SARS-CoV-2 ferritin nanoparticle vaccines elicit broad SARS coronavirus immunogenicity

M. Gordon Joyce; Wei Hung Chen; Rajeshwer S. Sankhala; Agnes Hajduczki; Paul V. Thomas; Misook Choe; Elizabeth J. Martinez; William C. Chang; Caroline E. Peterson; Elaine B. Morrison; Clayton Smith; Rita E. Chen; Aslaa Ahmed; Lindsay Wieczorek; Alexander Anderson; James Brett Case; Yifan Li; Therese Oertel; Lorean Rosado; Akshaya Ganesh; Connor Whalen; Joshua M. Carmen; Letzibeth Mendez-Rivera; Christopher P. Karch; Neelakshi Gohain; Zuzana Villar; David McCurdy; Zoltan Beck; Jiae Kim; Shikha Shrivastava; Ousman Jobe; Vincent Dussupt; Sebastian Molnar; Ursula Tran; Chandrika B. Kannadka; Sandrine Soman; Caitlin Kuklis; Michelle Zemil; Htet Khanh; Weimin Wu; Matthew A. Cole; Debra K. Duso; Larry W. Kummer; Tricia J. Lang; Shania E. Muncil; Jeffrey R. Currier; Shelly J. Krebs; Victoria R. Polonis; Saravanan Rajan; Patrick M. McTamney; Mark T. Esser; William W. Reiley; Morgane Rolland; Natalia de Val; Michael S. Diamond; Gregory D. Gromowski; Gary R. Matyas; Mangala Rao; Nelson L. Michael; Kayvon Modjarrad

doi:10.1016/j.celrep.2021.110143

SARS-CoV-2 ferritin nanoparticle vaccines elicit broad SARS coronavirus immunogenicity

M. Gordon Joyce^*, Wei Hung Chen, Rajeshwer S. Sankhala, Agnes Hajduczki, Paul V. Thomas, Misook Choe, Elizabeth J. Martinez, William C. Chang, Caroline E. Peterson, Elaine B. Morrison, Clayton Smith, Rita E. Chen, Aslaa Ahmed, Lindsay Wieczorek, Alexander Anderson, James Brett Case, Yifan Li, Therese Oertel, Lorean Rosado, Akshaya GaneshConnor Whalen, Joshua M. Carmen, Letzibeth Mendez-Rivera, Christopher P. Karch, Neelakshi Gohain, Zuzana Villar, David McCurdy, Zoltan Beck, Jiae Kim, Shikha Shrivastava, Ousman Jobe, Vincent Dussupt, Sebastian Molnar, Ursula Tran, Chandrika B. Kannadka, Sandrine Soman, Caitlin Kuklis, Michelle Zemil, Htet Khanh, Weimin Wu, Matthew A. Cole, Debra K. Duso, Larry W. Kummer, Tricia J. Lang, Shania E. Muncil, Jeffrey R. Currier, Shelly J. Krebs, Victoria R. Polonis, Saravanan Rajan, Patrick M. McTamney, Mark T. Esser, William W. Reiley, Morgane Rolland, Natalia de Val, Michael S. Diamond, Gregory D. Gromowski, Gary R. Matyas, Mangala Rao, Nelson L. Michael, Kayvon Modjarrad

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

42 Scopus citations

Abstract

The need for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) next-generation vaccines has been highlighted by the rise of variants of concern (VoCs) and the long-term threat of emerging coronaviruses. Here, we design and characterize four categories of engineered nanoparticle immunogens that recapitulate the structural and antigenic properties of the prefusion SARS-CoV-2 spike (S), S1, and receptor-binding domain (RBD). These immunogens induce robust S binding, ACE2 inhibition, and authentic and pseudovirus neutralizing antibodies against SARS-CoV-2. A spike-ferritin nanoparticle (SpFN) vaccine elicits neutralizing titers (ID₅₀ > 10,000) following a single immunization, whereas RBD-ferritin nanoparticle (RFN) immunogens elicit similar responses after two immunizations and also show durable and potent neutralization against circulating VoCs. Passive transfer of immunoglobulin G (IgG) purified from SpFN- or RFN-immunized mice protects K18-hACE2 transgenic mice from a lethal SARS-CoV-2 challenge. Furthermore, S-domain nanoparticle immunization elicits ACE2-blocking activity and ID₅₀ neutralizing antibody titers >2,000 against SARS-CoV-1, highlighting the broad response elicited by these immunogens.

Original language	English
Article number	110143
Journal	Cell Reports
Volume	37
Issue number	12
DOIs	https://doi.org/10.1016/j.celrep.2021.110143
State	Published - 21 Dec 2021
Externally published	Yes

Keywords

ALFQ
B.1.1.7
B.1.351
COVID-19
P.1
SARS-CoV-1
SARS-CoV-2
betacoronaviruses
ferritin nanoparticle
neutralizing antibodies
receptor-binding domain
spike
variants of concern

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10.1016/j.celrep.2021.110143

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Joyce, M. G., Chen, W. H., Sankhala, R. S., Hajduczki, A., Thomas, P. V., Choe, M., Martinez, E. J., Chang, W. C., Peterson, C. E., Morrison, E. B., Smith, C., Chen, R. E., Ahmed, A., Wieczorek, L., Anderson, A., Case, J. B., Li, Y., Oertel, T., Rosado, L., ... Modjarrad, K. (2021). SARS-CoV-2 ferritin nanoparticle vaccines elicit broad SARS coronavirus immunogenicity. Cell Reports, 37(12), [110143]. https://doi.org/10.1016/j.celrep.2021.110143

@article{fb0ded3730d940ef886439c0df19b2b4,

title = "SARS-CoV-2 ferritin nanoparticle vaccines elicit broad SARS coronavirus immunogenicity",

abstract = "The need for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) next-generation vaccines has been highlighted by the rise of variants of concern (VoCs) and the long-term threat of emerging coronaviruses. Here, we design and characterize four categories of engineered nanoparticle immunogens that recapitulate the structural and antigenic properties of the prefusion SARS-CoV-2 spike (S), S1, and receptor-binding domain (RBD). These immunogens induce robust S binding, ACE2 inhibition, and authentic and pseudovirus neutralizing antibodies against SARS-CoV-2. A spike-ferritin nanoparticle (SpFN) vaccine elicits neutralizing titers (ID50 > 10,000) following a single immunization, whereas RBD-ferritin nanoparticle (RFN) immunogens elicit similar responses after two immunizations and also show durable and potent neutralization against circulating VoCs. Passive transfer of immunoglobulin G (IgG) purified from SpFN- or RFN-immunized mice protects K18-hACE2 transgenic mice from a lethal SARS-CoV-2 challenge. Furthermore, S-domain nanoparticle immunization elicits ACE2-blocking activity and ID50 neutralizing antibody titers >2,000 against SARS-CoV-1, highlighting the broad response elicited by these immunogens.",

keywords = "ALFQ, B.1.1.7, B.1.351, COVID-19, P.1, SARS-CoV-1, SARS-CoV-2, betacoronaviruses, ferritin nanoparticle, neutralizing antibodies, receptor-binding domain, spike, variants of concern",

author = "Joyce, {M. Gordon} and Chen, {Wei Hung} and Sankhala, {Rajeshwer S.} and Agnes Hajduczki and Thomas, {Paul V.} and Misook Choe and Martinez, {Elizabeth J.} and Chang, {William C.} and Peterson, {Caroline E.} and Morrison, {Elaine B.} and Clayton Smith and Chen, {Rita E.} and Aslaa Ahmed and Lindsay Wieczorek and Alexander Anderson and Case, {James Brett} and Yifan Li and Therese Oertel and Lorean Rosado and Akshaya Ganesh and Connor Whalen and Carmen, {Joshua M.} and Letzibeth Mendez-Rivera and Karch, {Christopher P.} and Neelakshi Gohain and Zuzana Villar and David McCurdy and Zoltan Beck and Jiae Kim and Shikha Shrivastava and Ousman Jobe and Vincent Dussupt and Sebastian Molnar and Ursula Tran and Kannadka, {Chandrika B.} and Sandrine Soman and Caitlin Kuklis and Michelle Zemil and Htet Khanh and Weimin Wu and Cole, {Matthew A.} and Duso, {Debra K.} and Kummer, {Larry W.} and Lang, {Tricia J.} and Muncil, {Shania E.} and Currier, {Jeffrey R.} and Krebs, {Shelly J.} and Polonis, {Victoria R.} and Saravanan Rajan and McTamney, {Patrick M.} and Esser, {Mark T.} and Reiley, {William W.} and Morgane Rolland and {de Val}, Natalia and Diamond, {Michael S.} and Gromowski, {Gregory D.} and Matyas, {Gary R.} and Mangala Rao and Michael, {Nelson L.} and Kayvon Modjarrad",

note = "Funding Information: M.G.J. and K.M. are named as inventors on international patent application WO/2021/178971 A1 entitled “Vaccines against SARS-CoV-2 and other coronaviruses.” M.G.J. is named as an inventor on international patent application WO/2018/081318 and U.S. patent 10,960,070 entitled “Prefusion coronavirus spike proteins and their use.” Z.B. is named as an inventor on U.S. patent 10,434,167 entitled “Non-toxic adjuvant formulation comprising a monophosphoryl lipid A (MPLA)-containing liposome composition and a saponin.” Z.B. and G.R.M. are named as inventors on U.S. patent application 16/607,917 entitled “Compositions and methods for vaccine delivery.” M.S.D. is a consultant for Inbios, Vir Biotechnology, Fortress Biotech, and Carnival Corporation and on the scientific advisory boards of Moderna and Immunome. The Diamond laboratory has received funding support from sponsored research agreements from Moderna, Vir Biotechnology, Kaleido, and Emergent BioSolutions. S.R., P.M.M., and M.T.E. are employees of AstraZeneca and currently hold AstraZeneca stock or stock options. Z.B. is currently employed at Pfizer. Funding Information: Infectivity and neutralization titers were determined using ACE2-expressing HEK293 target cells (Integral Molecular) in a semi-automated assay format using robotic liquid handling (Biomek NXp Beckman Coulter). Test sera were diluted 1:40 in growth medium and serially diluted, then 25 μL/well was added to a white 96-well plate. An equal volume of diluted SARS-CoV-2 PSV was added to each well and plates were incubated for 1 hour at 37°C. Target cells were added to each well (40,000 cells/ well) and plates were incubated for an additional 48 hours. RLUs were measured with the EnVision Multimode Plate Reader (Perkin Elmer, Waltham, MA) using the Bright-Glo Luciferase Assay System (Promega Corporation, Madison, WI). Neutralization dose–response curves were fitted by nonlinear regression with a five-parameter curve fit using the LabKey Server{\textregistered} ( Piehler et al., 2011 ), and the final titers are reported as the reciprocal of the dilution of serum necessary to achieve 50% neutralization (ID50, 50% inhibitory dilution) and 80% neutralization (ID80, 80% inhibitory dilution). Assay equivalency for SARS-CoV-2 was established by participation in the SARS-CoV-2 Neutralizing Assay Concordance Survey (SNACS) run by the Virology Quality Assurance Program and External Quality Assurance Program Oversite Laboratory (EQAPOL) at the Duke Human Vaccine Institute, sponsored through programs supported by the National Institute of Allergy and Infectious Diseases, Division of AIDS. Funding Information: We thank Sandhya Vasan, Mihret Amare, Suzanne Mate, Paul Scott, and Sharon P. Daye for programmatic support and planning; Nathaniel Jackson for cell-culture maintenance; and Erin Kavusak and Jonah Heller for support with performance of the neutralization assays. Research was conducted in compliance with the Animal Welfare Act and other federal statutes and regulations relating to animals and experiments involving animals and adheres to principles stated in the Guide for the Care and Use of Laboratory Animals, NRC Publication, 1996 Edition. This work was funded by the U.S. Defense Health Agency , the U.S. Department of the Army , and a cooperative agreement between The Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc. and the U.S. Department of Defense ( W81XWH-18-2-0040 ). This study also was supported by grants from the NIH ( R01 AI157155 ). J.B.C. is supported by a Helen Hay Whitney Foundation postdoctoral fellowship. The material has been reviewed by the Walter Reed Army Institute of Research. There is no objection to its presentation and/or publication. The views expressed are those of the authors and should not be construed to represent the positions of the U.S. Army or the Department of Defense. Funding Information: We thank Sandhya Vasan, Mihret Amare, Suzanne Mate, Paul Scott, and Sharon P. Daye for programmatic support and planning; Nathaniel Jackson for cell-culture maintenance; and Erin Kavusak and Jonah Heller for support with performance of the neutralization assays. Research was conducted in compliance with the Animal Welfare Act and other federal statutes and regulations relating to animals and experiments involving animals and adheres to principles stated in the Guide for the Care and Use of Laboratory Animals, NRC Publication, 1996 Edition. This work was funded by the U.S. Defense Health Agency, the U.S. Department of the Army, and a cooperative agreement between The Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc. and the U.S. Department of Defense (W81XWH-18-2-0040). This study also was supported by grants from the NIH (R01 AI157155). J.B.C. is supported by a Helen Hay Whitney Foundation postdoctoral fellowship. The material has been reviewed by the Walter Reed Army Institute of Research. There is no objection to its presentation and/or publication. The views expressed are those of the authors and should not be construed to represent the positions of the U.S. Army or the Department of Defense. M.G.J. and K.M. designed the study. M.G.J. P.V.T. and K.M. designed the immunogens. M.G.J. W.-H.C. M.C. R.S.S. A.H. P.V.T. R.E.C. W.C.C. C.E.P. E.B.M. E.J.M. A. Ahmed, C.S. J.B.C. Y.L. A. Anderson, J.K. T.O. L.R. A.G. C.W. J.M.C. L.M.-R. C.P.K. N.G. Z.V. D.M. Z.B. J.K. S. Shrivastava, O.J. V.D. S.M. U.T. C.B.K. S. Soman, C.K. M.Z. H.K. W.W. M.A.C. D.K.D. L.W.K. T.J.L. S.E.M. J.R.C. S.J.K. S.M. V.R.P. W.W.R. N.d.V. M.S.D. G.D.G. and M. Rao performed protein purification, biophysical assays, immunologic assays, and animal studies. Z.B. M. Rao, G.R.M. and A. Anderson designed and provided the adjuvants. S.R. P.M.M. and M.T.E. provided the SR1–SR5 antibodies. M.G.J. W.-H.C. R.S.S. A.H. P.V.T. R.E.C. C.S. A. Ahmed, L.W. Z.B. W.W. W.W.R. M. Rolland, N.d.V. M.S.D. G.D.G. M. Rao, N.L.M. and K.M. analyzed and interpreted the data. M.G.J. wrote the paper with assistance from all coauthors. M.G.J. and K.M. are named as inventors on international patent application WO/2021/178971 A1 entitled “Vaccines against SARS-CoV-2 and other coronaviruses.” M.G.J. is named as an inventor on international patent application WO/2018/081318 and U.S. patent 10,960,070 entitled “Prefusion coronavirus spike proteins and their use.” Z.B. is named as an inventor on U.S. patent 10,434,167 entitled “Non-toxic adjuvant formulation comprising a monophosphoryl lipid A (MPLA)-containing liposome composition and a saponin.” Z.B. and G.R.M. are named as inventors on U.S. patent application 16/607,917 entitled “Compositions and methods for vaccine delivery.” M.S.D. is a consultant for Inbios, Vir Biotechnology, Fortress Biotech, and Carnival Corporation and on the scientific advisory boards of Moderna and Immunome. The Diamond laboratory has received funding support from sponsored research agreements from Moderna, Vir Biotechnology, Kaleido, and Emergent BioSolutions. S.R. P.M.M. and M.T.E. are employees of AstraZeneca and currently hold AstraZeneca stock or stock options. Z.B. is currently employed at Pfizer. Publisher Copyright: {\textcopyright} 2021",

year = "2021",

month = dec,

day = "21",

doi = "10.1016/j.celrep.2021.110143",

language = "English",

volume = "37",

journal = "Cell Reports",

issn = "2211-1247",

number = "12",

}

Joyce, MG, Chen, WH, Sankhala, RS, Hajduczki, A, Thomas, PV, Choe, M, Martinez, EJ, Chang, WC, Peterson, CE, Morrison, EB, Smith, C, Chen, RE, Ahmed, A, Wieczorek, L, Anderson, A, Case, JB, Li, Y, Oertel, T, Rosado, L, Ganesh, A, Whalen, C, Carmen, JM, Mendez-Rivera, L, Karch, CP, Gohain, N, Villar, Z, McCurdy, D, Beck, Z, Kim, J, Shrivastava, S, Jobe, O, Dussupt, V, Molnar, S, Tran, U, Kannadka, CB, Soman, S, Kuklis, C, Zemil, M, Khanh, H, Wu, W, Cole, MA, Duso, DK, Kummer, LW, Lang, TJ, Muncil, SE, Currier, JR, Krebs, SJ, Polonis, VR, Rajan, S, McTamney, PM, Esser, MT, Reiley, WW, Rolland, M, de Val, N, Diamond, MS, Gromowski, GD, Matyas, GR, Rao, M, Michael, NL & Modjarrad, K 2021, 'SARS-CoV-2 ferritin nanoparticle vaccines elicit broad SARS coronavirus immunogenicity', Cell Reports, vol. 37, no. 12, 110143. https://doi.org/10.1016/j.celrep.2021.110143

TY - JOUR

T1 - SARS-CoV-2 ferritin nanoparticle vaccines elicit broad SARS coronavirus immunogenicity

AU - Joyce, M. Gordon

AU - Chen, Wei Hung

AU - Sankhala, Rajeshwer S.

AU - Hajduczki, Agnes

AU - Thomas, Paul V.

AU - Choe, Misook

AU - Martinez, Elizabeth J.

AU - Chang, William C.

AU - Peterson, Caroline E.

AU - Morrison, Elaine B.

AU - Smith, Clayton

AU - Chen, Rita E.

AU - Ahmed, Aslaa

AU - Wieczorek, Lindsay

AU - Anderson, Alexander

AU - Case, James Brett

AU - Li, Yifan

AU - Oertel, Therese

AU - Rosado, Lorean

AU - Ganesh, Akshaya

AU - Whalen, Connor

AU - Carmen, Joshua M.

AU - Mendez-Rivera, Letzibeth

AU - Karch, Christopher P.

AU - Gohain, Neelakshi

AU - Villar, Zuzana

AU - McCurdy, David

AU - Beck, Zoltan

AU - Kim, Jiae

AU - Shrivastava, Shikha

AU - Jobe, Ousman

AU - Dussupt, Vincent

AU - Molnar, Sebastian

AU - Tran, Ursula

AU - Kannadka, Chandrika B.

AU - Soman, Sandrine

AU - Kuklis, Caitlin

AU - Zemil, Michelle

AU - Khanh, Htet

AU - Wu, Weimin

AU - Cole, Matthew A.

AU - Duso, Debra K.

AU - Kummer, Larry W.

AU - Lang, Tricia J.

AU - Muncil, Shania E.

AU - Currier, Jeffrey R.

AU - Krebs, Shelly J.

AU - Polonis, Victoria R.

AU - Rajan, Saravanan

AU - McTamney, Patrick M.

AU - Esser, Mark T.

AU - Reiley, William W.

AU - Rolland, Morgane

AU - de Val, Natalia

AU - Diamond, Michael S.

AU - Gromowski, Gregory D.

AU - Matyas, Gary R.

AU - Rao, Mangala

AU - Michael, Nelson L.

AU - Modjarrad, Kayvon

N1 - Funding Information: M.G.J. and K.M. are named as inventors on international patent application WO/2021/178971 A1 entitled “Vaccines against SARS-CoV-2 and other coronaviruses.” M.G.J. is named as an inventor on international patent application WO/2018/081318 and U.S. patent 10,960,070 entitled “Prefusion coronavirus spike proteins and their use.” Z.B. is named as an inventor on U.S. patent 10,434,167 entitled “Non-toxic adjuvant formulation comprising a monophosphoryl lipid A (MPLA)-containing liposome composition and a saponin.” Z.B. and G.R.M. are named as inventors on U.S. patent application 16/607,917 entitled “Compositions and methods for vaccine delivery.” M.S.D. is a consultant for Inbios, Vir Biotechnology, Fortress Biotech, and Carnival Corporation and on the scientific advisory boards of Moderna and Immunome. The Diamond laboratory has received funding support from sponsored research agreements from Moderna, Vir Biotechnology, Kaleido, and Emergent BioSolutions. S.R., P.M.M., and M.T.E. are employees of AstraZeneca and currently hold AstraZeneca stock or stock options. Z.B. is currently employed at Pfizer. Funding Information: Infectivity and neutralization titers were determined using ACE2-expressing HEK293 target cells (Integral Molecular) in a semi-automated assay format using robotic liquid handling (Biomek NXp Beckman Coulter). Test sera were diluted 1:40 in growth medium and serially diluted, then 25 μL/well was added to a white 96-well plate. An equal volume of diluted SARS-CoV-2 PSV was added to each well and plates were incubated for 1 hour at 37°C. Target cells were added to each well (40,000 cells/ well) and plates were incubated for an additional 48 hours. RLUs were measured with the EnVision Multimode Plate Reader (Perkin Elmer, Waltham, MA) using the Bright-Glo Luciferase Assay System (Promega Corporation, Madison, WI). Neutralization dose–response curves were fitted by nonlinear regression with a five-parameter curve fit using the LabKey Server® ( Piehler et al., 2011 ), and the final titers are reported as the reciprocal of the dilution of serum necessary to achieve 50% neutralization (ID50, 50% inhibitory dilution) and 80% neutralization (ID80, 80% inhibitory dilution). Assay equivalency for SARS-CoV-2 was established by participation in the SARS-CoV-2 Neutralizing Assay Concordance Survey (SNACS) run by the Virology Quality Assurance Program and External Quality Assurance Program Oversite Laboratory (EQAPOL) at the Duke Human Vaccine Institute, sponsored through programs supported by the National Institute of Allergy and Infectious Diseases, Division of AIDS. Funding Information: We thank Sandhya Vasan, Mihret Amare, Suzanne Mate, Paul Scott, and Sharon P. Daye for programmatic support and planning; Nathaniel Jackson for cell-culture maintenance; and Erin Kavusak and Jonah Heller for support with performance of the neutralization assays. Research was conducted in compliance with the Animal Welfare Act and other federal statutes and regulations relating to animals and experiments involving animals and adheres to principles stated in the Guide for the Care and Use of Laboratory Animals, NRC Publication, 1996 Edition. This work was funded by the U.S. Defense Health Agency , the U.S. Department of the Army , and a cooperative agreement between The Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc. and the U.S. Department of Defense ( W81XWH-18-2-0040 ). This study also was supported by grants from the NIH ( R01 AI157155 ). J.B.C. is supported by a Helen Hay Whitney Foundation postdoctoral fellowship. The material has been reviewed by the Walter Reed Army Institute of Research. There is no objection to its presentation and/or publication. The views expressed are those of the authors and should not be construed to represent the positions of the U.S. Army or the Department of Defense. Funding Information: We thank Sandhya Vasan, Mihret Amare, Suzanne Mate, Paul Scott, and Sharon P. Daye for programmatic support and planning; Nathaniel Jackson for cell-culture maintenance; and Erin Kavusak and Jonah Heller for support with performance of the neutralization assays. Research was conducted in compliance with the Animal Welfare Act and other federal statutes and regulations relating to animals and experiments involving animals and adheres to principles stated in the Guide for the Care and Use of Laboratory Animals, NRC Publication, 1996 Edition. This work was funded by the U.S. Defense Health Agency, the U.S. Department of the Army, and a cooperative agreement between The Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc. and the U.S. Department of Defense (W81XWH-18-2-0040). This study also was supported by grants from the NIH (R01 AI157155). J.B.C. is supported by a Helen Hay Whitney Foundation postdoctoral fellowship. The material has been reviewed by the Walter Reed Army Institute of Research. There is no objection to its presentation and/or publication. The views expressed are those of the authors and should not be construed to represent the positions of the U.S. Army or the Department of Defense. M.G.J. and K.M. designed the study. M.G.J. P.V.T. and K.M. designed the immunogens. M.G.J. W.-H.C. M.C. R.S.S. A.H. P.V.T. R.E.C. W.C.C. C.E.P. E.B.M. E.J.M. A. Ahmed, C.S. J.B.C. Y.L. A. Anderson, J.K. T.O. L.R. A.G. C.W. J.M.C. L.M.-R. C.P.K. N.G. Z.V. D.M. Z.B. J.K. S. Shrivastava, O.J. V.D. S.M. U.T. C.B.K. S. Soman, C.K. M.Z. H.K. W.W. M.A.C. D.K.D. L.W.K. T.J.L. S.E.M. J.R.C. S.J.K. S.M. V.R.P. W.W.R. N.d.V. M.S.D. G.D.G. and M. Rao performed protein purification, biophysical assays, immunologic assays, and animal studies. Z.B. M. Rao, G.R.M. and A. Anderson designed and provided the adjuvants. S.R. P.M.M. and M.T.E. provided the SR1–SR5 antibodies. M.G.J. W.-H.C. R.S.S. A.H. P.V.T. R.E.C. C.S. A. Ahmed, L.W. Z.B. W.W. W.W.R. M. Rolland, N.d.V. M.S.D. G.D.G. M. Rao, N.L.M. and K.M. analyzed and interpreted the data. M.G.J. wrote the paper with assistance from all coauthors. M.G.J. and K.M. are named as inventors on international patent application WO/2021/178971 A1 entitled “Vaccines against SARS-CoV-2 and other coronaviruses.” M.G.J. is named as an inventor on international patent application WO/2018/081318 and U.S. patent 10,960,070 entitled “Prefusion coronavirus spike proteins and their use.” Z.B. is named as an inventor on U.S. patent 10,434,167 entitled “Non-toxic adjuvant formulation comprising a monophosphoryl lipid A (MPLA)-containing liposome composition and a saponin.” Z.B. and G.R.M. are named as inventors on U.S. patent application 16/607,917 entitled “Compositions and methods for vaccine delivery.” M.S.D. is a consultant for Inbios, Vir Biotechnology, Fortress Biotech, and Carnival Corporation and on the scientific advisory boards of Moderna and Immunome. The Diamond laboratory has received funding support from sponsored research agreements from Moderna, Vir Biotechnology, Kaleido, and Emergent BioSolutions. S.R. P.M.M. and M.T.E. are employees of AstraZeneca and currently hold AstraZeneca stock or stock options. Z.B. is currently employed at Pfizer. Publisher Copyright: © 2021

PY - 2021/12/21

Y1 - 2021/12/21

N2 - The need for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) next-generation vaccines has been highlighted by the rise of variants of concern (VoCs) and the long-term threat of emerging coronaviruses. Here, we design and characterize four categories of engineered nanoparticle immunogens that recapitulate the structural and antigenic properties of the prefusion SARS-CoV-2 spike (S), S1, and receptor-binding domain (RBD). These immunogens induce robust S binding, ACE2 inhibition, and authentic and pseudovirus neutralizing antibodies against SARS-CoV-2. A spike-ferritin nanoparticle (SpFN) vaccine elicits neutralizing titers (ID50 > 10,000) following a single immunization, whereas RBD-ferritin nanoparticle (RFN) immunogens elicit similar responses after two immunizations and also show durable and potent neutralization against circulating VoCs. Passive transfer of immunoglobulin G (IgG) purified from SpFN- or RFN-immunized mice protects K18-hACE2 transgenic mice from a lethal SARS-CoV-2 challenge. Furthermore, S-domain nanoparticle immunization elicits ACE2-blocking activity and ID50 neutralizing antibody titers >2,000 against SARS-CoV-1, highlighting the broad response elicited by these immunogens.

AB - The need for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) next-generation vaccines has been highlighted by the rise of variants of concern (VoCs) and the long-term threat of emerging coronaviruses. Here, we design and characterize four categories of engineered nanoparticle immunogens that recapitulate the structural and antigenic properties of the prefusion SARS-CoV-2 spike (S), S1, and receptor-binding domain (RBD). These immunogens induce robust S binding, ACE2 inhibition, and authentic and pseudovirus neutralizing antibodies against SARS-CoV-2. A spike-ferritin nanoparticle (SpFN) vaccine elicits neutralizing titers (ID50 > 10,000) following a single immunization, whereas RBD-ferritin nanoparticle (RFN) immunogens elicit similar responses after two immunizations and also show durable and potent neutralization against circulating VoCs. Passive transfer of immunoglobulin G (IgG) purified from SpFN- or RFN-immunized mice protects K18-hACE2 transgenic mice from a lethal SARS-CoV-2 challenge. Furthermore, S-domain nanoparticle immunization elicits ACE2-blocking activity and ID50 neutralizing antibody titers >2,000 against SARS-CoV-1, highlighting the broad response elicited by these immunogens.

KW - ALFQ

KW - B.1.1.7

KW - B.1.351

KW - COVID-19

KW - P.1

KW - SARS-CoV-1

KW - SARS-CoV-2

KW - betacoronaviruses

KW - ferritin nanoparticle

KW - neutralizing antibodies

KW - receptor-binding domain

KW - spike

KW - variants of concern

UR - http://www.scopus.com/inward/record.url?scp=85121051681&partnerID=8YFLogxK

U2 - 10.1016/j.celrep.2021.110143

DO - 10.1016/j.celrep.2021.110143

M3 - Article

C2 - 34919799

AN - SCOPUS:85121051681

SN - 2211-1247

VL - 37

JO - Cell Reports

JF - Cell Reports

IS - 12

M1 - 110143

ER -

SARS-CoV-2 ferritin nanoparticle vaccines elicit broad SARS coronavirus immunogenicity

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