The lipid nanoparticle (LNP)-formulated mRNA vaccines BNT162b2 and mRNA-1273 are a widely adopted multi vaccination public health strategy to manage the COVID-19 pandemic. Clinical trial data has described the immunogenicity of the vaccine, albeit within a limited study time frame. Here, we use a within-host mathematical model for LNP-formulated mRNA vaccines, informed by available clinical trial data from 2020 to September 2021, to project a longer term understanding of immunity as a function of vaccine type, dosage amount, age, and sex. We estimate that two standard doses of either mRNA-1273 or BNT162b2, with dosage times separated by the company-mandated intervals, results in individuals losing more than 99% humoral immunity relative to peak immunity by 8 months following the second dose. We predict that within an 8 month period following dose two (corresponding to the original CDC time-frame for administration of a third dose), there exists a period of time longer than 1 month where an individual has lost more than 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 8 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 immune response and long-term IgG counts. Finally, we find that humoral immunity generated from two low doses of mRNA-1273 decays at a substantially slower rate relative to peak immunity gained compared to two standard doses of either mRNA-1273 or BNT162b2. Our predictions highlight the importance of the recommended third booster dose in order to maintain elevated levels of antibodies.
During the SARS-CoV-2 global pandemic, several vaccines, including mRNA and adenovirus vector approaches, have received emergency or full approval. However, supply chain logistics have hampered global vaccine delivery, which is impacting mass vaccination strategies. Recent studies have identified different strategies for vaccine dose administration so that supply constraints issues are diminished. These include increasing the time between consecutive doses in a two-dose vaccine regimen and reducing the dosage of the second dose. We consider both of these strategies in a mathematical modeling study of a non-replicating viral vector adenovirus vaccine in this work. We investigate the impact of different prime-boost strategies by quantifying their effects on immunological outcomes based on simple system of ordinary differential equations. The boost dose is administered either at a standard dose (SD) of 1000 or at a low dose (LD) of 500 or 250 vaccine particles. Results show dose-dependent immune response activity. Our model predictions show that by stretching the prime-boost interval to 18 or 20, in an SD/SD or SD/LD regimen, the minimum promoted antibody (Nab) response will be comparable with the neutralizing antibody level measured in COVID-19 recovered patients. Results also show that the minimum stimulated antibody in SD/SD regimen is identical with the high level observed in clinical trial data. We conclude that an SD/LD regimen may provide protective capacity, which will allow for conservation of vaccine doses.
The mean conditional fixation time of a mutant is an important measure of stochastic population dynamics, widely studied in ecology and evolution. Here, we investigate the effect of spatial randomness on the mean conditional fixation time of mutants in a constant population of cells, N. Specifically, we assume that fitness values of wild type cells and mutants at different locations come from given probability distributions and do not change in time. We study spatial arrangements of cells on regular graphs with different degrees, from the circle to the complete graph, and vary assumptions on the fitness probability distributions. Some examples include: identical probability distributions for wild types and mutants; cases when only one of the cell types has random fitness values while the other has deterministic fitness; and cases where the mutants are advantaged or disadvantaged. Using analytical calculations and stochastic numerical simulations, we find that randomness has a strong impact on fixation time. In the case of complete graphs, randomness accelerates mutant fixation for all population sizes, and in the case of circular graphs, randomness delays mutant fixation for N larger than a threshold value (for small values of N, different behaviors are observed depending on the fitness distribution functions). These results emphasize fundamental differences in population dynamics under different assumptions on cell connectedness. They are explained by the existence of randomly occurring “dead zones” that can significantly delay fixation on networks with low connectivity; and by the existence of randomly occurring “lucky zones” that can facilitate fixation on networks of high connectivity. Results for death-birth and birth-death formulations of the Moran process, as well as for the (haploid) Wright Fisher model are presented.
Cancer cachexia is a debilitating condition characterized by an extreme loss of skeletal muscle mass, which negatively impacts patients’ quality of life, reduces their ability to sustain anti-cancer therapies, and increases the risk of mortality. Recent discoveries have identified the myostatin/activin A/ActRIIB pathway as critical to muscle wasting by inducing satellite cell quiescence and increasing muscle-specific ubiquitin ligases responsible for atrophy. Remarkably, pharmacological blockade of the ActRIIB pathway has been shown to reverse muscle wasting and prolong the survival time of tumor-bearing animals. To explore the implications of this signaling pathway and potential therapeutic targets in cachexia, we construct a novel mathematical model of muscle tissue subjected to tumor-derived cachectic factors. The model formulation tracks the intercellular interactions between cancer cell, satellite cell, and muscle cell populations. The model is parameterized by fitting to colon-26 mouse model data, and the analysis provides insight into tissue growth in healthy, cancerous, and post-cachexia treatment conditions. Model predictions suggest that cachexia fundamentally alters muscle tissue health, as measured by the stem cell ratio, and this is only partially recovered by anti-cachexia treatment. Our mathematical findings suggest that after blocking the myostatin/activin A pathway, partial recovery of cancer-induced muscle loss requires the activation and proliferation of the satellite cell compartment with a functional differentiation program.
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