Predicting indirect effects of rotavirus vaccination programs on rotavirus mortality among children in 112 countries.

Rotavirus is a leading cause of diarrhea deaths in children, particularly in low-to-middle income countries (LMICs). Licensed rotavirus vaccines provide strong direct protection, but their indirect effect-the protection due to reduced transmission-is not fully understood. We aimed to quantify the population-level effects of rotavirus vaccination and identify factors that drive indirect protection. We used an SIR-like transmission model to estimate the indirect effects of vaccination on rotavirus deaths in 112 LMICs. We performed a regression analysis to identify predictors of indirect effect magnitude (linear regression) and the occurrence of negative indirect effects (logistic regression). Indirect effects contributed to vaccine impacts in all regions, with effect sizes 8-years post-vaccine introduction ranging from 16.9% in the WHO European region to 1.0% in the Western Pacific region. Indirect effect estimates were higher in countries with higher under-5 mortality, higher vaccine coverage, and lower birth rates. Of the 112 countries analyzed, 18 (16%) had at least 1 year with a predicted negative indirect effect. Negative indirect effects were more common in countries with higher birth rate, lower under-5 mortality and lower vaccine coverage. Rotavirus vaccination may have a larger impact than would be expected from direct effects alone, but the impact of these indirect effects is expected to vary by country.

Predicting the long-term impact of rotavirus vaccination in 112 countries from 2006 to 2034: A transmission modeling analysis.

Rotavirus vaccination has been shown to reduce rotavirus burden in many countries, but the long-term magnitude of vaccine impacts is unclear, particularly in low-income countries. We use a transmission model to estimate the long-term impact of rotavirus vaccination on deaths and disability adjusted life years (DALYs) from 2006 to 2034 for 112 low- and middle-income countries. We also explore the predicted effectiveness of a one- vs two- dose series and the relative contribution of direct vs indirect effects to overall impacts. To validate the model, we compare predicted percent reductions in severe rotavirus cases with the percent reduction in rotavirus positivity among gastroenteritis hospital admissions for 10 countries with pre- and post-vaccine introduction data. We estimate that vaccination would reduce deaths from rotavirus by 49.1 % (95 % UI: 46.6-54.3 %) by 2034 under realistic coverage scenarios, compared to a scenario without vaccination. Most of this benefit is due to direct benefit to vaccinated individuals (explaining 69-97 % of the overall impact), but indirect protection also appears to enhance impacts. We find that a one-dose schedule would only be about 57 % as effective as a two-dose schedule 12 years after vaccine introduction. Our model closely reproduced observed reductions in rotavirus positivity in the first few years after vaccine introduction in select countries. Rotavirus vaccination is likely to have a substantial impact on rotavirus gastroenteritis and its mortality burden. To sustain this benefit, the complete series of doses is needed.

The role of booster vaccination and ongoing viral evolution in seasonal circulation of SARS-CoV-2.

Periodic resurgences of COVID-19 in the coming years can be expected, while public health interventions may be able to reduce their intensity. We used a transmission model to assess how the use of booster doses and non-pharmaceutical interventions (NPIs) amid ongoing pathogen evolution might influence future transmission waves. We find that incidence is likely to increase as NPIs relax, with a second seasonally driven surge expected in autumn 2022. However, booster doses can greatly reduce the intensity of both waves and reduce cumulative deaths by 20% between 7 January 2022 and 7 January 2023. Reintroducing NPIs during the autumn as incidence begins to increase again could also be impactful. Combining boosters and NPIs results in a 30% decrease in cumulative deaths, with potential for greater impacts if variant-adapted boosters are used. Reintroducing these NPIs in autumn 2022 as transmission rates increase provides similar benefits to sustaining NPIs indefinitely (307 000 deaths with indefinite NPIs and boosters compared with 304 000 deaths with transient NPIs and boosters). If novel variants with increased transmissibility or immune escape emerge, deaths will be higher, but vaccination and NPIs are expected to remain effective tools to decrease both cumulative and peak health system burden, providing proportionally similar relative impacts.

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.

Norovirus transmission dynamics: a modelling review.

Norovirus is one of the leading causes of viral gastroenteritis worldwide and responsible for substantial morbidity, mortality and healthcare costs. To further understanding of the epidemiology and control of norovirus, there has been much recent interest in describing the transmission dynamics of norovirus through mathematical models. In this study, we review the current modelling approaches for norovirus transmission. We examine the data and methods used to estimate these models that vary structurally and parametrically between different epidemiological contexts. Many of the existing studies at population level have focused on the same case notification dataset, whereas models from outbreak settings are highly specific and difficult to generalise. In this review, we explore the consistency in the description of norovirus transmission dynamics and the robustness of parameter estimates between studies. In particular, we find that there is considerable variability in estimates of key parameters such as the basic reproduction number, which may mean that the effort required to control norovirus at the population level may currently be underestimated.

The unwelcome houseguest: secondary household transmission of norovirus.

Norovirus is the leading cause of acute gastroenteritis in the USA. Although secondary household transmission of norovirus is frequently reported in outbreaks, little is known about specific risk factors for susceptibility and infectiousness in the household. Three norovirus outbreaks were investigated and data were collected on individuals exposed in the primary outbreak setting and their household members. Potential individual- and household-level risk factors for susceptibility and infectiousness were assessed using univariate and multivariate generalised linear mixed models. In the univariate models, the secondary attack rate (SAR) was significantly higher when living in a household with two or more primary cases (incidence rate ratio (IRR) = 2·1; 95% confidence interval (CI) 1·37-3·29), more than one primary case with vomiting (IRR = 1·9; CI 1·11-3·37), and at least one primary case with diarrhoea (IRR = 3·0; CI 1·46-6·01). After controlling for other risk factors in the multivariate models, the SAR was significantly higher among those living in a household with two or more primary cases (adjusted IRR = 2·0; CI 1·17-3·47) and at least one primary case with diarrhoea (adjusted IRR = 2·8; CI 1·35-5·93). These findings underscore the importance of maintaining proper hygiene and isolating ill household members to prevent norovirus transmission in the household.

Burden of norovirus in healthcare facilities and strategies for outbreak control.

Norovirus is the most frequently occurring cause of community-acquired acute gastroenteritis in people of all ages. It is also one of the most frequent causes of outbreaks in healthcare settings, affecting both long-term care facilities and acute care hospitals. Whereas norovirus gastroenteritis is typically mild and resolves without medical attention, healthcare-associated infections often affect vulnerable populations, resulting in severe infections and disruption of healthcare services. Globally, most norovirus outbreaks in hospitals and residential care institutions are associated with genogroup II type 4 (GII.4) strains. Recent data demonstrate that excess mortality occurs during outbreak periods in healthcare facilities. Nosocomial outbreaks can result in large economic and societal costs. Current control measures for norovirus are largely based on general infection control principles, and treatment is mainly supportive and non-specific. While neither vaccines nor antiviral agents are currently available, both are being developed with encouraging results.

Association of host, agent and environment characteristics and the duration of incubation and symptomatic periods of norovirus gastroenteritis.

We analysed the reported duration of incubation and symptomatic periods of norovirus for a dataset of 1022 outbreaks, 64 of which reported data on the average incubation period and 87 on the average symptomatic period. We found the mean and median incubation periods for norovirus to be 32·8 [95% confidence interval (CI) 30·9-34·6] hours and 33·5 (95% CI 32·0-34·0) hours, respectively. For the symptomatic period we found the mean and median to be 44·2 (95% CI 38·9-50·7) hours and 43·0 (95% CI 36·0-48·0) hours, respectively. We further investigated how these average periods were associated with several reported host, agent and environmental characteristics. We did not find any strong, biologically meaningful associations between the duration of incubation or symptomatic periods and the reported host, pathogen and environmental characteristics. Overall, we found that the distributions of incubation and symptomatic periods for norovirus infections are fairly constant and showed little differences with regard to the host, pathogen and environmental characteristics we analysed.

The burden of norovirus gastroenteritis: an important foodborne and healthcare-related infection.

Human norovirus (NoV) is now recognized as one of the most important causative agents of gastroenteritis in all age groups worldwide. During the course of NoV infection, symptoms are usually mild and disappear within 48 h after onset. The incidence of NoV infection is high, with hundreds of cases per 10 000 of the population, although the number of infections is still underestimated. Epidemiological surveys conducted in Europe and North America have shown that NoV infections constitute a major disease burden, especially for young children and the elderly, in whom NoV infection leads to high rates of hospitalization and mortality. NoV infections are also of concern in hospitals, where viral infections can be persistent in immunocompromised patients. Although the cost of NoV infection in the hospital community has not yet been clearly established, it appears that NoV infections could cost hundreds of thousands of euros in terms of unit closure, and NoV-related sickness in patients and health workers. Besides their clinical burden, NoVs, as foodborne pathogens, also cause to millions of dollars of losses for the healthcare system and the food industry. Recent estimates in the USA showed that, annually, NoV illness cost $2 billion and led to a loss of approximately 5000 quality-adjusted life-years, making NoV one of the top five pathogens causing enteric illnesses. The highest cost among 14 foodborne pathogens is also attributed to human NoV in The Netherlands. This accumulation of evidence underlines the enormous impact of NoV on populations.

Infection control for norovirus.

Norovirus infections are notoriously difficult to prevent and control, owing to their low infectious dose, high shedding titre, and environmental stability. The virus can spread through multiple transmission routes, of which person-to-person and foodborne are the most important. Recent advances in molecular diagnostics have helped to establish norovirus as the most common cause of sporadic gastroenteritis and the most common cause of outbreaks of acute gastroenteritis across all ages. In this article, we review the epidemiology and virology of noroviruses, and prevention and control guidelines, with a focus on the principles of disinfection and decontamination. Outbreak management relies on sound infection control principles, including hand hygiene, limiting exposure to infectious individuals, and thorough environmental decontamination. Ideally, all infection control recommendations would rely on empirical evidence, but a number of challenges, including the inability to culture noroviruses in the laboratory and the challenges of outbreak management in complex environments, has made it difficult to garner clear evidence of efficacy in certain areas of infection control. New experimental data on cultivable surrogates for human norovirus and on environmental survivability and relative resistance to commonly used disinfectants are providing new insights for further refinining disinfection practices. Finally, clinical trials are underway to evaluate the efficacy of vaccines, which may shift the current infection control principles to more targeted interventions.

The development of Web-based surveillance provides new insights into the burden of norovirus outbreaks in hospitals in England.

A new surveillance system for outbreaks of norovirus in English hospitals, the hospital norovirus outbreak reporting system (HNORS), was launched in January 2009. On site investigators were enabled to enter data on outbreaks of norovirus directly onto a tailored system via an Internet-based front end. A standard dataset was designed to collect information describing the key epidemiological characteristics of each outbreak. In the period 1992-2008, 1817 suspected and confirmed outbreaks of norovirus in English hospitals were reported to national surveillance. After introduction of the new system there were 3980 reports of outbreaks of suspected and confirmed norovirus received in the years 2009-2011. Data from the new reporting system demonstrates that transmission of norovirus levies a heavy burden on English hospitals. On average, reported outbreaks are associated with 13,000 patients and 3400 staff becoming ill, 8900 days of ward closure and the loss of over 15,500 bed-days annually.

Risk factors for symptomatic and asymptomatic norovirus infection in the community.

The objective of this study was to investigate risk factors for norovirus-associated infectious intestinal disease (IID) and asymptomatic norovirus infection. Individuals with IID and healthy controls were recruited in a community-based study in England (1993-1996). This is the first risk-factor study to use viral load measurements, generated by real-time RT-PCR, to identify cases of norovirus-associated IID and asymptomatic infections. Using multivariable logistic regression the main risk factor identified for norovirus-associated IID was contact with a person with IID symptoms. Infectious contacts accounted for 54% of norovirus cases in young children and 39% of norovirus cases in older children and adults. For young children, contacts outside the household presented the highest risk; for older children and adults, the highest risk was associated with child contacts inside the household. Foreign travel and consumption of shellfish increased the risk of norovirus-associated IID. Lifestyle and dietary factors were associated with a decreased risk of both norovirus-associated IID and asymptomatic infection. No risk factors were identified for asymptomatic norovirus infection.

Causes and consequences of psychological distress among orphans in eastern Zimbabwe.

Substantial resources are invested in psychological support for children orphaned or otherwise made vulnerable in the context of HIV/AIDS (OVC). However, there is still only limited scientific evidence for greater psychological distress amongst orphans and even less evidence for the effectiveness of current support strategies. Furthermore, programmes that address established mechanisms through which orphanhood can lead to greater psychological distress should be more effective. We use quantitative and qualitative data from Eastern Zimbabwe to measure the effects of orphanhood on psychological distress and to test mechanisms for greater distress amongst orphans suggested in a recently published theoretical framework. Orphans were found to suffer greater psychological distress than non-orphans (sex- and age-adjusted co-efficient: 0.15; 95% CI 0.03-0.26; P=0.013). Effects of orphanhood contributing to their increased levels of distress included trauma, being out-of-school, being cared for by a non-parent, inadequate care, child labour, physical abuse, and stigma and discrimination. Increased mobility and separation from siblings did not contribute to greater psychological distress in this study. Over 40% of orphaned children in the sample lived in households receiving external assistance. However, receipt of assistance was not associated with reduced psychological distress. These findings and the ideas put forward by children and caregivers in the focus group discussions suggest that community-based programmes that aim to improve caregiver selection, increase support for caregivers, and provide training in parenting responsibilities and skills might help to reduce psychological distress. These programmes should be under-pinned by further efforts to reduce poverty, increase school attendance and support out-of-school youth.

Prevalence and characteristics of asymptomatic norovirus infection in the community in England.

Norovirus is a major cause of infectious intestinal disease, and a substantial prevalence of asymptomatic infection has been reported. We describe the prevalence, seasonality and characteristics of asymptomatic norovirus infection in England. Healthy individuals were recruited at random from the general population during the Study of Infectious Intestinal Disease (1993-1996). Norovirus was identified using real-time RT-PCR. The age-adjusted prevalence of asymptomatic norovirus infection was 12%; prevalence was highest in children aged <5 years and showed wintertime seasonality. More work is needed to understand whether asymptomatic infections are important for norovirus transmission leading to sporadic illness and outbreaks.

Vomiting calls to NHS Direct provide an early warning of norovirus outbreaks in hospitals.

A wintertime peak of norovirus activity occurs each year, affecting institutions including schools and hospitals. Traditional laboratory and outbreak surveillance systems for norovirus are too vulnerable to reporting delay to act as a timely signal of activity in the community. Calls to the National Health Service (NHS) telephone service NHS Direct have the potential to be an early warning tool for public health purposes. We investigated whether NHS Direct vomiting calls can be used as a reliable indicator of norovirus activity and, if so, whether the increase in calls precedes the epidemic of hospital outbreaks. Laboratory reports were used as the reference standard to define the norovirus season. From 2004 to 2008, four series of NHS Direct call data were compared with laboratory data held at the Health Protection Agency Centre for Infections in order to identify the best predictor of the season start. The four series included: (1) modelled and extracted the proportion of calls likely to be for 'non-rotavirus' gastroenteritis; (2) the mean proportion of weekly vomiting calls in children aged <5 years; (3) the mean proportion of weekly vomiting calls for all ages; (4) the slope of the vomiting call data. Issuing an alert when 4% or more of NHS Direct vomiting calls in all age groups for two weeks in a row should provide up to four weeks' advance warning of forthcoming norovirus pressures on the health service.

Verbal autopsy can consistently measure AIDS mortality: a validation study in Tanzania and Zimbabwe.

BACKGROUND: Verbal autopsy is currently the only option for obtaining cause of death information in most populations with a widespread HIV/AIDS epidemic. METHODS: With the use of a data-driven algorithm, a set of criteria for classifying AIDS mortality was trained. Data from two longitudinal community studies in Tanzania and Zimbabwe were used, both of which have collected information on the HIV status of the population over a prolonged period and maintained a demographic surveillance system that collects information on cause of death through verbal autopsy. The algorithm was then tested in different times (two phases of the Zimbabwe study) and different places (Tanzania and Zimbabwe). RESULTS: The trained algorithm, including nine signs and symptoms, performed consistently based on sensitivity and specificity on verbal autopsy data for deaths in 15-44-year-olds from Zimbabwe phase I (sensitivity 79%; specificity 79%), phase II (sensitivity 83%; specificity 75%) and Tanzania (sensitivity 75%; specificity 74%) studies. The sensitivity dropped markedly for classifying deaths in 45-59-year-olds. CONCLUSIONS: Verbal autopsy can consistently measure AIDS mortality with a set of nine criteria. Surveillance should focus on deaths that occur in the 15-44-year age group for which the method performs reliably. Addition of a handful of questions related to opportunistic infections would enable other widely used verbal autopsy tools to apply this validated method in areas for which HIV testing and hospital records are unavailable or incomplete.

Temperature-dependent transmission of rotavirus in Great Britain and The Netherlands.

In Europe, rotavirus gastroenteritis peaks in late winter or early spring suggesting a role for weather factors in transmission of the virus. In this study, multivariate regression models adapted for time-series data were used to investigate effects of temperature, humidity and rainfall on reported rotavirus infections and the infection-rate parameter, a derived measure of infection transmission that takes into account population immunity, in England, Wales, Scotland and The Netherlands. Delayed effects of weather were investigated by introducing lagged weather terms into the model. Meta-regression was used to pool together country-specific estimates. There was a 13 per cent (95% confidence interval (CI), 11-15%) decrease in reported infections per 1 degrees C increase in temperature above a threshold of 5 degrees C and a 4 per cent (95% CI, 3-5%) decrease in the infection-rate parameter per 1 degrees C increase in temperature across the whole temperature range. The effect of temperature was immediate for the infection-rate parameter but delayed by up to four weeks for reported infections. There was no overall effect of humidity or rainfall. There is a direct and simple relationship between cold weather and rotavirus transmission in Great Britain and The Netherlands. The more complex and delayed temperature effect on disease incidence is likely to be mediated through the effects of weather on transmission.

Infection control measures for norovirus: a systematic review of outbreaks in semi-enclosed settings.

We carried out a review of published, peer-reviewed articles to assess the evidence for effectiveness of control measures during norovirus outbreaks in enclosed settings. There were 47 papers identified for review, some of which reported more than one outbreak, providing 72 outbreaks for analysis. We extracted the following data items: attack rates; the number of people affected and at risk, case or outbreak definition; whether outbreak control measures were implemented; and claims of effectiveness of interventions. We analysed the data to identify any differences in the outbreaks experienced in different settings and any differences experienced during outbreaks according to whether control measures were implemented or not. All of the reviewed papers described outbreaks occurring in industrialised countries. We found no evidence that implementing infection control measures affected the duration of outbreaks, or the attack rates either overall (all settings combined) or within particular settings. The median outbreak duration was 16 days (range: 1-44) compared with 14 (range: 2-92) where control measures were and were not utilized, respectively. Sound infection control procedures are key to controlling norovirus outbreaks but unfortunately, the present body of the published literature does not provide an evidence-base for the value of specific measures.

Clinical laboratory practices for the detection of rotavirus in England and Wales: can surveillance based on routine laboratory testing data be used to evaluate the impact of vaccination?

Two rotavirus vaccines have recently been licensed in Europe. Rotavirus surveillance data in many European countries are based on reports of laboratory-confirmed rotavirus infections. If surveillance data based on routine laboratory testing data are to be used to evaluate the impact of vaccination programmes, it is important to determine how the data are influenced by differences in testing practices, and how these practices are likely to affect the ability of the surveillance data to represent trends in rotavirus disease in the community. We conducted a survey of laboratory testing policies for rotavirus gastroenteritis in England and Wales in 2008. 60% (94/156) of laboratories responded to the survey. 91% of reporting laboratories offered routine testing for rotavirus all year round and 89% of laboratories offered routine rotavirus testing of all stool specimens from children under the age of five years. In 96% of laboratories, rotavirus detection was presently done either by rapid immunochromatographic tests or by enzyme-linked immunosorbent assay. Currently, rotavirus testing policies among laboratories in England and Wales are relatively homogenous. Therefore, surveillance based on laboratory testing data is likely to be representative of rotavirus disease trends in the community in the most frequently affected age groups (children under the age of five years) and could be used to help determine the impact of a rotavirus vaccine.

Role of widows in the heterosexual transmission of HIV in Manicaland, Zimbabwe, 1998-2003.

BACKGROUND: AIDS is the main driver of young widowhood in southern Africa. METHODS: The demographic characteristics of widows, their reported risk behaviours and the prevalence of HIV were examined by analysing a longitudinal population-based cohort of men and women aged 15-54 years in Manicaland, eastern Zimbabwe. The results from statistical analyses were used to construct a mathematical simulation model with the aim of estimating the contribution of widow behaviour to heterosexual HIV transmission. RESULTS: 413 (11.4%) sexually experienced women and 31 (1.2%) sexually experienced men were reported to be widowed at the time of follow-up. The prevalence of HIV was exceptionally high among both widows (61%) and widowers (male widows) (54%). Widows were more likely to have high rates of partner change and engage in a pattern of transactional sex than married women. Widowers took partners who were a median of 10 years younger than themselves. Mathematical model simulations of different scenarios of sexual behaviour of widows suggested that the sexual activity of widow(er)s may underlie 8-17% of new HIV infections over a 20-year period. CONCLUSIONS: This combined statistical analysis and model simulation suggest that widowhood plays an important role in the transmission of HIV in this rural Zimbabwean population. High-risk partnerships may be formed when widowed men and women reconnect to the sexual network.