A live attenuated vaccine confers superior mucosal and systemic immunity to SARS-CoV-2 variants

  1. Geraldine Nouailles
  2. Julia M. Adler
  3. Peter Pennitz
  4. Stefan Peidli
  5. Gustavo Teixeira Alves
  6. Morris Baumgart
  7. Judith Bushe
  8. Anne Voss
  9. Alina Langenhagen
  10. Fabian Pott
  11. Julia Kazmierski
  12. Cengiz Goekeri
  13. Szandor Simmons
  14. Na Xing
  15. Christine Langner
  16. Ricardo Martin Vidal
  17. Azza Abdelgawad
  18. Susanne Herwig
  19. Günter Cichon
  20. Daniela Niemeyer
  21. Christian Drosten
  22. Christine Goffinet
  23. Markus Landthaler
  24. Nils Blüthgen
  25. Haibo Wu
  26. Martin Witzenrath
  27. Achim D. Gruber
  28. Samantha D. Praktiknjo
  29. Nikolaus Osterrieder
  30. Emanuel Wyler
  31. Dusan Kunec
  32. Jakob Trimpert

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Abstract

Vaccines are a cornerstone in COVID-19 pandemic management. Here, we compare immune responses to and preclinical efficacy of the mRNA vaccine BNT162b2, an adenovirus-vectored spike vaccine, and the live-attenuated-virus vaccine candidate sCPD9 after single and double vaccination in Syrian hamsters. All regimens containing sCPD9 showed superior efficacy. The robust immunity elicited by sCPD9 was evident in a wide range of immune parameters after challenge with heterologous SARS-CoV-2 including rapid viral clearance, reduced tissue damage, fast differentiation of pre-plasmablasts, strong systemic and mucosal humoral responses, and rapid recall of memory T cells from lung tissue. Our results demonstrate that use of live-attenuated vaccines may offer advantages over available COVID-19 vaccines, specifically when applied as booster, and may provide a solution for containment of the COVID-19 pandemic.

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  1. Rapid Reviews Infectious Diseases

    Rachel Palinski

    Review 2: "A live attenuated vaccine offers superior mucosal and systemic immunity to SARS-CoV-2"

    This preprint reports improved immune responses to and efficacy of a live attenuated SARS-CoV-2 vaccine, compared to Pfizer mRNA vaccine, and an adenovirus-vectored spike protein vaccine (Ad2) in hamsters. Reviewers find the study significant, with the data presented as reliable.

  2. Rapid Reviews Infectious Diseases

    Qiuhong Wang, Mingde Liu

    Review 1: "A live attenuated vaccine offers superior mucosal and systemic immunity to SARS-CoV-2"

    This preprint reports improved immune responses to and efficacy of a live attenuated SARS-CoV-2 vaccine, compared to Pfizer mRNA vaccine, and an adenovirus-vectored spike protein vaccine (Ad2) in hamsters. Reviewers find the study significant, with the data presented as reliable.

  4. ScreenIT

    SciScore for 10.1101/2022.05.16.492138: (What is this?)

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

    Table 1: Rigor

    EthicsField Sample Permit: All animal experiments were performed in compliance with relevant institutional, national, and international guidelines for care and humane use of animal and approved by the Landesamt für Gesundheit und Soziales in Berlin, Germany (permit number 0086/20).
    Sex as a biological variableHamsters were randomly assigned into groups, with 50 – 60 % of the animals in each group being female.
    RandomizationHamsters were randomly assigned into groups, with 50 – 60 % of the animals in each group being female.
    Blindingnot detected.
    Power Analysisnot detected.
    Cell Line Authenticationnot detected.

    Table 2: Resources

    Antibodies
    SentencesResources
    Antigen retrieval was performed using microwave heating (600 W) in 10 mM citric acid (pH 6.0) for 12 min for SARS-CoV-1 nucleoprotein antibody (Sino Biological Inc.; Beijing, China) and using recombinant protease from Streptomyces griseus (PanReac Applichem, Darmstadt, Germany) for 13 min at 37°C for IgA antibody.
    SARS-CoV-1 nucleoprotein
    suggested: None
    IgA
    suggested: None
    Anti-SARS-CoV-1 NP mouse monoclonal antibody (Sino Biological Inc.; Beijing, China, dilution: 1:500) and rabbit anti hamster IgA antibody (Brookwood Biomedical, Jemison, AL, dilution: 1:250) were incubated at 4°C overnight followed by washing and incubation with a secondary biotinylated goat anti-mouse IgG antibody (dilution: 1:200, Vector Laboratories, Burlingame, California, USA).
    Anti-SARS-CoV-1 NP
    suggested: None
    anti hamster IgA
    suggested: None
    anti-mouse IgG
    suggested: None
    The plates were covered and incubated for 2 h at room temperature before the washing step was repeated and 50 μL of secondary antibody (Brookwood biomedical, Rabbit Anti-Hamster IgA, HRP-conjugated) diluted 1:1000 was applied per well.
    Anti-Hamster IgA
    suggested: None
    Day 0 samples of the prime-boost trial could not be tested for neutralizing antibodies against B.1.351 (Beta) due to lack of material.
    B.1.351
    suggested: None
    Experimental Models: Cell Lines
    SentencesResources
    In addition, the cell culture medium for Vero-TMPRSS2 cells contained 1000 μg/mL geneticin (G418) to ensure selection for cells expressing the genes for neomycin resistance and TMPRSS2.
    Vero-TMPRSS2
    suggested: JCRB Cat# JCRB1818, RRID:CVCL_YQ48)
    , Beta – B.1.351 (hCoV-19/Netherlands/NoordHolland_20159/2021), and Delta – B.1.617.2 (SARS-CoV-2, Human, 2021, Germany ex India, 20A/452R (B.1.617) were propagated on VeroE6-TMPRSS2 cells.
    VeroE6-TMPRSS2
    suggested: JCRB Cat# JCRB1819, RRID:CVCL_YQ49)
    Omicron BA.1 - B.1.1.529.1 (hCoV-19/Germany/BE-ChVir26335/2021, EPI_ISL_7019047) was propagated on CaLu-3 cells.
    CaLu-3
    suggested: KCLB Cat# 30055, RRID:CVCL_0609)
    Mock-vaccinated hamsters were vaccinated by intranasal instillation with sterile cell culture supernatant obtained from uninfected VeroE6-TMPRSS cells.
    VeroE6-TMPRSS
    suggested: None
    Vaccine preparations: sCPD9 was grown on Vero-TMRSS cells and titrated on Vero E6 cells as described previously, final titers were adjusted to 2 × 106 FFU/mL in MEM.
    Vero-TMRSS
    suggested: None
    Vero E6
    suggested: None
    Experimental Models: Organisms/Strains
    SentencesResources
    Cell isolation from blood and lungs: White blood cells were isolated from EDTA-blood as previously described, steps included erylysis and cell filtration prior counting.
    lungs: White
    suggested: None
    Software and Algorithms
    SentencesResources
    Mesocricetus auratus genome annotation: For quantification of gene expression, we used the MesAur 2.0 genome assembly and annotation available via the NCBI genome database (https://www.ncbi.nlm.nih.gov/genome/11998?genome_assembly_id=1585474).
    MesAur
    suggested: None

    Results from OddPub: Thank you for sharing your code.

    Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:
    Our single-cell RNA-sequencing analysis has several limitations. This technique, as employed here, cannot fully capture processes such as reactivation of memory cells due to lack of surface markers and cell type-specific enrichment. Due to incomplete annotation of the Syrian hamster genome, we were not able to identify IgA-positive cells. Data quality of nasal mucosa cells was comparatively low due to the difficult dissociation of the tissue, which limits our observations at the site of initial infection. An important and frequently discussed issue with live attenuated vaccines is their potential susceptibility to previously established immunity (69), which would restrict vaccine virus replication and potentially limit their use as booster vaccines after initial immunization by vaccination or natural infection. Our results indicate however, that sCPD9 does effectively boost immune responses and greatly improves protection when applied three weeks after initial mRNA vaccination. Importantly, sCPD9 enhances humoral immune responses, especially against known immune escape variants such as Beta and Omicron BA.1, while also improving the virological outcome of a heterologous challenge infection when applied as a booster three weeks after initial vaccination. This indicates a wide scope for the use of live attenuated vaccines in populations that exhibit an already high degree of baseline immunity induced by previous vaccination or infection; a situation clearly present in many part...

    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.
    • 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.

  5. Version published to 10.1101/2022.05.16.492138v1 on bioRxiv