Intranasal Vaccination with a Lentiviral Vector Strongly Protects against SARS-CoV-2 in Mouse and Golden Hamster Preclinical Models

  1. Min-Wen Ku
  2. Maryline Bourgine
  3. Pierre Authié
  4. Jodie Lopez
  5. Kirill Nemirov
  6. Fanny Moncoq
  7. Amandine Noirat
  8. Benjamin Vesin
  9. Fabien Nevo
  10. Catherine Blanc
  11. Philippe Souque
  12. Houda Tabbal
  13. Emeline Simon
  14. Marine Le Dudal
  15. Françoise Guinet
  16. Laurence Fiette
  17. Hugo Mouquet
  18. François Anna
  19. Annette Martin
  20. Nicolas Escriou
  21. Laleh Majlessi
  22. Pierre Charneau

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Abstract

To develop a vaccine candidate against COVID-19, we generated a Lentiviral Vector (LV), eliciting neutralizing antibodies against the Spike glycoprotein of SARS-CoV-2. Systemic vaccination by this vector in mice, in which the expression of the SARS-CoV-2 receptor hACE2 has been induced by transduction of respiratory tract cells by an adenoviral vector, conferred only partial protection, despite an intense serum neutralizing activity. However, targeting the immune response to the respiratory tract through an intranasal boost with this LV resulted in > 3 log10 decrease in the lung viral loads and avoided local inflammation. Moreover, both integrative and non-integrative LV platforms displayed a strong vaccine efficacy and inhibited lung deleterious injury in golden hamsters, which are naturally permissive to SARS-CoV-2 replication and restitute the human COVID-19 physiopathology. Our results provide evidence of marked prophylactic effects of the LV-based vaccination against SARS-CoV-2 and designate the intranasal immunization as a powerful approach against COVID-19.

Highlights

A lentiviral vector encoding for Spike predicts a promising COVID-19 vaccine

Targeting the immune response to the upper respiratory tract is key to protection

Intranasal vaccination induces protective mucosal immunity against SARS-CoV-2

Lung anti-Spike IgA responses correlate with protection and reduced inflammation

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  1. ScreenIT

    SciScore for 10.1101/2020.07.21.214049: (What is this?)

    Please note, not all rigor criteria are appropriate for all manuscripts.

    Table 1: Rigor

    Institutional Review Board StatementIACUC: Experimentation on animals was performed in accordance with the European and French guidelines (Directive 86/609/CEE and Decree 87-848 of 19 October 1987) subsequent to approval by the Institut Pasteur Safety, Animal Care and Use Committee, protocol agreement delivered by local ethical committee (CETEA #DAP20007) and Ministry of High Education and Research APAFIS#24627-2020031117362508 v1.
    Consent: Each participant provided written consent to participate in the study, which was approved by the regional investigational review board (IRB; Comité de Protection des Personnes Ile-de-France VII, Paris, France), according to European guidelines and the Declaration of Helsinki.
    IRB: Each participant provided written consent to participate in the study, which was approved by the regional investigational review board (IRB; Comité de Protection des Personnes Ile-de-France VII, Paris, France), according to European guidelines and the Declaration of Helsinki.
    Randomizationnot detected.
    Blindingnot detected.
    Power Analysisnot detected.
    Sex as a biological variableMouse and hamster studies: Female C57BL/6JRj mice (Janvier, Le Genest Saint Isle, France) were used between the age of 6 and 10 weeks.
    Cell Line Authenticationnot detected.

    Table 2: Resources

    Experimental Models: Cell Lines
    SentencesResources
    Production and titration of LV: Non-replicative LV were produced in Human Embryonic Kidney (HEK)-293T cells, as previously detailed (Zennou et al., 2000).
    HEK)-293T
    suggested: None
    Vector titers were determined by transducing 293T cells treated with aphidicolin.
    293T
    suggested: NCBI_Iran Cat# C498, RRID:CVCL_0063)
    SARS-CoV-2 inoculation: Hamsters or Ad5::hACE2-pretreated mice were anesthetized by i.p. injection of mixture Ketamine and Xylazine, transferred into a biosafety cabinet 3 where they were inoculated i.n. with 0.3 or 1 × 105 TCID50 of the BetaCoV/France/IDF0372/2020 SARS-CoV-2 clinical isolate (Lescure et al., 2020), amplified in VeroE6 cells.
    VeroE6
    suggested: JCRB Cat# JCRB1819, RRID:CVCL_YQ49)
    NAb Detection: Serial dilutions of heat inactivated sera or clarified lung homogenates were assessed for NAbs via an inhibition assay which uses HEK293T cells transduced to stably express human ACE2 and non-replicative SCoV-2 pseudo-typed LV particles which harbor the reporter luciferase firefly gene, allowing quantitation of the host cell invasion by mimicking fusion step of native SARS-CoV-2 virus (Sterlin et al., 2020).
    HEK293T
    suggested: None
    HEK293-T cells, counted in a NucleoCounter NC.
    HEK293-T
    suggested: CCLV Cat# CCLV-RIE 1018, RRID:CVCL_0063)
    The Ad5 virions were generated by transfecting the E3-transcomplementing HEK-293A cell line with pAd CMV-GFP-WPRE-SV40 polyA or pAd CMV-hACE2-WPRE-SV40 polyA plasmid followed by subsequent vector amplification, according to the manufacturer’s protocol (ViraPower Adenoviral Promoterless Gateway Expression Kit, Thermo Fisher).
    HEK-293A
    suggested: None
    Experimental Models: Organisms/Strains
    SentencesResources
    Mouse and hamster studies: Female C57BL/6JRj mice (Janvier, Le Genest Saint Isle, France) were used between the age of 6 and 10 weeks.
    C57BL/6JRj
    suggested: None
    Software and Algorithms
    SentencesResources
    Plasmid were quantified with a NanoDrop 2000c spectrophotometer (Thermo Ficher, Illkirch, France), aliquoted and stored at −20°C.
    Thermo Ficher
    suggested: None
    The cells were acquired in an Attune NxT cytometer system (Invitrogen) and data were analyzed by FlowJo software (Treestar, OR, USA)
    FlowJo
    suggested: (FlowJo, RRID:SCR_008520)

    Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).

    Results from LimitationRecognizer: An explicit section about the limitations of the techniques employed in this study was not found. We encourage authors to address study limitations.

    Results from TrialIdentifier: We found the following clinical trial numbers in your paper:

    IdentifierStatusTitle
    NCT04325646RecruitingSero-epidemiological Study of the SARS-CoV-2 Virus Responsib…

    Results from Barzooka: We found bar graphs of continuous data. We recommend replacing bar graphs with more informative graphics, as many different datasets can lead to the same bar graph. The actual data may suggest different conclusions from the summary statistics. For more information, please see Weissgerber et al (2015).

    Results from JetFighter: We did not find any issues relating to colormaps.

    Results from rtransparent:
    • Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
    • Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
    • No protocol registration statement was detected.

    About SciScore

    SciScore is an automated tool that is designed to assist expert reviewers by finding and presenting formulaic information scattered throughout a paper in a standard, easy to digest format. SciScore checks for the presence and correctness of RRIDs (research resource identifiers), and for rigor criteria such as sex and investigator blinding. For details on the theoretical underpinning of rigor criteria and the tools shown here, including references cited, please follow this link.

  2. Version published to 10.1101/2020.07.21.214049 on bioRxiv