Phase I study of a SARS-CoV-2 mRNA vaccine PTX-COVID19-B

  1. Natalia Martin Orozco
  2. Noah Vale
  3. Alan Mihic
  4. Talya Amor
  5. Lawrence Reiter
  6. Yuko Arita
  7. Reuben Samson
  8. Queenie Hu
  9. Anne-Claude Gingras
  10. Brad Sorenson
  11. Eric G. Marcusson
  12. Piyush Patel

Reviewed by

Read the full article See related articles

Discuss this preprint

Start a discussion What are Sciety discussions?

Listed in

Log in to save this article

Abstract

PTX-COVID19-B mRNA vaccine encodes for SARS-CoV-2 Spike protein G614 variant and lacks the proline-proline (986-987 position) mutation present in other COVID-19 vaccines. This Phase 1 observer-blinded, randomized, placebo-controlled, ascending dose study evaluated the safety, tolerability, and immunogenicity of two doses of PTX-COVID19-B vaccine in healthy seronegative adults. Participants received two intramuscular doses, 4 weeks apart, of 16-μg, 40-μg, or 100-μg PTX-COVID19-B. Adverse events were generally mild to moderate, self-resolving, and transient. The most common solicited local and systemic adverse event was pain at the injection site and headache, respectively. After the first immunization, all participants seroconverted, producing high titers of anti-receptor-binding-domain, anti-Spike, and neutralizing antibodies, including neutralizing antibodies against the ancestral viral strain and the Alpha, Beta, and Delta variants of concern, in a dose-dependent way, further increasing over 10-20 times after the second dose. All tested doses of PTX-COVID19-B were safe, well-tolerated, and provided a strong immunogenicity response. The 40-μg dose showed fewer adverse reactions than the 100-μg dose, supporting further investigation of the 40-μg dose.

Clinical Trial Registration

ClinicalTrials.gov identifier: NCT04765436 ( https://clinicaltrials.gov/ct2/show/NCT04765436 )

Article activity feed

  1. ScreenIT

    SciScore for 10.1101/2022.05.06.22274690: (What is this?)

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

    Table 1: Rigor

    EthicsConsent: All participants provided written informed consent prior to enrollment.
    Sex as a biological variableEligible participants included healthy men and nonpregnant women between 18 to 64 years of age, with a body mass index of 18 to 30 kg/m2 at screening.
    RandomizationTrial Design: This observer-blinded, randomized, placebo-controlled, ascending dose Phase 1 study is being conducted at one site in Canada (Manna Research, Toronto, Ontario).
    BlindingThe pharmacist and staff members that prepared and administered the doses based on the paper randomization were unblinded; all others involved in the conduct of the study (Principal Investigator, site coordinator, site staff) and the participants were blinded.
    Power AnalysisNo formal sample size calculation was performed.
    Cell Line Authenticationnot detected.

    Table 2: Resources

    Antibodies
    SentencesResources
    The human IgG antibody concentration was determined by interpolation of the ECL count on the calibration curve.
    human IgG
    suggested: None
    To convert the results from MSD arbitrary units (AU/mL) to the World Health Organization (WHO) International Standard in binding antibody units (BAU)/mL, a conversion factor of 0.0272 was applied for anti-RBD IgG concentrations and 0.00901 for anti-S IgG concentrations.
    anti-RBD IgG
    suggested: None
    anti-S IgG
    suggested: None
    Anti-S ELISA: An indirect binding ELISA was also performed to determine if the elicited antibodies could bind the S protein.
    Anti-S
    suggested: None
    The SARS-CoV-2 pre-fusion S antigen was adsorbed onto a 96-well microplate and standard ELISA procedure was followed with anti-SARS-CoV-2 S IgG specific antibody (primary antibody) and anti-human IgG antibody (secondary antibody) conjugated to peroxidase.
    anti-SARS-CoV-2 S IgG
    suggested: None
    Pseudovirus Neutralization Assay: To evaluate the neutralizing effect of the sera from participants treated with PTX-COVID19-B, a pseudotyped virus neutralization assay developed and validated at Nexelis, Canada19 to quantify the titer of neutralizing antibody against SARS-CoV-2.
    SARS-CoV-2
    suggested: None
    Blocking antibodies bind to S protein in the plate and prevent the binding of ACE2 labeled with MSD-Sulfotag.
    ACE2
    suggested: None
    The data presented here are up to 6 months (day 180) for anti-RBD and anti-S IgG antibody levels by MSD and up to day 42 for all other safety and immunogenicity analyses, two weeks after the last participant received their last dose.
    anti-RBD
    suggested: None
    Experimental Models: Cell Lines
    SentencesResources
    For the neutralization assay, human sera were serially diluted and incubated with diluted pseudovirus at a 1:1 ratio for 1 hour at 37°C followed by transfer to plated HEK293T-ACE2/TMPRSS2 cells and incubated for 48 hours at 37°C and 5% CO2.
    HEK293T-ACE2/TMPRSS2
    suggested: None
    Software and Algorithms
    SentencesResources
    Immunogenicity Assessments: Anti-S and Anti-RBD MSD Assay: The responses induced by PTX-COVID19-B on anti-COVID-19 S-protein IgG and anti-COVID-19 RBD IgG were analyzed from serum samples using a multiplex immunoassay sandwich-based method with an electrochemiluminescent (ECL) readout on the MSD platform.
    Immunogenicity Assessments
    suggested: None
    The ID50 were calculated in GraphPad Prism 9 using a nonlinear regression algorithm (log[inhibitor] versus normalized response – variable slope).
    GraphPad Prism
    suggested: (GraphPad Prism, RRID:SCR_002798)
    Statistical Analysis: The statistical analysis was conducted using SAS® version 9.04 (SAS Institute, Cary, NC).
    SAS®
    suggested: (SASqPCR, RRID:SCR_003056)
    SAS Institute
    suggested: (Statistical Analysis System, RRID:SCR_008567)

    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:
    Critical limitations of this trial include a small study population and limited ethnic diversity as compared with the general population. Additionally, as a Phase 1 safety trial, the study population did not include those at increased risk of severe illness from COVID-19, including older adults and immunocompromised individuals that may mount a weaker immune response to vaccination. Although several COVID-19 vaccines have been approved globally (most under emergency or interim use), issues still remain with supply and delivery of vaccines to combat emerging variants. Additional safe, effective, and easily deployable SARS-CoV-2 vaccines are needed to meet the challenge for global immunization required to end the pandemic. Based on the reported results, PTX-COVID19-B vaccine is a promising candidate that warrants testing in the next phase of trials. A Phase 2 trial of PTX-COVID19-B in 525 healthy adults with the 40-μg dose is ongoing. A large Phase 3 trial will follow in 2022. The vaccine will be also tested as a 3rd dose booster in a Phase 2/3 clinical trial.

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

    IdentifierStatusTitle
    NCT04765436CompletedPTX-COVID19-B, an mRNA Humoral Vaccine, is Intended for Prev…

    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.

  2. Version published to 10.1101/2022.05.06.22274690 on medRxiv