Effect of developmental stage of HSC and recipient on transplant outcomes

The first hematopoietic stem cells (HSCs) that engraft irradiated adult mice arise in the aorta-gonad-mesonephros (AGM) on embryonic day 11.5 (E11.5). However, at this stage, there is a discrepancy between the apparent frequency of HSCs depicted with imaging and their rarity when measured with limiting dilution transplant. We have attempted to reconcile this difference using neonatal recipients, which are more permissive for embryonic HSC engraftment. We found that embryonic HSCs from E9.5 and E10.5 preferentially engrafted neonates, whereas developmentally mature, definitive HSCs from E14.5 fetal liver or adult bone marrow (BM) more robustly engrafted adults. Neonatal engraftment was enhanced after treating adult BM-derived HSCs with interferon. Adult BM-derived HSCs preferentially homed to the liver in neonatal mice yet showed balanced homing to the liver and spleen in adults. These findings emphasize the functional differences between nascent and mature definitive HSCs

Retrospective Analysis of the 2014-2015 Ebola Epidemic in Liberia.

The 2014-2015 Ebola epidemic has been the most protracted and devastating in the history of the disease. To prevent future outbreaks on this scale, it is imperative to understand the reasons that led to eventual disease control. Here, we evaluated the shifts of Ebola dynamics at national and local scales during the epidemic in Liberia. We used a transmission model calibrated to epidemiological data between June 9 and December 31, 2014, to estimate the extent of community and hospital transmission. We found that despite varied local epidemic patterns, community transmission was reduced by 40-80% in all the counties analyzed. Our model suggests that the tapering of the epidemic was achieved through reductions in community transmission, rather than accumulation of immune individuals through asymptomatic infection and unreported cases. Although the times at which this transmission reduction occurred in the majority of the Liberian counties started before any large expansion in hospital capacity and the distribution of home protection kits, it remains difficult to associate the presence of interventions with reductions in Ebola incidence

Cost-effectiveness of next-generation vaccines: The case of pertussis.

Despite steady vaccination coverage rates, pertussis incidence in the United States has continued to rise. This public health challenge has motivated calls for the development of a new vaccine with greater efficacy and duration of protection. Any next-generation vaccine would likely come at a higher cost, and must provide sufficient health benefits beyond those provided by the current vaccine in order to be deemed cost-effective. Using an age-structured transmission model of pertussis, we quantified the health and economic benefits of a next-generation vaccine that would enhance either the efficacy or duration of protection of the childhood series, the duration of the adult booster, or a combination. We developed a metric, the maximum cost-effective price increase (MCPI), to compare the potential value of such improvements. The MCPI estimates the per-dose price increase that would maintain the cost-effectiveness of pertussis vaccination. We evaluated the MCPI across a range of potential single and combined improvements to the pertussis vaccine. As an upper bound, we found that a next-generation vaccine which could achieve perfect efficacy for the childhood series would permit an MCPI of $18 per dose (95$12-$31). Pertussis vaccine improvements that extend the duration of protection to an average of 75 years would allow for an MCPI of$22 per dose for the childhood series (CI: $10-$33) or $12 for the adult booster (CI:$4-$18). Despite the short duration of the adult booster, improvements to the childhood series could be more valuable than improvements to the adult booster. Combining improvements in both efficacy and duration, a childhood series with perfect efficacy and average duration of 75 years would permit an MCPI of$39 per dose, the highest of any scenario evaluated. Our results highlight the utility of the MCPI metric in evaluating potential vaccines or other interventions when prices are unknown

ASSESSING OPTIMAL INTERVENTION TARGETS FOR RESPIRATORY INFECTIONS IN STRUCTURED POPULATIONS

Thesis (Ph.D.)--University of Washington, 2019Background: Respiratory Viral Infections (RVI) are one of the most common health conditions globally, and are an enormous burden to health systems and society in terms of direct medical expenses and indirect productivity losses. Despite progress made in the 20th century with the introduction of antibiotics, vaccines, and antivirals there are no specific interventions for most respiratory infections of viral origin. There remains a need for new rationally designed therapeutics, and non-pharmaceutical interventions to prevent transmission. The objective of this project is improve current public health decision tools through an improved understanding of respiratory virus transmission from key ‘driver’ subgroups and their interactions with other subgroups in a study population. Methods: This research utilizes clinical epidemiology, infectious disease modeling, and extensive sensitivity analysis, to describe and evaluate current health decision-making processes related to two RVI. In the first chapter we infer exposure routes of Human parainfluenza virus-3 (HPIV-3) infection using a case-control study at a cancer-specific hospital. We examine locations and treatment exposures among patients that are associated with illness and make recommendations for the current intervention protocol based on the results. In the last two chapters we deal with previously quantified contact patterns. Using these contact patterns we evaluate the optimal vaccination intervention using cost-effectiveness analysis to compare the status quo influenza vaccination program to seven alternative strategies targeted at school age subgroups Preschool (2-4 years old), Primary school (5-11 years old), and Secondary school (12-16 years old). In the final chapter we deliberately incorporate social contact uncertainty into the same model as chapter 2 by using contact surveys from other countries and examine the variation in our cost-effectiveness results. Results: In our case-control study, 50 case subjects with medical appointments during their exposure period were compared to 106 controls using matched conditional logistic regression. Although contact precautions were enforced for immunosuppressed patients, these patients were 9.59 times as likely to be infected. Contact with several healthcare workers, especially nonclinical staff (e.g. social workers) was also associated with increased infection odds. In chapter 2, the incremental analysis demonstrated vaccinating 5-11 year olds (Primary School) was the most cost-efficient strategy. Although all seven strategies had a 100% probability of being cost-effective at the current National Health Service (NHS) threshold of £20,000 per 1 QALY gained, vaccination of 5-11 year olds provided substantial indirect protection to other age groups. Additionally strategies which contained this age group were less sensitive to changes in total achieved coverage. The structural uncertainty analysis in chapter 3 revealed Bayesian model fits using the substituted prior information on contact patterns did not converge on the same posterior. Substitution of a counterfactual contact structure in lieu of country-specific structure decreased the probability a strategy was cost-effective by propagating uncertainty through the model. We also determined that when a model’s contact structure is substituted the relative importance of each age group to population-level disease transmission varies substantially, rendering inconsistent cost-effectiveness results. Conclusion: In this research we evaluated interventions aimed at reducing two respiratory viral infections: seasonal influenza and HPIV-3. In the latter our results suggest asymptomatic shedding among hospital staff, especially non-clinical staff (e.g. social workers), and viral persistence in environmental surfaces as possible exposure routes of patient HPIV-3 infection. In chapter 2, we determined improvement could be made to the current LAIV pediatric vaccination strategy of England and Wales by eliminating LAIV vaccination of 2-4 year olds and focusing on school-based delivery of LAIV to two key age groups, Primary and Secondary school-age children. However the conclusions of chapter 2, and all policy interventions based on simulating health outcomes and economic costs, are sensitive to the scientific judgements around social contact parameters. From chapter 3 we conclude there is added value in using country-specific contact data, and advocate that in the absence of country-specific contact patterns, structural uncertainty analysis should be undertaken when quantifying the effect of strategies that involve herd immunity

Effects of Response to 2014–2015 Ebola Outbreak on Deaths from Malaria, HIV/AIDS, and Tuberculosis, West Africa

Response to the 2014–2015 Ebola outbreak in West Africa overwhelmed the healthcare systems of Guinea, Liberia, and Sierra Leone, reducing access to health services for diagnosis and treatment for the major diseases that are endemic to the region: malaria, HIV/AIDS, and tuberculosis. To estimate the repercussions of the Ebola outbreak on the populations at risk for these diseases, we developed computational models for disease transmission and infection progression. We estimated that a 50% reduction in access to healthcare services during the Ebola outbreak exacerbated malaria, HIV/AIDS, and tuberculosis mortality rates by additional death counts of 6,269 (2,564–12,407) in Guinea; 1,535 (522–2,8780) in Liberia; and 2,819 (844–4,844) in Sierra Leone. The 2014–2015 Ebola outbreak was catastrophic in these countries, and its indirect impact of increasing the mortality rates of other diseases was also substantial

Under-reporting and case fatality estimates for emerging epidemics.

© BMJ Publishing Group Ltd 2015. All authors have completed the unified competing interest form at www.icmje.org/coi-disclosure.pdf (available on request from the corresponding author) and declare the work was supported by the National Institutes of Health (NIH U01 GM087719, U01 GM105627, and K24 DA017072), and the National Science Foundation (NSF RAPID 1514673). This research was partly funded by the National Institute for Health Research Health Protection Research Unit (NIHR HPRU) in Immunisation at the London School of Hygiene and Tropical Medicine in partnership with Public Health England (PHE). The views expressed are those of the authors and not necessarily those of the NIH, NSF, NHS, NIHR, the Department of Health or Public Health England

Under-reporting and case fatality estimates for emerging epidemics.

© BMJ Publishing Group Ltd 2015. All authors have completed the unified competing interest form at www.icmje.org/coi-disclosure.pdf (available on request from the corresponding author) and declare the work was supported by the National Institutes of Health (NIH U01 GM087719, U01 GM105627, and K24 DA017072), and the National Science Foundation (NSF RAPID 1514673). This research was partly funded by the National Institute for Health Research Health Protection Research Unit (NIHR HPRU) in Immunisation at the London School of Hygiene and Tropical Medicine in partnership with Public Health England (PHE). The views expressed are those of the authors and not necessarily those of the NIH, NSF, NHS, NIHR, the Department of Health or Public Health England

Spatial and Temporal Clustering of Chikungunya Virus Transmission in Dominica

Using geo-referenced case data, we present spatial and spatio-temporal cluster analyses of the early spread of the 2013–2015 chikungunya virus (CHIKV) in Dominica, an island in the Caribbean. Spatial coordinates of the locations of the first 417 reported cases observed between December 15th, 2013 and March 11th, 2014, were captured using the Global Positioning System (GPS). We observed a preponderance of female cases, which has been reported for CHIKV outbreaks in other regions. We also noted statistically significant spatial and spatio-temporal clusters in highly populated areas and observed major clusters prior to implementation of intensive vector control programs suggesting early vector control measures, and education had an impact on the spread of the CHIKV epidemic in Dominica. A dynamical identification of clusters can lead to local assessment of risk and provide opportunities for targeted control efforts for nations experiencing CHIKV outbreaks