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Heterogeneous susceptibility to rotavirus infection and gastroenteritis in two birth cohort studies: parameter estimation and epidemiological implications

Joseph A. Lewnard, Benjamin A. Lopman, Umesh D. Parashar, Aisleen Bennett, Naor Bar-Zeev, Nigel A. Cunliffe, Prasanna Samuel, M. Lourdes Guerrero, Guillermo Ruiz-Palacios, Gagandeep Kang, Virginia E. Pitzer
doi: https://doi.org/10.1101/242172
Joseph A. Lewnard
1Center for Communicable Disease Dynamics, Harvard TH Chan School of Public Health, Boston, Massachusetts, United States
2Department of Epidemiology of Microbial Diseases, Yale School of Public Health, New Haven, Connecticut, United States
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  • For correspondence: jlewnard@hsph.harvard.edu
Benjamin A. Lopman
3Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, Georgia, United States
4Division of Viral Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia, United States
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Umesh D. Parashar
4Division of Viral Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia, United States
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Aisleen Bennett
5Malawi-Liverpool-Wellcome Trust Clinical Research Programme, College of Medicine, University of Malawi, Blantyre, Malawi
6Institute of Infection and Global Health, University of Liverpool, University of Liverpool, Liverpool, United Kingdom
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Naor Bar-Zeev
5Malawi-Liverpool-Wellcome Trust Clinical Research Programme, College of Medicine, University of Malawi, Blantyre, Malawi
6Institute of Infection and Global Health, University of Liverpool, University of Liverpool, Liverpool, United Kingdom
7International Vaccine Access Center, Department of International Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, United States
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Nigel A. Cunliffe
5Malawi-Liverpool-Wellcome Trust Clinical Research Programme, College of Medicine, University of Malawi, Blantyre, Malawi
6Institute of Infection and Global Health, University of Liverpool, University of Liverpool, Liverpool, United Kingdom
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Prasanna Samuel
8Department of Gastrointestinal Sciences, Christian Medical College, Vellore, Tamil Nadu, India
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M. Lourdes Guerrero
9Instituto Nacional de Ciences Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico
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Guillermo Ruiz-Palacios
9Instituto Nacional de Ciences Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico
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Gagandeep Kang
8Department of Gastrointestinal Sciences, Christian Medical College, Vellore, Tamil Nadu, India
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Virginia E. Pitzer
2Department of Epidemiology of Microbial Diseases, Yale School of Public Health, New Haven, Connecticut, United States
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Abstract

Variation in susceptibility is a known contributor to bias in studies estimating immune protection acquired from vaccination or natural infection. However, difficulty measuring this heterogeneity hinders assessment of its influence on estimates. Cohort studies, randomized trials, and post-licensure studies have reported reduced natural and vaccine-derived protection against rotavirus gastroenteritis in low- and middle-income countries (LMICs). We sought to understand differences in susceptibility among children enrolled in two birth-cohort studies of rotavirus in LMICs, and to explore the implications for estimation of immune protection. We re-analyzed data from studies conducted in Mexico City, Mexico and Vellore, India. Cumulatively, 573 unvaccinated children experienced 1418 rotavirus infections and 371 episodes of rotavirus gastroenteritis (RVGE) over 17,636 child-months. We developed a model characterizing susceptibility to rotavirus infection and RVGE among children, accounting for aspects of the natural history of rotavirus and differences in transmission rates between settings, and tested whether modelgenerated susceptibility measurements were associated with demographic and anthropometric factors. We identified greater variation in susceptibility to rotavirus infection and RVGE in Vellore than in Mexico City. In both cohorts, susceptibility to rotavirus infection and RVGE were associated with male sex, lower birth weight, lower maternal education, and having fewer siblings; within Vellore, susceptibility was also associated with lower socioeconomic status. Children who were more susceptible to rotavirus also experienced higher rates of diarrhea due to other causes. Simulations suggest that discrepant estimates of naturally-acquired immunity against RVGE can be attributed, in part, to between-setting differences in transmission intensity and susceptibility of children. We found that more children in Vellore than in Mexico City belong to a high-risk group for rotavirus infection and RVGE, and demonstrate that bias owing to differences in rotavirus transmission intensity and population susceptibility may hinder comparison of estimated immune protection against RVGE.

Author summary Differences in susceptibility can help explain why some individuals, and not others, acquire infection and exhibit symptoms when exposed to infectious disease agents. However, it is difficult to distinguish between differences in susceptibility versus exposure in epidemiological studies. We developed a modeling approach to distinguish transmission intensity and susceptibility in data from cohort studies of rotavirus infection among children in Mexico City, Mexico, and Vellore, India, and evaluated how these factors may have contributed to differences in estimates of naturally-acquired immune protection between the studies. We found that more children were at “high risk” of acquiring rotavirus infection, and of experiencing gastroenteritis when infected, in Vellore versus Mexico City. The probability of belonging to this high-risk stratum was associated with recognized risk factors such as lower socioeconomic status, lower birth weight, and risk of diarrhea due to other causes. We also found the risk for rotavirus infections to cause symptoms declined with age, and was independent of acquired immunity. Together, these findings can account for estimates of lower protective efficacy of acquired immunity against rotavirus gastroenteritis in high-incidence settings, which mirrors estimates of reduced effectiveness of live oral rotavirus vaccines in low- and middle-income countries.

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Posted January 08, 2018.
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Heterogeneous susceptibility to rotavirus infection and gastroenteritis in two birth cohort studies: parameter estimation and epidemiological implications
Joseph A. Lewnard, Benjamin A. Lopman, Umesh D. Parashar, Aisleen Bennett, Naor Bar-Zeev, Nigel A. Cunliffe, Prasanna Samuel, M. Lourdes Guerrero, Guillermo Ruiz-Palacios, Gagandeep Kang, Virginia E. Pitzer
bioRxiv 242172; doi: https://doi.org/10.1101/242172
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Heterogeneous susceptibility to rotavirus infection and gastroenteritis in two birth cohort studies: parameter estimation and epidemiological implications
Joseph A. Lewnard, Benjamin A. Lopman, Umesh D. Parashar, Aisleen Bennett, Naor Bar-Zeev, Nigel A. Cunliffe, Prasanna Samuel, M. Lourdes Guerrero, Guillermo Ruiz-Palacios, Gagandeep Kang, Virginia E. Pitzer
bioRxiv 242172; doi: https://doi.org/10.1101/242172

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