Heterologous vaccination regimens with self-amplifying RNA and adenoviral COVID vaccines induce robust immune responses in mice

  1. Alexandra J. Spencer
  2. Paul F. McKay
  3. Sandra Belij-Rammerstorfer
  4. Marta Ulaszewska
  5. Cameron D. Bissett
  6. Kai Hu
  7. Karnyart Samnuan
  8. Anna K. Blakney
  9. Daniel Wright
  10. Hannah R. Sharpe
  11. Ciaran Gilbride
  12. Adam Truby
  13. Elizabeth R. Allen
  14. Sarah C. Gilbert
  15. Robin J. Shattock
  16. Teresa Lambe

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Abstract

Several vaccines have demonstrated efficacy against SARS-CoV-2 mediated disease, yet there is limited data on the immune response induced by heterologous vaccination regimens using alternate vaccine modalities. Here, we present a detailed description of the immune response, in mice, following vaccination with a self-amplifying RNA (saRNA) vaccine and an adenoviral vectored vaccine (ChAdOx1 nCoV-19/AZD1222) against SARS-CoV-2. We demonstrate that antibody responses are higher in two-dose heterologous vaccination regimens than single-dose regimens. Neutralising titres after heterologous prime-boost were at least comparable or higher than the titres measured after homologous prime boost vaccination with viral vectors. Importantly, the cellular immune response after a heterologous regimen is dominated by cytotoxic T cells and Th1 + CD4 T cells, which is superior to the response induced in homologous vaccination regimens in mice. These results underpin the need for clinical trials to investigate the immunogenicity of heterologous regimens with alternate vaccine technologies.

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  2. Rapid Reviews Infectious Diseases

    Adel Talaat, Sekar Chandrasekar

    Review of "Heterologous vaccination regimens with self-amplifying RNA and Adenoviral COVID vaccines induce superior immune responses than single dose vaccine regimens in mice"

    Reviewers: Adel Talaat, Sekar Chandrasekar (University of Wisconsin-Madison) | 📗📗📗📗◻️

  3. Version published to 10.1038/s41467-021-23173-1
  4. Version published to 10.1101/2021.01.28.428665v2 on bioRxiv
  5. ScreenIT

    SciScore for 10.1101/2021.01.28.428665: (What is this?)

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

    Table 1: Rigor

    Institutional Review Board Statementnot detected.
    RandomizationAge matched animals were purchased from commercial suppliers as a batch for each experiment and randomly split into groups on arrival at our facility.
    Blindingnot detected.
    Power Analysisnot detected.
    Sex as a biological variablenot detected.
    Cell Line Authenticationnot detected.

    Table 2: Resources

    Antibodies
    SentencesResources
    Following washing, bound antibodies were detected by addition of alkaline phosphatase (AP)-conjugated goat anti-mouse IgG (Sigma-Aldrich) or anti-mouse IgM (Abcam) or anti-mouse IgA (SouthernBiotech) for 1h at room temperature and addition of p-Nitrophenyl Phosphate, Disodium Salt substrate (Sigma-Aldrich).
    anti-mouse IgG
    suggested: None
    anti-mouse IgM
    suggested: None
    anti-mouse IgA
    suggested: None
    Avidity ELISA: Anti-SARS-CoV-2 spike-specific total IgG antibody avidity was assessed by sodium thiocyanate (NaSCN)-displacement ELISA.
    Anti-SARS-CoV-2 spike-specific total IgG
    suggested: None
    Splenocytes were stained with Live-Dead Aqua and Fc block (anti-CD16/32 mAb, Clone 93) prior to staining with the antibody cocktail containing NANP9C-Alexa488, GL7-PerCPCy5.5 (Clone GL7), CD138 BV421 (Clone 281-2), CD95-BV605 (Clone SA367H8), CD4-BV650 (Clone GK1.5), CD279-BV711 (Clone 29F.1A12), CD19-BV780 (6D5), RBD-A647, IgD-A700 (Clone 11-26c.2a), IgM-APCCy7 (Clone 11/41), Spike-PE, CD38-PECY5 (Clone 90), CD69 PeCy7 (Clone H1.2F3), CD45R-BUV395 (Clone RA3-6B2) and CD3-BUV496 (Clone 145-2C11), antibodies purchased from BioLegend, BD or Invitrogen.
    anti-CD16/32
    suggested: (SouthernBiotech Cat# 1630-11, RRID:AB_2795059)
    CD138
    suggested: (BioLegend Cat# 356511, RRID:AB_2562638)
    CD95-BV605
    suggested: None
    CD279-BV711
    suggested: None
    CD69
    suggested: None
    CD3-BUV496
    suggested: None
    Experimental Models: Cell Lines
    SentencesResources
    For the neutralization assay, heat-inactivated sera were first serially diluted and incubated with virus for 1 h, and then the serum-virus mixture was transferred into wells pre-seeded Caco2 cells.
    Caco2
    suggested: CLS Cat# 300137/p1665_CaCo-2, RRID:CVCL_0025)
    Experimental Models: Organisms/Strains
    SentencesResources
    Animals and Immunizations: Outbred CD1Hsd:ICR (CD-1) (Envigo) (n=8 per group), Crl:CD1 (ICR) (Charles River) (n=8 per group) and inbred BALB/cOlaHsd (BALB/c) (Envigo) (n=6 per group) mice of 7 weeks of age, were immunized intramuscularly (i.m.) in the musculus tibialis with 108 infectious units (iu) of ChAdOx1 nCoV-1912 or 1ÎĽg saRNA3.
    BALB/c
    suggested: None
    Software and Algorithms
    SentencesResources
    The IC50 neutralization was then calculated using GraphPad Prism (version 8.4).
    GraphPad Prism
    suggested: (GraphPad Prism, RRID:SCR_002798)
    Sample acquisition was performed on a Fortessa (BD) and data analyzed in FlowJo V10 (TreeStar).
    FlowJo
    suggested: (FlowJo, RRID:SCR_008520)
    All graphs and statistical analysis were performed using Prism v9 (Graphpad), total cell counts were log transformed prior to statistical analysis.
    Prism
    suggested: (PRISM, RRID:SCR_005375)

    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.
    • 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.

  6. Version published to 10.1101/2021.01.28.428665v1 on bioRxiv