Low Dose Regimens of BNT162b2 mRNA Vaccine Exceed SARS-Cov-2 Correlate of Protection Estimates for Symptomatic Infection, in those 19-55 Years of Age

  1. Graham Jurgens

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Abstract

Background

An exact correlate of protection (CoP) is not yet known for symptomatic COVID-19. However, it is still possible to show a new vaccine regimen exceeds an unknown CoP, provided the regimen shows an equivalent or greater immunological response in all measured indicators relative to the immunological response elicited by a clinically proven vaccine regimen. The principle of comparing immunogenicity between regimens is what the FDA, EMA, and Access Consortium use to authorize modifications to the vaccines for VOC, without requiring clinical efficacy studies before implementation. It is logical to apply the same principle to modifying vaccine doses if the data is available to do so. A two dose 30ug regimen of BNT162b2 has strong clinical evidence of efficacy, as does a single dose 30 ug regimen. The immunological markers for these regimens have been profiled in detail in Phase 1 and 2 trial data.

Methods

The immunological profile (including binding antibodies, viral neutralization, cytokine profiles, and CD4 and 8 expansion) of the 2 dose 30ug BNT162b2 vaccine is examined, referred to as a highly conservative CoP estimate. The single dose 30 ug BNT162b2 immunological profile is also examined, a tenable CoP estimate. Data from the phase 1 and 2 trials are examined to see if alternate regimens meet or exceed the level of each immune marker measured, relative to the regimens listed above that have proven clinical efficacy.

Results

For adults aged 19-55, a 2 dose 10ug BNT162b2 regimen elicits a comparable response to the standard 30 ug dose for each immune indicator, with viral neutralization nearly an order of magnitude greater than the tenable CoP estimate. Similarly, a single dose 10ug BNT 162b2 regimen or a two dose 1ug BNT 162b2 regimen equals or exceeds the immunogenicity of a single 30 ug dose.

Conclusion

If it is reasonable for the FDA, EMA, and Access Consortium to approve vaccine modifications without a clinical trial based on immunogenicity data, three alternate low dose regimens were identified that meet the requirements of having comparable immunogenicity relative to a protocol that has proven clinical efficacy. Immediate implementation of these lower dose regimens should be considered as they have major implications in alleviating vaccine supply, as well as improving vaccine side effect profile, and lowering total cost of vaccination.

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  1. ScreenIT

    SciScore for 10.1101/2021.03.06.21253058: (What is this?)

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

    Table 1: Rigor

    Institutional Review Board Statementnot detected.
    Randomizationnot detected.
    Blindingnot detected.
    Power Analysisnot detected.
    Sex as a biological variablenot detected.

    Table 2: Resources

    Antibodies
    SentencesResources
    First, the 2 dose 30ug BNT162b2 profile was examined, including antibodies, cytokine profiles, and CD4 and 8 expansion.
    CD4
    suggested: None

    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 found bar graphs of continuous data. We recommend replacing bar graphs with more informative graphics, as many different datasets can lead to the same bar graph. The actual data may suggest different conclusions from the summary statistics. For more information, please see Weissgerber et al (2015).

    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.

  2. Version published to 10.1101/2021.03.06.21253058v2 on medRxiv
  3. Version published to 10.1101/2021.03.06.21253058v1 on medRxiv