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.

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.

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.

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.

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.

Season of birth and risk of rotavirus diarrhoea in children aged <5 years.

This study investigates whether a child's risk of rotavirus diarrhoea is associated with season of birth in England and Wales, countries where rotavirus infections are highly seasonal. Poisson regression models were fitted to weekly counts of laboratory-confirmed rotavirus infections from children aged <5 years born between 1998 and 2007. In the first year of life, the risk of a laboratory-confirmed rotavirus infection was significantly higher for children born in summer compared with winter [relative risk (RR) 2.13, 95% confidence interval (CI) 2.07-2.19]. In the second to fifth years of life, the pattern reversed (second year of life: RR 0.73, 95% CI 0.71-0.75). The cumulative risk up to age 5 years remained significantly higher for children born in summer compared with winter due to the increased risk for summer births during their first year of life. Maternal immunity and age-specific levels of exposure to rotavirus could explain our findings.

Viral gastroenteritis outbreaks in deployed British troops during 2002-7.

OBJECTIVES: The aim of this study was to see what lessons could be learnt from the suspected viral gastroenteritis outbreaks that have occurred in deployed British troops during 2002-7. METHOD: Epidemiological and laboratory data from identifiable outbreaks were reviewed, including epidemic curves and the results of PCR testing for enteropathic viruses. RESULTS: The epidemic curves of outbreaks varied predictably in accordance with the size of the population at risk and whether this population was constant or expanding. Of 11 outbreaks identified, 10 (91%) had a proven viral cause and 10 (91%) occurred in Iraq. Of 84 enteropathic viruses identified, 61 (73%) were noroviruses and these included both unknown strains and those that were common in the UK and Europe. Of the 10 viral outbreaks, 3 (30%) occurred in medical units, 5 (50%) were associated with large-scale relief in place (RiP) deployments and 5 (50%) involved >3 different viruses, which is strongly suggestive of food or water contamination. CONCLUSION: These findings can help to predict future viral gastroenteritis outbreaks and target improved prevention strategies appropriately. However, more systematic studies are now required.

Behaviour change in generalised HIV epidemics: impact of reducing cross-generational sex and delaying age at sexual debut.

BACKGROUND: Sexual behavioural change is essential to prevent HIV infections in Africa and statistical analysis of risk factors at the individual-level may be used to design interventions. The importance of reducing cross-generational sex (young women having sex with older men) and delaying age at first sex on the spread of HIV at the population-level has been presumed but not scientifically investigated and quantified. METHODS: A mathematical model of heterosexual spread of HIV was developed to predict the population-level impact of reducing cross-generational sex and delaying sexual debut. RESULTS: The impact of behaviour change on the spread of HIV is sensitive to the structure and reaction of the sexual network. Reducing cross-generational sex could have little impact on the risk of infection unless it is accompanied by a reduction in the number of risky sexual contacts. Even peer-to-peer sexual mixing can support high endemic levels of HIV. The benefit of delaying sexual debut is comparatively small and is reduced if males continue to prefer young partners or if young women spend more time unmarried. In Manicaland, Zimbabwe, if older men were to use condoms as frequently as young men, the reduction in risk of infection could exceed that generated by a two-year delay in first sex. CONCLUSIONS: At the individual-level avoiding sex with older partners and delaying sexual debut can decrease the risk of infection but at the population-level these interventions may do little to limit the spread of HIV without wider-ranging behavioural changes throughout the sexual network.

Institutional risk factors for outbreaks of nosocomial gastroenteritis: survival analysis of a cohort of hospital units in South-west England, 2002-2003.

Nosocomial outbreaks of gastroenteritis are a major burden on hospital inpatient services, costing an estimated pound115 million annually to the English National Health Service. We actively followed-up 171 inpatient units from four major acute hospitals and 11 community hospitals in South-west England for one year. Outbreaks of gastroenteritis were ascertained through an active surveillance network using standard clinical definitions. Survival analysis Cox regression models using an outbreak of gastroenteritis as the endpoint were fitted to identify institutional and operational attributes related to increased outbreak rates at the level of the care unit. Greater number of beds in unit [hazard ratio (HR) 1.22 (per 10 additional beds), 95% confidence intervals (CI) 0.96-1.55] was associated with increased hazard, as were geriatric (HR 2.6, 95%CI 1.6-4.3) and general medical (HR 1.7, 95%CI 1.1-2.6) care units. The average length of stay on a unit was inversely associated with outbreak incidence [HR=0.89 (per additional week of stay), 95%CI 0.80-0.99]. Larger care units and those with higher throughput have increased rates of gastroenteritis outbreaks. These results should guide infection control policy and support the design of hospitals with smaller care units.

National epidemic of Lordsdale Norovirus in the UK.

BACKGROUND: In early 2002 reports of outbreaks of gastroenteritis reached unprecedented levels in the UK. Forty five Norovirus outbreaks were reported in January 2002. OBJECTIVES: The objective of the study was to determine whether the outbreaks were Noroviral in origin and if so whether they represented a homogeneous or heterogeneous collection of Noroviruses by applying EIA and sequence analysis to representative faecal samples. STUDY DESIGN: Faecal specimens were collected during the week of highest incidence from 21 outbreaks in a variety of health care settings including hospitals and nursing homes. The outbreaks occurred in geographically distinct regions of the UK and samples were collected by reference laboratories in Glasgow, Manchester, Bristol and Southampton. RESULTS: The samples were all positive for Noroviruses by negative stain electron microscopy (EM) and Lordsdale virus (LV) EIA, therefore reverse transcriptase polymerase chain reaction (RT-PCR) amplification and nucleotide sequencing of the Norovirus RNA polymerase gene was performed on amplicons from samples of each of the 21 outbreaks to investigate the nature and extent of diversity. All samples were very closely related to the reference Lordsdale virus genome sequence. LV was first discovered during an hospital outbreak of gastroenteritis in Southampton General Hospital in March 1993. CONCLUSIONS: Noroviruses are a major cause of outbreaks of gastroenteritis in health care settings. LV is the predominant Norovirus in the UK and was detected in outbreaks that occurred during the national peak of gastroenteritis reports in January 2002.

General outbreaks of infectious intestinal disease (IID) in hospitals, England and Wales, 1992-2000.

Between 1992 and 2000, 26.6% (1,396/5,257) of all general outbreaks of infectious intestinal disease (IID) reported to the Public Health Laboratory Service (PHLS) Communicable Disease Surveillance Centre (CDSC) occurred in hospitals. Over 29,000 patients and staff were affected and the mortality risk was higher than for outbreaks in other settings [relative risk 2.00 (95% CI: 1.52-2.63) P<0.001]. Person-to-person spread was the predominant mode of transmission. The mortality risk was highest in foodborne disease outbreaks [relative risk 3.22 (95% CI: 1.41-7.36); P=0.003]. Most outbreaks occurred between November and April. The pathogens most frequently reported were Norwalk-like virus (NLV) (54%) and Clostridium difficile (12.6%). These findings emphasize the public health importance of outbreaks of IID in hospitals, especially during the winter when pressures on hospitals are at their height.

Human caliciviruses in Europe.

Caliciviruses are single-stranded RNA viruses, which are divided into four genera based on their morphology and genomic structure. Viruses from two genera, the Norwalk like viruses and Sapporo like viruses, are a common cause of acute, nonbacterial gastroenteritis in humans. Although the first human calicivirus discovered nearly 30 years ago, much of the epidemiological and biological character of these viruses is only now beginning to unfold. Investigation has been difficult due to a number of factors, the viruses cannot be amplified by in vitro cell culture or animal models and electron microscopy (EM) is often not sensitive enough to detect the viruses in stool samples. Recent advances in molecular diagnostic techniques and the advent of a baculovirus expression system have highlighted the clinical and public health importance of calicivirus in all age groups, their ability to cause infection via a number of transmission routes as well as their considerable genetic diversity. These characteristics, in conjunction with the inability of humans to develop long-term immunity make HuCV an important public health issue in Europe and worldwide.