Vaccine value profile for norovirus.

Norovirus is attributed to nearly 1 out of every 5 episodes of diarrheal disease globally and is estimated to cause approximately 200,000 deaths annually worldwide, with 70,000 or more among children in developing countries. Noroviruses remain a leading cause of sporadic disease and outbreaks of acute gastroenteritis even in industrialized settings, highlighting that improved hygiene and sanitation alone may not be fully effective in controlling norovirus. Strengths in global progress towards a Norovirus vaccine include a diverse though not deep pipeline which includes multiple approaches, including some with proven technology platforms (e.g., VLP-based HPV vaccines). However, several gaps in knowledge persist, including a fulsome mechanistic understanding of how the virus attaches to human host cells, internalizes, and induces disease.

Changing social contact patterns among US workers during the COVID-19 pandemic: April 2020 to December 2021.

Non-pharmaceutical interventions minimize social contacts, hence the spread of respiratory pathogens such as influenza and SARS-CoV-2. Globally, there is a paucity of social contact data from the workforce. In this study, we quantified two-day contact patterns among USA employees. Contacts were defined as face-to-face conversations, involving physical touch or proximity to another individual and were collected using electronic self-kept diaries. Data were collected over 4 rounds from 2020 to 2021 during the COVID-19 pandemic. Mean (standard deviation) contacts reported by 1456 participants were 2.5 (2.5), 8.2 (7.1), 9.2 (7.1) and 10.1 (9.5) across round 1 (April-June 2020), 2 (November 2020-January 2021), 3 (June-August 2021), and 4 (November-December 2021), respectively. Between round 1 and 2, we report a 3-fold increase in the mean number of contacts reported per participant with no major increases from round 2-4. We then modeled SARS-CoV-2 transmission at home, work, and community settings. The model revealed reduced relative transmission in all settings in round 1. Subsequently, transmission increased at home and in the community but remained exceptionally low in work settings. To accurately parameterize models of infection transmission and control, we need empirical social contact data that capture human mixing behavior across time.

Combined Infection Control Interventions Protect Essential Food Workers from Occupational Exposures to SARS-CoV-2 in the Agricultural Environment.

Essential food workers experience elevated risks of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection due to prolonged occupational exposures in food production and processing areas, shared transportation (car or bus), and employer-provided shared housing. Our goal was to quantify the daily cumulative risk of SARS-CoV-2 infection for healthy susceptible produce workers and to evaluate the relative reduction in risk attributable to food industry interventions and vaccination. We simulated daily SARS-CoV-2 exposures of indoor and outdoor produce workers through six linked quantitative microbial risk assessment (QMRA) model scenarios. For each scenario, the infectious viral dose emitted by a symptomatic worker was calculated across aerosol, droplet, and fomite-mediated transmission pathways. Standard industry interventions (2-m physical distancing, handwashing, surface disinfection, universal masking, ventilation) were simulated to assess relative risk reductions from baseline risk (no interventions, 1-m distance). Implementation of industry interventions reduced an indoor worker's relative infection risk by 98.0% (0.020; 95% uncertainty interval [UI], 0.005 to 0.104) from baseline risk (1.00; 95% UI, 0.995 to 1.00) and an outdoor worker's relative infection risk by 94.5% (0.027; 95% UI, 0.013 to 0.055) from baseline risk (0.487; 95% UI, 0.257 to 0.825). Integrating these interventions with two-dose mRNA vaccinations (86 to 99% efficacy), representing a worker's protective immunity to infection, reduced the relative infection risk from baseline for indoor workers by 99.9% (0.001; 95% UI, 0.0002 to 0.005) and outdoor workers by 99.6% (0.002; 95% UI, 0.0003 to 0.005). Consistent implementation of combined industry interventions, paired with vaccination, effectively mitigates the elevated risks from occupationally acquired SARS-CoV-2 infection faced by produce workers. IMPORTANCE This is the first study to estimate the daily risk of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection across a variety of indoor and outdoor environmental settings relevant to food workers (e.g., shared transportation [car or bus], enclosed produce processing facility and accompanying breakroom, outdoor produce harvesting field, shared housing facility) through a linked quantitative microbial risk assessment framework. Our model has demonstrated that the elevated daily SARS-CoV-2 infection risk experienced by indoor and outdoor produce workers can be reduced below 1% when vaccinations (optimal vaccine efficacy, 86 to 99%) are implemented with recommended infection control strategies (e.g., handwashing, surface disinfection, universal masking, physical distancing, and increased ventilation). Our novel findings provide scenario-specific infection risk estimates that can be utilized by food industry managers to target high-risk scenarios with effective infection mitigation strategies, which was informed through more realistic and context-driven modeling estimates of the infection risk faced by essential food workers daily. Bundled interventions, particularly if they include vaccination, yield significant reductions (>99%) in daily SARS-CoV-2 infection risk for essential food workers in enclosed and open-air environments.

Predicting norovirus and rotavirus resurgence in the United States following the COVID-19 pandemic: a mathematical modelling study.

BACKGROUND: To reduce the burden from the COVID-19 pandemic in the United States, federal and state local governments implemented restrictions such as limitations on gatherings, restaurant dining, and travel, and recommended non-pharmaceutical interventions including physical distancing, mask-wearing, surface disinfection, and increased hand hygiene. Resulting behavioral changes impacted other infectious diseases including enteropathogens such as norovirus and rotavirus, which had fairly regular seasonal patterns prior to the COVID-19 pandemic. The study objective was to project future incidence of norovirus and rotavirus gastroenteritis as contacts resumed and other NPIs are relaxed. METHODS: We fitted compartmental mathematical models to pre-pandemic U.S. surveillance data (2012-2019) for norovirus and rotavirus using maximum likelihood estimation. Then, we projected incidence for 2022-2030 under scenarios where the number of contacts a person has per day varies from70%, 80%, 90%, and full resumption (100%) of pre-pandemic levels. RESULTS: We found that the population susceptibility to both viruses increased between March 2020 and November 2021. The 70-90% contact resumption scenarios led to lower incidence than observed pre-pandemic for both viruses. However, we found a greater than two-fold increase in community incidence relative to the pre-pandemic period under the 100% contact scenarios for both viruses. With rotavirus, for which population immunity is driven partially by vaccination, patterns settled into a new steady state quickly in 2022 under the 70-90% scenarios. For norovirus, for which immunity is relatively short-lasting and only acquired through infection, surged under the 100% contact scenario projection. CONCLUSIONS: These results, which quantify the consequences of population susceptibility build-up, can help public health agencies prepare for potential resurgence of enteric viruses.

Decontamination of SARS-CoV-2 from cold-chain food packaging provides no marginal benefit in risk reduction to food workers.

Countries continue to debate the need for decontamination of cold-chain food packaging to reduce possible severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) fomite transmission among frontline workers. While laboratory-based studies demonstrate persistence of SARS-CoV-2 on surfaces, the likelihood of fomite-mediated transmission under real-life conditions is uncertain. Using a quantitative microbial risk assessment model of a frozen food packaging facility, we simulated 1) SARS-CoV-2 fomite-mediated infection risks following worker exposure to contaminated plastic packaging; and 2) reductions in these risks from masking, handwashing, and vaccination. In a frozen food facility without interventions, SARS-CoV-2 infection risk to a susceptible worker from contact with contaminated packaging was 1.5 × 10-3 per 1h-period (5th - 95th percentile: 9.2 × 10-6, 1.2 × 10-2). Standard food industry infection control interventions, handwashing and masking, reduced risk (99.4%) to 8.5 × 10-6 risk per 1h-period (5th - 95th percentile: 2.8 × 10-8, 6.6 × 10-5). Vaccination of the susceptible worker (two doses Pfizer/Moderna, vaccine effectiveness: 86-99%) with handwashing and masking reduced risk to 5.2 × 10-7 risk per 1h-period (5th - 95th percentile: 1.8 × 10-9, 5.4 × 10-6). Simulating increased transmissibility of current and future variants (Delta, Omicron), (2-, 10-fold viral shedding) among a fully vaccinated workforce, handwashing and masking continued to mitigate risk (1.4 × 10-6 - 8.8 × 10-6 risk per 1h-period). Additional decontamination of frozen food plastic packaging reduced infection risks to 1.2 × 10-8 risk per 1h-period (5th - 95th percentile: 1.9 × 10-11, 9.5 × 10-8). Given that standard infection control interventions reduced risks well below 1 × 10-4 (World Health Organization water quality risk thresholds), additional packaging decontamination suggest no marginal benefit in risk reduction. Consequences of this decontamination may include increased chemical exposures to workers, food quality and hazard risks to consumers, and unnecessary added costs to governments and the global food industry.

Changing social contact patterns among US workers during the COVID-19 pandemic: April 2020 to December 2021.

Non-pharmaceutical interventions minimize social contacts, hence the spread of SARS-CoV-2. We quantified two-day contact patterns among USA employees from 2020-2021 during the COVID-19 pandemic. Contacts were defined as face-to-face conversations, involving physical touch or proximity to another individual and were collected using electronic diaries. Mean (standard deviation) contacts reported by 1,456 participants were 2.5 (2.5), 8.2 (7.1), 9.2 (7.1) and 10.1 (9.5) across round 1 (April-June 2020), 2 (November 2020-January 2021), 3 (June-August 2021), and 4 (November-December 2021), respectively. Between round 1 and 2, we report a 3-fold increase in the mean number of contacts reported per participant with no major increases from round 2-4. We modeled SARS-CoV-2 transmission at home, work, and community. The model revealed reduced relative transmission in all settings in round 1. Subsequently, transmission increased at home and in the community but remained very low in work settings. Contact data are important to parameterize models of infection transmission and control. Teaser: Changes in social contact patterns shape disease dynamics at workplaces in the USA.

Controlling risk of SARS-CoV-2 infection in essential workers of enclosed food manufacturing facilities.

The SARS-CoV-2 global pandemic poses significant health risks to workers who are essential to maintaining the food supply chain. Using a quantitative risk assessment model, this study characterized the impact of risk reduction strategies for controlling SARS-CoV-2 transmission (droplet, aerosol, fomite-mediated) among front-line workers in a representative indoor fresh fruit and vegetable manufacturing facility. We simulated: 1) individual and cumulative SARS-CoV-2 infection risks from close contact (droplet and aerosols at 1-3 m), aerosol, and fomite-mediated exposures to a susceptible worker following exposure to an infected worker during an 8 h-shift; and 2) the relative reduction in SARS-CoV-2 infection risk attributed to infection control interventions (physical distancing, mask use, ventilation, surface disinfection, hand hygiene, vaccination). Without mitigation measures, the SARS-CoV-2 infection risk was largest for close contact (droplet and aerosol) at 1 m (0.96, 5th - 95th percentile: 0.67-1.0). In comparison, risk associated with fomite (0.26, 5th - 95th percentile: 0.10-0.56) or aerosol exposure alone (0.05, 5th - 95th percentile: 0.01-0.13) at 1 m distance was substantially lower (73-95%). At 1 m, droplet transmission predominated over aerosol and fomite-mediated transmission, however, this changed by 3 m, with aerosols comprising the majority of the exposure dose. Increasing physical distancing reduced risk by 84% (1-2 m) and 91% (1-3 m). Universal mask use reduced infection risk by 52-88%, depending on mask type. Increasing ventilation (from 0.1 to 2-8 air changes/hour) resulted in risk reductions of 14-54% (1 m) and 55-85% (2 m). Combining these strategies, together with handwashing and surface disinfection, resulted in <1% infection risk. Partial or full vaccination of the susceptible worker resulted in risk reductions of 73-92% (1 m risk range: 0.08-0.26). However, vaccination paired with other interventions (ACH 2, mask use, or distancing) was necessary to achieve infection risks <1%. Current industry SARS-CoV-2 risk reduction strategies, particularly when bundled, provide significant protection to essential food workers.

Low risk of SARS-CoV-2 transmission via fomite, even in cold-chain.

BACKGROUND: Countries continue to debate the need for decontamination of cold-chain food packaging to reduce possible SARS-CoV-2 fomite transmission among workers. While laboratory-based studies demonstrate persistence of SARS-CoV-2 on surfaces, the likelihood of fomite-mediated transmission under real-life conditions is uncertain. METHODS: Using a quantitative risk assessment model, we simulated in a frozen food packaging facility 1) SARS-CoV-2 fomite-mediated infection risks following worker exposure to contaminated plastic packaging; and 2) reductions in these risks attributed to masking, handwashing, and vaccination. FINDINGS: In a representative facility with no specific interventions, SARS-CoV-2 infection risk to a susceptible worker from contact with contaminated packaging was 2·8 × 10 -3 per 1h-period (95%CI: 6·9 × 10 -6 , 2·4 × 10 -2 ). Implementation of standard infection control measures, handwashing and masks (9·4 × 10 -6 risk per 1h-period, 95%CI: 2·3 × 10 -8 , 8·1 × 10 -5 ), substantially reduced risk (99·7%). Vaccination of the susceptible worker (two doses Pfizer/Moderna, vaccine effectiveness: 86-99%) combined with handwashing and masking reduced risk to less than 1·0 × 10 -6 . Simulating increased infectiousness/transmissibility of new variants (2-, 10-fold viral shedding) among a fully vaccinated workforce, handwashing and masks continued to mitigate risk (2·0 × 10 -6 -1·1 × 10 -5 risk per 1h-period). Decontamination of packaging in addition to these interventions reduced infection risks to below the 1·0 × 10 -6 risk threshold. INTERPRETATION: Fomite-mediated SARS-CoV-2 infection risks were very low under cold-chain conditions. Handwashing and masking provide significant protection to workers, especially when paired with vaccination. FUNDING: U.S. Department of Agriculture.

Social contact patterns among employees in 3 U.S. companies during early phases of the COVID-19 pandemic, April to June 2020.

We measured contact patterns using online diaries for 304 employees of 3 U.S. companies working remotely. The median number of daily contacts was 2 (IQR 1-4); majority were conversation (55 %), occurred at home (64 %) and lasted >4 h (38 %). These data are crucial for modeling outbreak control among the workforces.

Controlling risk of SARS-CoV-2 infection in essential workers of enclosed food manufacturing facilities.

The SARS-CoV-2 global pandemic poses significant health risks to workers who are essential to maintaining the food supply chain. Using a quantitative risk assessment model, this study characterized the impact of risk reduction strategies for controlling SARS-CoV-2 transmission (droplet, aerosol, fomite-mediated) among front-line workers in a representative enclosed food manufacturing facility. We simulated: 1) individual and cumulative SARS-CoV-2 infection risks from close contact (droplet and aerosols at 1-3m), aerosol, and fomite-mediated exposures to a susceptible worker following exposure to an infected worker during an 8h-shift; and 2) the relative reduction in SARS-CoV-2 infection risk attributed to infection control interventions (physical distancing, mask use, ventilation, surface disinfection, hand hygiene). Without mitigation measures, the SARS-CoV-2 infection risk was largest for close contact (droplet and aerosol) at 1m (0.96, 95%CI: 0.67-1.0). In comparison, risk associated with fomite (0.26, 95%CI: 0.10-0.56) or aerosol exposure alone (0.05, 95%CI: 0.01-0.13) at 1m distance was substantially lower (73-95%). At 1m, droplet transmission predominated over aerosol and fomite-mediated transmission, however, this changed by 3m, with aerosols comprising the majority of the exposure dose. Increasing physical distancing reduced risk by 84% (1 to 2m) and 91% (1 to 3m). Universal mask use reduced infection risk by 52-88%, depending on mask type. Increasing ventilation (from 0.1 to 2-8 air changes/hour) resulted in risk reductions of 14-54% (1m) and 55-85% (2m). Combining these strategies, together with handwashing and surface disinfection, resulted in <1% infection risk. Current industry SARS-CoV-2 risk reduction strategies, particularly when bundled, provide significant protection to essential food workers. SIGNIFICANCE STATEMENT: Using mathematical modeling, we find that workers in enclosed food manufacturing facilities are at higher risk of SARS-CoV-2 infection from close contact transmission (exposure to large droplets and small aerosol particles) than fomite transmission. Thus, strategies protecting workers should prioritize close contact transmission pathways, such as physical distancing, universal mask use, and room air changes, with surface disinfection (reducing fomite transmission) and handwashing of secondary importance. Our work supports current international (EU-OSHA), domestic (FDA, OSHA), and food industry-standard guidance for managing COVID-19 transmission in essential workers in the food manufacturing sector. Although our model was designed for an indoor food manufacturing setting, it can be readily adapted to other indoor environments and infectious respiratory pathogens.

Characterizing Norovirus Transmission from Outbreak Data, United States.

Norovirus is the leading cause of acute gastroenteritis outbreaks in the United States. We estimated the basic (R0) and effective (Re) reproduction numbers for 7,094 norovirus outbreaks reported to the National Outbreak Reporting System (NORS) during 2009-2017 and used regression models to assess whether transmission varied by outbreak setting. The median R0 was 2.75 (interquartile range [IQR] 2.38-3.65), and median Re was 1.29 (IQR 1.12-1.74). Long-term care and assisted living facilities had an R0 of 3.35 (95% CI 3.26-3.45), but R0 did not differ substantially for outbreaks in other settings, except for outbreaks in schools, colleges, and universities, which had an R0 of 2.92 (95% CI 2.82-3.03). Seasonally, R0 was lowest (3.11 [95% CI 2.97-3.25]) in summer and peaked in fall and winter. Overall, we saw little variability in transmission across different outbreaks settings in the United States.

Changes in micronutrient and inflammation serum biomarker concentrations after a norovirus human challenge.

BACKGROUND: To accurately assess micronutrient status, it is necessary to characterize the effects of inflammation and the acute-phase response on nutrient biomarkers. OBJECTIVE: Within a norovirus human challenge study, we aimed to model the inflammatory response of C-reactive protein (CRP) and α-1-acid glycoprotein (AGP) by infection status, model kinetics of micronutrient biomarkers by inflammation status, and evaluate associations between inflammation and micronutrient biomarkers from 0 to 35 d post-norovirus exposure. METHODS: Fifty-two healthy adults were enrolled into challenge studies in a hospital setting and followed longitudinally; all were exposed to norovirus, half were infected. Post hoc analysis of inflammatory and nutritional biomarkers was performed. Subjects were stratified by inflammation resulting from norovirus exposure. Smoothed regression models analyzed the kinetics of CRP and AGP by infection status, and nutritional biomarkers by inflammation. Linear mixed-effects models were used to analyze the independent relations between CRP, AGP, and biomarkers for iron, vitamin A, vitamin D, vitamin B-12, and folate from 0 to 35 d post-norovirus exposure. RESULTS: Norovirus-infected subjects had median (IQR) peak concentrations for CRP [16.0 (7.9-29.5) mg/L] and AGP [0.9 (0.8-1.2) g/L] on day 3 and day 4 postexposure, respectively. Nutritional biomarkers that differed (P < 0.05) from baseline within the inflamed group were ferritin (elevated day 3), hepcidin (elevated days 2, 3), serum iron (depressed days 2-4), transferrin saturation (depressed days 2-4), and retinol (depressed days 3, 4, and 7). Nutritional biomarker concentrations did not differ over time within the uninflamed group. In mixed models, CRP was associated with ferritin (positive) and serum iron and retinol (negative, P < 0.05). CONCLUSION: Using an experimental infectious challenge model in healthy adults, norovirus infection elicited a time-limited inflammatory response associated with altered serum concentrations of certain iron and vitamin A biomarkers, confirming the need to consider adjustments of these biomarkers to account for inflammation when assessing nutritional status. These trials were registered at clinicaltrials.gov as NCT00313404 and NCT00674336.

National Estimates of Reductions in Acute Gastroenteritis-Related Hospitalizations and Associated Costs in US Children After Implementation of Rotavirus Vaccines.

We compared acute gastroenteritis (AGE)-related hospitalization rates among children <5 years of age during the pre-rotavirus vaccine (2000-2006) and post-rotavirus vaccine (2008-2013) periods to estimate national reductions in AGE-related hospitalizations and associated costs. We estimate that between 2008 and 2013, AGE-related hospitalizations declined by 382000, and $1.228 billion in medical costs were averted.

Potential for a booster dose of rotavirus vaccine to further reduce diarrhea mortality.

Concern has grown that children vaccinated against rotavirus in developing countries may be vulnerable to rotavirus diarrhea in the second year of life due to waning immunity. Adding a booster dose of rotavirus vaccine at 9 or 12 months of age with measles vaccine has been suggested as a strategy to address this. We evaluated the hypothetical potential benefits of a booster dose on reduction of rotavirus mortality. The projected number of deaths averted were calculated using national level full series vaccination coverage, estimated national rotavirus deaths by week of age, and VE at <12 months of age and ≥12 months of age derived from the published literature. We assumed three functional forms of waning based on the VE estimates: stepwise, linear, and logarithmic. We modeled three potential boosting scenarios: (a) reduced VE waning in the second year of life by 50%, (b) reestablished second year of life VE to the levels in the first year of life, and (c) boosted first year VE by 50% of the difference between VE in the first and second years. To express uncertainty resulting from the parameters, each of the nine models were run 1000 times using a random sample of input values. Across all WHO regions, with the stepwise models we estimated a median of 9800 (95%CI: 9400, 10,200), 19,600 (95%CI: 18,800, 20,400), and 29,400 (95%CI: 28,200, 30,700) additional rotavirus deaths averted in the reduced VE waning, reestablished VE, and boosted VE scenarios. These estimates were highly sensitive to the assumed functional form of waning with approximately 65-80% fewer deaths averted if immunity waned in a linear or logarithmic fashion compared to the stepwise model. While these projections will benefit from improved input data points, our resultsinform consideration of booster doses of rotavirus vaccine.

Assessment of the Status of Measles Elimination in the United States, 2001-2014.

We assessed the status of measles elimination in the United States using outbreak notification data. Measles transmissibility was assessed by estimation of the reproduction number, R, the average number of secondary cases per infection, using 4 methods; elimination requires maintaining R at <1. Method 1 estimates R as 1 minus the proportion of cases that are imported. Methods 2 and 3 estimate R by fitting a model of the spread of infection to data on the sizes and generations of chains of transmission, respectively. Method 4 assesses transmissibility before public health interventions, by estimating R for the case with the earliest symptom onset in each cluster (Rindex). During 2001-2014, R and Rindex estimates obtained using methods 1-4 were 0.72 (95% confidence interval (CI): 0.68, 0.76), 0.66 (95% CI: 0.62, 0.70), 0.45 (95% CI: 0.40, 0.49), and 0.63 (95% CI: 0.57, 0.69), respectively. Year-to-year variability in the values of R and Rindex and an increase in transmissibility in recent years were noted with all methods. Elimination of endemic measles transmission is maintained in the United States. A suggested increase in measles transmissibility since elimination warrants continued monitoring and emphasizes the importance of high measles vaccination coverage throughout the population.

Progress toward norovirus vaccines: considerations for further development and implementation in potential target populations.

Human norovirus infection causes significant medical and financial costs in the USA and abroad. Some populations, including young children, the elderly, and the immunocompromised, are at heightened risk of infection with this virus and subsequent complications, while others, such as healthcare workers and food handlers are at increased risk of transmitting it, and some are at risk of both. Human noroviruses are heterogeneous with new strains emerging periodically. In addition to viral diversity, incompletely understood characteristics, such as virus-host cell binding and duration of immunity after infection add to the challenges of creating a norovirus vaccine. Although much progress has been made in recent years, many questions remain to be answered. In this review, we discuss the important areas and relevant literature in considering human norovirus vaccine development and potential targets for implementation.

Global age distribution of pediatric norovirus cases.

Norovirus is increasingly recognized as a major cause of acute gastroenteritis among children <5 years of age. We searched for publications that reported detailed age distributions of pediatric norovirus cases, and assessed associations between age distribution and socio-demographic factors to identify the most critical age periods to prevent norovirus cases among young children. Approximately 70% of pediatric norovirus cases occurred between 6 and 23 months of age. A younger age distribution was found in lower income countries and inpatient settings. These findings suggest that a norovirus immunization schedule completed by 6 months could have the potential to prevent about 85% of pediatric cases, while a vaccine delivered at 12 months of age would only have the potential to prevent about 50% of pediatric cases. With a younger age distribution in lower income settings, early prevention would be even more critical.

Statistical power and validity of Ebola vaccine trials in Sierra Leone: a simulation study of trial design and analysis.

BACKGROUND: Safe and effective vaccines could help to end the ongoing Ebola virus disease epidemic in parts of west Africa, and mitigate future outbreaks of the virus. We assess the statistical validity and power of randomised controlled trial (RCT) and stepped-wedge cluster trial (SWCT) designs in Sierra Leone, where the incidence of Ebola virus disease is spatiotemporally heterogeneous, and is decreasing rapidly. METHODS: We projected district-level Ebola virus disease incidence for the next 6 months, using a stochastic model fitted to data from Sierra Leone. We then simulated RCT and SWCT designs in trial populations comprising geographically distinct clusters at high risk, taking into account realistic logistical constraints, and both individual-level and cluster-level variations in risk. We assessed false-positive rates and power for parametric and non-parametric analyses of simulated trial data, across a range of vaccine efficacies and trial start dates. FINDINGS: For an SWCT, regional variation in Ebola virus disease incidence trends produced increased false-positive rates (up to 0·15 at α=0·05) under standard statistical models, but not when analysed by a permutation test, whereas analyses of RCTs remained statistically valid under all models. With the assumption of a 6-month trial starting on Feb 18, 2015, we estimate the power to detect a 90% effective vaccine to be between 49% and 89% for an RCT, and between 6% and 26% for an SWCT, depending on the Ebola virus disease incidence within the trial population. We estimate that a 1-month delay in trial initiation will reduce the power of the RCT by 20% and that of the SWCT by 49%. INTERPRETATION: Spatiotemporal variation in infection risk undermines the statistical power of the SWCT. This variation also undercuts the SWCT's expected ethical advantages over the RCT, because an RCT, but not an SWCT, can prioritise vaccination of high-risk clusters. FUNDING: US National Institutes of Health, US National Science Foundation, and Canadian Institutes of Health Research.

Reduced rotavirus vaccine effectiveness among children born during the rotavirus season: a pooled analysis of 5 case-control studies from the Americas.

Using data from rotavirus vaccine effectiveness (VE) studies, we assessed whether rotavirus season modifies rotavirus VE in infants. In the first year of life, adjusted VE was 72% for children born during rotavirus season and 84% for children born in other months (P = .01). Seasonal factors may interfere with vaccine performance.