Mathematical Models of Ebola Virus Disease and Vaccine Preventable Diseases

This thesis focuses on applying mathematical models to studies on the transmission dynamics and control interventions of infectious diseases such as Ebola virus disease and vaccine preventable diseases. Many models in studies of Ebola transmission are based on the model by Legrand et al. (2007). However, there are potential issues with the Legrand model. First, the model was originally formulated in a complex form, leading to confusion and hindering its uses in practice. To overcome the difficulty, the Legrand model is reformulated in a much simpler but equivalent form in this thesis. The reformulated model also provides an intuitive understanding of its parameterization. Second, the underlying assumptions of the Legrand model are not mathematically clear for researchers, which might lead to inadvertent misuse of the model. The assumptions are clearly identified through comparison with three models developed with clear assumptions in this thesis, one of which simplifies to the Legrand model. This three models are also built with more realistic sojourns of epidemiological processes. The comparison among these models also demonstrates the importance of the underlying assumptions as they may provide different implications on control strategies. In addition, a concern about current Ebola models is that many of them consider only infections with typical symptoms, but Ebola presents clinically in a more complicated way. To account crudely for the wide spectrum of clinical symptoms that characterizes Ebola infection, a model is developed including asymptomatic, mild and severe infections. Comparing to the model with only typical symptoms, it shows that modeling the spectrum is important as it could affect estimation of the reproduction number and effectiveness of interventions. Possible effective control strategies are also evaluated. We show that the spectrum of Ebola infection is important in modeling as it has implications for policy-making. In many parts of the world, people seasonally migrate between rural and urban/peri-urban patches for economic opportunities. Migration meanwhile changes the immunity levels of patches and might increase the chance of recurrent outbreaks of vaccine preventable diseases. A three-patch meta-population model is developed that incorporates spatially explicit migration of individuals. The model is used to evaluate vaccination strategies to mitigate outbreaks. It suggests that rural-urban migration is an important factor in designing public health policies to mitigate vaccine-preventable diseases

Simulations for designing and interpreting intervention trials in infectious diseases.

BACKGROUND: Interventions in infectious diseases can have both direct effects on individuals who receive the intervention as well as indirect effects in the population. In addition, intervention combinations can have complex interactions at the population level, which are often difficult to adequately assess with standard study designs and analytical methods. DISCUSSION: Herein, we urge the adoption of a new paradigm for the design and interpretation of intervention trials in infectious diseases, particularly with regard to emerging infectious diseases, one that more accurately reflects the dynamics of the transmission process. In an increasingly complex world, simulations can explicitly represent transmission dynamics, which are critical for proper trial design and interpretation. Certain ethical aspects of a trial can also be quantified using simulations. Further, after a trial has been conducted, simulations can be used to explore the possible explanations for the observed effects. CONCLUSION: Much is to be gained through a multidisciplinary approach that builds collaborations among experts in infectious disease dynamics, epidemiology, statistical science, economics, simulation methods, and the conduct of clinical trials

Simulations for designing and interpreting intervention trials in infectious diseases.

BACKGROUND: Interventions in infectious diseases can have both direct effects on individuals who receive the intervention as well as indirect effects in the population. In addition, intervention combinations can have complex interactions at the population level, which are often difficult to adequately assess with standard study designs and analytical methods. DISCUSSION: Herein, we urge the adoption of a new paradigm for the design and interpretation of intervention trials in infectious diseases, particularly with regard to emerging infectious diseases, one that more accurately reflects the dynamics of the transmission process. In an increasingly complex world, simulations can explicitly represent transmission dynamics, which are critical for proper trial design and interpretation. Certain ethical aspects of a trial can also be quantified using simulations. Further, after a trial has been conducted, simulations can be used to explore the possible explanations for the observed effects. CONCLUSION: Much is to be gained through a multidisciplinary approach that builds collaborations among experts in infectious disease dynamics, epidemiology, statistical science, economics, simulation methods, and the conduct of clinical trials

Ebola Virus Disease: Progress So Far in the Management of the Disease

Ebola virus disease is one of the most deadly emerging infectious diseases in the world which causes severe haemorrhagic fever, with a mortality rate of 50–90%. Following the largest outbreak in West Africa in 2014 which was the most deadly of all time challenging global health, so much concern has been tilted towards the management of the disease. Some of the major global challenges that prolonged and escalated the gravity of the 2014 outbreak were the lack of prompt, reliable and affordable diagnostic tools, but most importantly no specific treatment and vaccines were available to manage the infection. Though certain non-licensed experimental drugs as well as vaccines were introduced during the 2014 outbreak that contributed towards the control of the epidemic, their efficacy was yet to be confirmed in randomized trials. Presently, a few rapid diagnostic test kits have been approved by FDA and WHO. Also, several experimental drugs and vaccines are undergoing randomized clinical trials with a few currently at phase III. Thus, it is our hope that most of these drugs and vaccines will be available in future to better manage re-emerging Ebola infections or outbreaks

VP24-Karyopherin alpha binding affinities differ between Ebolavirus species, nfluencing interferon inhibition and VP24 stability

Zaire ebolavirus (EBOV), Bundibugyo ebolavirus (BDBV), and Reston ebolavirus (RESTV) belong to the same genus but exhibit different virulence properties. VP24 protein, a structural protein present in all family members, blocks interferon (IFN) signaling and likely contributes to virulence. Inhibition of IFN signaling by EBOV VP24 (eVP24) involves its interaction with the NPI-1 subfamily of karyopherin alpha (KPNA) nuclear transporters. Here, we evaluated eVP24, BDBV VP24 (bVP24), and RESTV VP24 (rVP24) interactions with three NPI-1 subfamily KPNAs (KPNA1, KPNA5, and KPNA6). Using purified proteins, we demonstrated that each VP24 binds to each of the three NPI-1 KPNAs. bVP24, however, exhibited approximately 10-fold-lower KPNA binding affinity than either eVP24 or rVP24. Cell-based assays also indicate that bVP24 exhibits decreased KPNA interaction, decreased suppression of IFN induced gene expression, and a decreased half-life in transfected cells compared to eVP24 or rVP24. Amino acid sequence alignments between bVP24 and eVP24 also identified residues within and surrounding the previously defined eVP24-KPNA5 binding interface that decrease eVP24-KPNA affinity or bVP24-KPNA affinity. VP24 mutations that lead to reduced KPNA binding affinity also decrease IFN inhibition and shorten VP24 half-lives. These data identify novel functional differences in VP24-KPNA interaction and reveal a novel impact of the VP24-KPNA interaction on VP24 stability. IMPORTANCE The interaction of Ebola virus (EBOV) VP24 protein with host karyopherin alpha (KPNA) proteins blocks type I interferon (IFN) signaling, which is a central component of the host innate immune response to viral infection. Here, we quantitatively compared the interactions of VP24 proteins from EBOV and two members of the Ebolavirus genus, Bundibugyo virus (BDBV) and Reston virus (RESTV). The data reveal lower binding affinity of the BDBV VP24 (bVP24) for KPNAs and demonstrate that the interaction with KPNA modulates inhibition of IFN signaling and VP24 stability. The effect of KPNA interaction on VP24 stability is a novel functional consequence of this virus-host interaction, and the differences identified between viral species may contribute to differences in pathogenesis

The Economic Case for a Pandemic Fund

The rapid urban spread of Ebola virus in West Africa in 2014 and consequent breakdown of control measures led to a significant economic impact as well as the burden on public health and wellbeing. The US government appropriated $5.4 Billion for FY2015 and WHO proposed a$100 Million emergency fund largely to curtail the threat of future outbreaks. Using epidemiological analyses and economic modeling, we propose that the best use of these and similar funds would be to serve as global insurance against the continued threat of emerging infectious diseases. An effective strategy would involve the initial investment in strengthening mobile and adaptable capacity to deal with the threat and reality of disease emergence, coupled with repeated investment to maintain what is effectively a �national guard� for pandemic prevention and response. This investment would create a capital stock that could also provide access to safe treatment during and between crises in developing countries, lowering risk to developed countries.Ye

When Global Health Emergency Meets Chronic Emergency: Parsing Out (Inter)National and Local Optics in the Democratic Republic of the Congo’s Tenth Ebola Virus Disease Outbreak

This thesis examines community distrust as it has manifested in local responses to the national and international emergency response to the Democratic Republic of the Congo\u27s (DRC) tenth Ebola virus disease outbreak in the country\u27s war-torn east; in doing so it seeks to situate acts of resistance in locals\u27 lived experiences with the state and international community. Lack of trust in epidemic responses is not a new issue, and was thrown into sharp relief by the Ebola riposte in Sierra Leone, Guinea, and Liberia amidst the West Africa Ebola outbreak of 2014-16: affected populations displayed “resistance” toward a medical humanitarian response comprised of international forces that historically enslaved, colonized and exploited them, and domestic state military forces representing extensions of a corrupt and violent government. While lessons were learned from this outbreak as to the importance of engaging with local communities and conditions from the outset of an outbreak response and acknowledging the consequences of long-term neglect of social determinants of health, local distrust has resurfaced and led to considerable barriers to Ebola containment efforts in the emergency medical response in the eastern DRC. Seeking to work against narratives perpetuated by the media which have depicted resistance in West Africa and the eastern Congo as signs of the irrationality and dangerous nature of Africans which hamper disease containment efforts, this thesis relies upon primary data collection via interviews with scholars, and practitioners on-the-ground in the DRC or in previous outbreaks, as well as surveys of affected communities to contextualize opposition to the Ebola response. Primary data gleaned from these sources which illuminate the voices of impacted populations, along with secondary research providing historical background of the eastern DRC and theoretical insights, helps reveal the particular conditions of chronic, lived emergency in the east: genocide at the hands of the Belgian King Leopold\u27s imperial Congo, subsequent Belgian colonization, neocolonization under the Western-backed dictator Mobutu, 10 years of war leading to the greatest number of deaths sine WWII, and continual resource pillage and extraction by armed groups known to commit routine, murderous attacks against civilians. This thesis explores the disjuncture between an externally imposed notion of “emergency” in the form of the Public Health Emergency of International Concern (PHEIC), belonging to the international community’s lexicon of global health security, and a local, lived notion of crisis and insecurity in the eastern provinces. The project includes policy recommendations to better prioritize the voices of communities and their needs in future emergency health responses, and also facilitate the development of conditions in the country and the eastern region which render it less vulnerable to future Ebola outbreaks and in need of external medical aid