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

Abstract

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.

Determination of significant immunological timescales from mRNA-LNP-based vaccines in humans

“…We consider a compartmental ordinary differential equation model first published by Farhang-Sardroodi et al (2021) for adenovirus-based vaccines and later adapted by Korosec et al (2021) for LNP mRNA vaccines. The process being modelled begins with the injection of a concentration of LNP ( L ) that diffuses through inactive cells of which we assume there is an infinite reservoir.…”

“…Hernandez-Vargas and Velasco-Hernandez (2020); Perelson and Ke (2021); Kim et al (2021); Néant et al (2021); Sadria and Layton (2021); Lin et al (2022); Ke et al (2022)) and vaccination (cf. Farhang-Sardroodi et al (2021); Korosec et al (2021)).…”

“…In this paper we explore an in-host mathematical model for an LNP vaccine first considered by Korosec et al (2021) where computational mixed-effects modelling was used to identify model parameters from a variety of data sets. Their results demonstrated a diverse variability in the parameter estimates and consequently the model comparisons.…”

“…The paper is organized as follows. We introduce and summarize the model of Korosec et al (2021) in Section 2. We nondimensionalize the model in Section 2.1 where, through some assumption of scales, we are able to reduce the model to a simpler form.…”

Multiple cohort study of hospitalized SARS-CoV-2 in-host infection dynamics: parameter estimates, sensitivity and the eclipse phase profile

“…Mathematical models at the in-host level can estimate parameters and outcomes that may be difficult to measure at the population level. For example, SARS-CoV-2 in-host models have been used to model the immune response generated by vaccines, to predict which populations vaccines are likely to impact most [10], to estimate the efficacy of vaccines in individuals [11], as well as to model T cell dynamics and cytokine secretion in mild, moderate and severe cases of COVID-19 [12]. A major focus of SARS-CoV-2 in-host modelling has been understanding viral load dynamics: examples include correlating viral load with mortality [13]; linking viral load dynamics with host transmission [14, 15]; understanding the effects of antiviral therapy on the shedding dynamics [16]; assessing individual-level heterogeneity in mild cases [17]; and relating viral load with viral replication and the immune response [18].…”