SARS-CoV-2 preS dTM vaccine booster candidates increase functional antibody responses and cross-neutralization against SARS-CoV-2 variants of concern in non-human primates

  1. Vincent Pavot
  2. Catherine Berry
  3. Michael Kishko
  4. Natalie G. Anosova
  5. Dean Huang
  6. Tim Tibbitts
  7. Alice Raillard
  8. Sylviane Gautheron
  9. Cindy Gutzeit
  10. Marguerite Koutsoukos
  11. Roman Chicz
  12. Valerie Lecouturier

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Abstract

The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants that partly evade neutralizing antibodies has raised concerns of reduced vaccine effectiveness and increased infection. We previously demonstrated in preclinical models and in human clinical trials that our SARS-CoV-2 recombinant spike protein vaccine adjuvanted with AS03 (CoV2 preS dTM-AS03) elicits robust neutralizing antibody responses in naïve subjects. Here, the objective was to document the potency of various booster vaccine formulations in macaques previously vaccinated with mRNA or protein subunit vaccine candidates.

We show that one booster dose of AS03-adjuvanted CoV2 preS dTM, D614 (parental) or B.1.351 (Beta), in monovalent or bivalent (D614 + B.1.351) formulations, significantly boosted pre-existing neutralizing antibodies and elicited high and stable cross-neutralizing antibodies covering the four known SARS-CoV-2 variants of concern (Alpha, Beta, Gamma and Delta) and, unexpectedly, SARS-CoV-1, in primed macaques. Interestingly, the non-adjuvanted CoV2 preS dTM B.1.351 vaccine formulation also significantly boosted and broadened the neutralizing antibody responses.

Our findings show that these vaccine candidates used as a booster have the potential to offer cross-protection against a broad spectrum of variants. This has important implications for vaccine control of SARS-CoV-2 variants of concern and informs on the benefit of a booster with our vaccine candidates currently under evaluation in phase 2 and 3 clinical trials ( NCT04762680 and NCT04904549 ).

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    SciScore for 10.1101/2021.09.20.461023: (What is this?)

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

    Table 1: Rigor

    EthicsIACUC: Animals and study design: Animal experiments were carried out in compliance with all pertinent US National Institutes of Health regulations and were conducted with approved animal protocols from the Institutional Animal Care and Use Committee (IACUC) at the research facilities.
    Field Sample Permit: Animal studies were conducted in compliance with all relevant local, state, and federal regulations and were approved by the New Iberia Research Center.
    Sex as a biological variableIn the mRNA-primed cohort, 16 adult male and female Mauritius cynomolgus macaques (Macaca fascicularis) aged 4-10 years, selected based on their responses to the primary vaccination, were randomly allocated to 4 groups of 4 animals according to their baseline characteristics.
    RandomizationIn the mRNA-primed cohort, 16 adult male and female Mauritius cynomolgus macaques (Macaca fascicularis) aged 4-10 years, selected based on their responses to the primary vaccination, were randomly allocated to 4 groups of 4 animals according to their baseline characteristics.
    BlindingAll immunologic analyses were performed blinded on serum collected at 7, 14, 21 and 28 days post-boost injection.
    Power Analysisnot detected.
    Cell Line Authenticationnot detected.

    Table 2: Resources

    Experimental Models: Cell Lines
    SentencesResources
    Enzyme Linked Immunosorbent Assay (ELISA): Nunc microwell plates were coated with SARS-CoV S-GCN4 (GeneArt, expressed in Expi 293 cell line) protein at 0.5 ug/ml in PBS overnight at 4°C.
    293
    suggested: NCI-DTP Cat# NCI-293TT, RRID:CVCL_1D85)

    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:
    The study has several limitations. Firstly, the study included a small number of animals, namely 4-5 macaques per group. Secondly, the booster was evaluated in mRNA- and subunit-primed macaques only, as adenovirus vector vaccine primed macaques were not available, however, this priming vaccine is included in the booster vaccine clinical trial (NCT04762680). Thirdly, the interval between the primary vaccination and the booster was 7 months and evaluating shorter and longer intervals would be of interest. Finally, the mechanism underlying the cross-neutralization conferred by the booster, i.e. broadening of the repertoire of antibodies or selection of pre-existing specificities, would need to be further defined. While the antibody repertoire is not easily accessible due to limitation of the immunological tools in macaques, analysis of the Ab quality using system serology and of memory B cell population at later timepoints after the booster immunization are ongoing to better characterize the mechanism for cross-protection. In conclusion, a single dose of the CoV2 preS dTM recombinant vaccine (non-adjuvanted monovalent B.1.351, AS03-adjuvanted monovalent D614 or B.1.351 or bivalent D614 + B.1.351) used as a booster in macaques previously vaccinated with mRNA or subunit COVID-19 vaccines induced high and stable levels of cross-reactive neutralizing antibodies against the currently known SARS-CoV-2 variants of concerns (Alpha, Beta, Gamma and Delta) and against the two-decade old S...

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

    IdentifierStatusTitle
    NCT04762680RecruitingStudy of Recombinant Protein Vaccines With Adjuvant as a Pri…
    NCT04904549RecruitingStudy of Monovalent and Bivalent Recombinant Protein Vaccine…
    NCT04785144Active, not recruitingSafety and Immunogenicity Study of a SARS-CoV-2 (COVID-19) V…

    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.

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  2. Version published to 10.1101/2021.09.20.461023 on bioRxiv