npj Vaccines,
Journal Year:
2021,
Volume and Issue:
6(1)
Published: April 19, 2021
Abstract
Emergency
use
authorization
of
COVID
vaccines
has
brought
hope
to
mitigate
pandemic
coronavirus
disease
2019
(COVID-19).
However,
there
remains
a
need
for
additional
effective
meet
the
global
demand
and
address
potential
new
viral
variants.
mRNA
technologies
offer
an
expeditious
path
alternative
traditional
vaccine
approaches.
Here
we
describe
efforts
utilize
platform
rational
design
evaluations
candidates
based
on
spike
(S)
glycoprotein
SARS-CoV-2.
Several
constructs
S-protein,
including
wild
type,
pre-fusion
stabilized
mutant
(2P),
furin
cleavage-site
(GSAS)
double
form
(2P/GSAS),
as
well
others,
were
tested
in
animal
models
their
capacity
elicit
neutralizing
antibodies
(nAbs).
The
lead
2P/GSAS
candidate
was
further
assessed
dose-ranging
studies
mice
Cynomolgus
macaques,
efficacy
Syrian
golden
hamster
model.
selected
formulation,
designated
MRT5500,
elicited
potent
nAbs
measured
neutralization
assays
all
three
preclinical
more
importantly,
protected
against
SARS-CoV-2-induced
weight
loss
lung
pathology
hamsters.
In
addition,
MRT5500
T
H
1-biased
responses
both
mouse
non-human
primate
(NHP),
thus
alleviating
hypothetical
concern
vaccine-associated
enhanced
respiratory
diseases
known
associated
with
2-biased
responses.
These
data
position
viable
entering
clinical
development.
PLoS ONE,
Journal Year:
2021,
Volume and Issue:
16(2), P. e0247060 - e0247060
Published: Feb. 16, 2021
Mortality
due
to
Covid-19
is
highly
associated
with
advanced
age,
owing
in
large
part
severe
lower
respiratory
tract
infection.
SARS-CoV-2
utilizes
the
host
ACE2
receptor
for
Whether
abundance
lung
contributes
age-associated
vulnerability
currently
unknown.
We
set
out
characterize
RNA
and
protein
expression
profiles
of
aging
human
context
phenotypic
parameters
likely
affect
physiology.
Examining
publicly
available
sequencing
data,
we
discovered
that
mechanical
ventilation
a
critical
variable
affecting
levels.
Therefore,
investigated
patients
either
requiring
or
spontaneously
breathing.
distribution
were
determined
archival
samples
by
immunohistochemistry
(IHC).
Tissues
selected
from
specimen
inventory
at
teaching
hospital
collected
between
2010-2020.
Twelve
chosen
receiving
acute
hypoxic
failure
(AHRF).
Twenty
not
ventilation.
compared
across
ranging
40-83
years
old
ventilated
cohort
14-80
non-ventilated
cohort.
Within
alveolated
parenchyma,
predominantly
observed
type
II
pneumocytes
(or
alveolar
/
AT2
cells)
macrophages.
All
12
our
showed
histologic
features
diffuse
damage
including
reactive,
proliferating
cells.
In
these
cases,
was
strongly
upregulated
age
when
normalized
area
(p
=
0.004)
cellularity
0.003),
prominent
individuals,
cell
reactive
changes
did
change
0.231)
0.349).
summary,
increases
setting
on
ventilation,
providing
potential
mechanism
higher
mortality
elderly.
Journal of Translational Medicine,
Journal Year:
2020,
Volume and Issue:
18(1)
Published: Oct. 15, 2020
Abstract
While
the
COVID-19
pandemic
has
spurred
intense
research
and
collaborative
discovery
worldwide,
development
of
a
safe,
effective,
targeted
antiviral
from
ground
up
is
time
intensive.
Therefore,
most
efforts
are
focused
on
re-purposing
clinical
stage
or
approved
drugs.
emerging
data
drugs
undergoing
repurpose
intriguing,
there
an
undeniable
need
to
develop
broad-spectrum
antivirals
prevent
future
viral
pandemics
unknown
origin.
The
ideal
drug
curtail
rapid
spread
would
be
broad-acting
agent
with
activity
against
wide
range
viruses.
Such
work
by
modulating
host-proteins
that
often
shared
multiple
virus
families
thereby
enabling
preemptive
therefore
deployment
at
onset
outbreak.
Targeting
host-pathways
cellular
proteins
hijacked
viruses
can
potentially
offer
targets
for
host-directed
also
likely
higher
barrier
selection
resistant
mutations.
Given
do
not
target
host-proteins,
we
reinforce
such
used
in
pre-
post-exposure
populations.
npj Vaccines,
Journal Year:
2021,
Volume and Issue:
6(1)
Published: April 19, 2021
Abstract
Emergency
use
authorization
of
COVID
vaccines
has
brought
hope
to
mitigate
pandemic
coronavirus
disease
2019
(COVID-19).
However,
there
remains
a
need
for
additional
effective
meet
the
global
demand
and
address
potential
new
viral
variants.
mRNA
technologies
offer
an
expeditious
path
alternative
traditional
vaccine
approaches.
Here
we
describe
efforts
utilize
platform
rational
design
evaluations
candidates
based
on
spike
(S)
glycoprotein
SARS-CoV-2.
Several
constructs
S-protein,
including
wild
type,
pre-fusion
stabilized
mutant
(2P),
furin
cleavage-site
(GSAS)
double
form
(2P/GSAS),
as
well
others,
were
tested
in
animal
models
their
capacity
elicit
neutralizing
antibodies
(nAbs).
The
lead
2P/GSAS
candidate
was
further
assessed
dose-ranging
studies
mice
Cynomolgus
macaques,
efficacy
Syrian
golden
hamster
model.
selected
formulation,
designated
MRT5500,
elicited
potent
nAbs
measured
neutralization
assays
all
three
preclinical
more
importantly,
protected
against
SARS-CoV-2-induced
weight
loss
lung
pathology
hamsters.
In
addition,
MRT5500
T
H
1-biased
responses
both
mouse
non-human
primate
(NHP),
thus
alleviating
hypothetical
concern
vaccine-associated
enhanced
respiratory
diseases
known
associated
with
2-biased
responses.
These
data
position
viable
entering
clinical
development.
