Acute infectious diarrhea remains the world's second leading cause of death in children under 5 years old, and in Africa is responsible for one quarter of all deaths in this age group. The introduction of rotavirus vaccination represents an important step in reducing diarrhea mortality in developing countries; however estimates of vaccine performance are significantly lower than from developed countries. Accurate estimation of pathogen-specific disease burdens as well assessment of pathogen-specific interventions requires uniformly sensitive detection methods for a wide range of pathogens. However, traditional diagnostics, including culture, microscopy, and antigen-based testing, suffer from heterogeneity in test performance. In this K23 Mentored Career Development Award application, Dr. James Platts-Mills, a fellow in Infectious Diseases at the University of Virginia, proposes to 1) use next-generation quantitative molecular diagnostics to improve estimates of the pathogen-specific etiology and burden of diarrhea in children in developing countries, 2) develop speciation and typing assays for epidemiologically important pathogens that can be performed directly on stool and can be used to prioritize pathogen-specific interventions, and 3) apply these tools to understand the impact of infections with non-rotavirus enteropathogens on rotavirus vaccine performance. This work will be carried out in the context of 1) an ongoing multisite birth cohort study of enteropathogen infection, diarrhea, and childhood development in the developing world (MAL-ED); 2) an ongoing clinical trial on the impact of enteropathogen infections and tropical enteropathy on rotavirus vaccine immunogenicity and efficacy in children in Bangladesh (PROVIDE); and 3) a new case-control study of rotavirus vaccine effectiveness in rural Tanzania. Dr. Platts-Mills proposes a career development plan which includes mentorship, fieldwork, coursework, publications, and clinical time that will situate him as an independent investigator with expertise in the application of next-generation molecular diagnostic tools to field studies of enteric infections in children in developing countries.

Public Health Relevance

This work will help a) establish priorities for subsequent pathogen-specific interventions, in particular by providing revised estimates of pathogen-specific burdens of disease in diverse settings both before and after introduction of the rotavirus vaccine, b) validate diagnostics for epidemiologically important pathogens that can be employed in subsequent studies including clinical trials of pathogen-specific interventions, and c) identify strategies for improving rotavirus vaccine performance in developing countries. Successful completion of this work will facilitate a wide range of additional studies in the epidemiology of enteric infections, vaccine development, and therapeutics.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Mentored Patient-Oriented Research Career Development Award (K23)
Project #
5K23AI114888-04
Application #
9484228
Study Section
Microbiology and Infectious Diseases B Subcommittee (MID)
Program Officer
Glock, Jonathan A
Project Start
2015-06-15
Project End
2020-05-31
Budget Start
2018-06-01
Budget End
2019-05-31
Support Year
4
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Virginia
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
065391526
City
Charlottesville
State
VA
Country
United States
Zip Code
22904
Rogawski, Elizabeth T; Platts-Mills, James A; Colgate, E Ross et al. (2018) Quantifying the Impact of Natural Immunity on Rotavirus Vaccine Efficacy Estimates: A Clinical Trial in Dhaka, Bangladesh (PROVIDE) and a Simulation Study. J Infect Dis 217:861-868
Lertsethtakarn, Paphavee; Silapong, Sasikorn; Sakpaisal, Pimmada et al. (2018) Travelers' Diarrhea in Thailand: A Quantitative Analysis Using TaqMan® Array Card. Clin Infect Dis 67:120-127
Schnee, Amanda E; Haque, Rashidul; Taniuchi, Mami et al. (2018) Identification of Etiology-Specific Diarrhea Associated With Linear Growth Faltering in Bangladeshi Infants. Am J Epidemiol 187:2210-2218
Operario, Darwin J; Platts-Mills, James A; Nadan, Sandrama et al. (2017) Etiology of Severe Acute Watery Diarrhea in Children in the Global Rotavirus Surveillance Network Using Quantitative Polymerase Chain Reaction. J Infect Dis 216:220-227
Platts-Mills, James A; Amour, Caroline; Gratz, Jean et al. (2017) Impact of Rotavirus Vaccine Introduction and Postintroduction Etiology of Diarrhea Requiring Hospital Admission in Haydom, Tanzania, a Rural African Setting. Clin Infect Dis 65:1144-1151
Platts-Mills, James A; Taniuchi, Mami; Uddin, Md Jashim et al. (2017) Association between enteropathogens and malnutrition in children aged 6-23 mo in Bangladesh: a case-control study. Am J Clin Nutr 105:1132-1138
GBD Diarrhoeal Diseases Collaborators (2017) Estimates of global, regional, and national morbidity, mortality, and aetiologies of diarrhoeal diseases: a systematic analysis for the Global Burden of Disease Study 2015. Lancet Infect Dis 17:909-948
Liu, Jie; Platts-Mills, James A; Juma, Jane et al. (2016) Use of quantitative molecular diagnostic methods to identify causes of diarrhoea in children: a reanalysis of the GEMS case-control study. Lancet 388:1291-301
Bartelt, Luther A; Platts-Mills, James A (2016) Giardia: a pathogen or commensal for children in high-prevalence settings? Curr Opin Infect Dis 29:502-7
Taniuchi, Mami; Platts-Mills, James A; Begum, Sharmin et al. (2016) Impact of enterovirus and other enteric pathogens on oral polio and rotavirus vaccine performance in Bangladeshi infants. Vaccine 34:3068-3075

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