Unraveling the Role of Viral Interference in Disrupting Biennial RSV Epidemics in Northern Stockholm.

Respiratory syncytial virus (RSV) primarily impacts infants and older adults, with seasonal winter outbreaks in temperate countries. Biennial cycles of RSV activity have also been identified in Northern Europe and some states in the United States. Delayed RSV activity was reported worldwide during the 2009 influenza pandemic, and a disrupted biennial pattern of RSV activity was observed in northern Stockholm following the pandemic. Biennial patterns shifted to early/large outbreaks in even-numbered years and late/small outbreaks in odd-numbered years. However, the mechanisms underpinning this change in pattern remain unknown. In this work, we constructed an age-stratified mechanistic model to explicitly test three factors that could lead to the change in RSV transmission dynamics: 1) birth rates, 2) temperatures, and 3) viral interference. By fitting the model to weekly RSV admission data over a 20-year period and comparing different models, we found that viral interference from influenza was the only mechanism that explained the shifted biennial pattern. Our work demonstrates the complex interplay between different respiratory viruses, providing evidence that supports the presence of interactions between the H1N1 pandemic influenza virus and RSV at the population level, with implications for future public health interventions.

Impact of dosing schedules on performance of rotavirus vaccines in Ghana.

Background: Available live-oral rotavirus vaccines are associated with low to moderate performance in low- and middle-income settings. There is limited evidence relating to how the vaccine dosing schedule might be adjusted to improve vaccine performance in these settings. Methods: We used mathematical models fitted to rotavirus surveillance data for children <5 years of age from three different hospitals in Ghana (Korle-Bu Teaching Hospital in Accra, Komfo Anokye Teaching Hospital in Kumasi and War Memorial Hospital in Navrongo) to project the impact of rotavirus vaccination over a 10-year period (April 2012-March 2022). We quantified and compared the impact of the previous vaccination program in Ghana to the model-predicted impact for other vaccine dosing schedules across the three hospitals and the entire country, under different assumptions about vaccine protection. To project the rotavirus vaccine impact over Ghana, we sampled from the range of model parameters for Accra and Navrongo, assuming that these two settings represent the "extremes" of rotavirus epidemiology within Ghana. Results: For the previously implemented 6/10-week monovalent Rotarix vaccine (RV1) schedule, the model-estimated average annual incidence of moderate-to-severe rotavirus-associated gastroenteritis (RVGE) ranged between 1,151 and 3,002 per 100,000 people per year over the 10-year period for the three sites. Compared to no vaccination, the model-estimated median percentage reductions in RVGE ranged from 28-85% and 12-71% among children <1 year and <5 years of age respectively, with the highest and lowest percentage reductions predicted using model parameters estimated for Accra and Navrongo, respectively. The median predicted reductions in RVGE for the whole country ranged from 57-66% and 35-45% among children <1 year and <5 years of age, respectively. The 1/6/10- and 6/10/14-week schedules provided the best and comparable reductions in RVGE compared to the original 6/10-week schedule, whereas there was no improvement in impact for the 10/14-week schedule. Conclusions: We found that administering an additional dose of RV1 might be an effective strategy to improve rotavirus vaccine impact, particularly in settings with low vaccine effectiveness. The results could be extrapolated to other countries using a 2-dose vaccine schedule with low to moderate vaccine performance.

A low-cost culture- and DNA extraction-free method for the molecular detection of pneumococcal carriage in saliva.

Molecular methods have improved the sensitivity of the detection of pneumococcal carriage in saliva. However, they typically require sample culture enrichment and nucleic acid extraction prior to performing the detection assay and may limit scalability for extensive surveillance of pneumococcus, particularly in low-resource settings. We evaluated the performance of a DNA-extraction-free method for the detection of pneumococcus in saliva. We developed a streamlined qPCR-based protocol for the detection of pneumococcus, omitting culture enrichment and DNA extraction. Using saliva samples collected from children attending childcare centers (New Haven, CT, USA), we evaluated the detection of pneumococcus using saliva lysates as compared to purified DNA extracted from culture-enriched aliquots of the paired samples using qPCR targeting the pneumococcal piaB gene. Of the 759 saliva samples tested from 92 children [median age 3.65 years; IQR (2.46-4.78)], pneumococcus was detected in 358 (47.2%) saliva lysates prepared using the extraction-free protocol and in 369 (48.6%) DNA extracted from culture-enriched samples. We observed near-perfect agreement between the two protocols (Cohen's kappa: 0.92; 95% CI: 0.90-0.95). Despite a high correlation between CT values generated by the two methods (r = 0.93, P < 0.0001), the CT values generated from saliva lysates were higher (lower concentration) than those from culture-enriched samples (ΔCT = 6.69, P < 0.00001). The cost of detecting pneumococcus using saliva lysates was at least fivefold lower (US$2.53) compared to the cost of the culture-enriched method (range: US$13.60-US$19.46). For pneumococcal carriage surveillance in children, our findings suggest that a DNA extraction-free approach may offer a cost-effective alternative to the resource-intensive culture-enrichment method.IMPORTANCESurveillance for carriage of pneumococcus is a key component of evaluating the performance of pneumococcal vaccines and informing new vaccination strategies. To improve the scalability of pneumococcal carriage surveillance, we show that molecular detection of pneumococcus in saliva from children can be performed without culture enrichment and DNA extraction. Our findings show that using the extraction-free method can improve surveillance efforts for pneumococcal carriage in children, overcoming the resource-intensive hurdle that comes with the use of molecular methods, particularly in low-resource settings.

Pathogen diversity and antimicrobial resistance transmission of Salmonella enterica serovars Typhi and Paratyphi A in Bangladesh, Nepal, and Malawi: a genomic epidemiological study.

BACKGROUND: Enteric fever is a serious public health concern. The causative agents, Salmonella enterica serovars Typhi and Paratyphi A, frequently have antimicrobial resistance (AMR), leading to limited treatment options and poorer clinical outcomes. We investigated the genomic epidemiology, resistance mechanisms, and transmission dynamics of these pathogens at three urban sites in Africa and Asia. METHODS: S Typhi and S Paratyphi A bacteria isolated from blood cultures of febrile children and adults at study sites in Dhaka (Bangladesh), Kathmandu (Nepal), and Blantyre (Malawi) during STRATAA surveillance were sequenced. Isolates were charactered in terms of their serotypes, genotypes (according to GenoTyphi and Paratype), molecular determinants of AMR, and population structure. We used phylogenomic analyses incorporating globally representative genomic data from previously published surveillance studies and ancestral state reconstruction to differentiate locally circulating from imported pathogen AMR variants. Clusters of sequences without any single-nucleotide variants in their core genome were identified and used to explore spatiotemporal patterns and transmission dynamics. FINDINGS: We sequenced 731 genomes from isolates obtained during surveillance across the three sites between Oct 1, 2016, and Aug 31, 2019 (24 months in Dhaka and Kathmandu and 34 months in Blantyre). S Paratyphi A was present in Dhaka and Kathmandu but not Blantyre. S Typhi genotype 4.3.1 (H58) was common in all sites, but with different dominant variants (4.3.1.1.EA1 in Blantyre, 4.3.1.1 in Dhaka, and 4.3.1.2 in Kathmandu). Multidrug resistance (ie, resistance to chloramphenicol, co-trimoxazole, and ampicillin) was common in Blantyre (138 [98%] of 141 cases) and Dhaka (143 [32%] of 452), but absent from Kathmandu. Quinolone-resistance mutations were common in Dhaka (451 [>99%] of 452) and Kathmandu (123 [89%] of 138), but not in Blantyre (three [2%] of 141). Azithromycin-resistance mutations in acrB were rare, appearing only in Dhaka (five [1%] of 452). Phylogenetic analyses showed that most cases derived from pre-existing, locally established pathogen variants; 702 (98%) of 713 drug-resistant infections resulted from local circulation of AMR variants, not imported variants or recent de novo emergence; and pathogen variants circulated across age groups. 479 (66%) of 731 cases clustered with others that were indistinguishable by point mutations; individual clusters included multiple age groups and persisted for up to 2·3 years, and AMR determinants were invariant within clusters. INTERPRETATION: Enteric fever was associated with locally established pathogen variants that circulate across age groups. AMR infections resulted from local transmission of resistant strains. These results form a baseline against which to monitor the impacts of control measures. FUNDING: Wellcome Trust, Bill & Melinda Gates Foundation, EU Horizon 2020, and UK National Institute for Health and Care Research.

Cost per episode of diarrhea and respiratory syncytial virus (RSV) in 128 low- and middle-income countries: how well do disease-specific and WHO-CHOICE estimates align?

Objective: Non-disease-specific WHO-CHOICE unit costs are often used in cost and cost-effectiveness studies in the absence of country-specific data. This study aims to compare reported country-specific disease costs and the corresponding WHO-CHOICE estimates. We use generically defined "diarrhea" (including rotavirus diarrhea) and pathogen-specific "respiratory syncytial virus (RSV)" disease as examples. Methods: We updated systematic reviews for both diseases in low-income (LICs), lower-middle-income (LMICs) and upper-middle-income (UMICs) countries. Diarrheal (including a sub-analysis of rotavirus-specific) and RSV-specific outpatient and inpatient costs per episode were extracted and compared with WHO-CHOICE estimates in the same countries. If a consistent pattern of under- or over-estimation was identified, we quantified the magnitude of the discrepancy. All costs were updated to 2022 international dollar values. Results: Out of 1975 new records identified, 23 new cost studies were included. Including previous reviews, we retained 31 diarrhea and 16 RSV studies for comparison. WHO-CHOICE based direct medical costs were similar for diarrheal disease including rotavirus diarrhea, but lower for RSV-related disease. We estimated the cost per episode of diarrhea and RSV in 128 countries. RSV outpatient cost were adjusted by multiplying WHO-CHOICE costs by 6.89 (95% uncertainty interval: 5.58-8.58) in LICs and LMICs and 5.87 (4.95-6.96) in UMICs; RSV inpatient costs were multiplied by 1.43 (1.01-2.01) and 1.36 (0.82-2.27), respectively. Conclusion: WHO-CHOICE based costs should be used cautiously. They aligned well with studies for diarrheal disease, but underestimate costs of RSV-related disease. More country- and disease-specific cost data are needed, especially for RSV in LICs.

Global patterns of rebound to normal RSV dynamics following COVID-19 suppression.

BACKGROUND: Annual epidemics of respiratory syncytial virus (RSV) had consistent timing and intensity between seasons prior to the SARS-CoV-2 pandemic (COVID-19). However, starting in April 2020, RSV seasonal activity declined due to COVID-19 non-pharmaceutical interventions (NPIs) before re-emerging after relaxation of NPIs. We described the unusual patterns of RSV epidemics that occurred in multiple subsequent waves following COVID-19 in different countries and explored factors associated with these patterns. METHODS: Weekly cases of RSV from twenty-eight countries were obtained from the World Health Organisation and combined with data on country-level characteristics and the stringency of the COVID-19 response. Dynamic time warping and regression were used to cluster time series patterns and describe epidemic characteristics before and after COVID-19 pandemic, and identify related factors. RESULTS: While the first wave of RSV epidemics following pandemic suppression exhibited unusual patterns, the second and third waves more closely resembled typical RSV patterns in many countries. Post-pandemic RSV patterns differed in their intensity and/or timing, with several broad patterns across the countries. The onset and peak timings of the first and second waves of RSV epidemics following COVID-19 suppression were earlier in the Southern than Northern Hemisphere. The second wave of RSV epidemics was also earlier with higher population density, and delayed if the intensity of the first wave was higher. More stringent NPIs were associated with lower RSV growth rate and intensity and a shorter gap between the first and second waves. CONCLUSION: Patterns of RSV activity have largely returned to normal following successive waves in the post-pandemic era. Onset and peak timings of future epidemics following disruption of normal RSV dynamics need close monitoring to inform the delivery of preventive and control measures.

Impact of rotavirus vaccination in Malawi from 2012 to 2022 compared to model predictions before, during, and after the COVID-19 pandemic.

Background: Rotarix® rotavirus vaccine was introduced into the Malawi national immunization program in October 2012. We used a previously developed mathematical models to estimate overall vaccine effectiveness over a 10-year period following rotavirus vaccine introduction. Methods: We analyzed data on children <5 years old hospitalized with acute gastroenteritis in Blantyre, Malawi from January 2012 to June 2022, compared to pre-vaccination data. We estimated vaccine coverage before, during, and after the COVID-19 pandemic using data from rotavirus-negative children. We compared model predictions for the weekly number of rotavirus-associated gastroenteritis (RVGE) cases to the observed number by age to validate model predictions and estimate overall vaccine effectiveness. Results: The number of RVGE and rotavirus-negative acute gastroenteritis cases declined substantially following vaccine introduction. Vaccine coverage among rotavirus-negative controls was >90% with two doses by July 2014, and declined to a low of ~80% in October 2020, before returning to pre-pandemic levels by July 2021. Our models captured the post-vaccination trends in RVGE incidence, with 5.4% to 19.4% of observed weekly RVGE cases falling outside of the 95% prediction intervals. Comparing observed RVGE cases to the model-predicted incidence without vaccination, overall vaccine effectiveness was estimated to be 36.0% (95% prediction interval: 33.6%, 39.9%) peaking in 2014 and was highest in infants (52.5%; 95% prediction interval: 50.1%, 54.9%). Conclusions: Overall effectiveness of rotavirus vaccination in Malawi is modest despite high vaccine coverage and has plateaued since 2016. Our mathematical models provide a validated platform for assessing strategies to improve rotavirus vaccine impact.

Estimating the health effects of COVID-19-related immunisation disruptions in 112 countries during 2020-30: a modelling study.

BACKGROUND: There have been declines in global immunisation coverage due to the COVID-19 pandemic. Recovery has begun but is geographically variable. This disruption has led to under-immunised cohorts and interrupted progress in reducing vaccine-preventable disease burden. There have, so far, been few studies of the effects of coverage disruption on vaccine effects. We aimed to quantify the effects of vaccine-coverage disruption on routine and campaign immunisation services, identify cohorts and regions that could particularly benefit from catch-up activities, and establish if losses in effect could be recovered. METHODS: For this modelling study, we used modelling groups from the Vaccine Impact Modelling Consortium from 112 low-income and middle-income countries to estimate vaccine effect for 14 pathogens. One set of modelling estimates used vaccine-coverage data from 1937 to 2021 for a subset of vaccine-preventable, outbreak-prone or priority diseases (ie, measles, rubella, hepatitis B, human papillomavirus [HPV], meningitis A, and yellow fever) to examine mitigation measures, hereafter referred to as recovery runs. The second set of estimates were conducted with vaccine-coverage data from 1937 to 2020, used to calculate effect ratios (ie, the burden averted per dose) for all 14 included vaccines and diseases, hereafter referred to as full runs. Both runs were modelled from Jan 1, 2000, to Dec 31, 2100. Countries were included if they were in the Gavi, the Vaccine Alliance portfolio; had notable burden; or had notable strategic vaccination activities. These countries represented the majority of global vaccine-preventable disease burden. Vaccine coverage was informed by historical estimates from WHO-UNICEF Estimates of National Immunization Coverage and the immunisation repository of WHO for data up to and including 2021. From 2022 onwards, we estimated coverage on the basis of guidance about campaign frequency, non-linear assumptions about the recovery of routine immunisation to pre-disruption magnitude, and 2030 endpoints informed by the WHO Immunization Agenda 2030 aims and expert consultation. We examined three main scenarios: no disruption, baseline recovery, and baseline recovery and catch-up. FINDINGS: We estimated that disruption to measles, rubella, HPV, hepatitis B, meningitis A, and yellow fever vaccination could lead to 49 119 additional deaths (95% credible interval [CrI] 17 248-134 941) during calendar years 2020-30, largely due to measles. For years of vaccination 2020-30 for all 14 pathogens, disruption could lead to a 2·66% (95% CrI 2·52-2·81) reduction in long-term effect from 37 378 194 deaths averted (34 450 249-40 241 202) to 36 410 559 deaths averted (33 515 397-39 241 799). We estimated that catch-up activities could avert 78·9% (40·4-151·4) of excess deaths between calendar years 2023 and 2030 (ie, 18 900 [7037-60 223] of 25 356 [9859-75 073]). INTERPRETATION: Our results highlight the importance of the timing of catch-up activities, considering estimated burden to improve vaccine coverage in affected cohorts. We estimated that mitigation measures for measles and yellow fever were particularly effective at reducing excess burden in the short term. Additionally, the high long-term effect of HPV vaccine as an important cervical-cancer prevention tool warrants continued immunisation efforts after disruption. FUNDING: The Vaccine Impact Modelling Consortium, funded by Gavi, the Vaccine Alliance and the Bill & Melinda Gates Foundation. TRANSLATIONS: For the Arabic, Chinese, French, Portguese and Spanish translations of the abstract see Supplementary Materials section.

The role of viral interference in shaping RSV epidemics following the 2009 H1N1 influenza pandemic.

Respiratory syncytial virus (RSV) primarily affects infants, young children, and older adults, with seasonal outbreaks in the United States (US) peaking around December or January. Despite the limited implementation of non-pharmaceutical interventions, disrupted RSV activity was observed in different countries following the 2009 influenza pandemic, suggesting possible viral interference from influenza. Although interactions between the influenza A/H1N1 pandemic virus and RSV have been demonstrated at an individual level, it remains unclear whether the disruption of RSV activity at the population level can be attributed to viral interference. In this work, we first evaluated changes in the timing and intensity of RSV activity across 10 regions of the US in the years following the 2009 influenza pandemic using dynamic time warping. We observed a reduction in RSV activity following the pandemic, which was associated with intensity of influenza activity in the region. We then developed an age-stratified, two-pathogen model to examine various hypotheses regarding viral interference mechanisms. Based on our model estimates, we identified three mechanisms through which influenza infections could interfere with RSV: 1) reducing susceptibility to RSV coinfection; 2) shortening the RSV infectious period in coinfected individuals; and 3) reducing RSV infectivity in coinfection. Our study offers statistical support for the occurrence of atypical RSV seasons following the 2009 influenza pandemic. Our work also offers new insights into the mechanisms of viral interference that contribute to disruptions in RSV epidemics and provides a model-fitting framework that enables the analysis of new surveillance data for studying viral interference at the population level.

Mapping the incidence rate of typhoid fever in sub-Saharan Africa.

BACKGROUND: With more than 1.2 million illnesses and 29,000 deaths in sub-Saharan Africa in 2017, typhoid fever continues to be a major public health problem. Effective control of the disease would benefit from an understanding of the subnational geospatial distribution of the disease incidence. METHOD: We collated records of the incidence rate of typhoid fever confirmed by culture of blood in Africa from 2000 to 2022. We estimated the typhoid incidence rate for sub-Saharan Africa on 20 km × 20 km grids by exploring the association with geospatial covariates representing access to improved water and sanitation, health conditions of the population, and environmental conditions. RESULTS: We identified six published articles and one pre-print representing incidence rate estimates in 22 sites in 2000-2022. Estimated incidence rates showed geospatial variation at sub-national, national, and regional levels. The incidence rate was high in Western and Eastern African subregions followed by Southern and Middle African subregions. By age, the incidence rate was highest among 5-14 yo followed by 2-4 yo, > 14 yo, and 0-1 yo. When aggregated across all age classes and grids that comprise each country, predicted incidence rates ranged from 43.7 (95% confidence interval: 0.6 to 591.2) in Zimbabwe to 2,957.8 (95% CI: 20.8 to 4,245.2) in South Sudan per 100,000 person-years. Sub-national heterogeneity was evident with the coefficient of variation at the 20 km × 20 km grid-level ranging from 0.7 to 3.3 and was generally lower in high-incidence countries and widely varying in low-incidence countries. CONCLUSION: Our study provides estimates of 20 km × 20 km incidence rate of typhoid fever across sub-Saharan Africa based on data collected from 2000 through 2020. Increased understanding of the subnational geospatial variation of typhoid fever in Africa may inform more effective intervention programs by better targeting resources to heterogeneously disturbed disease risk.

Report from the World Health Organization's immunization and vaccines related implementation research advisory committee (IVIR-AC) meeting, Geneva, 11-13 September 2023.

Evaluating vaccine-related research is critical to maximize the potential of vaccination programmes. The WHO Immunization and Vaccine-related Implementation Research Advisory Committee (IVIR-AC) provides an independent review of research that estimates the performance, impact and value of vaccines, with a particular focus on transmission and economic modelling. On 11-13 September 2023, IVIR-AC was convened for a bi-annual meeting where the committee reviewed research and presentations across eight different sessions. This report summarizes the background information, proceedings and recommendations from that meeting. Sessions ranged in topic from timing of measles supplementary immunization activities, analyses of conditions necessary to meet measles elimination in the South-East Asia region, translating modelled evidence into policy, a risk-benefit analysis of dengue vaccine, COVID-19 scenario modelling in the African region, therapeutic vaccination against human papilloma virus, the Vaccine Impact Modelling Consortium, and the Immunization Agenda 2030 vaccine impact estimates.

Incorporating Efficacy Data from Initial Trials Into Subsequent Evaluations: Application to Vaccines Against Respiratory Syncytial Virus.

BACKGROUND: When a randomized controlled trial fails to demonstrate statistically significant efficacy against the primary endpoint, a potentially costly new trial would need to be conducted to receive licensure. Incorporating data from previous trials might allow for more efficient follow-up trials to demonstrate efficacy, speeding the availability of effective vaccines. METHODS: Based on the outcomes from a failed trial of a maternal vaccine against respiratory syncytial virus (RSV), we simulated data for a new Bayesian group-sequential trial. We analyzed the data either ignoring data from the previous trial (i.e., weakly informative prior distributions) or using prior distributions incorporating the historical data into the analysis. We evaluated scenarios where efficacy in the new trial was the same, greater than, or less than that in the original trial. For each scenario, we evaluated the statistical power and type I error rate for estimating the vaccine effect following interim analyses. RESULTS: When we used a stringent threshold to control the type I error rate, analyses incorporating historical data had a small advantage over trials that did not. If control of type I error is less important (e.g., in a postlicensure evaluation), the incorporation of historical data can provide a substantial boost in efficiency. CONCLUSIONS: Due to the need to control the type I error rate in trials used to license a vaccine, incorporating historical data provides little additional benefit in terms of stopping the trial early. However, these statistical approaches could be promising in evaluations that use real-world evidence following licensure.

Typhoid fever.

Typhoid fever is an invasive bacterial disease associated with bloodstream infection that causes a high burden of disease in Africa and Asia. Typhoid primarily affects individuals ranging from infants through to young adults. The causative organism, Salmonella enterica subsp. enterica serovar Typhi is transmitted via the faecal-oral route, crossing the intestinal epithelium and disseminating to systemic and intracellular sites, causing an undifferentiated febrile illness. Blood culture remains the practical reference standard for diagnosis of typhoid fever, where culture testing is available, but novel diagnostic modalities are an important priority under investigation. Since 2017, remarkable progress has been made in defining the global burden of both typhoid fever and antimicrobial resistance; in understanding disease pathogenesis and immunological protection through the use of controlled human infection; and in advancing effective vaccination programmes through strategic multipartner collaboration and targeted clinical trials in multiple high-incidence priority settings. This Primer thus offers a timely update of progress and perspective on future priorities for the global scientific community.

Survey of white-footed mice in Connecticut, USA reveals low SARS-CoV-2 seroprevalence and infection with divergent betacoronaviruses.

Diverse mammalian species display susceptibility to and infection with SARS-CoV-2. Potential SARS-CoV-2 spillback into rodents is understudied despite their host role for numerous zoonoses and human proximity. We assessed exposure and infection among white-footed mice (Peromyscus leucopus) in Connecticut, USA. We observed 1% (6/540) wild-type neutralizing antibody seroprevalence among 2020-2022 residential mice with no cross-neutralization of variants. We detected no SARS-CoV-2 infections via RT-qPCR, but identified non-SARS-CoV-2 betacoronavirus infections via pan-coronavirus PCR among 1% (5/468) of residential mice. Sequencing revealed two divergent betacoronaviruses, preliminarily named Peromyscus coronavirus-1 and -2. Both belong to the Betacoronavirus 1 species and are ~90% identical to the closest known relative, Porcine hemagglutinating encephalomyelitis virus. Low SARS-CoV-2 seroprevalence suggests white-footed mice may not be sufficiently susceptible or exposed to SARS-CoV-2 to present a long-term human health risk. However, the discovery of divergent, non-SARS-CoV-2 betacoronaviruses expands the diversity of known rodent coronaviruses and further investigation is required to understand their transmission extent.

Floods and Diarrhea Risk in Young Children in Low- and Middle-Income Countries.

Importance: Climate change is associated with more frequent and intense floods. Current research on the association between flood exposure and diarrhea risk is limited mainly to short-term and event-specific analyses. Moreover, how prior drought or water, sanitation, and hygiene (WaSH) practices influence this association remains largely unknown. Objective: To examine the association between flood exposure and diarrhea risk among children younger than 5 years and to evaluate the compounding influence of prior drought and effect modification by WaSH. Design, Setting, and Participants: This cross-sectional study included multicluster surveys conducted by the Demographic and Health Surveys Program in 43 low- and middle-income countries during 2009 through 2019. This study included children younger than 5 years in all households from each survey cluster. Collected data were analyzed between September 1 and December 31, 2022. Exposures: Historical flood events during 2009 through 2019 were obtained from the Dartmouth Flood Observatory. Main Outcome and Measures: The main outcome was diarrhea prevalence among children younger than 5 years in the 2 weeks before the survey was conducted. Results were analyzed by binomial generalized linear mixed-effects logistic regression models with nested random intercepts for country and survey cluster. Results: Among 639 250 children making up the complete data series (excluding 274 847 children with missing values for diarrhea or baseline characteristics), 6365 (mean [SD] age, 28.9 [17.2] months; 3214 boys [50.5%]; 3151 girls [49.5%]) were exposed to floods during the 8 weeks after a flood started. The prevalence of diarrhea was 13.2% (n = 839) among exposed children and 12.7% (n = 80 337) among unexposed children. Exposure to floods was associated with increased diarrhea risk, with the highest odds ratio (OR) observed during the second to fourth weeks after floods started (OR, 1.35; 95% CI, 1.05-1.73). When floods were stratified by severity and duration, significant associations were observed only for extreme floods (OR during the third to fifth weeks, 2.07; 95% CI, 1.37-3.11) or floods lasting more than 2 weeks (OR during the second to fourth weeks, 1.47; 95% CI, 1.13-1.92), with significantly stronger associations than for less extreme floods or shorter-duration floods, respectively. The OR during the first 4 weeks after the start of floods was significantly higher for floods preceded by a 6-month or longer drought (12-month drought OR, 1.96; 95% CI, 1.53-2.52) than for floods not preceded by a 6-month or longer drought (12-month drought OR, 1.00; 95% CI, 0.79-1.27). Conclusions: These findings suggest that floods, especially severe floods, long-duration floods, and floods preceded by drought, are associated with an increased risk of diarrhea among children younger than 5 years living in low- and middle-income countries. With the projected increasing frequency and intensity of floods and drought under climate change, greater collective efforts are needed to protect children's health from these compounding events.

Assessing the global risk of typhoid outbreaks caused by extensively drug resistant Salmonella Typhi.

Since its emergence in 2016, extensively drug resistant (XDR) Salmonella enterica serovar Typhi (S. Typhi) has become the dominant cause of typhoid fever in Pakistan. The establishment of sustained XDR S. Typhi transmission in other countries represents a major public health threat. We show that the annual volume of air travel from Pakistan strongly discriminates between countries that have and have not imported XDR S. Typhi in the past, and identify a significant association between air travel volume and the rate of between-country movement of the H58 haplotype of S. Typhi from fitted phylogeographic models. Applying these insights, we analyze flight itinerary data cross-referenced with model-based estimates of typhoid fever incidence to identify the countries at highest risk of importation and sustained onward transmission of XDR S. Typhi. Future outbreaks of XDR typhoid are most likely to occur in countries that can support efficient local S. Typhi transmission and have strong travel links to regions with ongoing XDR typhoid outbreaks (currently Pakistan). Public health activities to track and mitigate the spread of XDR S. Typhi should be prioritized in these countries.

Year-Round Respiratory Syncytial Virus Transmission in The Netherlands Following the COVID-19 Pandemic: A Prospective Nationwide Observational and Modeling Study.

We initiated a nationwide prospective study to monitor respiratory syncytial virus (RSV)-related pediatric hospitalizations in 46 hospitals throughout the Netherlands between May 2021 and August 2022. We showed year-round RSV transmission in the Netherlands after an initial 2021 summer outbreak. The pattern was unprecedented and distinct from neighboring countries. We extended a dynamic simulation model to evaluate the impact of waning immunity on pediatric RSV hospitalizations in the Netherlands using 4 different scenarios. Our results suggest that the observed continuous RSV transmission pattern could be associated with waning immunity due to the period of very low RSV circulation during the COVID-19 pandemic.

Assessment of vaccine herd protection in a cluster-randomised trial of Vi conjugate vaccine against typhoid fever: results of further analysis.

Background: A cluster-randomised trial of Vi-tetanus toxoid (Vi-TT) conjugate vaccine conducted in urban Bangladeshi children found a high level of direct protection by Vi-TT but no significant vaccine herd protection. We reassessed the trial using a "fried egg" analysis to evaluate whether herd protection might have been obscured by transmission of typhoid into the clusters from the outside. Methods: A participant- and observer-blind, cluster-randomised trial was conducted between February 14, 2018 and August 12, 2019 in three wards of Mirpur, a densely populated urban area of Dhaka, Bangladesh. Children 9 months to under 16 years of age in 150 geographic clusters, which had a total of 311,289 persons present at baseline or entering during follow-up, were randomised by cluster to a single-dose of Vi-TT or Japanese encephalitis (JE) vaccine. Vi-TT protection against typhoid fever, detected at 8 treatment centres serving the study population, was compared in the original clusters for the trial, and for progressively more central subclusters ("yolks" of the "fried egg") of the cluster residents. If transmission of typhoid into the clusters had diluted observed vaccine herd protection, we hypothesised that analysis of the innermost "yolks" would reveal vaccine herd protection that was not evident in analysis of the entire clusters. The trial is registered at www.isrctn.com as ISRCTN11643110. Findings: At ≤18 months of follow-up, total vaccine effectiveness (protection of Vi-TT recipients relative to JE vaccine recipients) was 85% (95% CI: 76%, 90%); indirect effectiveness (protection of non-Vi-TT recipients in Vi-TT clusters relative to non-JE vaccine recipients in JE vaccine clusters) was 17% (95% CI: -13%, 40%); and overall effectiveness (protection of all residents in the Vi-TT clusters relative to all residents of the JE vaccine clusters) was 57% (95% CI: 44%, 66%). Analyses of subpopulations in inner 75%, 50% and 25% "yolks" of the clusters failed to reveal significant changes in any of these estimates. Interpretation: Our analysis did not reveal Vi-TT herd protection in the trial. Consideration should be given to exploring whether targeting adults as well as children with Vi-TT yields appreciable levels of vaccine herd protection. Funding: Bill & Melinda Gates Foundation (OPP1151153, INV-025388).