Time scale theory on stability of explicit and implicit discrete epidemic models: applications to Swine flu outbreak.

Time scales theory has been in use since the 1980s with many applications. Only very recently, it has been used to describe within-host and between-hosts dynamics of infectious diseases. In this study, we present explicit and implicit discrete epidemic models motivated by the time scales modeling approach. We use these models to formulate the basic reproduction number, which determines whether an outbreak occurs or the disease dies out. We discuss the stability of the disease-free and endemic equilibrium points using the linearization method and Lyapunov function. Furthermore, we apply our models to swine flu outbreak data to demonstrate that the discrete models can accurately describe the epidemic dynamics. Our comparison analysis shows that the implicit discrete model can best describe the data regardless of the data frequency. In addition, we perform the sensitivity analysis on the key parameters of the models to study how these parameters impact the basic reproduction number.

Effects of vaccination on the two-strain transmission dynamics of COVID-19: Dougherty County, Georgia, USA, as a case study.

The emergence of multiple strains of SARS-COV-2 has made it complicated to predict and control the COVID-19 pandemic. Although some vaccines have been effective in reducing the severity of the disease, these vaccines are designed for a specific strain of the virus and are usually less effective for other strains. In addition, the waning of vaccine-induced immunity, reinfection of recovered people, and incomplete vaccination are challenging to the vaccination program. In this study, we developed a detailed model to describe the multi-strain transmission dynamics of COVID-19 under vaccination. We implemented our model to examine the impact of inter-strain transmission competition under vaccination on the critical outbreak indicators: hospitalized cases, undiagnosed cases, basic reproduction numbers, and the overtake-time by a new strain to the existing strain. In particular, our results on the dependence of the overtake-time on vaccination rates, progression-to-infectious rate, and relative transmission rates provide helpful information for managing a pandemic with circulating two strains. Furthermore, our results suggest that a reduction in the relative transmission rates and a decrease in vaccination dropout rates or an increase in vaccination rates help keep the reproduction number of both strains below unity and keep the number of hospitalized cases and undiagnosed cases at their lowest levels. Moreover, our analysis shows that the second and booster-dose vaccinations are useful for further reducing the reproduction number.

Modeling Antiretrovial Treatment to Mitigate HIV in the Brain: Impact of the Blood-Brain Barrier.

Current research in Human Immunodeficiency Virus (HIV) focuses on eradicating virus reservoirs that prevent or dampen the effectiveness of antiretroviral treatment (ART). One such reservoir, the brain, reduces treatment efficacy via the blood-brain barrier (BBB), causing an obstacle to drug penetration into the brain. In this study, we develop a mathematical model to examine the impact of the BBB on ART effectiveness for mitigating brain HIV. A thorough analysis of the model allowed us to fully characterize the global threshold dynamics with the viral clearance and persistence in the brain for the basic reproduction number less than unity and greater than unity, respectively. Our model showed that the BBB has a significant role in inhibiting the effect of ART within the brain despite the effective viral load suppression in the plasma. The level of impact, however, depends on factors such as the CNS Penetration Effectiveness (CPE) score, the slope of the drug dose-response curves, the ART initiation timing, and the number of drugs in the ART protocol. These results suggest that reducing the plasma viral load to undetectable levels due to some drug regimen may not necessarily indicate undetectable levels of HIV in the brain. Thus, the effect of the BBB on viral suppression in the brain must be considered for developing proper treatment protocols against HIV infection.

Data-driven models for the risk of infection and hospitalization during a pandemic: Case study on COVID-19 in Nepal.

The newly emerging pandemic disease often poses unexpected troubles and hazards to the global health system, particularly in low and middle-income countries like Nepal. In this study, we developed mathematical models to estimate the risk of infection and the risk of hospitalization during a pandemic which are critical for allocating resources and planning health policies. We used our models in Nepal's unique data set to explore national and provincial-level risks of infection and risk of hospitalization during the Delta and Omicron surges. Furthermore, we used our model to identify the effectiveness of non-pharmaceutical interventions (NPIs) to mitigate COVID-19 in various groups of people in Nepal. Our analysis shows no significant difference in reproduction numbers in provinces between the Delta and Omicron surge periods, but noticeable inter-provincial disparities in the risk of infection (for example, during Delta (Omicron) surges, the risk of infection of Bagmati province is: ∼ 98.94 (89.62); Madhesh province: ∼ 12.16 (5.1); Karnali province ∼31.16 (3) per hundred thousands). Our estimates show a significantly low level of hospitalization risk during the Omicron surge compared to the Delta surge (hospitalization risk is: ∼10% in Delta and ∼2.5% in Omicron). We also found significant inter-provincial disparities in the hospitalization rate (for example, ∼ 6% in Madhesh province and ∼ 21% in Sudur Paschim) during the Delta surge. Moreover, our results show that closing only schools, colleges, and workplaces reduces the risk of infection by one-third, while a complete lockdown reduces the infections by two-thirds. Our study provides a framework for the computation of the risk of infection and the risk of hospitalization and offers helpful information for controlling the pandemic.

Modeling the effects of drugs of abuse on within-host dynamics of two HIV species.

Injection drug use is one of the most significant risk factors associated with contracting human immunodeficiency virus (HIV), and drug users infected with HIV suffer from a higher viral load and rapid disease progression. While replication of HIV may result in many mutant viruses that can escape recognition of the host's immune response, the presence of morphine (a drug of abuse) can decrease the viral mutation rate and cellular immune responses. This study develops a mathematical model to explore the effects of morphine-altered mutation and cellular immune response on the within-host dynamics of two HIV species, a wild-type and a mutant. Our model predicts that the morphine-altered mutation rate and cellular immune response allow the wild-type virus to outcompete the mutant virus, resulting in a higher set point viral load and lower CD4 count. We also compute the basic reproduction numbers and show that the dominant species is determined by morphine concentration, with the mutant dominating below and the wild-type dominating above a threshold. Furthermore, we identified three biologically relevant equilibria, infection-free, mutant-only, and coexistence, which are completely characterized by the fitness cost of mutation, mutant escape rate, and morphine concentration.

Insight into Delta variant dominated second wave of COVID-19 in Nepal.

OBJECTIVE: To study the spreading nature of Delta variant (B.1.617.2) dominated COVID-19 in Nepal to help the policymakers assess and manage health care facilities and vaccination programs. METHODS: Deterministic mathematical models in the form of systems of ordinary differential equations were developed to describe the COVID-19 transmission in the high- and the low-risk regions of Nepal. The models were validated using the multiple data sets containing daily new cases in the whole country, the high-risk region, the low-risk region, and cases needing medical care, ICU, and ventilator. RESULTS: We found the reproduction number of Rt=4.2 at the beginning of the second wave, larger than the first wave (∼1.8 estimated previously), indicating that the transmissibility of Delta variant is higher than the wild-type circulated during the first wave. Model predicts that ∼5% of the COVID-19 cases were reported in Nepal, estimating the seroprevalence of ∼63.9% as of July 2021, consistent with the survey conducted by the Government of Nepal. The seroprevalence was expected to reach 94.46% by April 2022, among which ∼46% would have both infection and vaccination. The expected cases from September 2021 to April 2022 is 111,300, among which 11,890 people might need medical care, 3590 need ICU, and 953 need ventilators. The COVID-19 cases and medical care needs could be significantly reduced with proper implementation of vaccination and social distancing. CONCLUSIONS: The data-driven mathematical models are useful to assess control programs in resource-limited countries. The appropriate combination of vaccination and social distancing are necessary to keep the pandemic under-control and manage the medical care facilities in Nepal.

Modeling transmission dynamics of measles in Nepal and its control with monitored vaccination program.

Measles is one of the highly contagious human viral diseases. Despite the availability of vaccines, measles outbreak frequently occurs in many places, including Nepal, partly due to the lack of compliance with vaccination. In this study, we develop a novel transmission dynamics model to evaluate the effects of monitored vaccination programs to control and eliminate measles. We use our model, parameterized with the data from the measles outbreak in Nepal, to calculate the vaccinated reproduction number, $ R_v $, of measles in Nepal. We perform model analyses to establish the global asymptotic stability of the disease-free equilibrium point for $ R_v < 1 $ and the uniform persistence of the disease for $ R_v > 1 $. Moreover, we perform model simulations to identify monitored vaccination strategies for the successful control of measles in Nepal. Our model predicts that the monitored vaccination programs can help control the potential resurgence of the disease.

Modeling malaria transmission in Nepal: impact of imported cases through cross-border mobility.

The cross-border mobility of malaria cases poses an obstacle to malaria elimination programmes in many countries, including Nepal. Here, we develop a novel mathematical model to study how the imported malaria cases through the Nepal-India open-border affect the Nepal government's goal of eliminating malaria by 2026. Mathematical analyses and numerical simulations of our model, validated by malaria case data from Nepal, indicate that eliminating malaria from Nepal is possible if strategies promoting the absence of cross-border mobility, complete protection of transmission abroad, or strict border screening and isolation are implemented. For each strategy, we establish the conditions for the elimination of malaria. We further use our model to identify the control strategies that can help maintain a low endemic level. Our results show that the ideal control strategies should be designed according to the average mosquito biting rates that may depend on the location and season.

Effectiveness of alternative semester break schedules on reducing COVID-19 incidence on college campuses.

Despite COVID-19 vaccination programs, the threat of new SARS-CoV-2 strains and continuing pockets of transmission persists. While many U.S. universities replaced their traditional nine-day spring 2021 break with multiple breaks of shorter duration, the effects these schedules have on reducing COVID-19 incidence remains unclear. The main objective of this study is to quantify the impact of alternative break schedules on cumulative COVID-19 incidence on university campuses. Using student mobility data and Monte Carlo simulations of returning infectious student size, we developed a compartmental susceptible-exposed-infectious-asymptomatic-recovered (SEIAR) model to simulate transmission dynamics among university students. As a case study, four alternative spring break schedules were derived from a sample of universities and evaluated. Across alternative multi-break schedules, the median percent reduction of total semester COVID-19 incidence, relative to a traditional nine-day break, ranged from 2 to 4% (for 2% travel destination prevalence) and 8-16% (for 10% travel destination prevalence). The maximum percent reduction from an alternate break schedule was estimated to be 37.6%. Simulation results show that adjusting academic calendars to limit student travel can reduce disease burden. Insights gleaned from our simulations could inform policies regarding appropriate planning of schedules for upcoming semesters upon returning to in-person teaching modalities.

Modeling Within-Host Dynamics of SARS-CoV-2 Infection: A Case Study in Ferrets.

The pre-clinical development of antiviral agents involves experimental trials in animals and ferrets as an animal model for the study of SARS-CoV-2. Here, we used mathematical models and experimental data to characterize the within-host infection dynamics of SARS-CoV-2 in ferrets. We also performed a global sensitivity analysis of model parameters impacting the characteristics of the viral infection. We provide estimates of the viral dynamic parameters in ferrets, such as the infection rate, the virus production rate, the infectious virus proportion, the infected cell death rate, the virus clearance rate, as well as other related characteristics, including the basic reproduction number, pre-peak infectious viral growth rate, post-peak infectious viral decay rate, pre-peak infectious viral doubling time, post-peak infectious virus half-life, and the target cell loss in the respiratory tract. These parameters and indices are not significantly different between animals infected with viral strains isolated from the environment and isolated from human hosts, indicating a potential for transmission from fomites. While the infection period in ferrets is relatively short, the similarity observed between our results and previous results in humans supports that ferrets can be an appropriate animal model for SARS-CoV-2 dynamics-related studies, and our estimates provide helpful information for such studies.

Inter-provincial disparity of COVID-19 transmission and control in Nepal.

Despite the global efforts to mitigate the ongoing COVID-19 pandemic, the disease transmission and the effective controls still remain uncertain as the outcome of the epidemic varies from place to place. In this regard, the province-wise data from Nepal provides a unique opportunity to study the effective control strategies. This is because (a) some provinces of Nepal share an open-border with India, resulting in a significantly high inflow of COVID-19 cases from India; (b) despite the inflow of a considerable number of cases, the local spread was quite controlled until mid-June of 2020, presumably due to control policies implemented; and (c) the relaxation of policies caused a rapid surge of the COVID-19 cases, providing a multi-phasic trend of disease dynamics. In this study, we used this unique data set to explore the inter-provincial disparities of the important indicators, such as epidemic trend, epidemic growth rate, and reproduction numbers. Furthermore, we extended our analysis to identify prevention and control policies that are effective in altering these indicators. Our analysis identified a noticeable inter-province variation in the epidemic trend (3 per day to 104 per day linear increase during third surge period), the median daily growth rate (1 to 4% per day exponential growth), the basic reproduction number (0.71 to 1.21), and the effective reproduction number (maximum values ranging from 1.20 to 2.86). Importantly, results from our modeling show that the type and number of control strategies that are effective in altering the indicators vary among provinces, underscoring the need for province-focused strategies along with the national-level strategy in order to ensure the control of a local spread.

Modeling Intracellular Delay in Within-Host HIV Dynamics Under Conditioning of Drugs of Abuse.

Drugs of abuse, such as opiates, have been widely associated with the enhancement of HIV replication, the acceleration of disease progression, and severe neuropathogenesis. Specifically, the presence of drugs of abuse (morphine) switches target cells (CD4[Formula: see text] T cells) from lower-to-higher susceptibility to HIV infection. The effect of such switching behaviors on viral dynamics may be altered due to the intracellular delay (the replication time between viral entry into a target cell and the production of new viruses by the infected cell). In this study, we develop, for the first time, a viral dynamics model that includes an intracellular delay under the conditioning of drugs of abuse. We parameterize the model using experimental data from simian immunodeficiency virus infection of morphine-addicted macaques. Results from thorough mathematical analyses and numerical simulations of our model show that the intracellular delay can play a significant role in HIV dynamics under the conditioning of drugs of abuse, particularly during the acute phase of infection. Our model and the related results provide new insights into the HIV dynamics and may help develop strategies to control HIV infections in drug abusers.

Transmission dynamics of COVID-19 in Nepal: Mathematical model uncovering effective controls.

While most of the countries around the globe are combating the pandemic of COVID-19, the level of its impact is quite variable among different countries. In particular, the data from Nepal, a developing country having an open border provision with highly COVID-19 affected country India, has shown a biphasic pattern of epidemic, a controlled phase (until July 21, 2020) followed by an outgrown phase (after July 21, 2020). To uncover the effective strategies implemented during the controlled phase, we develop a mathematical model that is able to describe the data from both phases of COVID-19 dynamics in Nepal. Using our best parameter estimates with 95% confidence interval, we found that during the controlled phase most of the recorded cases were imported from outside the country with a small number generated from the local transmission, consistent with the data. Our model predicts that these successful strategies were able to maintain the reproduction number at around 0.21 during the controlled phase, preventing 442,640 cases of COVID-19 and saving more than 1,200 lives in Nepal. However, during the outgrown phase, when the strategies such as border screening and quarantine, lockdown, and detection and isolation, were altered, the reproduction number raised to 1.8, resulting in exponentially growing cases of COVID-19. We further used our model to predict the long-term dynamics of COVID-19 in Nepal and found that without any interventions the current trend may result in about 18.76 million cases (10.70 million detected and 8.06 million undetected) and 89 thousand deaths in Nepal by the end of 2021. Finally, using our predictive model, we evaluated the effects of various control strategies on the long-term outcome of this epidemics and identified ideal strategies to curb the epidemic in Nepal.

Modeling transmission dynamics of rabies in Nepal.

Even though vaccines against rabies are available, rabies still remains a burden killing a significant number of humans as well as domestic and wild animals in many parts of the world, including Nepal. In this study, we develop a mathematical model to describe transmission dynamics of rabies in Nepal. In particular, an indirect interspecies transmission from jackals to humans through dogs, which is relevant to the context of Nepal, is one of the novel features of our model. Our model utilizes annual dog-bite data collected from Nepal for a decade long period, allowing us to reasonably estimate parameters related to rabies transmission in Nepal. Using our model, we calculated the basic reproduction number ( R 0 = 1.16 ) as well as intraspecies basic reproduction numbers of dogs ( R 0 D = 1.14 ) and jackals ( R 0 J = 0.07 ) for Nepal, and identified that the dog-related parameters are primary contributors to R 0 . Our results show that, along with dogs, jackals may also play an important role, albeit lesser extent, in the persistence of rabies in Nepal. Our model also suggests that control strategies may help reduce the prevalence significantly but the jackal vaccination may not be as effective as dog-related preventive strategies. To get deeper insight into the role of intraspecies and interspecies transmission between dog and jackal populations in the persistence of rabies, we also extended our model analysis into a wider parameter range. Interestingly, for some feasible parameters, even though rabies is theoretically controlled in each dog and jackal populations ( R 0 D < 1 , R 0 J < 1 ) if isolated, the rabies epidemic may still occur ( R 0 > 1 ) due to interspecies transmission. These results may be useful to design effective prevention and control strategies for mitigating rabies burden in Nepal and other parts of the world.

Early events in hepatitis B infection: the role of inoculum dose.

The relationship between the inoculum dose and the ability of the pathogen to invade the host is poorly understood. Experimental studies in non-human primates infected with different inoculum doses of hepatitis B virus have shown a non-monotonic relationship between dose magnitude and infection outcome, with high and low doses leading to 100% liver infection and intermediate doses leading to less than 0.1% liver infection, corresponding to CD4 T-cell priming. Since hepatitis B clearance is CD8 T-cell mediated, the question of whether the inoculum dose influences CD8 T-cell dynamics arises. To help answer this question, we developed a mathematical model of virus-host interaction following hepatitis B virus infection. Our model explains the experimental data well, and predicts that the inoculum dose affects both the timing of the CD8 T-cell expansion and the quality of its response, especially the non-cytotoxic function. We find that a low-dose challenge leads to slow CD8 T-cell expansion, weak non-cytotoxic functions, and virus persistence; high- and medium-dose challenges lead to fast CD8 T-cell expansion, strong cytotoxic and non-cytotoxic function, and virus clearance; while a super-low-dose challenge leads to delayed CD8 T-cell expansion, strong cytotoxic and non-cytotoxic function, and virus clearance. These results are useful for designing immune cell-based interventions.

Modelling the risk of HIV infection for drug abusers.

Drugs of abuse, such as opiates, are one of the leading causes for transmission of HIV in many parts of the world. Drug abusers often face a higher risk of acquiring HIV because target cell (CD4+ T-cell) receptor expression differs in response to morphine, a metabolite of common opiates. In this study, we use a viral dynamics model that incorporates the T-cell expression difference to formulate the probability of infection among drug abusers. We quantify how the risk of infection is exacerbated in morphine conditioning, depending on the timings of morphine intake and virus exposure. With in-depth understanding of the viral dynamics and the increased risk for these individuals, we further evaluate how preventive therapies, including pre- and post-exposure prophylaxis, affect the infection risk in drug abusers. These results are useful to devise ideal treatment protocols to combat the several obstacles those under drugs of abuse face.

Modeling HIV-1 infection in the brain.

While highly active antiretroviral therapy (HAART) is successful in controlling the replication of Human Immunodeficiency Virus (HIV-1) in many patients, currently there is no cure for HIV-1, presumably due to the presence of reservoirs of the virus. One of the least studied viral reservoirs is the brain, which the virus enters by crossing the blood-brain barrier (BBB) via macrophages, which are considered as conduits between the blood and the brain. The presence of HIV-1 in the brain often leads to HIV associated neurocognitive disorders (HAND), such as encephalitis and early-onset dementia. In this study we develop a novel mathematical model that describes HIV-1 infection in the brain and in the plasma coupled via the BBB. The model predictions are consistent with data from macaques infected with a mixture of simian immunodeficiency virus (SIV) and simian-human immunodeficiency virus (SHIV). Using our model, we estimate the rate of virus transport across the BBB as well as viral replication inside the brain, and we compute the basic reproduction number. We also carry out thorough sensitivity analysis to define the robustness of the model predictions on virus dynamics inside the brain. Our model provides useful insight into virus replication within the brain and suggests that the brain can be an important reservoir causing long-term viral persistence.

Effects of periodic intake of drugs of abuse (morphine) on HIV dynamics: Mathematical model and analysis.

Drugs of abuse, such as opiates, have been widely associated with diminishing host-immune responses, including suppression of HIV-specific antibody responses. In particular, periodic intake of the drugs of abuse can result in time-varying periodic antibody level within HIV-infected individuals, consequently altering the HIV dynamics. In this study, we develop a mathematical model to analyze the effects of periodic intake of morphine, a widely used opiate. We consider two routes of morphine intake, namely, intravenous morphine (IVM) and slow-release oral morphine (SROM), and integrate several morphine pharmacodynamic parameters into HIV dynamics model. Using our non-autonomous model system we formulate the infection threshold, Ri, for global stability of infection-free equilibrium, which provides a condition for avoiding viral infection in a host. We demonstrate that the infection threshold highly depends on the morphine pharmacodynamic parameters. Such information can be useful in the design of antibody-based vaccines. In addition, we also thoroughly evaluate how alteration of the antibody level due to periodic intake of morphine can affect the viral load and the CD4 count in HIV infected drug abusers.

Modeling of the Coral Microbiome: the Influence of Temperature and Microbial Network.

Host-associated microbial communities are shaped by extrinsic and intrinsic factors to the holobiont organism. Environmental factors and microbe-microbe interactions act simultaneously on the microbial community structure, making the microbiome dynamics challenging to predict. The coral microbiome is essential to the health of coral reefs and sensitive to environmental changes. Here, we develop a dynamic model to determine the microbial community structure associated with the surface mucus layer (SML) of corals using temperature as an extrinsic factor and microbial network as an intrinsic factor. The model was validated by comparing the predicted relative abundances of microbial taxa to the relative abundances of microbial taxa from the sample data. The SML microbiome from Pseudodiploria strigosa was collected across reef zones in Bermuda, where inner and outer reefs are exposed to distinct thermal profiles. A shotgun metagenomics approach was used to describe the taxonomic composition and the microbial network of the coral SML microbiome. By simulating the annual temperature fluctuations at each reef zone, the model output is statistically identical to the observed data. The model was further applied to six scenarios that combined different profiles of temperature and microbial network to investigate the influence of each of these two factors on the model accuracy. The SML microbiome was best predicted by model scenarios with the temperature profile that was closest to the local thermal environment, regardless of the microbial network profile. Our model shows that the SML microbiome of P. strigosa in Bermuda is primarily structured by seasonal fluctuations in temperature at a reef scale, while the microbial network is a secondary driver.IMPORTANCE Coral microbiome dysbiosis (i.e., shifts in the microbial community structure or complete loss of microbial symbionts) caused by environmental changes is a key player in the decline of coral health worldwide. Multiple factors in the water column and the surrounding biological community influence the dynamics of the coral microbiome. However, by including only temperature as an external factor, our model proved to be successful in describing the microbial community associated with the surface mucus layer (SML) of the coral P. strigosa The dynamic model developed and validated in this study is a potential tool to predict the coral microbiome under different temperature conditions.

Modeling Zika Virus Transmission Dynamics: Parameter Estimates, Disease Characteristics, and Prevention.

Because of limited data, much remains uncertain about parameters related to transmission dynamics of Zika virus (ZIKV). Estimating a large number of parameters from the limited information in data may not provide useful knowledge about the ZIKV. Here, we developed a method that utilizes a mathematical model of ZIKV dynamics and the complex-step derivative approximation technique to identify parameters that can be estimated from the available data. Applying our method to epidemic data from the ZIKV outbreaks in French Polynesia and Yap Island, we identified the parameters that can be estimated from these island data. Our results suggest that the parameters that can be estimated from a given data set, as well as the estimated values of those parameters, vary from Island to Island. Our method allowed us to estimate some ZIKV-related parameters with reasonable confidence intervals. We also computed the basic reproduction number to be from 2.03 to 3.20 across islands. Furthermore, using our model, we evaluated potential prevention strategies and found that peak prevalence can be reduced to nearly 10% by reducing mosquito-to-human contact by at least 60% or increasing mosquito death by at least a factor of three of the base case. With these preventions, the final outbreak-size is predicted to be negligible, thereby successfully controlling ZIKV epidemics.