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.

An investigation of tuberculosis progression revealing the role of macrophages apoptosis via sensitivity and bifurcation analysis.

Mycobacterium tuberculosis infection features various disease outcomes: clearance, latency, active disease, and latent tuberculosis infection (LTBI) reactivation. Identifying the decisive factors for disease outcomes and progression is crucial to elucidate the macrophages-tuberculosis interaction and provide insights into therapeutic strategies. To achieve this goal, we first model the disease progression as a dynamical shift among different disease outcomes, which are characterized by various steady states of bacterial concentration. The causal mechanisms of steady-state transitions can be the occurrence of transcritical and saddle-node bifurcations, which are induced by slowly changing parameters. Transcritical bifurcation, occurring when the basic reproduction number equals to one, determines whether the infection clears or spreads. Saddle-node bifurcation is the key mechanism to create and destroy steady states. Based on these two steady-state transition mechanisms, we carry out two sample-based sensitivity analyses on transcritical bifurcation conditions and saddle-node bifurcation conditions. The sensitivity analysis results suggest that the macrophage apoptosis rate is the most significant factor affecting the transition in disease outcomes. This result agrees with the discovery that the programmed cell death (apoptosis) plays a unique role in the complex microorganism-host interplay. Sensitivity analysis narrows down the parameters of interest, but cannot answer how these parameters influence the model outcomes. To do this, we employ bifurcation analysis and numerical simulation to unfold various disease outcomes induced by the variation of macrophage apoptosis rate. Our findings support the hypothesis that the regulation mechanism of macrophage apoptosis affects the host immunity against tuberculosis infection and tuberculosis virulence. Moreover, our mathematical results suggest that new treatments and/or vaccines that regulate macrophage apoptosis in combination with weakening bacillary viability and/or promoting adaptive immunity could have therapeutic value.

Modelling the linkage between influenza infection and cardiovascular events via thrombosis.

There is a heavy burden associated with influenza including all-cause hospitalization as well as severe cardiovascular and cardiorespiratory events. Influenza associated cardiac events have been linked to multiple biological pathways in a human host. To study the contribution of influenza virus infection to cardiovascular thrombotic events, we develop a dynamic model which incorporates some key elements of the host immune response, inflammatory response, and blood coagulation. We formulate these biological systems and integrate them into a cohesive modelling framework to show how blood clotting may be connected to influenza virus infection. With blood clot formation inside an artery resulting from influenza virus infection as the primary outcome of this integrated model, we demonstrate how blood clot severity may depend on circulating prothrombin levels. We also utilize our model to leverage clinical data to inform the threshold level of the inflammatory cytokine TNFα which initiates tissue factor induction and subsequent blood clotting. Our model provides a tool to explore how individual biological components contribute to blood clotting events in the presence of influenza infection, to identify individuals at risk of clotting based on their circulating prothrombin levels, and to guide the development of future vaccines to optimally interact with the immune system.

HPV Screening and Vaccination Strategies in an Unscreened Population: A Mathematical Modeling Study.

Human papillomavirus (HPV), a sexually transmitted infection, is the necessary cause of cervical cancer, the third most common cancer affecting women worldwide. Prevention and control strategies include vaccination, screening, and treatment. While HPV prevention and control efforts are important worldwide, they are especially important in low-income areas with a high infection rate or high rate of cervical cancer. This study uses mathematical modeling to explore various vaccination and treatment strategies to control for HPV and cervical cancer while using Nepal as a case study. Two sets of deterministic models were created with the goal of understanding the impact of various prevention and control strategies. The first set of models examines the relative importance of screening and vaccination in an unscreened population, while the second set examines various screening scenarios. Partial rank correlation coefficients confirm the importance of screening and treatment in the reduction of HPV infections and cancer cases even when vaccination uptake is high. Results also indicate that less expensive screening technologies can achieve the same overall goal as more expensive screening technologies.

Interleukin-21 enhances rituximab activity in a cynomolgus monkey model of B cell depletion and in mouse B cell lymphoma models.

Rituximab, a monoclonal antibody targeting CD20 on B cells, is currently used to treat many subtypes of B cell lymphomas. However, treatment is not curative and response rates are variable. Recombinant interleukin-21 (rIL-21) is a cytokine that enhances immune effector function and affects both primary and transformed B cell differentiation. We hypothesized that the combination of rIL-21 plus rituximab would be a more efficacious treatment for B cell malignancies than rituximab alone. We cultured human and cynomolgus monkey NK cells with rIL-21 and found that their activity was increased and proteins associated with antibody dependent cytotoxicity were up-regulated. Studies in cynomolgus monkeys modeled the effects of rIL-21 on rituximab activity against CD20 B cells. In these studies, rIL-21 activated innate immune effectors, increased ADCC and mobilized B cells into peripheral blood. When rIL-21 was combined with rituximab, deeper and more durable B cell depletion was observed. In another series of experiments, IL-21 was shown to have direct antiproliferative activity against a subset of human lymphoma cell lines, and combination of murine IL-21 with rituximab yielded significant survival benefits over either agent alone in xenogeneic mouse tumor models of disseminated lymphoma. Therefore, our results do suggest that the therapeutic efficacy of rituximab may be improved when used in combination with rIL-21.

Epidemiological impact of a genital herpes type 2 vaccine for young females.

Genital Herpes, which is caused by Herpes Simplex Virus-1 or -2 (HSV-1, -2, predominantly HSV-2) is a sexually transmitted infection (STI) that causes a chronic latent infection with outbreak episodes linked to transmission. Antiviral therapies are effective in reducing viral shedding during these episodes, but are ineffective as a whole since many outbreaks are asymptomatic or have mild symptoms. Thus, the development of a vaccine for genital herpes is needed to control this disease. The question of how to implement such a vaccine program is an important one, and may be similar to the vaccination program for Human Papilloma Virus (HPV) for young females. We have developed a mathematical model to describe the epidemiology of vaccination targeting young females against HSV-2. The model population is delineated with respect to age group, sexual activity and infection status including oral infection of HSV-1, which may affect vaccine efficacy. A threshold parameter R(C), which determines the level of vaccine uptake needed to eradicate HSV-2, is found. Computer simulation shows that an adolescent-only vaccination program may be effective in eliminating HSV-2 disease, however, the success of extinction greatly depends on the level of vaccine uptake, the vaccine efficacy, the age of sexual maturity and safe sex practices. However, the time course of eradication would take many years. We also investigate the prevalence of infection in the total population and in women between 16-30 years of age before and after vaccination has been introduced, and show that the adolescent-only vaccination program can be effective in reducing disease prevalence in these populations depending on the level of vaccine uptake and vaccine efficacy. This will also result in a decrease of maternal-fetal transmission of HSV-2 infection. Another important, if commonsense, conclusion is that vaccination of some females reduces infection in men, which then reduces infection in women.

Oscillatory viral dynamics in a delayed HIV pathogenesis model.

We consider an HIV pathogenesis model incorporating antiretroviral therapy and HIV replication time. We investigate the existence and stability of equilibria, as well as Hopf bifurcations to sustained oscillations when drug efficacy is less than 100%. We derive sufficient conditions for the global asymptotic stability of the uninfected steady state. We show that time delay has no effect on the local asymptotic stability of the uninfected steady state, but can destabilize the infected steady state, leading to a Hopf bifurcation to periodic solutions in the realistic parameter ranges.