A
malaria
vaccine
that
prevents
infection
will
be
an
important
new
tool
in
continued
efforts
of
elimination,
and
such
vaccines
are
under
intense
development
for
the
major
human
parasite
Plasmodium
falciparum
(Pf).
Antibodies
elicited
by
can
block
initial
phases
when
sporozoites
deposited
into
skin
mosquito
bite
then
target
liver
further
development.
However,
there
currently
no
standardized
vivo
preclinical
models
measure
inhibitory
activity
antibody
specificities
against
Pf
sporozoite
via
bite.
Here,
we
use
liver-chimeric
mice
as
a
challenge
model
to
assess
prevention
natural
antibodies.
We
demonstrate
these
consistently
infected
with
this
combined
passive
transfer
either
monoclonal
antibodies
or
polyclonal
IgG
from
immune
serum
antibody-mediated
blocking
using
bioluminescent
imaging.
This
methodology
is
useful
down-select
functional
investigate
mechanisms
correlates
protection
clinical
trials,
thereby
informing
rational
optimization.
Cell Host & Microbe,
Год журнала:
2018,
Номер
24(1), С. 43 - 56
Опубликована: Июль 1, 2018
The
development
of
highly
effective
and
durable
vaccines
against
the
human
malaria
parasites
Plasmodium
falciparum
P.
vivax
remains
a
key
priority.
Decades
endeavor
have
taught
that
achieving
this
goal
will
be
challenging;
however,
recent
innovation
in
vaccine
research
diverse
pipeline
novel
candidates
for
clinical
assessment
provides
optimism.
With
first-generation
pre-erythrocytic
aiming
licensure
coming
years,
it
is
important
to
reflect
on
how
next-generation
approaches
can
improve
their
success.
Here
we
review
latest
seek
prevent
infection,
disease,
transmission
highlight
some
major
underlying
immunological
molecular
mechanisms
protection.
synthesis
rational
antigen
selection,
immunogen
design,
immunization
strategies
induce
quantitatively
qualitatively
improved
immune
effector
offers
promise
sustained
high-level
Abstract
Plasmodium
sporozoites
deposited
in
the
skin
following
a
mosquito
bite
must
migrate
and
invade
blood
vessels
to
complete
their
development
liver.
Once
bloodstream,
arrest
liver
sinusoids,
but
molecular
determinants
that
mediate
this
specific
homing
are
not
yet
genetically
defined.
Here
we
investigate
involvement
of
thrombospondin-related
sporozoite
protein
(TRSP)
process
using
knockout
berghei
parasites
vivo
bioluminescence
imaging
mice.
Resorting
assay,
trsp
were
found
similar
control
parasites.
Moreover,
no
defects
establishment
infection
mice
inoculation
via
intravenous
cutaneous
injection
or
bite.
Accordingly,
mutant
also
able
successfully
hepatocytes
vitro
.
Altogether,
these
results
suggest
TRSP
may
have
redundant
role
completion
pre-erythrocytic
phase
malaria
parasite.
Nonetheless,
identifying
molecules
with
paramount
roles
could
aid
search
for
new
antigens
needed
design
protective
vaccine
against
malaria.
Nature Communications,
Год журнала:
2019,
Номер
10(1)
Опубликована: Окт. 31, 2019
Abstract
Plasmodium
sporozoites
are
transmitted
from
infected
mosquitoes
to
mammals,
and
must
navigate
the
host
skin
vasculature
infect
liver.
This
journey
requires
distinct
proteomes.
Here,
we
report
dynamic
transcriptomes
proteomes
of
both
oocyst
salivary
gland
in
rodent-infectious
yoelii
parasites
human-infectious
falciparum
parasites.
The
data
robustly
define
mRNAs
proteins
that
upregulated
(UOS)
or
infectious
(UIS)
within
glands,
including
many
essential
for
sporozoite
functions
vector
host.
Moreover,
find
malaria
use
two
overlapping,
extensive,
independent
programs
translational
repression
across
maturation
temporally
regulate
protein
expression.
Together
with
gene-specific
validation
experiments,
these
indicate
waves
implemented
relieved
at
different
times
during
maturation,
migration
infection,
thus
promoting
their
successful
development
vector-to-host
transition.
The Journal of Experimental Medicine,
Год журнала:
2017,
Номер
215(1), С. 63 - 75
Опубликована: Ноя. 22, 2017
Antibodies
against
the
central
repeat
of
Plasmodium
falciparum
(Pf)
circumsporozoite
protein
(CSP)
inhibit
parasite
activity
and
correlate
with
protection
from
malaria.
However,
humoral
response
to
PfCSP
C
terminus
(C-PfCSP)
is
less
well
characterized.
Here,
we
describe
B
cell
responses
C-PfCSP
European
donors
who
underwent
immunization
live
Pf
sporozoites
(PfSPZ
Challenge)
under
chloroquine
prophylaxis
(PfSPZ-CVac),
were
protected
controlled
human
malaria
infection.
Out
215
PfCSP-reactive
monoclonal
antibodies,
only
two
unique
antibodies
specific
for
C-PfCSP,
highlighting
rare
occurrence
C-PfCSP–reactive
cells
in
PfSPZ-CVac–induced
protective
immunity.
These
showed
poor
sporozoite
binding
weak
inhibition
traversal
development,
did
not
protect
mice
infection
transgenic
berghei
sporozoites.
Structural
analyses
demonstrated
that
one
antibody
interacts
a
polymorphic
region
overlapping
T
epitopes,
suggesting
variability
may
benefit
escape
cellular
Our
data
identify
important
features
underlying
shortcomings
as
vaccine
target.
Science Translational Medicine,
Год журнала:
2017,
Номер
9(371)
Опубликована: Янв. 4, 2017
Immunization
of
humans
with
whole
sporozoites
confers
complete,
sterilizing
immunity
against
malaria
infection.
However,
achieving
consistent
safety
while
maintaining
immunogenicity
parasite
vaccines
remains
a
formidable
challenge.
We
generated
genetically
attenuated
Plasmodium
falciparum
(Pf)
by
deleting
three
genes
expressed
in
the
pre-erythrocytic
stage
(Pf
p52-/p36-/sap1-).
then
tested
and
engineered
GAP3KO)
human
volunteers.
Pf
GAP3KO
were
delivered
to
10
volunteers
using
infected
mosquito
bites
single
exposure
consisting
150
200
per
subject.
All
subjects
remained
blood
stage-negative
developed
inhibitory
antibodies
sporozoites.
rodent
parasites
engendered
protracted
infectious
sporozoite
challenge
mice.
The
results
warrant
further
clinical
testing
its
potential
development
into
vaccine
strain.
The
most
advanced
monoclonal
antibodies
(mAbs)
and
vaccines
against
malaria
target
the
central
repeat
region
or
closely
related
sequences
within
Plasmodium
falciparum
circumsporozoite
protein
(PfCSP).
Here,
using
an
antigen-agnostic
strategy
to
investigate
human
antibody
responses
whole
sporozoites,
we
identified
a
class
of
mAbs
that
cryptic
PfCSP
epitope
is
only
exposed
after
cleavage
subsequent
pyroglutamylation
(pGlu)
newly
formed
N
terminus.
This
pGlu-CSP
not
targeted
by
current
anti-PfCSP
included
in
licensed
vaccines.
MAD21-101,
potent
mAb
this
class,
confers
sterile
protection
Pf
infection
liver–chimeric
mouse
model.
These
findings
reveal
site
vulnerability
on
sporozoite
surface
can
be
next-generation
antimalarial
interventions.
