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Dietary pyridoxine controls efficacy of vitamin B6-auxotrophic tuberculosis vaccine bacillus Calmette-Guérin ΔureC::hly Δpdx1 in mice.
[severe combined immunodeficiency]
The
only
tuberculosis
(
TB
)
vaccine
in
use
today
,
bacillus
Calmette-
Guérin
(
BCG
)
,
provides
insufficient
protection
and
can
cause
adverse
events
in
immunocompromised
individuals
,
such
as
BCGosis
in
HIV
(
+
)
newborns
.
We
previously
reported
improved
preclinical
efficacy
and
safety
of
the
recombinant
vaccine
candidate
BCG
ΔureC
:
:
hly
,
which
secretes
the
pore-forming
listeriolysin
O
of
Listeria
monocytogenes
.
Here
,
we
evaluate
a
second
-generation
construct
,
BCG
ΔureC
:
:
hly
Δpdx
1
,
which
is
deficient
in
pyridoxine
synthase
,
an
enzyme
that
is
required
for
biosynthesis
of
the
essential
cofactor
vitamin
B
6
.
This
candidate
was
auxotrophic
for
vitamin
B
6
in
a
concentration-dependent
manner
,
as
was
its
survival
in
vivo
.
BCG
ΔureC
:
:
hly
Δpdx
1
showed
markedly
restricted
dissemination
in
subcutaneously
vaccinated
mice
,
which
was
ameliorated
by
dietary
supplementation
with
vitamin
B
6
.
The
construct
was
safer
in
severe
combined
immunodeficiency
mice
than
the
parental
BCG
ΔureC
:
:
hly
.
A
prompt
innate
immune
response
to
vaccination
,
measured
by
secretion
of
interleukin-
6
,
granulocyte
colony-stimulating
factor
,
keratinocyte
cytokine
,
and
macrophage
inflammatory
protein-
1
α
,
remained
independent
of
vitamin
B
6
administration
,
while
acquired
immunity
,
notably
stimulation
of
antigen-
specific
CD
4
T
cells
,
B
cells
,
and
memory
T
cells
,
was
contingent
on
vitamin
B
6
administration
.
The
early
protection
provided
by
BCG
ΔureC
:
:
hly
Δpdx
1
in
a
murine
Mycobacterium
tuberculosis
aerosol
challenge
model
consistently
depended
on
vitamin
B
6
supplementation
.
Prime-boost
vaccination
increased
protection
against
the
canonical
M
.
tuberculosis
H
37
Rv
laboratory
strain
and
a
clinical
isolate
of
the
Beijing
/
W
lineage
.
We
demonstrate
that
the
efficacy
of
a
profoundly
attenuated
recombinant
BCG
vaccine
construct
can
be
modulated
by
external
administration
of
a
small
molecule
.
This
principle
fosters
the
development
of
safer
vaccines
required
for
immunocompromised
individuals
,
notably
HIV
(
+
)
infants
.
Mycobacterium
tuberculosis
can
synthesize
the
essential
cofactor
vitamin
B
6
,
while
humans
depend
on
dietary
supplementation
.
Unlike
the
lipophilic
vitamins
A
,
D
,
and
E
,
water-soluble
vitamin
B
6
is
well
tolerated
at
high
doses
.
We
generated
a
vitamin
B
6
auxotroph
of
the
phase
II
clinical
tuberculosis
vaccine
candidate
bacillus
Calmette-
Guérin
ΔureC
:
:
hly
.
The
next
-generation
candidate
was
profoundly
attenuated
compared
to
the
parental
strain
.
Adaptive
immunity
and
protection
in
mice
consistently
depended
on
increased
dietary
vitamin
B
6
above
the
daily
required
dose
.
Control
of
vaccine
efficacy
via
food
supplements
such
as
vitamin
B
6
could
provide
a
fast
track
toward
improved
safety
.
Safer
vaccines
are
urgently
needed
for
HIV-infected
individuals
at
high
risk
of
adverse
events
in
response
to
live
vaccines
.
Diseases
Validation
Diseases presenting
"restricted dissemination in subcutaneously vaccinated mice"
symptom
severe combined immunodeficiency
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