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A bivalent typhoid live vector vaccine expressing both chromosomal and plasmid-encoded Y. pestis antigens fully protects against murine lethal pulmonary plague infection.
[typhoid]
Live
attenuated
bacteria
hold
great
promise
as
multivalent
mucosal
vaccines
against
a
variety
of
pathogens
.
A
major
challenge
of
this
approach
has
been
the
successful
delivery
of
sufficient
amounts
of
vaccine
antigens
to
adequately
prime
the
immune
system
without
over-attenuating
the
live
vaccine
.
Here
we
have
used
a
live
attenuated
Salmonella
enterica
serovar
Typhi
strain
to
create
a
bivalent
mucosal
plague
vaccine
that
produces
both
the
protective
F
1
capsular
antigen
of
Yersinia
pestis
as
well
as
the
LcrV
protein
required
for
secretion
of
virulence
effector
proteins
.
To
reduce
metabolic
burden
associated
with
the
co
-expression
of
F
1
and
LcrV
within
the
live
vector
,
we
balanced
expression
of
both
antigens
by
combining
plasmid-based
expression
of
F
1
with
chromosomal
expression
of
LcrV
from
three
independent
loci
.
The
immunogenicity
and
protective
efficacy
of
this
novel
vaccine
were
assessed
in
mice
using
a
heterologous
prime-boost
immunization
strategy
,
and
compared
to
a
conventional
strain
in
which
F
1
and
LcrV
were
expressed
from
a
single
low
copy
number
plasmid
.
The
serum
antibody
responses
to
LPS
induced
by
the
optimized
bivalent
vaccine
were
indistinguishable
from
those
elicited
by
the
parent
strain
,
suggesting
adequate
immunogenic
capacity
maintained
through
preservation
of
bacterial
fitness
;
by
contrast
,
LPS
titers
were
10
-
fold
lower
in
mice
immunized
with
the
conventional
vaccine
strain
.
Importantly
,
mice
receiving
the
optimized
bivalent
vaccine
were
fully
protected
against
lethal
pulmonary
challenge
.
These
results
demonstrate
the
feasibility
of
distributing
foreign
antigen
expression
across
both
chromosomal
and
plasmid
locations
within
a
single
vaccine
organism
for
induction
of
protective
immunity
.