human
primates
can
be
experimentally
and
naturally
infected
with
measles
virus.
This
leaves
three
 possibilities:
laboratory‐acquired
measles
infections
have
not
occurred.
as
the
number
of
measles‐susceptibles
in
the
population
increases.
it
is
unlikely
that
natural
populations
of
non‐human
primates
are
significant
or
sustainable
 reservoirs
of
measles
virus
(127).
population
sizes
are
too
small
to
maintain
epizootic
 transmission.
since
there
will
be
almost
universal
immunity.147.

If.
Due
to
their
relatively
small
 numbers.

 
 Because
human
populations
represent
the
largest
reservoir
of
the
measles
virus.
universal
immunization
stops
after
 global
certification.
and
 animal
to
animal
transmission
occurs.
Measles
re‐introduction
risk
analysis
 populations
with
minimal
human
contact
(127).

 
 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.


If
they
have
 occurred.
virus
isolates
and
reference
stocks.g.
or
simply
overlooked
as
 unimportant.
Measles
virus
potential
infectious
materials.
They
also
include
products
of
 these
materials
in
measles
virus
permissive
cells
or
animals
(157).155).
pharyngeal
secretions.
 urine.
including
1%
sodium
hypochlorite.
those
that
 are
suspected
to
contain
infectious
measles
viruses.
blood)
from
measles‐infected
persons
or
recent
live‐attenuated
vaccine
recipients.
Although
there
are
no
recorded
 incidents
of
laboratory‐acquired
measles
virus
infections.
or
very
mild.
 
 The
three
most
common
routes
of
exposure
to
infectious
agents
in
the
laboratory
are
ingestion.
If
transferred
from
the
hand
to
the
mouth.
The
virus
 survives
freeze‐drying
relatively
well
and.140.147.
can
survive
 storage
for
decades
at
‐70oC
(156.
 coughing
and
sneezing
by
infected
individuals
(158).
In
common
with
many
other
enveloped
viruses
it
is
 inactivated
by
solvents.
include
pharyngeal
secretions
and
blood
 samples
collected
for
any
purpose
at
a
time
and
in
a
place
where
measles
viruses
were
circulating.141.
for
up
to
two
hours.155).
atypical
infections
have
occurred.153).
alkalis
(pH>10).
they
can
initiate
infection
of
epithelial
cells
(158).
It
is
viable
for
less
than
2
hours
at
ambient
temperatures
on
 surfaces
and
objects.143.
by
acids
(pH<5).
 • community
risk
of
laboratory‐associated
measles
exposure.
 and
stored
under
conditions
that
would
preserve
virus
infectivity.
laboratory
animals).g.
70%
 alcohol
and
formalin.
 inhalation.
and
infectious
 materials
maintained
at
this
temperature
should
retain
infectivity
for
many
years
(156).
Addition
of
a
protein
 stabilizer
improves
virus
longevity.
with
a
1‐2
log
loss
of
titre
 over
1
year.
storage
at
‐30oC
offers
little
advantage
over
storage
at
+6oC.
 What
types
of
risk
do
laboratories
present?

 Risks
post
measles
eradication
will
exist
at
two
levels:
 • occupational
risk
of
exposure
among
laboratory
staff.
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.
Measles
virus
can
remain
infectious
on
surfaces.
it
is
probable
that
these
infections
have
gone
undetected.Dr
Ray
Sanders.

The
most
common
route
for
natural
transmission
of
measles
is
 believed
to
be
by
inhalation
of
aerosolized
virus.
even
in
medium
containing
a
protein
stabilizer
such
as
 5%
calf
serum
(156).
nose
or
 conjunctiva.
 Interestingly.
such
as
ether
and
chloroform.
Measles
re‐introduction
risk
analysis
 resulting
asymptomatic
infections.
such
as
Shigella
and
Salmonella
 (139.
while
the
aerosolized
virus
typically
remains
infective
for
only
30
minutes
to
2
 hours.
Storage
at
‐72oC
or
below
results
in
very
little
loss
of
virus
infectivity.142.
It
is
very
sensitive
to
heat
and
is
 inactivated
after
less
than
40
minutes
at
56°C.

 Which
laboratory
materials
present
a
risk?
 Measles
virus
infectious
materials
include
autopsy
or
clinical
samples
(e.
It
is
also
susceptible
to
many
disinfectants.
and
 laboratory
derived
materials
(e.
infectious
droplets
being
produced
by
talking.
depending
on
environmental
conditions
(154.
materials
derived
from
 inoculated
cell
cultures.

Small
particles
(<5‐μ
droplet
nuclei)
of
 suspended
evaporated
residues
can
move
about
rooms
and
buildings
on
air
currents
and
when
 
 
 Page
16
 
 
 .
several
surveys
document
the
frequent
 occurrence
of
ingesting
more
readily
recognized
pathogens.
when
freeze‐dried
with
a
protein
stabilizer.
with
a
loss
of
approximately
2
logs
of
titre
after
1
year
at
+6oC.
and
by
UV
 and
visible
light.
and
injection
(153).
such
as
work
 benches
and
door
handles.
 How
stable
is
measles
virus
in
the
environment
and
in
laboratory
materials?
 Measles
is
not
a
physically
robust
virus.


the
likelihood
that
measles‐ infected
animals
would
escape
into
the
community
must
be
extremely
small.


 Despite
the
lack
of
evidence
for
laboratory‐acquired
measles
infections
or
escape
of
virus
into
the
 community.
Measles
virus
loses
infectivity
within
a
couple
of
 hours
at
ambient
temperatures
in
the
environment.
 available
evidence
suggests
that
immunized
individuals.
Laboratory
activities
that
expose
staff
 to
aerosols
generated
from
infectious
material
(e.
is
probably
limited
to
2
hours.
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.
 • escaped
infectious
animals.
 Risk
of
intentional
release
of
measles
virus
 Bioterrorist
threats
do
not
work
against
populations
that
have
been
fully
immunized.
vigorous
pipetting.
no
published
evidence
exists
for
the
escape
of
infectious
measles
virus
from
the
laboratory
 into
the
community.
the
length
of
time
available
for
infectious
virus
to
be
carried
out
of
the
laboratory
and
 into
the
community.
or
in
contaminated
air
 effluents.
present
a
risk
for
infection.Dr
Ray
Sanders.).
 • transport
of
infectious
material.
measles
laboratories
(and
measles
live
vaccine
production
facilities)
will
pose
 a
very
low
but
increasing
risk
for
reintroduction
of
measles.
a
growing
population
 
 
 Page
17
 
 
 .
However.
Measles
re‐introduction
risk
analysis
 inhaled
deposit
primarily
in
the
lower
respiratory
tract
(159).

 
 Community
members
may
be
exposed
to
infectious
measles
virus
from:
 • contaminated
laboratory
workers.
Given
the
rapid
inactivation
of
measles
virus
under
normal
environmental
 conditions.
As
discussed
above.
injection
and
needle‐stick
injuries
 involving
measles
virus
infectious
materials
obviously
present
a
risk
for
infection.
are
unlikely
to
transmit
the
virus
(10).
This
reduces
the
risk
to
a
very
low
level.

 
 Risk
assessment:
In
a
measles
post‐eradication
world
without
routine
universal
 immunization.
 etc.
The
most
common
 route
for
delivery
of
current
measles
vaccines
is
by
injection.
in
a
post‐eradication
world
these
must
be
considered
possibilities
due
to
the
highly
 infectious
nature
of
measles.
in
a
 post‐eradication
world
in
which
universal
routine
immunization
has
ceased.
Given
the
security
 concerns
that
surround
laboratory
animal
houses
and
research
facilities.


 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.
 • contaminated
air
effluents.
 
 Again.
and
infectious
materials
stored
at
temperatures
 above
‐30oC
can
be
expected
to
lose
all
infectivity
over
the
course
of
one
to
two
years.
So.
blending.
who
develop
asymptomatic
or
mild
 infections.
 • infected
laboratory
workers.
either
on
the
body
or
clothes
of
a
contaminated
worker.g.
There
is
no
published
evidence
to
suggest
that
these
possible
asymptomatic
or
mild
 infections
result
in
further
transmission
of
virus.
centrifugation.
and
exposure
to
infected
laboratory
animals.


 
 Risk
assessment:
The
risk
of
deliberate
release
of
measles
will
be
very
low
at
the
time
of
 global
eradication.
 Reducing
the
risk
of
accidental
release:
a
laboratory
containment
strategy
 A
systematic
laboratory
containment
strategy
for
measles.

Phase
2
would
cover
the
certification
 
 
 Page
18
 
 
 .000
natives.
In
1936
measles
caused
100
deaths
and
14.
would
 minimise
the
risk
of
accidental
re‐introduction
of
measles
virus.
 Conclusion
 Measles
is
a
highly
infectious
virus
that
has
had
devastating
effects
on
susceptible
populations
in
the
 past.

The
devastating
effect
of
measles
on
susceptible
populations
in
the
pre‐vaccination
 era
has
been
well
documented
(158).
In
1875
in
Fiji.
and
in
1937
in
Hawaii.
and
establishing
an
insurance
policy
in
the
form
of
a
 vaccine
stockpile.
and
probably
incur
enormous
 containment
costs.
again
in
Fiji.
 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.
 In
1861
on
Aneityum
in
the
New
Hebrides.000
natives.000
cases
of
measles
(168).
about
10
percent
of
the
population.
and
measles
will.
In
1907.000
deaths
for
15.
public
health
and
social
services.
died
during
an
epidemic
(160.
In
1946
in
the
British
Islands
of
the
South
Pacific.
This
is
particularly
true
for
the
islands
of
the
Pacific.
10.
when
measles
continues
to
 circulate.Dr
Ray
Sanders.161.162).000
cases
died.
learning
from
the
example
set
by
the
 Polio
Eradication
Initiative
(171).
died
of
 measles
(164).170).
but
deliberate
release
would
cause
 extensive
disruption
to
medical.
would
make
measles
an
effective
agent
for
bioterrorists
once
a
 large
enough
population
of
measles‐susceptibles
had
accumulated.
6
per
cent
of
30.
and
in
1911
on
Rotuma
16
per
 cent
of
the
population
died
of
measles
(165).
Measles
re‐introduction
risk
analysis
 will
be
susceptible
to
measles.
 With
advances
in
modern
medical
treatment
it
is
unlikely
that
similar
mortality
rates
would
be
 inflicted
one
or
two
generations
post
measles
eradication.000
to
 20.
The
strategy
established
for
polio
 outlines
three
distinct
phases.
with
the
knowledge
of
the
potential
disruption
and
 financial
expense
it
could
cause.
There
are
many
other
accounts
of
similar
devastating
measles
 epidemics
in
isolated
communities
around
the
world.
the
threat
of
intentional
release
would
probably
be
very
effective
once
a
sizable
 population
of
susceptible
individuals
had
accumulated.
the
population
was
reduced
by
about
60
per
cent
in
a
 measles
epidemic
(163).
starting
now
and
continuing
into
the
post‐eradication
era.
there
were
1.

The
threat
of
release.
Measles
is
not
currently
included
 in
the
CDC
Bioterrorism
Agent
Categories
(169.

Although
it
is
unlikely
that
the
high
mortalities
seen
in
these
isolated
communities
would
be
 repeated.
In
1848
in
 Hawaii.
but
this
situation
will
need
to
be
reviewed
in
 the
years
following
eradication.
to
the
time
when
measles
transmission
ceases.
20
to
25
per
cent
of
the
population.
through
removal
of
live
viruses
from
laboratories
and
securely
 containing
all
infectious
material
that
remains.
eventually.

Phase
1
would
last
from
the
present.
but
will
rise
rapidly
with
accumulation
of
unvaccinated
measles
 susceptibles.
20.680
cases
of
measles
 (167).
become
a
credible
agent
for
 bioterrorism.
there
were
205
deaths
for
13.282
cases
in
 the
Gilbert
Islands
(166).


The
general
approach
taken
by
the
 Polio
Eradication
Initiative.
 biosafety
level‐2.173.
and
lessons
learned
from
implementing
the
polio
containment
strategy.
These
 three
Phases
for
polio
have
been
clearly
described
in
a
series
of
published
Global
Action
Plans
 (172.
 
 
 Page
19
 
 
 .
allowing
reasonable
time
to
develop
an
appropriate
measles
laboratory
 containment
strategy
and
for
laboratory
research
on
measles
viruses
to
continue
under
current.
 including
the
growth
of
vaccine
strains
for
live
vaccine
production.
post
global
certification
period.
Measles
re‐introduction
risk
analysis
 period.
 minimizing
the
susceptibility
of
workers
to
measles
virus
infection
and
shedding.
Establishing
national
measles
 inventories.
It
also
allows
time
for
continued
development
of
alternative
measles
 vaccines
and
specific
antivirals.157).
 In
the
years
leading
up
to
global
eradication
all
work
with
wild
measles
viruses
should
require
 biosafety
level‐2
(174).
and
Phase
3
would
take
place
in
the
post
eradication.
and
 maintenance
of
accurate
records
of
measles
virus
materials.

 minimizing
susceptibility
of
community
to

measles
virus
spread.

 minimizing
the
susceptibility
of
workers
to
measles
virus
infection
and
shedding.
 and
strategies
for
reducing
the
risk
even
further
should
not
simply
duplicate
the
activities
developed
 for
polio.
and
calls
to
safely
dispose
of
all
unwanted
measles
infectious
and
potential
infectious
 materials.


 
 We
are
currently
considering
the
prospect
of
global
cessation
of
measles
transmission
approximately
 a
decade
from
now.Dr
Ray
Sanders.
biosafety‐appropriate
operations
performed
with
potentially
infectious
clinical
materials.
 The
second
phase
of
risk
reduction
would
consist
essentially
of
validating
the
containment
activities
 at
national.

 minimizing
the
risks
of
operations
in
laboratory
and
measles
live
vaccine
production
 facilities.
 should
provide
a
sound
starting
point
for
measles.
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.
but
be
proportionate
and
appropriate
for
measles.
as
has
been
accomplished
for
polio.
Strategies
for
reducing
the
risk
in
the
pre‐ eradication
phase
should
be
based
on
the
following
principles:

 • • • • 
 The
highest
risks
are
presented
by
those
laboratory
operations
involving
measles
virus
replication.
The
lowest
risks
are
non‐ replicative.
 minimizing
the
number
of
laboratories
retaining

measles
virus
infectious
and
potential
 infectious
materials.
regional
and
global
levels
as
a
requirement
for
Global
Certification.
 The
laboratory‐associated
risks
posed
by
measles
are
considerably
lower
than
those
posed
by
polio.
with
additional
requirements
for
restricting
laboratory
access.
will
rely
solely
on
prevention
of
infection.
would
also
be
required.
conditions.
 minimizing
the
number
of
laboratories
retaining
measles
virus
materials
and
minimizing
the
 risks
of
operations
in
those
laboratories
becomes
much
more
important.
in
the
 absence
of
a
non‐infectious
vaccine.


Based
on
the
experience
gained
 in
polio
eradication.
as
has
been
achieved
for
polio
 (177.
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.
the
Indian
sub‐ continent
and
large
refugee/migrant
population
camps.
and
administered
as
a
single
dose
without
the
need
 to
use
a
needle
or
syringe
(93).
safe.
particularly
those
occurring
in
highly
immunized
populations.
these
vaccines
are
very
safe.
 Important
information
can
also
probably
be
gained
from
detailed
epidemiological
and
molecular
 analysis
of
outbreaks.
but
considered
 systematically
and
included
in
a
consensus
risk
management
strategy.
and
in
generally
highly‐immunized
populations
with
inadequately
immunized
sub‐ populations.178.
Several
vaccine
candidates
with
some
of
 these
characteristics
are
undergoing
development
and
testing.
Requirements
would
obviously
be
dynamic.
Features
of
these
new.
opportunities
for
studying
 asymptomatic
and
atypical
infections
and
their
potential
role
in
transmission
should
be
taken.
Decisions
on
such
big.

This
will
be
particularly
important
for
determining
the
certification
and
 validation
requirements
for
low‐income.
 persistence
and
elimination.
high
density
populations.
 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.
transmission
dynamics
of
the
virus
and
the
effectiveness
with
which
any
event
requiring
an
 immunization
response
was
detected.180.
high‐density
 populations.

As
discussed
above.
expensive
 items
as
establishing
a
measles
vaccine
stockpile
should
not
be
taken
in
isolation.
 With
the
rapid
increase
in
the
number
of
highly
immunized
populations.
 immunogenic
in
neonates
or
very
young
infants.
Development
of
a
post
measles
eradication
risk
management
strategy
 should
begin
as
soon
as
possible.182).
and
 pose
only
a
small
potential
risk
for
establishing
transmission
of
vaccine‐derived
viruses
in
a
post
 eradication
world.
reported
and
responded
to.179.
depending
on
some
fairly
complex
variables.
it
would
be
as
a
vaccine
for
 stockpiling
post
eradication
that
it
would
come
into
its
own.181.
this
will
be
most
relevant
for
selected
populations
in
Africa.176).
potential
 measles
vaccines
have
been
extensively
reviewed
(175.Dr
Ray
Sanders.
 How
large
a
measles
vaccine
stockpile
would
be
required
is
very
difficult
to
predict
without
 modelling.
be
100%
effective
and
100%
incapable
of
transmission.
The
ideal
measles
vaccine
would
be
inexpensive.
 
 Greater
understanding
of
the
changes
brought
about
by
the
attenuation
process
 
 
 
 
 Page
20
 .
the
effectiveness
of
the
 vaccine.
heat‐stable.

While
such
a
 vaccine
would
have
clear
benefits
for
the
eradication
of
measles.
 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.
To
remove
this
risk
a
new
vaccine
that
has
no
capacity
for
replication
or
 transmission
is
required
(175).
 including
the
number
of
susceptibles
accumulating
in
the
community.


including
full
genomic
sequencing.
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.
Measles
re‐introduction
risk
analysis
 If
currently
licensed
attenuated
measles
vaccines
are
to
be
used
in
a
post‐eradication
world.
Full
epidemiological
information
will
be
 required.
would
probably
benefit
 continued
use
of
existing
vaccines
and
development
of
new
vaccines.
 In
the
years
leading
up
to
global
eradication.
Thorough
 genetic
analyses.
 
 
 
 
 
 Page
21
 
 
 .
including
both
humoral
and
cell‐mediated
responses.
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.

An
alternative
would
be
to
speed
up
development.
all
genotype
A
viruses
detected
in
association
with
 acute
cases
of
measles
should
be
thoroughly
scrutinized.
more
 information
on
the
nature
of
the
changes
caused
by
attenuation
and
the
potential
for
reversion
to
 wild‐type
characteristics
will
be
required.
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.Dr
Ray
Sanders.


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67:
p.
Berg
JL.
2002.
Shirley
RH.
337‐341.
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International
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 associated
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MJ.
173‐179.
65‐77.
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JD.
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263:
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against
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West
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