Critical analysis (5 pages)

Neutralizing antibody vaccine for pandemic
and pre-emergent coronaviruses

Kevin O. Saunders, Esther Lee, Robert Parks, David R. Martinez, Dapeng Li, Haiyan Chen,
Robert J. Edwards, Sophie Gobeil, Maggie Barr, Katayoun Mansouri, S. Munir Alam,
Laura L. Sutherland, Fangping Cai, Aja M. Sanzone, Madison Berry, Kartik Manne,
Kevin W. Bock, Mahnaz Minai, Bianca M. N ag at a , A ny wa y B. Kapingidza, Mihai Azoitei,
Longping V. Tse, Trevor D. Scobey, Rachel L. Spreng, R. Wes Rountree, C. Todd DeMarco,
Thomas N. D en ny , C hr is to ph er W. Woods, Elizabeth W. Petzold, Juanjie Tang,
Thomas H. Oguin I II , G re go ry D. Sempowski, Matthew Gagne, Daniel C. Douek,
Mark A. Tomai, Christopher B. Fox, Robert Seder, Kevin Wiehe, Drew Weissman,
Norbert Pardi, Hana Golding, Surender K hu ra na , P ri yamvada Acharya, Hanne Andersen,
Mark G. Lewis, Ian N. Moore, David C. Montefiori, Ralph S. Baric & Barton F. Haynes

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Received: 7 February 2021

Accepted: 29 April 2021

Accelerated Article Preview Published
online 10 May 2021

Cite this article as: Saunders, K. O. et al.
Neutralizing antibody vaccine for pandemic
and pre-emergent coronaviruses. Nature
https://doi.org/10.1038/s41586-021-
03594-0 (2021).

https://doi.org/10.1038/s41586-021-03594-0

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https://doi.org/10.1038/s41586-021-03594-0

Nature | www.nature.com | 1

Article

Neutralizing antibody vaccine for pandemic
and pre-emergent coronaviruses

Kevin O. Saunders1,2,3,4 ✉, Esther Lee1,5, Robert Parks1,5, David R. Martinez6, Dapeng Li1,5,
Haiyan Chen1,5, Robert J. Edwards1,5, Sophie Gobeil1,5, Maggie Barr1,5, Katayoun Mansouri1,5,
S. Munir Alam1,5, Laura L. Sutherland1,5, Fangping Cai1,5, Aja M. Sanzone1,5, Madison Berry1,5,
Kartik Manne1,5, Kevin W. Bock7, Mahnaz Minai7, Bianca M. Nagata7, Anyway B. Kapingidza1,5,
Mihai Azoitei1,5, Longping V. Tse6, Trevor D. Scobey6, Rachel L. Spreng1,5, R. Wes Rountree1,5,
C. Todd DeMarco1,5, Thomas N. Denny1,5, Christopher W. Woods1,5,8, Elizabeth W. Petzold8,
Juanjie Tang9, Thomas H. Oguin III1,5, Gregory D. Sempowski1,5, Matthew Gagne10,
Daniel C. Douek10, Mark A. Tomai11, Christopher B. Fox12, Robert Seder10, Kevin Wiehe1,5,
Drew Weissman13, Norbert Pardi13, Hana Golding9, Surender Khurana9,
Priyamvada Acharya1,2, Hanne Andersen14, Mark G. Lewis14, Ian N. Moore7,
David C. Montefiori1,2, Ralph S. Baric6 & Barton F. Haynes1,3,5 ✉

Betacoronaviruses (betaCoVs) caused the severe acute respiratory syndrome (SARS)
and Middle East Respiratory Syndrome (MERS) outbreaks, and the SARS-CoV-2
pandemic1–4. Vaccines that elicit protective immunity against SARS-CoV-2 and
betaCoVs circulating in animals have the potential to prevent future betaCoV
pandemics. Here, we show that macaque immunization with a multimeric SARS-CoV-2
receptor binding domain (RBD) nanoparticle adjuvanted with 3M-052/Alum elicited
cross-neutralizing antibody (cross-nAb) responses against batCoVs, SARS-CoV-1,
SARS-CoV-2, and SARS-CoV-2 variants B.1.1.7, P.1, and B.1.351. Nanoparticle
vaccination resulted in a SARS-CoV-2 reciprocal geometric mean neutralization ID50
titer of 47,216, and protection against SARS-CoV-2 in macaque upper and lower
respiratory tracts. Importantly, nucleoside-modified mRNA encoding a stabilized
transmembrane spike or monomeric RBD also induced SARS-CoV-1 and batCoV
cross-nAbs, albeit at lower titers. These results demonstrate current mRNA vaccines
may provide some protection from future zoonotic betaCoV outbreaks, and provide a
platform for further development of pan-betaCoV vaccines.

SARS coronavirus 1 (SARS-CoV-1), SARS coronavirus 2 (SARS-CoV-2),
and MERS coronavirus (MERS-CoV) emerged from transmission events
where humans were infected with bat or camel CoVs5–8. BetaCoVs that
circulate in civets, bats, and Malayan pangolins are genetically similar
to SARS-CoV-1 and SARS-CoV-2, and use human ACE2 as a receptor5,6,9–11.
These SARS-related animal coronaviruses have the potential to be trans-
mitted to humans12. Cross-nAbs capable of neutralizing multiple beta-
CoVs and preventing or treating betaCoV infection have been isolated
from SARS-CoV-1 infected humans13–24, providing proof-of-concept for
development of betaCoV vaccines against Sarbecoviruses25.

In mice, vaccine induction of cross-nAbs has been reported for
CoV pseudoviruses26,27. However, it is unknown whether spike vac-
cination of primates can elicit cross-nAbs against SARS-CoV-1, bat
betaCoVs, or SARS-CoV-2 escape viruses. A target of cross-nAbs is
the RBD of spike14,24,25. One such RBD cross-nAb is antibody DH1047,

which cross-neutralizes SARS-CoV-1, SARS-CoV-2 and bat CoVs15. RBD
immunogenicity can be augmented by arraying multiple copies on
nanoparticles, mimicking virus-like particles26–29. Thus, we designed
a 24-mer SARS-CoV-2 RBD-ferritin nanoparticle vaccine. The RBD nan-
oparticle was constructed by expressing recombinant SARS-CoV-2
RBD with a C-terminal sortase A donor sequence, and by expressing a
24-subunit, self-assembling protein nanoparticle Helicobacter pylori
ferritin with an N-terminal sortase A acceptor sequence30. The RBD
and ferritin nanoparticle were conjugated together by a sortase A reac-
tion (Fig. 1a, Extended Data Fig. 1)30. Analytical size exclusion chro-
matography and negative stain electron microscopy confirmed that
RBD was conjugated to the surface of the ferritin nanoparticle (Fig. 1a,
Extended Data Fig. 1b,c). The RBD sortase A conjugated nanoparti-
cle (RBD-scNP) bound to human ACE2, the receptor for SARS-CoV-2,
and to potently neutralizing SARS-CoV-2-specific RBD antibodies

https://doi.org/10.1038/s41586-021-03594-0

Received: 7 February 2021

Accepted: 29 April 2021

Published online: 10 May 2021

1Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC, USA. 2Department of Surgery, Duke University, Durham, NC, USA. 3Department of Immunology, Duke
University School of Medicine, Durham, NC, USA. 4Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, NC, USA. 5Department of Medicine, Duke
University School of Medicine, Durham, NC, USA. 6Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. 7Infectious Disease Pathogenesis Section,
Comparative Medicine Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA. 8Center for Applied Genomics and Precision Medicine,
Duke University Medical Center, Durham, NC, USA. 9Division of Viral Products, Center for Biologics Evaluation and Research (CBER), Food and Drug Administration, Silver Spring, MD, USA.
10Vaccine Research Center, National Institute of Allergy and Infectious Diseases (NIAID), NIH, Bethesda, MD, USA. 11Corporate Research Materials Lab, 3M Company, St Paul, MN, USA.
12Infectious Disease Research Institute, Seattle, WA, USA. 13Department of Medicine, University of Pennsylvania, Philadelphia, PA, USA. 14BIOQUAL, Rockville, MD, USA.
✉e-mail: [email protected]; [email protected]

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mailto:[email protected]

mailto:[email protected]

2 | Nature | www.nature.com

Article
(Abs) DH1041, DH1042, DH1043, DH1044, and DH104515 (Fig. 1b). The
cross-nAb DH1047 also bound to the RBD-scNP (Fig. 1b). The RBD-scNP
lacked binding to SARS-CoV-2 spike Abs that bound outside of the RBD
(Fig. 1b).

Five cynomolgus macaques were immunized three times intramus-
cularly four weeks apart with 100 μg of RBD-scNP adjuvanted with
5 μg of the TLR7/8 agonist 3M-052 absorbed to 500 μg of alum (Fig. 1c
and Extended Data Fig. 1d,e)31. Immunizations were well-tolerated
in macaques (Extended Data Fig. 2). Immunization with RBD-scNP
adjuvanted with 3M-052/Alum elicited binding IgG against SARS-CoV-2
RBD and stabilized Spike ectodomain (S-2P) (Fig. 1d), but immuni-
zation with 3M-052/Alum alone did not (Extended Data Fig. 3a,b).
Boosting once maximally increased SARS-CoV-2 binding IgG titers
(Fig. 1d). ACE2 competitive binding assays demonstrated the pres-
ence of ACE2-binding site Abs in the serum of vaccinated macaques
(Fig. 1e). Similarly, plasma Abs blocked the binding of ACE2-binding
site-focused, RBD neutralizing antibody DH1041 (Fig. 1e). Vaccine
induction of nAbs was assessed against a SARS-CoV-2 pseudovirus
with an aspartic acid to glycine substitution at position 614 (D614G)32.
Two RBD-scNP immunizations induced potent serum nAbs with fifty
percent inhibitory reciprocal serum dilution (ID50) neutralization
titers ranging from 21,292 to 162,603 (Fig. 1f,g). We compared these nAb
titers to those elicited by cynomolgus macaques immunized twice with
50 μg of lipid-encapsulated nucleoside-modified mRNA (mRNA-LNP)
encoding stabilized transmembrane (TM) Spike (S-2P) that is analogous
to COVID-19 vaccines authorized for emergency use (Extended Data
Fig. 1f ). Serum neutralization titers against SARS-CoV-2 D614G pseu-
dovirus elicited by RBD-scNP immunization were significantly higher
than titers elicited by two S-2P mRNA-LNP immunizations (Fig. 1i, group
geometric mean ID50 47,216 versus 6,469, P = 0.0079 Exact Wilcoxon
test, n=5)33,34. When compared to natural human infection, RBD-scNP
vaccination elicited higher ID50 neutralization titers (Fig. 1j). Thus,
RBD-scNP adjuvanted with 3M-052/Alum elicits significantly higher
neutralizing titers in macaques compared to current vaccine platforms
or natural human infection.

The SARS-CoV-2 variant B.1.1.7 or United Kingdom variant is spread-
ing globally, and has been suggested to have higher infectivity than
the Wuhan-1 strain35,36. B.1.351 lineage viruses are widespread in the
Republic of South Africa36–38, and along with Brazilian variant P.1 are
of concern due to their neutralization-resistant phenotype mediated
by mutations in the RBD at K417N, E484K, and N501Y39. Each of these
mutations were distal to the cross-nAb DH1047 binding site owing to
its long HCDR3 used to contact RBD; however, the E484K mutation was
within the binding site of RBD nAb DH1041 (Fig. 2a,b)15. Thus, DH1041
binding to SARS-CoV-2 RBD was knocked out by the E484K mutation,
but DH1047 binding to RBD was unaffected by K417N, E484K, or N501Y
(Fig. 2c,d and Extended Data Fig. 3).

We determined whether RBD-scNP or mRNA-LNP immunization
elicited nAbs against these particular SARS-CoV-2 variants. RBD-scNP
macaque serum potently neutralized a pseudovirus bearing the
D614G spike and the B.1.1.7 spike (Fig. 2d,e). Similarly, S-2P mRNA-LNP
immunization elicited equivalent titers of nAbs against the B.1.1.7
and D614G variants of SARS-CoV-2, although titers were lower than
RBD-scNP immunization (Fig. 2d,e). Macaque serum from RBD-scNP
or mRNA-LNP immunization neutralized SARS-CoV-2 WA-1, B.1.351, and
P.1 pseudoviruses, with ID80 titers being more potent for the RBD-scNP
group (Fig. 2f-i). On average, the RBD-scNP group neutralization titers
decreased by 3-fold against B.1.351 or P.1, whereas the mRNA-LNP group
decreased by 6-fold for B.1.351 and 10-fold for P.1 based on ID50 titers
(Fig. 2g,i). Additionally, we observed RBD-scNP and S-2P mRNA-LNP
immune plasma IgG binding to SARS-CoV-2 S was unaffected by muta-
tions observed in Danish minks, B.1.351, P.1, and B.1.1.7 SARS-CoV-2
strains36,37,40 (Extended Data Fig. 3). In summary, both vaccines tested
here elicited nAbs that were unaffected by the mutations in the B.1.1.7
strain. However, nAbs elicited by RBD-scNP more potently neutralized

the difficult-to-neutralize B.1.351 and P.1 virus strains than nAbs elicited
with S-2P mRNA-LNP immunization.

SARS-related CoVs that circulate in humans and animals remain a
threat for future outbreaks12,41,42. Therefore, we examined neutrali-
zation of SARS-CoV-1 and SARS-related group 2b batCoV-WIV-1 and
SARS-related batCoV-SHC014 viruses by immune sera from macaques
vaccinated with the RBD-scNP, mRNA-LNP encoding monomeric
RBD or S-2P (Extended Data Fig. 1e-g)6,9,41,42. After two immunizations,
RBD-scNP, S-2P mRNA-LNP, and the RBD monomer mRNA-LNP elic-
ited nAbs against SARS-CoV-1, batCoV-WIV-1, and batCoV-SHC014
(Fig. 3a, Extended Data Fig. 4). Neutralization was more potent for
replication-competent SARS-CoV-2 virus compared to the other
three SARS-related viruses (Fig. 3a, Extended Data Fig. 4), with neu-
tralization titers varying up to 4-fold within the RBD-scNP group
(Extended Data Fig. 4). Overall, RBD-scNP immunization elicited the
highest neutralization titers (Fig. 3a, Extended Data Fig. 4). Small
increases in neutralization potency were gained by boosting a third
time with the RBD-scNP (Fig. 3b). Moreover, RBD-scNP immunization
elicited cross-reactive plasma IgG against SARS-CoV-2, SARS-CoV-1,
batCoV-RaTG13, batCoV-SHC014, pangolin CoV-GXP4L Spike proteins
(Fig. 3c and Extended Data Fig. 5a,c). Binding antibody titers were high
for these spikes, even in instances where neutralization titers were low
suggesting non-nAbs contributed to binding titers. RBD-scNP immune
plasma IgG did not bind spike from the four endemic human CoVs or
MERS-CoV (Extended Data Fig. 5a,c). The lack of binding by plasma IgG
to these latter five S ectodomains was consistent with RBD sequence
divergence among groups 1, 2a, 2b and 2c coronaviruses (Fig. 3f and
Extended Data Fig. 6-7). The SARS-CoV-2 spike induced cross-nAbs
against multiple group 2b SARS-related betaCoVs, with the highest
titers induced by RBD-scNP.

Immune sera from RBD-scNP-immunized macaques exhibited a
similar cross-neutralizing profile as the cross-nAb DH1047. DH1047
bound with <0.02 nM affinity to monomeric SARS-CoV-2 RBD (Extended Data Fig. 5b), and bound the RBD-scNP (Fig. 1b). The cross-reactive DH1047 epitope is adjacent to the N-terminus of the ACE2-binding site, distinguishing it from dominant ACE2 binding site-focused nAbs such as DH1041 (Fig. 3d)15, and it has high group 2b sequence conserva- tion (Fig. 3e). Overall RBD sequences within betaCoV groups are more conserved than sequences from different groups (Fig. 3f and Extended Data Fig. 6-7). The presence of DH1047-like antibodies was determined with DH1047 blocking assays. Plasma from all RBD-scNP-immunized macaques blocked the binding of ACE2 and DH1047 to SARS-CoV-2 S-2P ectodomain (Fig. 3g and Extended Data Fig. 5d). The DH1047-blocking antibodies were cross-reactive as they also potently blocked DH1047 binding to batCoV-SHC014 S-2P (Fig. 3g). RBD-scNP immunization elic- ited higher magnitudes of DH1047 blocking Abs than S-2P mRNA-LNP immunization of macaques, Pfizer/BNT162b2 mRNA-LNP immuniza- tion of humans, or SARS-CoV-2 human infection (Fig. 3h and Extended Data Fig. 5d). ACE2 blocking was high in all groups (Fig. 3h). While 5 of 5 RBD-scNP-vaccinated macaques exhibited potent DH1047 serum blocking activity, 3 of 4 immunized humans and 9 of 22 of COVID-19 convalescent humans had detectable serum DH1047 blocking activity (Fig. 3h). Thus, the DH1047-like antibody response was subdominant in infected or immunized humans and S-2P mRNA-LNP-immunized macaques, but was a dominant antibody response to RBD-scNP vac- cination. To determine vaccine protection against coronavirus infection, we challenged RBD-scNP-vaccinated and S-2P mRNA-LNP primed/ RBD-scNP boosted monkeys with 105 plaque forming units of SARS-CoV-2 virus via intratracheal and intranasal routes after their last boost (Fig. 4a). NAbs were detectable in all macaques 2 weeks after the final immunization (Fig. 3b and Extended Data Fig. 4b,c). Bronchoalveolar lavage (BAL) fluid was collected 2 days post chal- lenge (Fig. 4a). Infectious SARS-CoV-2 was detectable in BAL fluid from 5 of 6 unimmunized macaques, and undetectable in all RBD-scNP and AC CE LE RA TE D AR TI CL E PR EV IE W AC CE LE RA TE D AR TI CL E PR EV IE W Nature | www.nature.com | 3 S-2P mRNA-LNP/RBD-scNP-immunized macaques (Fig. 4b). Copies of Envelope (E) and Nucleocapsid (N) subgenomic RNA in fluid from nasal swabs and bronchoalveolar lavage (BAL) two and four days after challenge was used to quantify SARS-CoV-2 replication (Fig. 4a). On day 2 after challenge, unimmunized macaques had an average of 1.3x105 and 1.2x104 copies/mL of E sgRNA in the nasal swab and BAL fluids, respectively (Fig. 4c,d). In contrast, RBD-scNP-vaccinated monkeys and 4 of 5 S-2P mRNA-LNP monkeys had undetectable levels of E sgRNA in the upper and lower respiratory tract (Fig. 4c,d). We sampled mon- keys again 2 days later, and found no detectable E sgRNA in any vac- cinated monkey BAL or nasal swab samples (Fig. 4b,c). Similarly, all RBD-scNP-vaccinated macaque had undetectable N sgRNA in BAL and the nasal swab fluid, except one macaque that had 234 copies/mL of N sgRNA detected on day 2 in nasal swab fluid (Fig. 4e,f ). Virus replication was undetectable in this macaque by the fourth day after challenge (Fig. 4e). Additionally, all but one mRNA-LNP/RBD-scNP-immunized macaque had undetectable N sgRNA in BAL or nasal swab samples (Fig. 4e,f ). Moreover, SARS-CoV-2 nucleocapsid antigen was undetect- able in the lung tissue of all vaccinated macaques, but was detected in all control macaques (Fig. 4g and Extended Data Fig. 8). Hematoxylin and eosin staining of lung tissue showed a reduction in inflammation in immunized macaques compared to control macaques (Extended Data Fig. 8 and Extended Data Table 1). Finally, mucosal immunity to SARS-CoV-2 were examined when possible both before and after SARS-CoV-2 challenge (Extended Data Fig. 9). IgG from concentrated BAL bound to spike and blocked ACE-2, DH1041, and DH1047 binding to spike (Extended Data Fig. 9b-d). Each response was higher in the BAL from monkeys immunized three times with RBD-scNP compared to monkeys immunized two times with S-2P mRNA-LNP and boosted once with RBD-scNP, although the BAL was collected from each group at different timepoints. Unconcentrated nasal wash samples from monkeys immunized with either RBD-scNPs or S-2P mRNA-LNP prime/RBD-scNP boost showed similar low levels of spike-binding IgG post challenge (Extended Data Fig. 9e). Nonetheless, RBD-scNP-immunization elicited RBD-specific mucosal antibodies. As three coronavirus epidemics have occurred in the past 20 years, there is a need to develop effective pancoronavirus vaccines prior to the next pandemic25. The epitopes of betaCoV cross-nAbs, such as DH1047, provide clear targets for vaccines aiming to protect against multiple CoVs13–15,43. We have shown that immunization with RBD-scNP adju- vanted with a toll-like receptor agonist 3M-052, and spike mRNA-LNP to a lesser extent, induces cross-nAbs against multiple SARS-related human and bat betaCoVs in primates. These results demonstrate that SARS-CoV-2 vaccination with either the RBD-scNP or spike mRNA-LNP vaccines similar to those authorized for use in humans, will likely elicit cross-nAbs with the potential to prevent future group 2b betaCoV spillo- ver from bats to humans12,26. The emergence of SARS-CoV-2 neutralization-resistant and highly infectious variants continues to be a concern for vaccine efficacy. RBD-scNP and SARS-CoV-2 spike mRNA-LNP immunizations elicited SARS-CoV-2 nAbs against SARS-CoV-2 D614G, B.1.1.7, P.1, and B.1.351 strains. The nAbs elicited by RBD-scNP and S-2P mRNA-LNP were of different specificities since RBD-scNP-induced nAbs showed a smaller reduction in neutralization potency across the different variants compared to S-2P mRNA-LNP immune sera. Our results are consistent with the demonstration that current COVID-19 vaccines have reduced efficacy against the B.1.351 SARS-CoV-2 variant44–49. The RBD-scNP vaccine is a promising platform for pancoronavi- rus vaccine development for the following reasons. The RBD-scNP vaccine induced apparent sterilizing immunity in the upper respira- tory tract, which has not been routinely achieved with SARS-CoV-2 vaccination in macaques50,51. Additionally, the extraordinarily high neutralization titers achieved by RBD-scNP vaccination bode well for an extended duration of protection. 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