An
investigational
tuberculosis
(TB)
vaccine
didn’t
top
the
standard
bacillus
Calmette-Guérin
(BCG)
vaccine
at
preventing
infections
in
infants,
a
multicenter,
phase
III
trial
showed.

Among
nearly
6,900
newborns
in
sub-Saharan
Africa,
QuantiFERON-TB
Gold
Plus
(QFT)
conversion,
indicating

Mycobacterium

tuberculosis
infection
or
exposure,
occurred
in
5.3%
of
those
who
received
the
VPM1002
vaccine
compared
with
4.3%
of
those
who
received
the
BCG
vaccine,
reported
Sina
Brückner,
PhD,
of
Serum
Life
Science
Europe
in
Hanover,
Germany,
and
colleagues
in


Lancet
Infectious
Diseases.

For
events
meeting
the
first-case
definition
for
QFT
conversion
in
the
VPM1002
group
versus
the
BCG
group,
the
HR
was
1.23
(95%
CI
0.99-1.53,

P=0.057).
Noninferiority
required
the
upper
bound
of
the
confidence
interval
to
be
less
than
1.25.

The
trial
also
delivered
uncertainty
about
VPM1002’s
relative
efficacy
at
preventing
TB
disease.
Among
588
participants
evaluated
for
suspected
TB
disease
during
follow-up,
3.2%
of
those
who
received
VPM1002
and
1.7%
of
those
in
the
BCG
group
developed
microbiologically
confirmed
or
unconfirmed
TB.

With
fewer
QFT
conversions
overall
than
predicted
(344
vs
632),
the
investigators
terminated
the
trial
early
in
October
2024.

“These
findings
highlight
the
methodological
challenges
of
using
QFT-based
infection
endpoints
in
infant
vaccine
trials
and
the
importance
of
accounting
for
differential
tuberculosis
exposure
in
the
design
and
analysis
of
future
prevention
of
infection
trials,”
Brückner
and
colleagues
wrote.
“Given
these
findings,
tuberculosis
disease
is
a
more
appropriate
endpoint
in
infant
vaccine
trials.”

BCG
is
the
only
licensed
TB
vaccine.
While
it
protects
young
children
against
severe
TB,
it
delivers
waning
and
inconsistent
protection
against
TB
disease
and
transmission
in
adolescence
and
adulthood.
VPM1002
is
a
recombinant
BCG
vaccine
strain
that
showed
similar
immunogenicity
to
BCG,
with
fewer
adverse
injection-site
events
in

early-phase
trials.

Finding
a
more
effective
TB
vaccine
than
BCG
“is
an
urgent
global
health
priority,”
noted
Helen
McShane,
PhD,
of
the
University
of
Oxford
in
England,
in
an

accompanying
editorial.
But
better
TB
trial
designs
and
endpoints
are
crucial
to
achieving
that
goal,
she
added.

Results
from
interferon-γ
release
assays
such
as
QFT
have
been
used
widely
as
surrogate

Mycobacterium
tuberculosis
infection
markers
in
clinical
trials.
However,
the
gold-standard
endpoint
in
TB
trials
is
microbiologically
confirmed
disease,
a
challenging
metric
that
requires
large
sample
sizes
and
long
follow-up
periods.

VPM1002’s
relative
performance
was
worse
when
measured
using
microbiologically
confirmed
disease
as
the
endpoint.
That
result
shows
that
the
trial’s
surrogate
infection
endpoint
of
incident
QFT
conversion
“might
not
be
a
sufficiently
robust
endpoint
for
tuberculosis
vaccine
efficacy
trials,”
McShane
wrote.

“Overall,
this
trial
teaches
us
that
there
are
no
obvious
short
cuts
in
tuberculosis
vaccine
efficacy
trials,”
she
noted.
“We
need
to
continue
to
explore
viable
efficacy
endpoints
and
trial
design.”

There
are
relatively
few
early-stage
TB
vaccine
candidates
and
only
a
handful
of
late-stage
vaccine
candidates,
McShane
pointed
out.
“As
we
encourage
vaccine
developers
and
funders
to
develop
and
support
diverse
and
innovative
vaccine
candidates,
we
must
in
parallel
work
to
design
robust
but
feasible
efficacy
trials,”
she
added.

This
double-blind,
active-controlled
trial
randomized
6,940
newborns
to
vaccination
with
either
VPM1002
or
BCG,
of
whom
6,897
received
shots.
The
trial
ran
from
November
2020
to
June
2022.
Eligible
infants
were
ages
0
to
14
days
and
had
a
birthweight
of
at
least
2.3
kg.
Mothers
were
at
least
18
years
old,
had
no
active
TB,
and
had
no
household
contacts
with
TB
in
the
3
months
prior
to
study
enrollment.

Median
post-vaccination
follow-up
was
35
months,
50.3%
of
infants
were
female,
median
enrollment
age
was
3
days,
and
95.1%
of
infants
were
Black
African.

The
study’s
primary
efficacy
endpoint
was
the
occurrence
of
QFT
conversion,
indicating

M.
tuberculosis
infection
or
exposure.
Secondary
endpoints
included
protective
efficacy
against
microbiologically
confirmed
and
unconfirmed
TB
disease.

Among
720
HIV-exposed,
uninfected
infants,
7%
of
those
receiving
VMP1002
had
a
QFT
conversion
compared
with
8%
of
those
receiving
BCG.
The
6,220
infants
who
were
HIV-unexposed
had
a
5.1%
QFT
conversion
rate
with
VPM1002
and
a
3.9%
rate
with
BCG.

Although
more
of
the
VPM1002
group
had
household
TB
exposures
than
the
BCG
group,
adjustment
for
that
increased
exposure
status
showed
similar
QFT
conversion
rates
between
the
two
groups.

Safety
profiles
were
similar
for
both
vaccines.
There
was
at
least
one
solicited
adverse
event
in
75%
of
those
in
the
VPM1002
group
versus
67%
of
those
in
the
BCG
group;
nearly
all
events
were
mild.
Rates
of
serious
adverse
events
were
also
similar
(10.7%
vs
9.4%,
respectively).

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