Timing the race of vaccination, new variants, and relaxing restrictions during COVID-19 pandemic.

Late in 2019, China identified a new type of coronavirus, SARS-CoV-2, and due to its fast spread, the World Health Organisation (WHO) declared a pandemic named COVID-19. Some variants of this virus were detected, including the Delta, which caused new waves of infections. This work uses an extended version of a SIRD model that includes vaccination effects to measure the impact of the Delta variant in three countries: Germany, Israel and Brazil. The calibrated models were able to reproduce the dynamics of the above countries. In addition, hypothetical scenarios were simulated to quantify the impact of vaccination and mitigation policies during the Delta wave. The results showed that the model could reproduce the complex dynamics observed in the different countries. The estimated increase of transmission rate due to the Delta variant was highest in Israel (7.9), followed by Germany (2.7) and Brazil (1.5). These values may support the hypothesis that people immunised against COVID-19 may lose their defensive antibodies with time since Israel, Germany, and Brazil fully vaccinated half of the population in March, July, and October. The scenario to study the impact of vaccination revealed relative reductions in the total number of deaths between 30% and 250%; an absolute reduction of 300 thousand deaths in Brazil due to vaccination during the Delta wave. The second hypothetical scenario revealed that mitigation policies saved up to 300 thousand Brazilians; relative reductions in the total number of deaths between 24% and 120% in the three analysed countries. Therefore, the results suggest that both vaccination and mitigation policies were crucial in decreasing the spread and the number of deaths during the Delta wave.

A Mathematical Model of the Dynamics of Cytokine Expression and Human Immune Cell Activation in Response to the Pathogen Staphylococcus aureus.

Cell-based mathematical models have previously been developed to simulate the immune system in response to pathogens. Mathematical modeling papers which study the human immune response to pathogens have predicted concentrations of a variety of cells, including activated and resting macrophages, plasma cells, and antibodies. This study aims to create a comprehensive mathematical model that can predict cytokine levels in response to a gram-positive bacterium, S. aureus by coupling previous models. To accomplish this, the cytokines Tumor Necrosis Factor Alpha (TNF-α), Interleukin 6 (IL-6), Interleukin 8 (IL-8), and Interleukin 10 (IL-10) are included to quantify the relationship between cytokine release from macrophages and the concentration of the pathogen, S. aureus, ex vivo. Partial differential equations (PDEs) are used to model cellular response and ordinary differential equations (ODEs) are used to model cytokine response, and interactions between both components produce a more robust and more complete systems-level understanding of immune activation. In the coupled cellular and cytokine model outlined in this paper, a low concentration of S. aureus is used to stimulate the measured cellular response and cytokine expression. Results show that our cellular activation and cytokine expression model characterizing septic conditions can predict ex vivo mechanisms in response to gram-negative and gram-positive bacteria. Our simulations provide new insights into how the human immune system responds to infections from different pathogens. Novel applications of these insights help in the development of more powerful tools and protocols in infection biology.

A Validated Mathematical Model of the Cytokine Release Syndrome in Severe COVID-19.

By June 2021, a new contagious disease, the Coronavirus disease 2019 (COVID-19), has infected more than 172 million people worldwide, causing more than 3.7 million deaths. Many aspects related to the interactions of the disease's causative agent, SAR2-CoV-2, and the immune response are not well understood: the multiscale interactions among the various components of the human immune system and the pathogen are very complex. Mathematical and computational tools can help researchers to answer these open questions about the disease. In this work, we present a system of fifteen ordinary differential equations that models the immune response to SARS-CoV-2. The model is used to investigate the hypothesis that the SARS-CoV-2 infects immune cells and, for this reason, induces high-level productions of inflammatory cytokines. Simulation results support this hypothesis and further explain why survivors have lower levels of cytokines levels than non-survivors.

The Quixotic Task of Forecasting Peaks of COVID-19: Rather Focus on Forward and Backward Projections.

Over the last months, mathematical models have been extensively used to help control the COVID-19 pandemic worldwide. Although extremely useful in many tasks, most models have performed poorly in forecasting the pandemic peaks. We investigate this common pitfall by forecasting four countries' pandemic peak: Austria, Germany, Italy, and South Korea. Far from the peaks, our models can forecast the pandemic dynamics 20 days ahead. Nevertheless, when calibrating our models close to the day of the pandemic peak, all forecasts fail. Uncertainty quantification and sensitivity analysis revealed the main obstacle: the misestimation of the transmission rate. Inverse uncertainty quantification has shown that significant changes in transmission rate commonly precede a peak. These changes are a key factor in forecasting the pandemic peak. Long forecasts of the pandemic peak are therefore undermined by the lack of models that can forecast changes in the transmission rate, i.e., how a particular society behaves, changes of mitigation policies, or how society chooses to respond to them. In addition, our studies revealed that even short forecasts of the pandemic peak are challenging. Backward projections have shown us that the correct estimation of any temporal change in the transmission rate is only possible many days ahead. Our results suggest that the distance between a change in the transmission rate and its correct identification in the curve of active infected cases can be as long as 15 days. This is intrinsic to the phenomenon and how it affects epidemic data: a new case is usually only reported after an incubation period followed by a delay associated with the test. In summary, our results suggest the phenomenon itself challenges the task of forecasting the peak of the COVID-19 pandemic when only epidemic data is available. Nevertheless, we show that exciting results can be obtained when using the same models to project different scenarios of reduced transmission rates. Therefore, our results highlight that mathematical modeling can help control COVID-19 pandemic by backward projections that characterize the phenomena' essential features and forward projections when different scenarios and strategies can be tested and used for decision-making.