Preliminary Analysis of Safety and Immunogenicity of a SARS-CoV-2 Variant Vaccine Booster

  1. Kai Wu
  2. Angela Choi
  3. Matthew Koch
  4. LingZhi Ma
  5. Anna Hill
  6. Naveen Nunna
  7. Wenmei Huang
  8. Judy Oestreicher
  9. Tonya Colpitts
  10. Hamilton Bennett
  11. Holly Legault
  12. Yamuna Paila
  13. Biliana Nestorova
  14. Baoyu Ding
  15. Rolando Pajon
  16. Jacqueline M Miller
  17. Brett Leav
  18. Andrea Carfi
  19. Roderick McPhee
  20. Darin K Edwards

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Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of a global pandemic of coronavirus disease 2019 (COVID-19) that has led to more than 3 million deaths worldwide. Safe and effective vaccines are now available, including the mRNA-1273 prototype vaccine, which encodes for the Wuhan SARS-CoV-2 spike (S) protein stabilized in the prefusion conformation by 2 proline substitutions. This vaccine showed 94% efficacy in prevention of symptomatic COVID-19 disease in a phase 3 clinical study. Recently, SARS-CoV-2 variants have emerged, some of which have shown decreased susceptibility to neutralization by vaccine-induced antibody, most notably the B.1.351 variant, although the overall impact on vaccine efficacy remains to be determined. In addition, recent evidence of waning antibody levels after infection or vaccination point to the need for periodic boosting of immunity. Here we present the preliminary evaluation of a clinical study on the use of the prototype mRNA-1273 or modified COVID-19 mRNA vaccines, designed to target emerging SARS-CoV-2 variants as booster vaccines in participants previously vaccinated approximately 6 months earlier with two doses of the prototype vaccine, mRNA-1273. The modified vaccines include a monovalent mRNA-1273.351 encoding for the S protein found in the B.1.351 variant and multivalent mRNA-1273.211 comprising a 1:1 mix of mRNA-1273 and mRNA-1273.351. As single 50 µg booster vaccinations, both mRNA-1273 and mRNA-1273.351 had acceptable safety profiles and were immunogenic. Antibody neutralization titers against B.1.351 and P.1 variants measured by SARS-CoV-2 pseudovirus neutralization (PsVN) assays before the booster vaccinations, approximately 6 to 8 months after the primary series, were low or below the assay limit of quantification, although geometric mean titers versus the wild-type strain remained above levels likely to be protective. Two weeks after the booster vaccinations, titers against the wild-type original strain, B.1.351, and P.1 variants increased to levels similar to or higher than peak titers after the primary series vaccinations. Although both mRNA-1273 and mRNA-1273.351 boosted neutralization of the wild-type original strain, and B.1.351 and P.1 variants, mRNA-1273.351 appeared to be more effective at increasing neutralization of the B.1.351 virus versus a boost with mRNA-1273. The vaccine trial is ongoing and boosting of clinical trial participants with the multivalent mRNA-1273.211 is currently being evaluated.

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  1. ScreenIT

    SciScore for 10.1101/2021.05.05.21256716: (What is this?)

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

    Table 1: Rigor

    EthicsConsent: In Part B, all participants in the phase 2 mRNA-1273 study who previously received two doses of 50 ug or 100 µg of mRNA-1273 and provided a written consent to participate in this Part B, were administered a booster dose of 50 µg of mRNA-1273 vaccine at 177 to 226 days (5.9 to 7.5 months) after receiving the second dose of mRNA-1273.
    Sex as a biological variablePregnant or breastfeeding females, and sexually active males and females unwilling to use adequate contraception for at least 3 months after the second study vaccination were also excluded.
    Randomizationnot detected.
    BlindingGiven that the primary efficacy endpoint for mRNA-1273 against COVID-19 was met in the phase 3 COVE trial and that EUA for the vaccine was granted, both the phase 2 and 3 trial protocols were amended to include open-label interventional phases offering participants in the placebo arm an option to receive mRNA-1273 vaccine at the end of the blinded phases.
    Power Analysisnot detected.
    Cell Line Authenticationnot detected.

    Table 2: Resources

    Experimental Models: Cell Lines
    SentencesResources
    To make SARS-CoV-2 full-length spike pseudotyped recombinant VSV-ΔG-firefly luciferase virus, BHK-21/WI-2 cells (Kerafast, EH1011) were transfected with the spike expression plasmid and subsequently infected with VSVΔG-firefly-luciferase as previously described (18).
    BHK-21/WI-2
    suggested: RRID:CVCL_HB78)
    The virus-serum mix was subsequently used to infect A549-hACE2-TMPRSS2 cells for 18 hours at 37 °C before adding ONE-Glo reagent (Promega E6120) for measurement of luciferase signal (relative luminescence unit; RLU).
    A549-hACE2-TMPRSS2
    suggested: None
    Recombinant DNA
    SentencesResources
    Neutralizing Antibody Assay: To perform the recombinant VSV-based pseudovirus neutralization assay, codon-optimized full-length spike protein of the D614G, B.1.351 and P.1 variant sequences were cloned into pCAGGS vector.
    pCAGGS
    suggested: RRID:Addgene_18926)

    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:
    There are some limitations related to the preliminary analysis of this study. First, the results presented here are based on a limited sample size. The trial is ongoing, and key evaluations of the multivalent mRNA-1273.211 arm of the trial have not yet been performed. The neutralization assay used in the evaluations of these pre-boost and two-week post-boost samples is a preclinical SARS-CoV-2 PsVN assay, and although this assay has consistently been used to evaluate the impact on neutralization against variant viruses, the assay has not been qualified (16). All samples from this trial will be evaluated in qualified assays and the results will be reported at a later date. As analysis of sera for the trial participants collected on day 57 after the primary series of mRNA-1273 has not yet been performed in this preclinical assay, it cannot yet be definitively determined how the neutralization titers after the 3rd dose will compare to peak measurements after the primary vaccination series. Further, evaluations of the sera collected two weeks after the booster have not yet been performed against other VOC, including B.1.526, B.1.427/B.1.429, or B.1.617; therefore, it remains to be seen if the breadth of protection against other variants has increased after the booster was given. Also, as a correlate of protection for neutralizing antibodies has not yet been established for SARS-CoV-2, it can’t be definitively determined from these preliminary results whether the significant neutr...

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

    IdentifierStatusTitle
    NCT04283461Active, not recruitingSafety and Immunogenicity Study of 2019-nCoV Vaccine (mRNA-1…
    NCT04405076Active, not recruitingDose-Confirmation Study to Evaluate the Safety, Reactogenici…
    NCT04470427Active, not recruitingA Study to Evaluate Efficacy, Safety, and Immunogenicity of …

    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 10.1101/2021.05.05.21256716v1 on medRxiv