An Intranasal OMV-Based Vaccine Induces High Mucosal and Systemic Protecting Immunity Against a SARS-CoV-2 Infection

  1. Peter A. van der Ley
  2. Afshin Zariri
  3. Elly van Riet
  4. Dinja Oosterhoff
  5. Corine P. Kruiswijk

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Abstract

The development of more effective, accessible, and easy to administer COVID-19 vaccines next to the currently marketed mRNA, viral vector, and whole inactivated virus vaccines is essential to curtailing the SARS-CoV-2 pandemic. A major concern is reduced vaccine-induced immune protection to emerging variants, and therefore booster vaccinations to broaden and strengthen the immune response might be required. Currently, all registered COVID-19 vaccines and the majority of COVID-19 vaccines in development are intramuscularly administered, targeting the induction of systemic immunity. Intranasal vaccines have the capacity to induce local mucosal immunity as well, thereby targeting the primary route of viral entry of SARS-CoV-2 with the potential of blocking transmission. Furthermore, intranasal vaccines offer greater practicality in terms of cost and ease of administration. Currently, only eight out of 112 vaccines in clinical development are administered intranasally. We developed an intranasal COVID-19 subunit vaccine, based on a recombinant, six-proline-stabilized, D614G spike protein (mC-Spike) of SARS-CoV-2 linked via the LPS-binding peptide sequence mCramp (mC) to outer membrane vesicles (OMVs) from Neisseria meningitidis . The spike protein was produced in CHO cells, and after linking to the OMVs, the OMV-mC-Spike vaccine was administered to mice and Syrian hamsters via intranasal or intramuscular prime-boost vaccinations. In all animals that received OMV-mC-Spike, serum-neutralizing antibodies were induced upon vaccination. Importantly, high levels of spike-binding immunoglobulin G (IgG) and A (IgA) antibodies in the nose and lungs were only detected in intranasally vaccinated animals, whereas intramuscular vaccination only induced an IgG response in the serum. Two weeks after their second vaccination, hamsters challenged with SARS-CoV-2 were protected from weight loss and viral replication in the lungs compared to the control groups vaccinated with OMV or spike alone. Histopathology showed no lesions in lungs 7 days after challenge in OMV-mC-Spike-vaccinated hamsters, whereas the control groups did show pathological lesions in the lung. The OMV-mC-Spike candidate vaccine data are very promising and support further development of this novel non-replicating, needle-free, subunit vaccine concept for clinical testing.

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  1. Version published to 10.3389/fimmu.2021.781280
  2. Version published to 10.1101/2021.08.25.457644v2 on bioRxiv
  3. ScreenIT

    SciScore for 10.1101/2021.08.25.457644: (What is this?)

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

    Table 1: Rigor

    EthicsEuthanasia Agents: On day 4 post challenge half of the animals per group were euthanized by exsanguination under isoflurane anesthesia and necropsy was performed, with the remaining half of the animals following on day 7 post challenge.
    Sex as a biological variableVaccinations: BALB/c mice (OlaHSD; Envigo, female, 8-9 weeks old at day 0) were immunized on day 0 and 21 via the intranasal or intramuscular route.
    Randomizationnot detected.
    Blindingnot detected.
    Power Analysisnot detected.
    Cell Line Authenticationnot detected.

    Table 2: Resources

    Antibodies
    SentencesResources
    On day 0, 21 and 35, blood was collected for assessment of induction antibodies against spike and SARS-CoV-2 specific neutralizing antibodies.
    SARS-CoV-2 specific neutralizing antibodies .
    suggested: None
    On day 35 nasal washes and the lungs were also collected for IgA antibody determination.
    IgA
    suggested: None
    After washing another three times the HRP conjugated antibody (Goat-anti-mouse HRP IgG 1:8000, IgG1 1:4000
    HRP IgG
    suggested: (Bioss Cat# bs-4000R-HRP, RRID:AB_11081943)
    IgG1
    suggested: None
    Experimental Models: Cell Lines
    SentencesResources
    Next, the virus-antibody mixtures are transferred to plates with Vero E6 cell culture monolayers, followed by an incubation period of 5-6 days at 37°C.
    Vero E6
    suggested: None
    Experimental Models: Organisms/Strains
    SentencesResources
    Vaccinations: BALB/c mice (OlaHSD; Envigo, female, 8-9 weeks old at day 0) were immunized on day 0 and 21 via the intranasal or intramuscular route.
    BALB/c
    suggested: None

    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: We detected the following sentences addressing limitations in the study:
    A significant limitation for the use of viral vector-based vaccines is the development of anti-vector immunity, which restricts the number of possible booster vaccinations. With OMV based vaccines we assume this is less of an issue, as they are non-replicating and do not depend on a specific host receptor for cellular entry. In addition, major antigens can be removed by gene deletion, as we did with the immunodominant PorA outer membrane protein in our vaccine strain, thus limiting the response against neisserial antigens. OMV-spike vaccination might thus also find an application as a heterologous boost after primary vaccination with viral vector-based vaccines. Overall, here we show that OMV-mC-Spike is safe and effective in both mice and hamsters. In these animal models, intranasal vaccination with OMV-mC-Spike is superior to intramuscular vaccination, since the amount of IgG induced is higher and in addition a strong mucosal response is induced. Our study demonstrates how adding an mCRAMP tag to the Spike protein and combining it with meningococcal OMVs improves its immunogenicity, thus warranting further development of this vaccine concept towards clinical trials in humans.

    Results from TrialIdentifier: No clinical trial numbers were referenced.

    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.

    Results from scite Reference Check: We found no unreliable references.

    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.

  4. Version published to 10.1101/2021.08.25.457644v1 on bioRxiv