Direct and indirect effects of rotavirus vaccination: Comparing predictions from transmission dynamic models

Early observations from countries that have introduced rotavirus vaccination suggest that there may be indirect protection for unvaccinated individuals, but it is unclear whether these benefits will extend to the long term. Transmission dynamic models have attempted to quantify the indirect protection that might be expected from rotavirus vaccination in developed countries, but results have varied. To better understand the magnitude and sources of variability in model projections, we undertook a comparative analysis of transmission dynamic models for rotavirus. We fit five models to reported rotavirus gastroenteritis (RVGE) data from England and Wales, and evaluated outcomes for short- and long-term vaccination effects. All of our models reproduced the important features of rotavirus epidemics in England and Wales. Models predicted that during the initial year after vaccine introduction, incidence of severe RVGE would be reduced 1.8-2.9 times more than expected from the direct effects of the vaccine alone (28-50% at 90% coverage), but over a 5-year period following vaccine introduction severe RVGE would be reduced only by 1.1-1.7 times more than expected from the direct effects (54-90% at 90% coverage). Projections for the long-term reduction of severe RVGE ranged from a 55% reduction at full coverage to elimination with at least 80% coverage. Our models predicted short-term reductions in the incidence of RVGE that exceeded estimates of the direct effects, consistent with observations from the United States and other countries. Some of the models predicted that the short-term indirect benefits may be offset by a partial shifting of the burden of RVGE to older unvaccinated individuals. Nonetheless, even when such a shift occurs, the overall reduction in severe RVGE is considerable. Discrepancies among model predictions reflect uncertainties about age variation in the risk and reporting of RVGE, and the duration of natural and vaccine-induced immunity, highlighting important questions for future research

A Bayesian approach for estimating typhoid fever incidence from large-scale facility-based passive surveillance data

Decisions about typhoid fever prevention and control are based on estimates of typhoid incidence and their uncertainty. Lack of specific clinical diagnostic criteria, poorly sensitive diagnostic tests, and scarcity of accurate and complete datasets contribute to difficulties in calculating age-specific population-level typhoid incidence. Using data from the Strategic Typhoid Alliance across Africa and Asia program, we integrated demographic censuses, healthcare utilization surveys, facility-based surveillance, and serological surveillance from Malawi, Nepal, and Bangladesh to account for under-detection of cases. We developed a Bayesian approach that adjusts the count of reported blood-culture-positive cases for blood culture detection, blood culture collection, and healthcare seeking—and how these factors vary by age—while combining information from prior published studies. We validated the model using simulated data. The ratio of observed to adjusted incidence rates was 7.7 (95% credible interval [CrI]: 6.0-12.4) in Malawi, 14.4 (95% CrI: 9.3-24.9) in Nepal, and 7.0 (95% CrI: 5.6-9.2) in Bangladesh. The probability of blood culture collection led to the largest adjustment in Malawi, while the probability of seeking healthcare contributed the most in Nepal and Bangladesh; adjustment factors varied by age. Adjusted incidence rates were within or below the seroincidence rate limits of typhoid infection. Estimates of blood-culture-confirmed typhoid fever without these adjustments results in considerable underestimation of the true incidence of typhoid fever. Our approach allows each phase of the reporting process to be synthesized to estimate the adjusted incidence of typhoid fever while correctly characterizing uncertainty, which can inform decision-making for typhoid prevention and control

Community transmission of rotavirus infection in a vaccinated population in Blantyre, Malawi: a prospective household cohort study.

BACKGROUND: Rotavirus vaccine effectiveness is reduced among children in low-income countries. Indirect (transmission-mediated) effects of rotavirus vaccine might contribute to the total population effect of vaccination. We aimed to examine risk factors for transmission of rotavirus to household contacts in Blantyre, Malawi, and estimated the effectiveness of rotavirus vaccine in preventing transmission of infection to household contacts. METHODS: In this prospective household cohort study, we recruited children born after Sept 17, 2012, and aged at least 6 weeks (vaccine-eligible children) with acute rotavirus gastroenteritis and their household contacts, in four government health facilities in Blantyre, Malawi. Clinical data, a bulk stool sample, and 1-2 mL of serum were collected from case children at presentation. Clinical data and stool samples were also prospectively collected from household contacts over 14 days from presentation. A single stool sample was collected from control households containing asymptomatic children who were frequency age-matched to case children. Samples were tested for rotavirus using semi-quantitative real-time PCR and for anti-rotavirus IgA using a semi-quantitative sandwich ELISA. Risk factors for household transmission of rotavirus infection and clinical disease, including disease severity and faecal shedding density, were identified using mixed effects logistic regression. Vaccine effectiveness against transmission was estimated as 1 minus the ratio of secondary attack rates in vaccinated and counterfactual unvaccinated populations, using vaccine effectiveness estimates from the associated diarrhoeal surveillance platform to estimate the counterfactual secondary attack rate without vaccination. FINDINGS: Between Feb 16, 2015, and Nov 11, 2016, we recruited 196 case households (705 members) and 55 control households (153 members). Household secondary attack rate for rotavirus infection was high (434 [65%] of 665 individuals) and secondary attack rate for clinical disease was much lower (37 [5%] of 698). Asymptomatic infection in control households was common (40 [28%] of 144). Increasing disease severity in an index child (as measured by Vesikari score) was associated with increased risk of transmission of infection (odds ratio 1·17 [95% CI 1·06-1·30) and disease (1·28 [1·08-1·52]) to household contacts. Estimated vaccine effectiveness against transmission was 39% (95% CI 16-57). INTERPRETATION: Rotavirus vaccine has the potential to substantially reduce household rotavirus transmission. This finding should be considered in clinical and health economic assessments of vaccine effectiveness. FUNDING: Wellcome Trust, US National Institutes of Health, and US National Institute of Allergy and Infectious Diseases

The impact of migration and antimicrobial resistance on the transmission dynamics of typhoid fever in Kathmandu, Nepal: A mathematical modelling study.

BACKGROUND: A substantial proportion of the global burden of typhoid fever occurs in South Asia. Kathmandu, Nepal experienced a substantial increase in the number of typhoid fever cases (caused by Salmonella Typhi) between 2000 and 2003, which subsequently declined but to a higher endemic level than in 2000. This epidemic of S. Typhi coincided with an increase in organisms with reduced susceptibility against fluoroquinolones, the emergence of S. Typhi H58, and an increase in the migratory population in Kathmandu. METHODS: We devised a mathematical model to investigate the potential epidemic drivers of typhoid in Kathmandu and fit this model to weekly data of S. Typhi cases between April 1997 and June 2011 and the age distribution of S. Typhi cases. We used this model to determine if the typhoid epidemic in Kathmandu was driven by heightened migration, the emergence of organisms with reduced susceptibility against fluoroquinolones or a combination of these factors. RESULTS: Models allowing for the migration of susceptible individuals into Kathmandu alone or in combination with the emergence of S. Typhi with reduced susceptibility against fluoroquinolones provided a good fit for the data. The emergence of organisms with reduced susceptibility against fluoroquinolones organisms alone, either through an increase in disease duration or increased transmission, did not fully explain the pattern of S. Typhi infections. CONCLUSIONS: Our analysis is consistent with the hypothesis that the increase in typhoid fever in Kathmandu was associated with the migration of susceptible individuals into the city and aided by the emergence of reduced susceptibility against fluoroquinolones. These data support identifying and targeting migrant populations with typhoid immunization programmes to prevent transmission and disease

Meeting Report: WHO Workshop on modelling global mortality and aetiology estimates of enteric pathogens in children under five. Cape Town, 28-29th November 2018.

Investment in vaccine product development should be guided by up-to-date and transparent global burden of disease estimates, which are also fundamental to policy recommendation and vaccine introduction decisions. For low- and middle-income countries (LMICs), vaccine prioritization is primarily driven by the number of deaths caused by different pathogens. Enteric diseases are known to be a major cause of death in LMICs. The two main modelling groups providing mortality estimates for enteric diseases are the Institute for Health Metrics and Evaluation (IHME) at the University of Washington, Seattle and the Maternal Child Epidemiology Estimation (MCEE) group, led by Johns Hopkins Bloomberg School of Public Health. Whilst previous global diarrhoea mortality estimates for under five-year-olds from these two groups were closely aligned, more recent estimates for 2016 have diverged, particularly with respect to numbers of deaths attributable to different enteric pathogens. This has impacted prioritization and investment decisions for vaccines in the development pipeline. The mission of the Product Development for Vaccines Advisory Committee (PDVAC) at the World Health Organisation (WHO) is to accelerate product development of vaccines and technologies that are urgently needed and ensure they are appropriately targeted for use in LMICs. At their 2018 meeting, PDVAC recommended the formation of an independent working group of subject matter experts to explore the reasons for the difference between the IHME and MCEE estimates, and to assess the respective strengths and limitations of the estimation approaches adopted, including a review of the data on which the estimates are based. Here, we report on the proceedings and recommendations from a consultation with the working group of experts, the IHME and MCEE modelling groups, and other key stakeholders. We briefly review the methodological approaches of both groups and provide a series of proposals for investigating the drivers for the differences in enteric disease burden estimates

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

Cohort studies, randomized trials, and post-licensure studies have reported reduced natural and vaccine-derived protection against rotavirus gastroenteritis (RVGE) in low- and middle-income countries. While susceptibility of children to rotavirus is known to vary within and between settings, implications for estimation of immune protection are not well understood. We sought to re-estimate naturally-acquired protection against rotavirus infection and RVGE, and to understand how differences in susceptibility among children impacted estimates. We re-analyzed data from studies conducted in Mexico City, Mexico and Vellore, India. Cumulatively, 573 rotavirus-unvaccinated children experienced 1418 rotavirus infections and 371 episodes of RVGE over 17,636 child-months. We developed a model that characterized susceptibility to rotavirus infection and RVGE among children, accounting for aspects of the natural history of rotavirus and differences in transmission rates between settings. We tested whether model-generated susceptibility measurements were associated with demographic and anthropometric factors, and with the severity of RVGE symptoms. 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 rotavirus-negative diarrhea, and higher risk of moderate-to-severe symptoms when experiencing RVGE. Simulations suggested that discrepant estimates of naturally-acquired immunity against RVGE can be attributed, in part, to between-setting differences in susceptibility of children, but result primarily from the interaction of transmission rates with age-dependent risk for infections to cause RVGE. 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 unmeasured individual- and age-dependent susceptibility may influence estimates of naturally-acquired immune protection against RVGE

Burden of enteric fever at three urban sites in Africa and Asia: a multicentre population-based study

Summary Background Enteric fever is a serious public health concern in many low-income and middle-income countries. Numerous data gaps exist concerning the epidemiology of Salmonella enterica serotype Typhi (S Typhi) and Salmonella enterica serotype Paratyphi (S Paratyphi), which are the causative agents of enteric fever. We aimed to determine the burden of enteric fever in three urban sites in Africa and Asia. Methods In this multicentre population-based study, we did a demographic census at three urban sites in Africa (Blantyre, Malawi) and Asia (Kathmandu, Nepal and Dhaka, Bangladesh) between June 1, 2016, and Sept 25, 2018. Households were selected randomly from the demographic census. Participants from within the geographical census area presenting to study health-care facilities were approached for recruitment if they had a history of fever for 72 h or more (later changed to >48 h) or temperature of 38·0°C or higher. Facility-based passive surveillance was done between Nov 11, 2016, and Dec 31, 2018, with blood-culture collection for febrile illness. We also did a community-based serological survey to obtain data on Vi-antibody defined infections. We calculated crude incidence for blood-culture-confirmed S Typhi and S Paratyphi infection, and calculated adjusted incidence and seroincidence of S Typhi blood-culture-confirmed infection. Findings 423 618 individuals were included in the demographic census, contributing 626 219 person-years of observation for febrile illness surveillance. 624 S Typhi and 108 S Paratyphi A isolates were collected from the blood of 12 082 febrile patients. Multidrug resistance was observed in 44% S Typhi isolates and fluoroquinolone resistance in 61% of S Typhi isolates. In Blantyre, the overall crude incidence of blood-culture confirmed S Typhi was 58 cases per 100 000 person-years of observation (95% CI 48–70); the adjusted incidence was 444 cases per 100 000 person-years of observation (95% credible interval [CrI] 347–717). The corresponding rates were 74 (95% CI 62–87) and 1062 (95% CrI 683–1839) in Kathmandu, and 161 (95% CI 145–179) and 1135 (95% CrI 898–1480) in Dhaka. S Paratyphi was not found in Blantyre; overall crude incidence of blood-culture-confirmed S Paratyphi A infection was 6 cases per 100 000 person-years of observation (95% CI 3–11) in Kathmandu and 42 (95% CI 34–52) in Dhaka. Seroconversion rates for S Typhi infection per 100 000 person-years estimated from anti-Vi seroconversion episodes in serological surveillance were 2505 episodes (95% CI 1605–3727) in Blantyre, 7631 (95% CI 5913–9691) in Kathmandu, and 3256 (95% CI 2432–4270) in Dhaka. Interpretation High disease incidence and rates of antimicrobial resistance were observed across three different transmission settings and thus necessitate multiple intervention strategies to achieve global control of these pathogens. Funding Wellcome Trust and the Bill & Melinda Gates Foundation

Etiology of Diarrhea Among Hospitalized Children in Blantyre, Malawi, Following Rotavirus Vaccine Introduction: A Case-Control Study.

Despite rotavirus vaccination, diarrhea remains a leading cause of child mortality. We collected stool specimens from 684 children <5 years of age hospitalized with diarrhea (cases) and 527 asymptomatic community controls for 4 years after rotavirus vaccine introduction in Malawi. Specimens were tested for 29 pathogens, using polymerase chain reaction analysis. Three or more pathogens were detected in 71% of cases and 48% of controls. Pathogens significantly associated with diarrhea included rotavirus (in 34.7% of cases and 1.5% of controls), enteric adenovirus (in 29.1% and 2.7%, respectively), Cryptosporidium (in 27.8% and 8.2%, respectively), heat-stable enterotoxin-producing Escherichia coli (in 21.2% and 8.5%, respectively), typical enteropathogenic E. coli (in 18.0% and 8.3%, respectively), and Shigella/enteroinvasive E. coli (in 15.8% and 5.7%, respectively). Additional interventions are required to prevent diarrhea due to rotavirus and other common causal pathogens

Direct and possible indirect effects of vaccination on rotavirus hospitalisations among children in Malawi four years after programmatic introduction.

IntroductionDespite increased use of vaccine in routine immunisation, rotavirus remains a major cause of acute gastroenteritis (AGE) in low-income countries. We describe rotavirus prevalence and hospitalisation in Malawi pre and four years post vaccine introduction; provide updated vaccine effectiveness (VE) estimates; and assess rotavirus vaccine indirect effects.MethodsChildren under five years of age presenting to a referral hospital in Blantyre with AGE were recruited. Stool samples were tested for rotavirus using Enzyme Immunoassay. The change in rotavirus prevalence was evaluated using Poisson regression. Time series analysis was used to further investigate trends in prevalence over time. VE against rotavirus diarrhoea of any severity was estimated using logistic regression. Indirect effects were estimated by evaluating rotavirus prevalence in unvaccinated children over time, and by comparing observed reductions in incidence of rotavirus hospitalisation to those expected based on vaccine coverage and trial efficacy estimates.Results2320 children were included. Prevalence of rotavirus in hospitalised infants (ConclusionsFollowing rotavirus vaccine introduction in Malawi, prevalence of rotavirus in hospitalised children with AGE has declined significantly, with some evidence of an indirect effect in infants. Despite this, rotavirus remains an important cause of severe diarrhoea in Malawian children, particularly in the second year of life