Intranasal fusion inhibitory lipopeptide prevents direct-contact SARS-CoV-2 transmission in ferrets

Abstract

Halting transmission
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike (S) glycoprotein binds to host cells and initiates membrane fusion and cell infection. This stage in the virus life history is currently a target for drug inhibition. De Vries et al. designed highly stable lipoprotein fusion inhibitors complementary to a conserved repeat in the C terminus of S that integrate into host cell membranes and inhibit conformational changes in S necessary for membrane fusion. The authors tested the performance of the lipoproteins as a preexposure prophylactic in a ferret-to-ferret transmission study. Intranasal administration of the peptide 2 days before cohousing with an infected ferret for 24 hours completely protected animals in contact from infection and showed efficacy against mutant viruses. Because ferrets do not get sick from SARS-CoV-2, disease prevention could not be tested in this model.
Science , this issue p. 1379

Full text

Cite as: R. D. de Vries et al., Science
10.1126/science.abf4896 (2021).
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First release: 17 February 2021 www.sciencemag.org (Page numbers not final at time of first release) 1
Infection by SARS-CoV-2 requires membrane fusion between
the viral envelope and the host cell, at either the cell surface
or the endosomal membrane. The fusion process is mediated
by the viral transmembrane spike glycoprotein (S). Upon vi-
ral attachment or uptake, host factors trigger large-scale con-
formational rearrangements in S, including a refolding step
that leads directly to membrane fusion and viral entry (1–3).
Peptides corresponding to the highly conserved heptad re-
peat (HR, Fig. 1A) domain at the C terminus of the S protein
(HRC peptides, Fig. 1B) can prevent this refolding and inhibit
fusion, thereby preventing infection (4–8). The HRC peptides
form six-helix bundle-like assemblies with the extended in-
termediate form of the S protein trimer, disrupting the struc-
tural rearrangement of S that drives membrane fusion (4)
(see also movie S1).
Our approach in designing SARS-CoV-2 S-specific fusion
inhibitors builds on our previous work that demonstrated
that lipid conjugation of HRC-derived inhibitory peptides
markedly increases antiviral potency and in vivo half-life (9,
10). These peptides successfully inhibit human parainfluenza
virus type 3 (HPIV-3), measles virus, influenza virus, and
Nipah virus infection (9, 11–13). Furthermore, the
combination of dimerization and lipopeptide integration into
cell membranes protects the respiratory tract and prevents
systemic lipopeptide dissemination (14). Lipid-conjugated
peptides administered intranasally to animals reached high
concentrations both in the upper and lower respiratory tract,
and the lipid could be designed to modulate the extent of
transit from the lung to the blood and organs (9, 14). We pro-
pose a SARS-CoV-2 specific lipopeptide as a candidate antivi-
ral for pre-exposure and early post-exposure prophylaxis for
SARS-CoV-2 transmission in humans.
We recently described a monomeric SARS-CoV-2 HRC-
lipopeptide fusion inhibitor (4) against SARS-CoV-2 with in
vitro and ex vivo efficacy superior to previously described
HRC-derived fusion inhibitory peptides (6, 7). To further im-
prove antiviral potency, we compared monomeric and di-
meric HRC-peptide derivatives (Fig. 1C). Figure 1D shows
antiviral potency in a quantitative cell-cell fusion assay of
four monomeric and two dimeric SARS-CoV-2 S-derived 36-
amino acid HRC-peptides (Fig. 1B, see also figs. S1A and S3
for structure and characterization), without or with ap-
pended cholesterol. Dimerization increased the peptide po-
tency for both non-lipidated peptides and their lipidated
Intranasal fusion inhibitory lipopeptide prevents
direct-contact SARS-CoV-2 transmission in ferrets
Rory D. de Vries1*, Katharina S. Schmitz1*, Francesca T. Bovier2,3,4*, Camilla Predella2,5, Jonathan Khao6,
Danny Noack1, Bart L. Haagmans1, Sander Herfst1, Kyle N. Stearns2,3,7, Jennifer Drew-Bear2,3, Sudipta Biswas8,
Barry Rockx1, Gaël McGill6,9, N. Valerio Dorrello2, Samuel H. Gellman10, Christopher A. Alabi8†,
Rik L. de Swart1†, Anne Moscona2,3,7,11†, Matteo Porotto2,3,4†
1Department of Viroscience, Erasmus MC, Rotterdam, Netherlands. 2Department of Pediatrics, Columbia University Irving Medical Center, New York, NY, USA. 3Center for
Host–Pathogen Interaction, Columbia University Irving Medical Center, New York, NY, USA. 4Department of Experimental Medicine, University of Campania “Luigi
Vanvitelli,” Caserta, Italy. 5Department of Biomedical Engineering, Politecnico di Milano, Milan, Italy. 6Digizyme Inc., Brookline, MA, USA. 7Department of Physiology and
Cellular Biophysics, Columbia University Irving Medical Center, New York, NY, USA. 8Robert Frederick Smith School of Chemical and Biomolecular Engineering, Cornell
University, Ithaca, NY, USA. 9Center for Molecular and Cellular Dynamics, Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School,
Boston, MA, USA. 10Department of Chemistry, University of Wisconsin–Madison, Madison, WI, USA. 11Department of Microbiology and Immunology, Columbia University
Irving Medical Center, New York, NY, USA.
*These authors contributed equally to this work.
†Corresponding author. Email: caa238@cornell.edu (C.A.A.); r.deswart@erasmusmc.nl (R.L.d.S.);
am939@cumc.columbia.edu (A.M.); mp3509@cumc.columbia.edu (M.P.)
Containment of the COVID-19 pandemic requires reducing viral transmission. SARS-CoV-2 infection is
initiated by membrane fusion between the viral and host cell membranes, mediated by the viral spike
protein. We have designed lipopeptide fusion inhibitors that block this critical first step of infection, and
based on in vitro efficacy and in vivo biodistribution selected a dimeric form for evaluation in an animal
model. Daily intranasal administration to ferrets completely prevented SARS-CoV-2 direct-contact
transmission during 24-hour co-housing with infected animals, under stringent conditions that resulted in
infection of 100% of untreated animals. These lipopeptides are highly stable and thus may readily translate
into safe and effective intranasal prophylaxis to reduce transmission of SARS-CoV-2.
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counterparts (Fig. 1D). A dimeric cholesterol-conjugated
lipopeptide based on the HPIV-3 F protein HRC domain, used
as a negative control, did not inhibit fusion at any concentra-
tion tested (black line in Fig. 1D, see fig. S1, B and C, for ad-
ditional negative controls). Among the monomeric
lipopeptides, the peptide bearing PEG24 was most potent. The
dimeric cholesterol-conjugated peptide ([SARSHRC-PEG4]2-
chol; red line in Fig. 1D) was the most potent lipopeptide
against SARS-CoV-2 among our panel. This peptide also ro-
bustly inhibited fusion mediated by the S proteins of several
emerging SARS-CoV-2 variants [including D614G (15)], the
recent variants of concern B.1.1.7 and B.1.351 (16, 17) and the
S protein of SARS-CoV and MERS-CoV (Fig. 1E). Proposed an-
choring of the dimeric lipopeptide in the host cell membrane
and interactions with the viral S protein are shown in fig. S2
and movie S1. Collectively, these data suggest that the
[SARSHRC-PEG4]2-chol lipopeptide is equipped to combat an
evolving pandemic.
For other enveloped respiratory viruses, we previously
showed that both ex vivo and in vivo dimeric lipopeptides
(administered intranasally) displayed increased retention in
the respiratory tract compared to monomeric compounds
(14). Here, we compared local and systemic biodistribution of
our most potent monomeric and dimeric lipopeptides
(SARSHRC-PEG24-chol and [SARSHRC-PEG4]2-chol) at 1, 8, and
24 hours after intranasal inoculation or subcutaneous injec-
tion in humanized K18 hACE2 mice (Fig. 2 and fig. S4). The
two lipopeptides reached a similar lung concentration at 1
hour after intranasal administration (~1 to 2 μM). At 8 and
24 hours, the dimeric [SARSHRC-PEG4]2-chol lipopeptide re-
mained at high levels in the lung with minimal entry into the
blood, but the monomeric peptide entered the circulation
and the lung concentration decreased (Fig. 2A). The dimeric
[SARSHRC-PEG4]2-chol lipopeptide was distributed through-
out the lung after intranasal administration (Fig. 2B). A cel-
lular toxicity (MTT) assay in primary HAE cells showed
minimal toxicity even after 6 days at the highest concentra-
tions tested (<20% at 100 μM), and no toxicity at its IC90 entry
inhibitory concentrations (~35 nM) (fig. S5). The longer res-
piratory tract persistence of [SARSHRC-PEG4]2-chol, in concert
with its in vitro efficacy, led us to advance this dimeric
lipopeptide.
The lead peptide, [SARSHRC-PEG4]2-chol, was assessed for
its ability to block entry of SARS-CoV-2 in VeroE6 cells or
VeroE6 cells overexpressing the protease TMPRSS2, one of
the host factors thought to facilitate viral entry at the cell
membrane (2). Whereas viral fusion in VeroE6 cells predom-
inantly occurs after endocytosis, the virus enters TMPRSS2-
overexpressing cells by fusion at the cell surface, reflecting
the entry route in airway cells (18). This difference is high-
lighted by chloroquine’s effectiveness against SARS-CoV-2 in-
fection in Vero cells but failure in TMPRSS2-expressing Vero
cells and human lung (19). The [SARSHRC-PEG4]2-chol peptide
dissolved in an aqueous buffer containing 2% dimethylsulfox-
ide (DMSO) inhibited virus entry after 8 hours with an IC50
~300 nM in VeroE6 and ~5 nM in VeroE6-TMPRSS2 cells
(Fig. 3A). To strengthen translational potential toward hu-
man use, the lipopeptide was reformulated in sucrose instead
of DMSO, resulting in equivalent in vitro potency (Fig. 3B). A
control dimeric fusion-inhibitory lipopeptide directed
against HPIV-3 blocked infection by HPIV-3, but did not in-
hibit SARS-CoV-2 infection. The in vitro efficacy data are
summarized in table S1.
Ferrets are an ideal model for assessing respiratory virus
transmission, either by direct contact or by aerosol transmis-
sion (20, 21). Mustelids are highly susceptible to infection
with SARS-CoV-2, as also illustrated by frequent COVID-19
outbreaks at mink farms. Direct contact transmission of
SARS-CoV in ferrets was demonstrated in 2003 (22), and both
direct contact and airborne transmission have been shown in
ferrets for SARS-CoV-2 (20, 23). Direct contact transmission
in the ferret model is highly reproducible (100% transmission
from donor to acceptor animals), but ferrets display limited
clinical signs. After infection via direct inoculation or trans-
mission, SARS-CoV-2 can readily be detected in and isolated
from the throat and nose, and viral replication leads to sero-
conversion.
To assess the efficacy of [SARSHRC-PEG4]2-chol in prevent-
ing SARS-CoV-2 transmission, naïve ferrets were dosed
prophylactically with the lipopeptide before being co-housed
with SARS-CoV-2 infected ferrets. In this setup, transmission
via multiple routes can theoretically occur (aerosol, orofecal,
and scratching or biting), and ferrets are continuously ex-
posed to infectious virus during the period of co-housing,
providing a stringent test for antiviral efficacy. The study de-
sign is shown in fig. S6. Three donor ferrets (gray in diagram)
were inoculated intranasally with 5 × 105 TCID50 SARS-CoV-2
on day 0. Twelve recipient ferrets housed separately were
treated by nose drops with a mock preparation (red) or
[SARSHRC-PEG4]2-chol peptide (green) 1 and 2 days post-inoc-
ulation (DPI) of the donor animals. The [SARSHRC-PEG4]2-chol
peptides for intranasal administration were dissolved to a
concentration of 6 mg/ml in an aqueous buffer containing 2%
DMSO, administering a final dose of 2.7 mg/kg to ferrets
(450 μl, equally divided over both nostrils). Peptide stocks
and working dilutions had similar IC50’s, confirming that pep-
tide-treated ferrets were dosed daily with comparable
amounts (fig. S7, A and B). Six hours after the second treat-
ment on 2 DPI, one infected donor ferret (highly positive for
SARS-CoV-2 by RT-qPCR) was co-housed with four naïve re-
cipient ferrets (two mock-treated, two peptide-treated). After
a 24-hour transmission period in three separate, negatively
pressurized HEPA-filtered ABSL3-isolator cages, co-housing
was stopped and donor, mock-treated and peptide-treated
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ferrets were housed as separate groups. Additional [SARSHRC-
PEG4]2-chol peptide treatments were given to recipient ani-
mals on 3 and 4 DPI.
The viral loads (detection of viral genomes via RT-qPCR)
for directly inoculated donor animals (gray), mock-treated re-
cipient animals (red) and lipopeptide-treated recipient ani-
mals (green) are shown in Fig. 4, A and B. All directly
inoculated donor ferrets were productively infected, as
shown by SARS-CoV-2 genome detection in throat and nose
swabs, and efficiently and reproducibly transmitted the virus
to all mock-treated acceptor ferrets (Fig. 4, A and B, red
curves). Productive SARS-CoV-2 infection was not detected in
the throat or nose of any of the peptide-treated recipient an-
imals (Fig. 4, A and B, green curves). A slight rise in viral
loads in samples collected at 3 DPI was detected (at the end
of the co-housing), confirming that peptide-treated animals
were exposed to SARS-CoV-2. In Fig. 4C the area under the
curve (AUC) shows the striking difference between the mock
treated and the peptide treated animals. No infectious virus
was isolated from lipopeptide-treated ferrets, while infectious
virus was detected in all mock-treated ferrets (Fig. 4D). Virus
isolation data correlated with genome detection (Fig. 4E).
Seroconversion occurred in donor ferrets and 6/6 mock-
treated animals by 21 DPI, but in none of the peptide-treated
recipient animals, as shown by S- and N-specific IgG enzyme-
linked immunosorbent assay (ELISA) and virus neutraliza-
tion (Fig. 4, F to H). Successful challenge infection confirmed
that in-host virus replication had been completely blocked by
the [SARSHRC-PEG4]2-chol treatment (Fig. 4I and fig. S8) and
that none of the peptide-animals were protected, whereas the
mock-treated animals (which had seroconverted) were all
protected. Collectively, these data show that intranasal
prophylactic administration of the [SARSHRC-PEG4]2-chol
peptide had protected 6/6 ferrets from transmission and pro-
ductive infection.
In light of the persistence of the dimeric lipopeptide in
the murine lung (Fig. 2 and fig. S4), we assessed the potential
for a single administration of sucrose-formulated lipopeptide
in a ferret transmission experiment two hours before co-
housing to prevent or delay infection. In this experiment, we
used a dimeric HPIV-3-specific lipopeptide as mock control
(fig. S9). Although sucrose formulation had resulted in prom-
ising results in vitro at small scale (Fig. 3B), formulation at
larger scale resulted in incomplete dissolution. As a conse-
quence, the sucrose-formulated [SARSHRC-PEG4]2-chol
lipopeptide was administered at a substantially lower con-
centration than in the experiment with the DMSO-
formulated lipopeptide (fig. S7, C and D). Nevertheless, the
SARS-CoV-2 lipopeptide provided a significant level of pro-
tection as compared to the HPIV-3 control group, and four
out of six SARS-CoV-2 lipopeptide-treated animals were pro-
tected against infection. This experiment suggests that single-
administration pre-exposure prophylaxis is promising, while
the optimal formulation and dosing regimen is an area of on-
going experimentation.
The intranasal [SARSHRC-PEG4]2-chol peptide presented in
this study is the first successful prophylaxis that prevents
SARS-CoV-2 transmission in a relevant animal model, provid-
ing complete protection during a 24-hour period of intense
direct contact. Parallel approaches to prevent transmission
that target the interaction between S and ACE2 have shown
promise in vitro [e.g., the “miniprotein” approach (24)]. The
lipopeptide described here acts on the S2 domain after shed-
ding of S1 (fig. S2 and movie S1), and is complementary to
strategies that target S1’s functions or maintain S in its pre-
fusion conformation, e.g., synthetic nanobodies (25, 26). Fu-
sion-inhibitory lipopeptides could be used for pre- and post-
exposure prophylaxis in combination with these strategies,
and in conjunction with treatments [e.g., ribonucleoside an-
alogs (27)] that reduce replication in a treated infected indi-
vidual. A combination of drugs that target different aspects
of the viral life cycle is likely ideal for this rapidly-evolving
virus. Of note, the [SARSHRC-PEG4]2-chol lipopeptide is
equally active against several emerging SARS-CoV-2 variants
including the D614G as well as the recent variants of concerns
(B.1.1.7 and B.1.351). The [SARSHRC-PEG4]2-chol peptide has a
long shelf life, does not require refrigeration and can easily
be administered, making it particularly suited to treating
hard-to-reach populations. This is key in the context of
COVID-19, which has reached every community with the bur-
den falling disproportionately on low-income and otherwise
marginalized communities. This HRC lipopeptide fusion in-
hibitor is feasible for advancement to human use and should
readily translate into a safe and effective nasal spray or inha-
lation administered fusion inhibitor for SARS-CoV-2 prophy-
laxis, supporting containment of the ongoing COVID-19
pandemic.
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ACKNOWLEDGMENTS
We thank J. S. Orange, S. G. Kernie, M. Lamers, E. Verveer, A. Mykytyn and
M. Koopmans for their contributions to this study. Funding: This work was
supported by funding from the National Institutes of Health (AI146980,
AI121349, and NS091263 to M.P., AI114736 to A.M., HHSN272201400008C to
S.H.), the Sharon Golub Fund at Columbia University Irving Medical Center
(CUIMC), the Children’s Health Innovation Nucleation Fund of the Pediatrics
Department at CUIMC and a Harrington Discovery Institute COVID-19 Award to
A.M. A.M. is the inaugural Sherie L. Morrison Professor of Immunology.
Author contributions: Conceptualization: R.D.d.V., S.H.G., C.A.A., R.L.d.S.,
A.M., M.P. Formal analysis: R.D.d.V., K.S.S., F.T.B., C.P., N.V.D., C.A.A.,
R.L.d.S., A.M., M.P. Funding acquisition: B.L.H., R.L.d.S., A.M., M.P.
Investigation: R.D.d.V., K.S.S., F.T.B., C.P., J.K., D.N., K.N.S., S.H., J.D.-B.,
S.B., G.M., N.V.D., S.H.G., C.A.A., R.L.d.S., A.M., M.P. Resources: B.L.H., B.R.,
N.V.D., C.A.A., R.L.d.S., A.M., M.P. Supervision: R.L.d.S., N.V.D., C.A.A.,
A.M., M.P. Visualization: R.D.d.V., K.S., F.T.B., J.K., G.M., N.V.D., S.H.G., C.A.A.,
A.M., M.P. Writing – original draft: R.D.d.V., R.L.d.S., A.M., M.P. Writing – final
version: all co-authors provided feedback to the final draft. Competing
interests: R.D.d.V., F.T.B., R.L.d.S., A.M. and M.P. are listed as inventors of
[SARSHRC-PEG4]2-chol on a provisional patent application covering findings
reported in this manuscript. Data and materials availability: All data are
available in the manuscript or the supplementary materials. Materials are
available by MTA with the Trustees of Columbia University, NYC. This work is
licensed under a Creative Commons Attribution 4.0 International (CC BY 4.0)
license, which permits unrestricted use, distribution, and reproduction in any
medium, provided the original work is properly cited. To view a copy of this
license, visit https://creativecommons.org/licenses/by/4.0/. This license does
not apply to figures/photos/artwork or other content included in the article that
is credited to a third party; obtain authorization from the rights holder before
using such material. Reagents are available from the corresponding authors
under a material agreement with Columbia University.
SUPPLEMENTARY MATERIALS
science.sciencemag.org/cgi/content/full/science.abf4896/DC1
Materials and Methods
Figs. S1 to S10
Table S1
References (28–34)
MDAR Reproducibility Checklist
Movie S1
29 October 2020; resubmitted 4 January 2021
Accepted 9 February 2021
Published online 17 February 2021
10.1126/science.abf4896
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Fig. 1. Peptide-lipid conjugates that inhibit SARS-CoV-2 spike (S)–mediated fusion
.
(
A
) The functional domains of SARS-CoV-2 S protein: receptor-binding domain (RBD)
and heptad repeats (HRN and HRC) are indicated. (
B
) Sequence of the peptides derived
from the HRC domain of SARS-CoV-2 S. (
C
) Monomeric and dimeric forms of lipid
tagged SARS-CoV-2 inhibitory peptides that were assessed in cell-cell fusion assays.
(
D
) Cell-cell fusion assays with different inhibitory peptides. The percentage inhibition
is shown for six different SARS-CoV-2-specific peptides and a control HPIV-3-specific
peptide at increasing concentrations. Percent inhibition was calculated as the ratio of
the relative luminescence units in the presence of a specific concentration of inhibitor
and the relative luminescence units in the absence
of inhibitor, corrected for
background luminescence. % inhibition = 100 × [1 − (luminescence at X −
background)/(luminescence in absence of inhibitor − background)]. The difference
between the results for [SARSHRC-PEG4]2-chol and SARSHRC-PEG4-chol lipopeptides was
statistically significant (two-way ANOVA, P < 0.0001). (
E
) Fusion inhibitory activity of
[SARSHRC-PEG4]2-chol peptide against emerging SARS-CoV-2 S variants, MERS-CoV-2
S, and SARS-CoV S. Data in (D) and (E) are means ± standard error of the mean (SEM)
from three separate experiments with the curve representing a four-parameter dose-
response model.
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Fig. 2. Biodistribution of [SARSHRC-PEG4]2-chol and
SARSHRC-PEG24 peptides after intranasal administration
to mice.
(
A
) The concentration of lipopeptides (y axis) was
measured by ELISA in lung homogenates and plasma
samples (peptide-treated n = 3 to 4, mock n =1). Median is
indicated by horizontal bar. (
B
) Lung sections of [SARSHRC-
PEG4]2-chol-treated (or vehicle-treated) mice were stained
with anti-SARS-
HRC antibody (red) confirming broad
distribution of [SARSHRC-PEG4]2-chol in the lung (8 hours
post-inoculation, 8HPI). Scale bar = 500 μm in lung tile scan,
50 μm in magnification, representative images and a full tile
scan are shown. Nuclei were counterstained with DAPI
(blue).
Fig. 3. Inhibition of infectious SARS-CoV-2 entry by [SARSHRC-PEG4]2-
chol and [HPIV-3HRC-PEG4]2-chol peptides.
(
A
and
B
) The percentage
inhibition of infection is shown on VeroE6 and VeroE6-TMPRSS2 cells
with increasing concentrations of [SARSHRC-PEG4]2-chol (red lines) and
[HPIV-3HRC-PEG4]2-chol (gray lines). DMSO-formulated (A) and sucrose-
formulated stocks (B) were tested side-by-side. Mean ± SEM of
triplicates are shown, dotted lines show 50% and 90% inhibition.
Additionally, the potency of [HPIV-3HRC-PEG4]2-chol was confirmed by
inhibition of infectious HPIV-3 entry (dotted green lines, performed on
Vero cells).
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Fig. 4. [SARSHRC-PEG4]2-chol prevents SARS-CoV-2 transmission in
vivo.
(
A
and
B
) Viral loads detected in throat (A) and nose (B) swabs by
RT-qPCR. (
C
) Comparison of the area under the curve (AUC) from
genome loads reported in B for mock- and peptide-treated sentinels.
(
D
) Viral loads detected in throat swabs by virus isolation on VeroE6.
(
E
) Correlation between viral loads in the throat as detected via RT-qPCR
and virus isolation. Presence of anti-S (
F
) or anti-N (
G
) antibodies was
determined by IgG ELISA assay. Presence of neutralizing antibodies was
determined in a virus neutralization assay (
H). Virus neutralizing
antibodies are displayed as the endpoint serum dilution factor that
blocks SARS-CoV-2 replication. Direct inoculation of peptide-treated or
mock-treated animals with SARS-CoV-2 led to productive infection in
only the previously peptide-treated animals (
I
), in the absence of S-
specific, N-specific and neutralizing antibodies. Donor animals shown in
gray, mock-treated animals in red, peptide-treated animals in green.
Symbols correspond to individual animals (defined in fig. S6). Line
graphs in (A), (B), (D), and (F) to (I) connect the median of individual
animals per time point. Mock- and peptide-
treated groups were
compared via two-way ANOVA repeated measures [(A), (B), and (F) to
(I)] or Mann-Whitney test (C).
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ferrets
Intranasal fusion inhibitory lipopeptide prevents direct-contact SARS-CoV-2 transmission in
Gellman, Christopher A. Alabi, Rik L. de Swart, Anne Moscona and Matteo Porotto
Sander Herfst, Kyle N. Stearns, Jennifer Drew-Bear, Sudipta Biswas, Barry Rockx, Gaël McGill, N. Valerio Dorrello, Samuel H.
Rory D. de Vries, Katharina S. Schmitz, Francesca T. Bovier, Camilla Predella, Jonathan Khao, Danny Noack, Bart L. Haagmans,
published online February 17, 2021
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REFERENCES http://science.sciencemag.org/content/early/2021/02/16/science.abf4896#BIBL
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