Safety, immunogenicity, and protection provided by unadjuvanted and adjuvanted formulations of a recombinant plant-derived virus-like particle vaccine candidate for COVID-19 in nonhuman primates

  1. Stéphane Pillet
  2. Prabhu S. Arunachalam
  3. Guadalupe Andreani
  4. Nadia Golden
  5. Jane Fontenot
  6. Pyone Pyone Aye
  7. Katharina Röltgen
  8. Gabrielle Lehmicke
  9. Philipe Gobeil
  10. Charlotte Dubé
  11. Sonia Trépanier
  12. Nathalie Charland
  13. Marc-André D’Aoust
  14. Kasi Russell-Lodrigue
  15. Christopher Monjure
  16. Robert V. Blair
  17. Scott D. Boyd
  18. Rudolf P. Bohm
  19. Jay Rappaport
  20. François Villinger
  21. Nathalie Landry
  22. Bali Pulendran
  23. Brian J. Ward

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Abstract

Although antivirals are important tools to control severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, effective vaccines are essential to control the current coronavirus disease 2019 (COVID-19) pandemic. Plant-derived virus-like particle (VLP) vaccine candidates have previously demonstrated immunogenicity and efficacy against influenza. Here, we report the immunogenicity and protection induced in rhesus macaques by intramuscular injections of a VLP bearing a SARS-CoV-2 spike protein (CoVLP) vaccine candidate formulated with or without Adjuvant System 03 (AS03) or cytidine-phospho-guanosine (CpG) 1018. Although a single dose of the unadjuvanted CoVLP vaccine candidate stimulated humoral and cell-mediated immune responses, booster immunization (at 28 days after priming) and adjuvant administration significantly improved both responses, with higher immunogenicity and protection provided by the AS03-adjuvanted CoVLP. Fifteen micrograms of CoVLP adjuvanted with AS03 induced a polyfunctional interleukin-2 (IL-2)-driven response and IL-4 expression in CD4 T cells. Animals were challenged by multiple routes (i.e., intratracheal, intranasal, and ocular) with a total viral dose of 10 6 plaque-forming units of SARS-CoV-2. Lower viral replication in nasal swabs and bronchoalveolar lavage fluid (BALF) as well as fewer SARS-CoV-2-infected cells and immune cell infiltrates in the lungs concomitant with reduced levels of proinflammatory cytokines and chemotactic factors in the BALF were observed in animals immunized with the CoVLP adjuvanted with AS03. No clinical, pathologic, or virologic evidence of vaccine-associated enhanced disease was observed in vaccinated animals. The CoVLP adjuvanted with AS03 was therefore selected for vaccine development and clinical trials.

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  1. Version published to 10.1038/s41423-021-00809-2
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    SciScore for 10.1101/2021.05.15.444262: (What is this?)

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

    Table 1: Rigor

    EthicsIACUC: Animals were housed and maintained as per National Institutes of Health (NIH) guidelines at NIRC of the University of Louisiana at Lafayette in accordance with the rules and regulations of the Committee on the Care and Use of Laboratory Animal Resources.
    Field Sample Permit: For the challenge, animals were transferred to the Regional Biosafety Level 3 (BSL3) facility at the Tulane National Primate Research Center, where the study was reviewed and approved by the Tulane University IACUC (Protocol P0450).
    Sex as a biological variableAnimal model: Male Indian rhesus macaques from 3.5 to 8 years old were sourced from the breeding colonies of the New Iberia Research Center (NIRC) of the University of Louisiana et Lafayette and distributed evenly among the treatment groups based on their age and weight to assure comparable distribution across treatments.
    Randomizationnot detected.
    Blindingnot detected.
    Power Analysisnot detected.
    Cell Line Authenticationnot detected.

    Table 2: Resources

    Antibodies
    SentencesResources
    Protection and Post-challenge safety evaluation: Statistical analysis: Differences over the time on IgA, IgM, IgG and neutralizing antibody levels in the different vaccine formulations were assessed by repeated measures two-way ANOVA on log-transformed values.
    IgM, IgG
    suggested: None
    Experimental Models: Cell Lines
    SentencesResources
    The virus stock was generated by expansion of a seed stock on Vero E6 cells and titrated by plaque assay on Vero E6 cells.
    Vero E6
    suggested: RRID:CVCL_XD71)
    Software and Algorithms
    SentencesResources
    Animal model: Male Indian rhesus macaques from 3.5 to 8 years old were sourced from the breeding colonies of the New Iberia Research Center (NIRC) of the University of Louisiana et Lafayette and distributed evenly among the treatment groups based on their age and weight to assure comparable distribution across treatments.
    NIRC
    suggested: None
    Approximately one week before challenge, the animals were transferred to the Tulane National Primate Research Center (TNPRC) for viral challenge.
    TNPRC
    suggested: None
    All flow cytometry data were analyzed using Flowjo software v10 (TreeStar Inc.). Challenge: Animals were infected under anesthesia with viral isolate SARS-CoV-2 USA-WA1/2020 (originally obtained from a patient in Seattle, USA, kindly provided by University of Texas, Medical Branch, Galveston, Texas) as previously described21,22.
    Flowjo
    suggested: (FlowJo, RRID:SCR_008520)
    The descriptive statistics and statistical comparisons were performed using GraphPad Prism software (Version 8.4.2; GraphPad Software, La Jolla, CA).
    GraphPad Prism
    suggested: (GraphPad Prism, RRID:SCR_002798)
    GraphPad
    suggested: (GraphPad Prism, RRID:SCR_002798)

    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.

    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.

  3. Version published to 10.1101/2021.05.15.444262v1 on bioRxiv