Long-term predictions of humoral immunity after two doses of BNT162b2 and mRNA-1273 vaccines based on dosage, age and sex

  1. Chapin S. Korosec
  2. Suzan Farhang-Sardroodi
  3. David W. Dick
  4. Samaneh Gholami
  5. Mohammad Sajjad Ghaemi
  6. Iain R. Moyles
  7. Morgan Craig
  8. Hsu Kiang Ooi
  9. Jane M. Heffernan

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Abstract

Summary

Background

The lipid nanoparticle (LNP)-formulated mRNA vaccines are a widely adopted two-dose vaccination public health strategy to manage the COVID-19 pandemic. Clinical trial data has described the immunogeneicity of the vaccine, albeit within a limited study time frame. Our aims were to use a within-host mathematical model for LNP-formulated mRNA vaccines, informed by available clinical trial data, to project a longer term understanding of humoral immunity as a function of vaccine type, dosage amount, age, and sex.

Methods

We developed a mathematical model describing the immunization process of LNP-formulated mRNA vaccines, and fit our model to twenty-two clinical humoral and cytokine BNT162b2 or mRNA-1273 human two-dose vaccination data sets. We incorporated multi-dose effects in our model to specify whether the dosage is standard or low-dose. We further specify the age groups 18-55, 56-70, and 70+ in our fits for two-standard doses of mRNA-1273, and sex in our fits for two-standard doses of BNT162b2. We used non-linear mixed effect models to fit to all similar data types (e.g. standard two-dose BNT162b2 or mRNA-1273, or two low-dose mRNA-1273). Therefore, in our fits all estimated parameters are statistically correlated, which allowed us to determine the underlying ‘population-dynamics’ structure common to a data type. We therefore made accurate long-term predictions informed by all clinical data used in this study.

Findings

We estimate that two standard doses of either mRNA-1273 or BNT162b2, with dosage times separated by the company-mandated intervals, results in individuals loosing more than 99% humoral immunity relative to peak immunity by eight months following the second dose. We predict that within an eight month period following dose two (corresponding to the CDC time-frame for administration of a third dose), there exists a period of time longer than one month where an individual has less then 99% humoral immunity relative to peak immunity, regardless of which vaccine was administered. We further find that age has a strong influence in maintaining humoral immunity; by eight months following dose two we predict that individuals aged 18-55 have a four-fold humoral advantage compared to aged 56-70 and 70+ individuals. We find that sex has little effect on the vaccine uptake and long-term IgG counts. Finally, we find that humoral immunity generated from two low doses of mRNA-1273 decays substantially slower relative to peak immunity gained than compared to two standard doses of either mRNA-1273 or BNT162b2.

Interpretation

For the two dose mRNA vaccines, our predictions highlight the importance of the recommended third booster dose in order to maintain elevated levels of antibodies. We further show that age plays a critical role in determining the antibody levels. Hence, a third booster dose may confer an immuno-protective advantage in older individuals.

Funding

This research is supported by NSERC Discovery Grant (RGPIN-2018-04546), NSERC COVID-19 Alliance Grant ALLRP 554923-20, CIHR-Fields COVID Immunity Task Force, NRC Pandemic Response Challenge Program Grant No. PR016-1.

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  1. ScreenIT

    SciScore for 10.1101/2021.10.13.21264957: (What is this?)

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

    Table 1: Rigor

    NIH rigor criteria are not applicable to paper type.

    Table 2: Resources

    Antibodies
    SentencesResources
    We modelled the time dependence of eight state variables: lipid nanoparticles (L), vaccinated cells (V), CD4+ T cells (T), plasma B cells (B), antibody (A), CD8+ T cells (C), and the cytokines interferon (F) and interleukin (I).
    B
    suggested: None
    Software and Algorithms
    SentencesResources
    If unavailable directly from the published source, we digitized the data directly using the software WebPlotDigitizer (version 4.5) [25]. 2.2.
    WebPlotDigitizer
    suggested: (WebPlotDigitizer, RRID:SCR_013996)

    Results from OddPub: Thank you for sharing your data.

    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.
    • 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 10.1101/2021.10.13.21264957 on medRxiv