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

A compartment model for an in-host liquid nanoparticle delivered mRNA vaccine is presented. Through non-dimensionalisation, five timescales are identified that dictate the lifetime of the vaccine in-host: decay of interferon gamma, antibody priming, autocatalytic growth, antibody peak and decay, and interleukin cessation. Through asymptotic analysis we are able to obtain semi-analytical solutions in each of the time regimes which allows us to predict maximal concentrations and better understand parameter dependence in the model. We compare our model to 22 data sets for the BNT162b2 and mRNA-1273 mRNA vaccines demonstrating good agreement. Using our analysis, we estimate the values for each of the five timescales in each data set and predict maximal concentrations of plasma B-cells, antibody, and interleukin. Through our comparison, we do not observe any discernible differences between vaccine candidates and sex. However, we do identify an age dependence, specifically that vaccine activation takes longer and that peak antibody occurs sooner in patients aged 55 and greater.

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

Within-host SARS-CoV-2 modelling studies have been published throughout the COVID-19 pandemic. These studies contain highly variable numbers of individuals and capture varying timescales of pathogen dynamics; some studies capture the time of disease onset, the peak viral load and subsequent heterogeneity in clearance dynamics across individuals, while others capture late-time post-peak dynamics. In this study, we curate multiple previously published SARS-CoV-2 viral load data sets, fit these data with a consistent modelling approach, and estimate the variability of in-host parameters including the basic reproduction number, R0, as well as the best-fit eclipse phase profile. We find that fitted dynamics can be highly variable across data sets, and highly variable within data sets, particularly when key components of the dynamic trajectories (e.g. peak viral load) are not represented in the data. Further, we investigated the role of the eclipse phase time distribution in fitting SARS-CoV-2 viral load data. By varying the shape parameter of an Erlang distribution, we demonstrate that models with either no eclipse phase, or with an exponentially-distributed eclipse phase, offer significantly worse fits to these data, whereas models with less dispersion around the mean eclipse time (shape parameter two or more) offered the best fits to the available data across all data sets used in this work. This manuscript was submitted as part of a theme issue on "Modelling COVID-19 and Preparedness for Future Pandemics".

A mathematical model of protein subunits COVID-19 vaccines.

We consider a general mathematical model for protein subunit vaccine with a focus on the MF59-adjuvanted spike glycoprotein-clamp vaccine for SARS-CoV-2, and use the model to study immunological outcomes in the humoral and cell-mediated arms of the immune response from vaccination. The mathematical model is fit to vaccine clinical trial data. We elucidate the role of Interferon-γ and Interleukin-4 in stimulating the immune response of the host. Model results, and results from a sensitivity analysis, show that a balance between the TH1 and TH2 arms of the immune response is struck, with the TH1 response being dominant. The model predicts that two-doses of the vaccine at 28 days apart will result in approximately 85% humoral immunity loss relative to peak immunity approximately 6 months post dose 1.

Long-term durability of immune responses to the BNT162b2 and mRNA-1273 vaccines based on dosage, age and sex.

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.

Longitudinal Assessment of SARS-CoV-2-Specific T Cell Cytokine-Producing Responses for 1 Year Reveals Persistence of Multicytokine Proliferative Responses, with Greater Immunity Associated with Disease Severity.

Cell-mediated immunity is critical for long-term protection against most viral infections, including coronaviruses. We studied 23 severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-infected survivors over a 1-year post-symptom onset (PSO) interval by ex vivo cytokine enzyme-linked immunosorbent spot assay (ELISpot) assay. All subjects demonstrated SARS-CoV-2-specific gamma interferon (IFN-γ), interleukin 2 (IL-2), and granzyme B (GzmB) T cell responses at presentation, with greater frequencies in severe disease. Cytokines, mainly produced by CD4+ T cells, targeted all structural proteins (nucleocapsid, membrane, and spike) except envelope, with GzmB and IL-2 greater than IFN-γ. Mathematical modeling predicted that (i) cytokine responses peaked at 6 days for IFN-γ, 36 days for IL-2, and 7 days for GzmB, (ii) severe illness was associated with reduced IFN-γ and GzmB but increased IL-2 production rates, and (iii) males displayed greater production of IFN-γ, whereas females produced more GzmB. Ex vivo responses declined over time, with persistence of IL-2 in 86% and of IFN-γ and GzmB in 70% of subjects at a median of 336 days PSO. The average half-life of SARS-CoV-2-specific cytokine-producing cells was modeled to be 139 days (~4.6 months). Potent T cell proliferative responses persisted throughout observation, were CD4 dominant, and were capable of producing all 3 cytokines. Several immunodominant CD4 and CD8 epitopes identified in this study were shared by seasonal coronaviruses or SARS-CoV-1 in the nucleocapsid and membrane regions. Both SARS-CoV-2-specific CD4+ and CD8+ T cell clones were able to kill target cells, though CD8 tended to be more potent. IMPORTANCE Our findings highlight the relative importance of SARS-CoV-2-specific GzmB-producing T cell responses in SARS-CoV-2 control and shared CD4 and CD8 immunodominant epitopes in seasonal coronaviruses or SARS-CoV-1, and they indicate robust persistence of T cell memory at least 1 year after infection. Our findings should inform future strategies to induce T cell vaccines against SARS-CoV-2 and other coronaviruses.

Analysis of Host Immunological Response of Adenovirus-Based COVID-19 Vaccines.

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.