A bacterial extracellular vesicle-based intranasal vaccine against SARS-CoV-2 protects against disease and elicits neutralizing antibodies to wild-type and Delta variants

Linglei Jiang; Tom A.P. Driedonks; Wouter S.P. Jong; Santosh Dhakal; H. Bart van den Berg van Saparoea; Ioannis Sitaras; Ruifeng Zhou; Christopher Caputo; Kirsten Littlefield; Maggie Lowman; Mengfei Chen; Gabriela Lima; Olesia Gololobova; Barbara Smith; Vasiliki Mahairaki; M. Riley Richardson; Kathleen R. Mulka; Andrew P. Lane; Sabra L. Klein; Andrew Pekosz; Cory Brayton; Joseph L. Mankowski; Joen Luirink; Jason S. Villano; Kenneth W. Witwer

doi:10.1002/jev2.12192

A bacterial extracellular vesicle-based intranasal vaccine against SARS-CoV-2 protects against disease and elicits neutralizing antibodies to wild-type and Delta variants

Linglei Jiang, Tom A.P. Driedonks, Wouter S.P. Jong, Santosh Dhakal, H. Bart van den Berg van Saparoea, Ioannis Sitaras, Ruifeng Zhou, Christopher Caputo, Kirsten Littlefield, Maggie Lowman, Mengfei Chen, Gabriela Lima, Olesia Gololobova, Barbara Smith, Vasiliki Mahairaki, M. Riley Richardson, Kathleen R. Mulka, Andrew P. Lane, Sabra L. Klein, Andrew PekoszCory Brayton, Joseph L. Mankowski, Joen Luirink, Jason S. Villano^*, Kenneth W. Witwer

^*Corresponding author for this work

Research output: Contribution to Journal › Article › Academic › peer-review

Abstract

Several vaccines have been introduced to combat the coronavirus infectious disease-2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Current SARS-CoV-2 vaccines include mRNA-containing lipid nanoparticles or adenoviral vectors that encode the SARS-CoV-2 Spike (S) protein of SARS-CoV-2, inactivated virus, or protein subunits. Despite growing success in worldwide vaccination efforts, additional capabilities may be needed in the future to address issues such as stability and storage requirements, need for vaccine boosters, desirability of different routes of administration, and emergence of SARS-CoV-2 variants such as the Delta variant. Here, we present a novel, well-characterized SARS-CoV-2 vaccine candidate based on extracellular vesicles (EVs) of Salmonella typhimurium that are decorated with the mammalian cell culture-derived Spike receptor-binding domain (RBD). RBD-conjugated outer membrane vesicles (RBD-OMVs) were used to immunize the golden Syrian hamster (Mesocricetus auratus) model of COVID-19. Intranasal immunization resulted in high titres of blood anti-RBD IgG as well as detectable mucosal responses. Neutralizing antibody activity against wild-type and Delta variants was evident in all vaccinated subjects. Upon challenge with live virus, hamsters immunized with RBD-OMV, but not animals immunized with unconjugated OMVs or a vehicle control, avoided body mass loss, had lower virus titres in bronchoalveolar lavage fluid, and experienced less severe lung pathology. Our results emphasize the value and versatility of OMV-based vaccine approaches.

Original language	English
Article number	e12192
Pages (from-to)	1-16
Number of pages	16
Journal	Journal of Extracellular Vesicles
Volume	11
Issue number	3
Early online date	14 Mar 2022
DOIs	https://doi.org/10.1002/jev2.12192
Publication status	Published - Mar 2022

Bibliographical note

Funding Information:
We thank the National Institute of Infectious Diseases, Japan, for providing VeroE6TMPRSS2 cells and acknowledge the Centers for Disease Control and Prevention, BEI Resources, NIAID, NIH for SARS-related coronavirus 2, isolate USA-WA1/2020, NR-52281. This work was supported by Molecular and Comparative Pathobiology departmental funds (to KWW), the NIH Center of Excellence in Influenza Research and Surveillance (HHSN272201400007C, AP and S.L.K.), and the Johns Hopkins Excellence in Pathogenesis, Immunology Center for SARS-CoV-2 (U54CA260492 S.L.K. and A.P.). KWW and TD are also supported in part by AI144997. The authors thank other members of the Molecular and Comparative Pathobiology Retrovirus Lab for support and helpful comments. Prof. Florian Krammer's lab (Icahn School of Medicine at Mount Sinai) are acknowledged for providing SARS-CoV-2 protein expression plasmids.

Funding Information:
We thank the National Institute of Infectious Diseases, Japan, for providing VeroE6TMPRSS2 cells and acknowledge the Centers for Disease Control and Prevention, BEI Resources, NIAID, NIH for SARS‐related coronavirus 2, isolate USA‐WA1/2020, NR‐52281. This work was supported by Molecular and Comparative Pathobiology departmental funds (to KWW), the NIH Center of Excellence in Influenza Research and Surveillance (HHSN272201400007C, AP and S.L.K.), and the Johns Hopkins Excellence in Pathogenesis, Immunology Center for SARS‐CoV‐2 (U54CA260492 S.L.K. and A.P.). KWW and TD are also supported in part by AI144997. The authors thank other members of the Molecular and Comparative Pathobiology Retrovirus Lab for support and helpful comments. Prof. Florian Krammer's lab (Icahn School of Medicine at Mount Sinai) are acknowledged for providing SARS‐CoV‐2 protein expression plasmids.

Publisher Copyright:
© 2022 The Authors. Journal of Extracellular Vesicles published by Wiley Periodicals, LLC on behalf of the International Society for Extracellular Vesicles

Funding

We thank the National Institute of Infectious Diseases, Japan, for providing VeroE6TMPRSS2 cells and acknowledge the Centers for Disease Control and Prevention, BEI Resources, NIAID, NIH for SARS-related coronavirus 2, isolate USA-WA1/2020, NR-52281. This work was supported by Molecular and Comparative Pathobiology departmental funds (to KWW), the NIH Center of Excellence in Influenza Research and Surveillance (HHSN272201400007C, AP and S.L.K.), and the Johns Hopkins Excellence in Pathogenesis, Immunology Center for SARS-CoV-2 (U54CA260492 S.L.K. and A.P.). KWW and TD are also supported in part by AI144997. The authors thank other members of the Molecular and Comparative Pathobiology Retrovirus Lab for support and helpful comments. Prof. Florian Krammer's lab (Icahn School of Medicine at Mount Sinai) are acknowledged for providing SARS-CoV-2 protein expression plasmids. We thank the National Institute of Infectious Diseases, Japan, for providing VeroE6TMPRSS2 cells and acknowledge the Centers for Disease Control and Prevention, BEI Resources, NIAID, NIH for SARS‐related coronavirus 2, isolate USA‐WA1/2020, NR‐52281. This work was supported by Molecular and Comparative Pathobiology departmental funds (to KWW), the NIH Center of Excellence in Influenza Research and Surveillance (HHSN272201400007C, AP and S.L.K.), and the Johns Hopkins Excellence in Pathogenesis, Immunology Center for SARS‐CoV‐2 (U54CA260492 S.L.K. and A.P.). KWW and TD are also supported in part by AI144997. The authors thank other members of the Molecular and Comparative Pathobiology Retrovirus Lab for support and helpful comments. Prof. Florian Krammer's lab (Icahn School of Medicine at Mount Sinai) are acknowledged for providing SARS‐CoV‐2 protein expression plasmids.

Funders	Funder number
BEI Resources
Immunology Center for SARS-CoV-2
Johns Hopkins Excellence in Pathogenesis
Molecular and Comparative Pathobiology departmental funds
National Institute of Infectious Diseases
National Institutes of Health	HHSN272201400007C, NR-52281, AI144997
Centers for Disease Control and Prevention
National Cancer Institute	U54CA260492
National Institute of Allergy and Infectious Diseases
Icahn School of Medicine at Mount Sinai

Keywords

COVID-19
Delta variant
exosomes
extracellular vesicles
outer membrane vesicles
SARS-CoV-2
vaccines

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1002/jev2.12192

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Cite this

Jiang, L., Driedonks, T. A. P., Jong, W. S. P., Dhakal, S., Bart van den Berg van Saparoea, H., Sitaras, I., Zhou, R., Caputo, C., Littlefield, K., Lowman, M., Chen, M., Lima, G., Gololobova, O., Smith, B., Mahairaki, V., Riley Richardson, M., Mulka, K. R., Lane, A. P., Klein, S. L., ... Witwer, K. W. (2022). A bacterial extracellular vesicle-based intranasal vaccine against SARS-CoV-2 protects against disease and elicits neutralizing antibodies to wild-type and Delta variants. Journal of Extracellular Vesicles, 11(3), 1-16. Article e12192. https://doi.org/10.1002/jev2.12192

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abstract = "Several vaccines have been introduced to combat the coronavirus infectious disease-2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Current SARS-CoV-2 vaccines include mRNA-containing lipid nanoparticles or adenoviral vectors that encode the SARS-CoV-2 Spike (S) protein of SARS-CoV-2, inactivated virus, or protein subunits. Despite growing success in worldwide vaccination efforts, additional capabilities may be needed in the future to address issues such as stability and storage requirements, need for vaccine boosters, desirability of different routes of administration, and emergence of SARS-CoV-2 variants such as the Delta variant. Here, we present a novel, well-characterized SARS-CoV-2 vaccine candidate based on extracellular vesicles (EVs) of Salmonella typhimurium that are decorated with the mammalian cell culture-derived Spike receptor-binding domain (RBD). RBD-conjugated outer membrane vesicles (RBD-OMVs) were used to immunize the golden Syrian hamster (Mesocricetus auratus) model of COVID-19. Intranasal immunization resulted in high titres of blood anti-RBD IgG as well as detectable mucosal responses. Neutralizing antibody activity against wild-type and Delta variants was evident in all vaccinated subjects. Upon challenge with live virus, hamsters immunized with RBD-OMV, but not animals immunized with unconjugated OMVs or a vehicle control, avoided body mass loss, had lower virus titres in bronchoalveolar lavage fluid, and experienced less severe lung pathology. Our results emphasize the value and versatility of OMV-based vaccine approaches.",

keywords = "COVID-19, Delta variant, exosomes, extracellular vesicles, outer membrane vesicles, SARS-CoV-2, vaccines",

author = "Linglei Jiang and Driedonks, {Tom A.P.} and Jong, {Wouter S.P.} and Santosh Dhakal and {Bart van den Berg van Saparoea}, H. and Ioannis Sitaras and Ruifeng Zhou and Christopher Caputo and Kirsten Littlefield and Maggie Lowman and Mengfei Chen and Gabriela Lima and Olesia Gololobova and Barbara Smith and Vasiliki Mahairaki and {Riley Richardson}, M. and Mulka, {Kathleen R.} and Lane, {Andrew P.} and Klein, {Sabra L.} and Andrew Pekosz and Cory Brayton and Mankowski, {Joseph L.} and Joen Luirink and Villano, {Jason S.} and Witwer, {Kenneth W.}",

note = "Funding Information: We thank the National Institute of Infectious Diseases, Japan, for providing VeroE6TMPRSS2 cells and acknowledge the Centers for Disease Control and Prevention, BEI Resources, NIAID, NIH for SARS-related coronavirus 2, isolate USA-WA1/2020, NR-52281. This work was supported by Molecular and Comparative Pathobiology departmental funds (to KWW), the NIH Center of Excellence in Influenza Research and Surveillance (HHSN272201400007C, AP and S.L.K.), and the Johns Hopkins Excellence in Pathogenesis, Immunology Center for SARS-CoV-2 (U54CA260492 S.L.K. and A.P.). KWW and TD are also supported in part by AI144997. The authors thank other members of the Molecular and Comparative Pathobiology Retrovirus Lab for support and helpful comments. Prof. Florian Krammer's lab (Icahn School of Medicine at Mount Sinai) are acknowledged for providing SARS-CoV-2 protein expression plasmids. Funding Information: We thank the National Institute of Infectious Diseases, Japan, for providing VeroE6TMPRSS2 cells and acknowledge the Centers for Disease Control and Prevention, BEI Resources, NIAID, NIH for SARS‐related coronavirus 2, isolate USA‐WA1/2020, NR‐52281. This work was supported by Molecular and Comparative Pathobiology departmental funds (to KWW), the NIH Center of Excellence in Influenza Research and Surveillance (HHSN272201400007C, AP and S.L.K.), and the Johns Hopkins Excellence in Pathogenesis, Immunology Center for SARS‐CoV‐2 (U54CA260492 S.L.K. and A.P.). KWW and TD are also supported in part by AI144997. The authors thank other members of the Molecular and Comparative Pathobiology Retrovirus Lab for support and helpful comments. Prof. Florian Krammer's lab (Icahn School of Medicine at Mount Sinai) are acknowledged for providing SARS‐CoV‐2 protein expression plasmids. Publisher Copyright: {\textcopyright} 2022 The Authors. Journal of Extracellular Vesicles published by Wiley Periodicals, LLC on behalf of the International Society for Extracellular Vesicles",

year = "2022",

month = mar,

doi = "10.1002/jev2.12192",

language = "English",

volume = "11",

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Jiang, L, Driedonks, TAP, Jong, WSP, Dhakal, S, Bart van den Berg van Saparoea, H, Sitaras, I, Zhou, R, Caputo, C, Littlefield, K, Lowman, M, Chen, M, Lima, G, Gololobova, O, Smith, B, Mahairaki, V, Riley Richardson, M, Mulka, KR, Lane, AP, Klein, SL, Pekosz, A, Brayton, C, Mankowski, JL, Luirink, J, Villano, JS & Witwer, KW 2022, 'A bacterial extracellular vesicle-based intranasal vaccine against SARS-CoV-2 protects against disease and elicits neutralizing antibodies to wild-type and Delta variants', Journal of Extracellular Vesicles, vol. 11, no. 3, e12192, pp. 1-16. https://doi.org/10.1002/jev2.12192

A bacterial extracellular vesicle-based intranasal vaccine against SARS-CoV-2 protects against disease and elicits neutralizing antibodies to wild-type and Delta variants. / Jiang, Linglei; Driedonks, Tom A.P.; Jong, Wouter S.P. et al.
In: Journal of Extracellular Vesicles, Vol. 11, No. 3, e12192, 03.2022, p. 1-16.

Research output: Contribution to Journal › Article › Academic › peer-review

TY - JOUR

T1 - A bacterial extracellular vesicle-based intranasal vaccine against SARS-CoV-2 protects against disease and elicits neutralizing antibodies to wild-type and Delta variants

AU - Jiang, Linglei

AU - Driedonks, Tom A.P.

AU - Jong, Wouter S.P.

AU - Dhakal, Santosh

AU - Bart van den Berg van Saparoea, H.

AU - Sitaras, Ioannis

AU - Zhou, Ruifeng

AU - Caputo, Christopher

AU - Littlefield, Kirsten

AU - Lowman, Maggie

AU - Chen, Mengfei

AU - Lima, Gabriela

AU - Gololobova, Olesia

AU - Smith, Barbara

AU - Mahairaki, Vasiliki

AU - Riley Richardson, M.

AU - Mulka, Kathleen R.

AU - Lane, Andrew P.

AU - Klein, Sabra L.

AU - Pekosz, Andrew

AU - Brayton, Cory

AU - Mankowski, Joseph L.

AU - Luirink, Joen

AU - Villano, Jason S.

AU - Witwer, Kenneth W.

N1 - Funding Information: We thank the National Institute of Infectious Diseases, Japan, for providing VeroE6TMPRSS2 cells and acknowledge the Centers for Disease Control and Prevention, BEI Resources, NIAID, NIH for SARS-related coronavirus 2, isolate USA-WA1/2020, NR-52281. This work was supported by Molecular and Comparative Pathobiology departmental funds (to KWW), the NIH Center of Excellence in Influenza Research and Surveillance (HHSN272201400007C, AP and S.L.K.), and the Johns Hopkins Excellence in Pathogenesis, Immunology Center for SARS-CoV-2 (U54CA260492 S.L.K. and A.P.). KWW and TD are also supported in part by AI144997. The authors thank other members of the Molecular and Comparative Pathobiology Retrovirus Lab for support and helpful comments. Prof. Florian Krammer's lab (Icahn School of Medicine at Mount Sinai) are acknowledged for providing SARS-CoV-2 protein expression plasmids. Funding Information: We thank the National Institute of Infectious Diseases, Japan, for providing VeroE6TMPRSS2 cells and acknowledge the Centers for Disease Control and Prevention, BEI Resources, NIAID, NIH for SARS‐related coronavirus 2, isolate USA‐WA1/2020, NR‐52281. This work was supported by Molecular and Comparative Pathobiology departmental funds (to KWW), the NIH Center of Excellence in Influenza Research and Surveillance (HHSN272201400007C, AP and S.L.K.), and the Johns Hopkins Excellence in Pathogenesis, Immunology Center for SARS‐CoV‐2 (U54CA260492 S.L.K. and A.P.). KWW and TD are also supported in part by AI144997. The authors thank other members of the Molecular and Comparative Pathobiology Retrovirus Lab for support and helpful comments. Prof. Florian Krammer's lab (Icahn School of Medicine at Mount Sinai) are acknowledged for providing SARS‐CoV‐2 protein expression plasmids. Publisher Copyright: © 2022 The Authors. Journal of Extracellular Vesicles published by Wiley Periodicals, LLC on behalf of the International Society for Extracellular Vesicles

PY - 2022/3

Y1 - 2022/3

N2 - Several vaccines have been introduced to combat the coronavirus infectious disease-2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Current SARS-CoV-2 vaccines include mRNA-containing lipid nanoparticles or adenoviral vectors that encode the SARS-CoV-2 Spike (S) protein of SARS-CoV-2, inactivated virus, or protein subunits. Despite growing success in worldwide vaccination efforts, additional capabilities may be needed in the future to address issues such as stability and storage requirements, need for vaccine boosters, desirability of different routes of administration, and emergence of SARS-CoV-2 variants such as the Delta variant. Here, we present a novel, well-characterized SARS-CoV-2 vaccine candidate based on extracellular vesicles (EVs) of Salmonella typhimurium that are decorated with the mammalian cell culture-derived Spike receptor-binding domain (RBD). RBD-conjugated outer membrane vesicles (RBD-OMVs) were used to immunize the golden Syrian hamster (Mesocricetus auratus) model of COVID-19. Intranasal immunization resulted in high titres of blood anti-RBD IgG as well as detectable mucosal responses. Neutralizing antibody activity against wild-type and Delta variants was evident in all vaccinated subjects. Upon challenge with live virus, hamsters immunized with RBD-OMV, but not animals immunized with unconjugated OMVs or a vehicle control, avoided body mass loss, had lower virus titres in bronchoalveolar lavage fluid, and experienced less severe lung pathology. Our results emphasize the value and versatility of OMV-based vaccine approaches.

AB - Several vaccines have been introduced to combat the coronavirus infectious disease-2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Current SARS-CoV-2 vaccines include mRNA-containing lipid nanoparticles or adenoviral vectors that encode the SARS-CoV-2 Spike (S) protein of SARS-CoV-2, inactivated virus, or protein subunits. Despite growing success in worldwide vaccination efforts, additional capabilities may be needed in the future to address issues such as stability and storage requirements, need for vaccine boosters, desirability of different routes of administration, and emergence of SARS-CoV-2 variants such as the Delta variant. Here, we present a novel, well-characterized SARS-CoV-2 vaccine candidate based on extracellular vesicles (EVs) of Salmonella typhimurium that are decorated with the mammalian cell culture-derived Spike receptor-binding domain (RBD). RBD-conjugated outer membrane vesicles (RBD-OMVs) were used to immunize the golden Syrian hamster (Mesocricetus auratus) model of COVID-19. Intranasal immunization resulted in high titres of blood anti-RBD IgG as well as detectable mucosal responses. Neutralizing antibody activity against wild-type and Delta variants was evident in all vaccinated subjects. Upon challenge with live virus, hamsters immunized with RBD-OMV, but not animals immunized with unconjugated OMVs or a vehicle control, avoided body mass loss, had lower virus titres in bronchoalveolar lavage fluid, and experienced less severe lung pathology. Our results emphasize the value and versatility of OMV-based vaccine approaches.

KW - COVID-19

KW - Delta variant

KW - exosomes

KW - extracellular vesicles

KW - outer membrane vesicles

KW - SARS-CoV-2

KW - vaccines

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DO - 10.1002/jev2.12192

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SN - 2001-3078

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JO - Journal of Extracellular Vesicles

JF - Journal of Extracellular Vesicles

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ER -

Jiang L, Driedonks TAP, Jong WSP, Dhakal S, Bart van den Berg van Saparoea H, Sitaras I et al. A bacterial extracellular vesicle-based intranasal vaccine against SARS-CoV-2 protects against disease and elicits neutralizing antibodies to wild-type and Delta variants. Journal of Extracellular Vesicles. 2022 Mar;11(3):1-16. e12192. Epub 2022 Mar 14. doi: 10.1002/jev2.12192

A bacterial extracellular vesicle-based intranasal vaccine against SARS-CoV-2 protects against disease and elicits neutralizing antibodies to wild-type and Delta variants

Abstract

Bibliographical note

Funding

Keywords

UN SDGs

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