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 JournalArticleAcademicpeer-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 languageEnglish
Article numbere12192
Pages (from-to)1-16
Number of pages16
JournalJournal of Extracellular Vesicles
Volume11
Issue number3
DOIs
Publication statusPublished - 14 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

Keywords

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

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