Multiscale model for forecasting Sabin 2 vaccine virus household and community transmission.

Since the global withdrawal of Sabin 2 oral poliovirus vaccine (OPV) from routine immunization, the Global Polio Eradication Initiative (GPEI) has reported multiple circulating vaccine-derived poliovirus type 2 (cVDPV2) outbreaks. Here, we generated an agent-based, mechanistic model designed to assess OPV-related vaccine virus transmission risk in populations with heterogeneous immunity, demography, and social mixing patterns. To showcase the utility of our model, we present a simulation of mOPV2-related Sabin 2 transmission in rural Matlab, Bangladesh based on stool samples collected from infants and their household contacts during an mOPV2 clinical trial. Sabin 2 transmission following the mOPV2 clinical trial was replicated by specifying multiple, heterogeneous contact rates based on household and community membership. Once calibrated, the model generated Matlab-specific insights regarding poliovirus transmission following an accidental point importation or mass vaccination event. We also show that assuming homogeneous contact rates (mass action), as is common of poliovirus forecast models, does not accurately represent the clinical trial and risks overestimating forecasted poliovirus outbreak probability. Our study identifies household and community structure as an important source of transmission heterogeneity when assessing OPV-related transmission risk and provides a calibratable framework for expanding these analyses to other populations. Trial Registration: ClinicalTrials.gov This trial is registered with clinicaltrials.gov, NCT02477046.

A Ten Year Immunopersistence Study of Hepatitis E Antibodies in Rural Bangladesh.

Hepatitis E virus (HEV) is a major cause of acute, viral hepatitis in Southeast Asia. Several studies have suggested that antibody persistence after HEV infection may be transient, possibly increasing the risk of re-infection and contributing to the frequency of outbreaks in HEV endemic regions. The specific conditions under which antibodies to HEV are lost, or "sero-reversion" occurs, are poorly understood. Here, one hundred participants from population-based studies in rural Bangladesh were revisited in 2015, ten years after a documented HEV infection to examine long-term antibody persistence. Twenty percent (95% confidence interval: 12.0, 28.0) no longer had detectable antibodies at follow-up, suggesting that antibodies generally persist for at least a decade after infection in rural Bangladesh. Those who were seronegative at follow-up were generally younger at infection than those who remained positive (14.4 years versus 33.6 years, P > 0.0001). This age-dependent antibody loss could partially explain cross-sectional sero-prevalence data from South East Asia where children have reportedly low antibody prevalence. The results of this study provide new insight into the immunological persistence of HEV infection in a micronutrient deficient rural population of South Asia, highlighting the importance of age at infection in the ability to produce long-lasting antibodies against HEV.

Screening utility, local perceptions, and care-seeking for reported jaundeesh among respondents lacking signs of icterus in rural Bangladesh.

In rural Bangladesh, acute viral hepatitis presents a significant burden on the public-health system. As part of the formative work for a large epidemiologic study of hepatitis E in rural Bangladesh, we sought to identify local terms that could be used for population-based screening of acute viral hepatitis. Exploration of the local term jaundeesh for screening utility identified a high burden of reported jaundeesh among individuals without symptoms of icterus. Recognizing that local perceptions of illness may differ from biomedical definitions of disease, we also sought to characterize the perceived aetiology, care-seeking patterns, diagnostic symptoms, and treatments for reported jaundeesh in the absence of icteric symptoms to inform future population-based studies on reported morbidities. We conducted a cross-sectional survey among 1,441 randomly-selected subjects to identify the prevalence of reported jaundeesh and to test the validity of this local term to detect signs of icterus. To characterize the perceived aetiology and care-seeking patterns for jaundeesh among the majority of respondents, we conducted in-depth interviews with 100 respondents who self-reported jaundeesh but lacked clinical signs of icterus. To describe diagnostic symptoms and treatments, in-depth interviews were also performed with 25 kabirajs or traditional faith healers commonly visited for jaundeesh. Of the 1,441 randomly-selected participants, one-fourth (n=361) reported jaundeesh, with only a third (n=122) reporting yellow eyes or skin, representative of icterus; Jaundeesh had a positive predictive value of 34% for detection of yellow eyes or skin. Anicteric patients with reported jaundeesh perceived their illnesses to result from humoral imbalances, most commonly treated by amulets, ritual handwashing, and bathing with herbal medicines. Jaundeesh patients primarily sought folk and spiritual remedies from informal care providers, with only 19% visiting allopathic care providers. Although the local term jaundeesh appeared to have limited epidemiologic utility to screen for acute symptomatic viral hepatitis, this term described a syndrome perceived to occur frequently in this population. Future population-based studies conducting surveillance for acute hepatitis should use caution in the use and interpretation of self-reported jaundeesh. Further study of jaundeesh may provide insight into the appropriate public-health response to this syndrome.

Epidemiology and risk factors of incident hepatitis E virus infections in rural Bangladesh.

Hepatitis E virus (HEV) is the most common cause of acute viral hepatitis in the world. Most of South Asia is HEV endemic, with frequent seasonal epidemics of hepatitis E and continuous sporadic cases. This author group's epidemiologic work and clinical reports suggest that Bangladesh is HEV endemic, but there have been few population-based studies of this country's HEV burden. The authors calculated HEV infection rates, over an 18-month interval between 2003 and 2005, by following a randomly selected cohort of 1,134 subjects between the ages of 1 and 88 years, representative of rural communities in southern Bangladesh. Baseline prevalence of antibody to hepatitis E virus (anti-HEV) was 22.5%. Seroincidence was 60.3 per 1,000 person-years during the first 12 months and 72.4 per 1,000 person-years from >12 to 18 months (during the monsoon season), peaking by age 50 years and with low rates during childhood. Few of the seroconverting subjects reported hepatitis-like illness. Overall incidence was calculated to be 64 per 1,000 person-years, with 1,172 person-years followed. No significant associations were found between anti-HEV incidence and demographic or socioeconomic factors for which data were available. This is the first study to document annual HEV infection rates among "healthy" and very young to elderly subjects in a rural Bangladeshi population.

Community transmission of type 2 poliovirus after cessation of trivalent oral polio vaccine in Bangladesh: an open-label cluster-randomised trial and modelling study.

BACKGROUND: Trivalent oral polio vaccine (tOPV) was replaced worldwide from April, 2016, by bivalent types 1 and 3 oral polio vaccine (bOPV) and one dose of inactivated polio vaccine (IPV) where available. The risk of transmission of type 2 poliovirus or Sabin 2 virus on re-introduction or resurgence of type 2 poliovirus after this switch is not understood completely. We aimed to assess the risk of Sabin 2 transmission after a polio vaccination campaign with a monovalent type 2 oral polio vaccine (mOPV2). METHODS: We did an open-label cluster-randomised trial in villages in the Matlab region of Bangladesh. We randomly allocated villages (clusters) to either: tOPV at age 6 weeks, 10 weeks, and 14 weeks; or bOPV at age 6 weeks, 10 weeks, and 14 weeks and either one dose of IPV at age 14 weeks or two doses of IPV at age 14 weeks and 18 weeks. After completion of enrolment, we implemented an mOPV2 vaccination campaign that targeted 40% of children younger than 5 years, regardless of enrolment status. The primary outcome was Sabin 2 incidence in the 10 weeks after the campaign in per-protocol infants who did not receive mOPV2, as assessed by faecal shedding of Sabin 2 by reverse transcriptase quantitative PCR (RT-qPCR). The effect of previous immunity on incidence was also investigated with a dynamical model of poliovirus transmission to observe prevalence and incidence of Sabin 2 virus. This trial is registered at ClinicalTrials.gov, number NCT02477046. FINDINGS: Between April 30, 2015, and Jan 14, 2016, individuals from 67 villages were enrolled to the study. 22 villages (300 infants) were randomly assigned tOPV, 23 villages (310 infants) were allocated bOPV and one dose of IPV, and 22 villages (329 infants) were assigned bOPV and two doses of IPV. Faecal shedding of Sabin 2 in infants who did not receive the mOPV2 challenge did not differ between children immunised with bOPV and one or two doses of IPV and those who received tOPV (15 of 252 [6%] vs six of 122 [4%]; odds ratio [OR] 1·29, 95% CI 0·45-3·72; p=0·310). However, faecal shedding of Sabin 2 in household contacts was increased significantly with bOPV and one or two doses of IPV compared with tOPV (17 of 751 [2%] vs three of 353 [1%]; OR 3·60, 95% CI 0·82-15·9; p=0·045). Dynamical modelling of within-household incidence showed that immunity in household contacts limited transmission. INTERPRETATION: In this study, simulating 1 year of tOPV cessation, Sabin 2 transmission was higher in household contacts of mOPV2 recipients in villages receiving bOPV and either one or two doses of IPV, but transmission was not increased in the community as a whole as shown by the non-significant difference in incidence among infants. Dynamical modelling indicates that transmission risk will be higher with more time since cessation. FUNDING: Bill & Melinda Gates Foundation.

An exploratory case control study of risk factors for hepatitis E in rural Bangladesh.

Hepatitis E virus (HEV) is the major cause of epidemic and sporadic hepatitis globally. Outbreaks are associated with fecal contamination of drinking water, yet the environmental reservoir of HEV between epidemics remains unclear. In contrast to neighboring countries, where epidemics and sporadic disease co-occur, HEV-endemic communities in rural Bangladesh seldom report outbreaks; sporadic hepatitis E is reported from urban and rural areas of the country. Besides typical enteric risk factors, other routes for HEV infection and disease are unclear. We conducted monthly household surveillance of a southern Bangladeshi community of 23,500 people to find incident cases of acute hepatitis E over a 22 month period. An algorithm was used to capture 279 candidate cases, of which 46 were confirmed acute HEV infections. An exploratory case-control study was conducted to identify putative risk factors for disease. Nearly 70% of cases were over 15 years old. Female gender seemed protective (OR:0.34) against hepatitis E in this conservative setting, as was the use of sanitary latrines (OR:0.28). Socioeconomic status or animal exposures were not significant predictors of disease, although outdoor employment and recent urban travel were. Unexpectedly, recent contact with a "jaundiced" patient and a history of injection exposure in the 3 months prior to disease (OR:15.50) were significant. Susceptible individuals from "endemic" communities share similar enteric exposure risks to those commonly associated with tourists from non-endemic countries. This study also raises the novel possibility of parenteral and person-to-person transmission of HEV in non-epidemic, sporadic disease settings.

Population seroprevalence of hepatitis E virus antibodies in rural Bangladesh.

Hepatitis E virus (HEV) causes a substantial burden of sporadic and epidemic disease worldwide. HEV infections result in serious morbidity and mortality, especially among pregnant women, and have significant economic costs. Few population-based studies have characterized the epidemiology of HEV. A rural Bangladeshi population was studied to determine the age- and gender- specific population seroprevalence of antibodies to HEV. Of 1,134 specimens tested from a representative, random population sample, 255 (22.5%) were anti-HEV IgG seropositive. Seroprevalence was lower among women (19.7%) than among men (25.8%). We found anti-HBc (hepatitis B core) in 380 of 1080(35.2%) tested, anti-HCV (hepatitis C) in 14 of 917(1.5%) tested, and anti-HAV (hepatitis A) in 116 of 124(93.5%) tested individuals. Our data suggest that viral hepatitis, especially HEV, remains an under-recognized and significant public health problem in rural Bangladeshi populations, warranting further attention.