An alphavirus replicon-based vaccine expressing a stabilized Spike antigen induces protective immunity and prevents transmission of SARS-CoV-2 between cats

  1. Martijn A. Langereis
  2. Irina C. Albulescu
  3. Judith Stammen-Vogelzangs
  4. Morindy Lambregts
  5. Ken Stachura
  6. Suzan Miller
  7. Angela M. Bosco-Lauth
  8. Airn E. Hartwig
  9. Stephanie M. Porter
  10. Michelle Allen
  11. Mark Mogler
  12. Frank J. M. van Kuppeveld
  13. Berend-Jan Bosch
  14. Paul Vermeij
  15. Ad de Groof
  16. Richard A. Bowen
  17. Randy Davis
  18. Zach Xu
  19. Ian Tarpey

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Abstract

Early in the SARS-CoV-2 pandemic concerns were raised regarding infection of new animal hosts and the effect on viral epidemiology. Infection of other animals could be detrimental by causing clinical disease, allowing further mutations, and bares the risk for the establishment of a non-human reservoir. Cats were the first reported animals susceptible to natural and experimental infection with SARS-CoV-2. Given the concerns these findings raised, and the close contact between humans and cats, we aimed to develop a vaccine candidate that could reduce SARS-CoV-2 infection and in addition to prevent spread among cats. Here we report that a Replicon Particle (RP) vaccine based on Venezuelan equine encephalitis virus, known to be safe and efficacious in a variety of animal species, could induce neutralizing antibody responses in guinea pigs and cats. The design of the SARS-CoV-2 spike immunogen was critical in developing a strong neutralizing antibody response. Vaccination of cats was able to induce high neutralizing antibody responses, effective also against the SARS-CoV-2 B.1.1.7 variant. Interestingly, in contrast to control animals, the infectious virus could not be detected in oropharyngeal or nasal swabs of vaccinated cats after SARS-CoV-2 challenge. Correspondingly, the challenged control cats spread the virus to in-contact cats whereas the vaccinated cats did not transmit the virus. The results show that the RP vaccine induces protective immunity preventing SARS-CoV-2 infection and transmission. These data suggest that this RP vaccine could be a multi-species vaccine useful to prevent infection and spread to and between animals should that approach be required.

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  1. Version published to 10.1038/s41541-021-00390-9
  2. ScreenIT

    SciScore for 10.1101/2021.04.01.436305: (What is this?)

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

    Table 1: Rigor

    Institutional Review Board Statementnot detected.
    RandomizationAnimals and husbandry: Female SPF guinea pigs (Dunkin Hartley) were obtained from Envigo at a minimum weight of 350 grams, randomly allocated to experimental groups and individually marked using color coded tags.
    Blindingnot detected.
    Power Analysisnot detected.
    Sex as a biological variableDomestic short hair male and female SPF cats were obtained from Marshall BioResources (Waverly, NY), identified by microchip and randomly allocated to experimental groups.
    Cell Line Authenticationnot detected.

    Table 2: Resources

    Antibodies
    SentencesResources
    After incubation, the cells were fixed and stained with the primary antibody (anti-VEEV nsp2 monoclonal antibody) followed by a FITC conjugated anti-murine IgG secondary antibody.
    anti-VEEV nsp2
    suggested: None
    anti-murine IgG
    suggested: None
    ELISA for estimating anti RBD and SED antibody titers in sera: Purified SARS-CoV-2 RBD and SED (Spike ectodomain) were diluted in DPBS (without Ca and Mg, Lonza, 17-512F) and coated onto 96-well plates (MaxiSorp - ThermoFisher or High binding - Greiner Bio-one) using 10nM (10 pmols/mL), and incubated overnight at 4°C.
    anti RBD
    suggested: None
    17-512F
    suggested: None
    Plates were washed again 3 times before being incubated with the HRP-containing antibody – Goat anti-Guinea pig (IgG-HRPO, Jackson Lab 106-035-003, 1:8000) for 1 hour at RT.
    anti-Guinea pig ( IgG-HRPO
    suggested: None
    Experimental Models: Cell Lines
    SentencesResources
    The virus was propagated for one passage on Vero cells.
    Vero
    suggested: CLS Cat# 605372/p622_VERO, RRID:CVCL_0059)
    Confluent monolayers of Vero E6 cells in 6 well plates were washed once with PBS and seeded with 100ul of serial ten-fold dilutions of swab/wash samples, incubated at 37°C for one hour then overlaid with 0.5% agarose in MEM containing 2% FBS.
    Vero E6
    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: 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: No clinical trial numbers were referenced.

    Results from Barzooka: We did not find any issues relating to the usage of bar graphs.

    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.
    • No funding statement was detected.
    • 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.

  3. Version published to 10.1101/2021.04.01.436305v1 on bioRxiv