Short-, mid-, and long-term complications after multisystem inflammatory syndrome in children over a 24-month follow-up period in a hospital in Lima-Peru, 2020-2022.

Objective: To determine the short-, mid-, and long-term complications after multisystem inflammatory syndrome in children (MIS-C) over a 24-month follow-up period in a hospital in Lima, Peru, 2020-2022, and to explore differences according to the immunomodulatory treatment received and type of SARS-CoV-2 virus circulating. Methods: Ambispective 24-month follow-up study in children <14 years of age diagnosed with MIS-C at the Hospital Nacional Edgardo Rebagliati Martins (HNERM). Results: A total of 62 children were admitted with MIS-C. The most common short-term complications and serious events were intensive care unit (ICU) admission, invasive mechanical ventilation (IMV) due to respiratory failure, and shock; predominantly during the second pandemic wave (lambda predominance) and in children that received intravenous immunoglobulin (IVIG) plus a corticosteroid. Two patients died during the first wave due to MIS-C. During prospective follow-up (median of 24 months; IQR: 16.7-24), only 46.7% of patients were followed for >18-24 months. Of the total, seven (11.3%) patients were identified with some sequelae on discharge. Among the 43 remaining children, sequelae persisted in five (11.6%) cases (neurological, hematological, and skin problems). Six patients (13.9%) presented with new onset disease (hematologic, respiratory, neurological, and psychiatric disorders). One patient died due to acute leukemia during the follow-up period. None of them were admitted to the ICU or presented with MIS-C reactivation. Two patients presented persistence of coronary aneurysm until 8- and 24-month post-discharge. Conclusion: In our hospital, children with MIS-C frequently developed short-term complications and serious events during the acute phase, with less frequent complications in the mid- and long-term. More studies are required to confirm these findings.

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.

Pooling of six respiratory samples for the detection of SARS-CoV-2: A validation and cost study in a cohort in Lima, Peru.

Background: The continuous evolution of the SARS-CoV-2 pandemic has led to a high demand for diagnostic testing and major shortages in testing materials, especially in low- and middle-income countries. As an alternative to testing individual samples, pooling of respiratory samples has been suggested. Previous studies have assessed performance of pooling, mainly using nasopharyngeal samples for the detection of SARS-CoV-2, but few studies have examined the performance of pooling the more practical nasal swabs or saliva samples. Objective: To evaluate the sensitivity, specificity, and potential cost reduction of pooling of nasal swab (NS) and saliva (SL) samples for detection of SARS-CoV-2 in a community-based cohort study in Lima, Peru. Study design: A prospective cohort study was conducted in a community setting in San Juan de Lurigancho, Lima-Peru. NS and SL samples were collected from 132 participants twice-a-week for a 2-month period. Pools of 2 to 12 samples of the same type, from participants of the same household, were tested by RT-PCR. After pooled testing, all individual samples from positive pools and all individual samples from randomly chosen negative pools were evaluated. For assessment of diagnostic performance, pool testing results were compared with results from individual testing, which served as reference, and concordance in pooled and individual test detections was evaluated. Laboratory costs for both types of samples and testing were compared. Results: A total of 2008 NS and 2002 SL samples were collected from 132 study participants. We tested 329 NS and 333 SL pools. The mean pool size for NS and SL pools was 6.22 (SD = 0.92) and 6.39 (SD = 1.71), respectively. Using individual testing as reference, NS pooling of 6 had a sensitivity and specificity of 94% and 100%, respectively, with kappa of 0.97 (CI 95%: 0.93-1.00). The corresponding values for SL pooling of 6 were 83%, 100%, and 0.90 (CI 95%: 0.83-0.97). Compared with individual testing, pooling resulted in a cost reduction of 74.8% for NS and 72.4% for SL samples. Conclusions: Pooling easy-to-collect respiratory samples, especially NS, demonstrated very high diagnostic performance for detection of SARS-CoV-2 with substantial cost savings. This approach could be considered in large population screening programs, especially in LMIC.

Association between nasopharyngeal colonization with multiple pneumococcal serotypes and total pneumococcal colonization density in young Peruvian children.

OBJECTIVES: We examined the association of nasopharyngeal (NP) pneumococcal co-colonization (>1 pneumococcal serotype) and pneumococcal density in young Peruvian children enrolled in a prospective cohort study. METHODS: NP swabs collected monthly from children aged <3 years during both asymptomatic and acute respiratory illness (ARI) periods underwent culture-enriched microarray for pneumococcal detection and serotyping and lytA polymerase chain reaction for density assessment. We examined the serotypes commonly associated with co-colonization and the distribution of densities by co-colonization, age, current ARI, and other covariates. The association of co-colonization and pneumococcal density was assessed using a multivariable mixed-effects linear regression model, accounting for repeated measures and relevant covariates. RESULTS: A total of 27 children contributed 575 monthly NP samples. Pneumococcus was detected in 302 of 575 (53%) samples, and co-colonization was detected in 61 of these 302 (20%). The total densities were higher during ARI than non-ARI periods and lowest among the youngest children, increasing with age. In the multivariable analysis, there was no significant association between pneumococcal density and co-colonization (coefficient estimate 0.22, 95% confidence interval 0.11-0.55; reference: single-serotype detections). Serotypes 23B and 19F were detected significantly more frequently as single isolates. CONCLUSION: Pneumococcal co-colonization was common and not associated with increased pneumococcal density. Differential propensity for co-colonization was observed among individual serotypes.

Burden of disease attributable to unsafe drinking water, sanitation, and hygiene in domestic settings: a global analysis for selected adverse health outcomes.

BACKGROUND: Assessments of disease burden are important to inform national, regional, and global strategies and to guide investment. We aimed to estimate the drinking water, sanitation, and hygiene (WASH)-attributable burden of disease for diarrhoea, acute respiratory infections, undernutrition, and soil-transmitted helminthiasis, using the WASH service levels used to monitor the UN Sustainable Development Goals (SDGs) as counterfactual minimum risk-exposure levels. METHODS: We assessed the WASH-attributable disease burden of the four health outcomes overall and disaggregated by region, age, and sex for the year 2019. We calculated WASH-attributable fractions of diarrhoea and acute respiratory infections by country using modelled WASH exposures and exposure-response relationships from two updated meta-analyses. We used the WHO and UNICEF Joint Monitoring Programme for Water Supply, Sanitation and Hygiene public database to estimate population exposure to different WASH service levels. WASH-attributable undernutrition was estimated by combining the population attributable fractions (PAF) of diarrhoea caused by unsafe WASH and the PAF of undernutrition caused by diarrhoea. Soil-transmitted helminthiasis was fully attributed to unsafe WASH. FINDINGS: We estimate that 1·4 (95% CI 1·3-1·5) million deaths and 74 (68-80) million disability-adjusted life-years (DALYs) could have been prevented by safe WASH in 2019 across the four designated outcomes, representing 2·5% of global deaths and 2·9% of global DALYs from all causes. The proportion of diarrhoea that is attributable to unsafe WASH is 0·69 (0·65-0·72), 0·14 (0·13-0·17) for acute respiratory infections, and 0·10 (0·09-0·10) for undernutrition, and we assume that the entire disease burden from soil-transmitted helminthiasis was attributable to unsafe WASH. INTERPRETATION: WASH-attributable burden of disease estimates based on the levels of service established under the SDG framework show that progress towards the internationally agreed goal of safely managed WASH services for all would yield major public-health returns. FUNDING: WHO and Foreign, Commonwealth & Development Office.

Characteristics of pediatric patients hospitalized with COVID-19 during the third wave (omicron variant) at a referral hospital in Peru. / Características de los pacientes pediátricos hospitalizados con COVID-19 durante la tercera ola (variante ómicron) en un hospital de referencia del Perú.

OBJECTIVES.: Motivation for the study. There are few reports on the clinical experience of the population infected with the omicron variant of COVID-19 in Latin America, particularly in pediatric population. Main findings. There was a rapid increase in the number of hospitalizations compared to previous waves, mainly due to respiratory conditions; most patients progressed favorably. Antibiotics and corticosteroids were the most used drugs. Implications. Studying the characteristics of children hospitalized during the third wave of COVID-19 in Peru may increase the knowledge of how the omicron variant affects this population group, which will allow comparisons with possible new waves or diseases.

Could a Shigella vaccine impact long-term health outcomes?: Summary report of an expert meeting to inform a Shigella vaccine public health value proposition, March 24 and 29, 2021.

Shigellosis is a leading cause of diarrhea and dysentery in young children from low to middle-income countries and adults experiencing traveler's diarrhea worldwide. In addition to acute illness, infection by Shigella bacteria is associated with stunted growth among children, which has been linked to detrimental long-term health, developmental, and economic outcomes. On March 24 and 29, 2021, PATH convened an expert panel to discuss the potential impact of Shigella vaccines on these long-term outcomes. Based on current empirical evidence, this discussion focused on whether Shigella vaccines could potentially alleviate the long-term burden associated with Shigella infections. Also, the experts provided recommendations about how to best model the burden, health and vaccine impact, and economic consequences of Shigella infections. This international multidisciplinary panel included 13 scientists, physicians, and economists from multiple relevant specialties. According to the panel, while the relationship between Shigella infections and childhood growth deficits is complex, this relationship likely exists. Vaccine probe studies are the crucial next step to determine whether vaccination could ameliorate Shigella infection-related long-term impacts. Infants should be vaccinated during their first year of life to maximize their protection from severe acute health outcomes and ideally reduce stunting risk and subsequent negative long-term developmental and health impacts. With vaccine schedule crowding, targeted or combination vaccination approaches would likely increase vaccine uptake in high-burden areas. Shigella impact and economic assessment models should include a wider range of linear growth outcomes. Also, these models should produce a spectrum of results-ones addressing immediate benefits for usual health care decision-makers and others that include broader health impacts, providing a more comprehensive picture of vaccination benefits. While many of the underlying mechanisms of this relationship need better characterization, the remaining gaps can be best addressed by collecting data post-vaccine introduction or through large trials.

Concordance in RT-PCR detection of SARS-CoV-2 between samples preserved in viral and bacterial transport medium.

BACKGROUND: While the detection of SARS-CoV-2 in samples preserved in viral transport medium (VTM) by RT-PCR is a standard diagnostic method, this may preclude the study of bacterial respiratory pathogens from the same specimen. It is unclear if the use of skim milk, tryptone, glucose, and glycerin (STGG) transport media, used for study of respiratory bacteria, allows an efficient and concurrent study of SARS-CoV-2 infections. OBJECTIVES: To determine the concordance in SARS-CoV-2 detection by real time RT-PCR between paired nasopharyngeal (NP) swabs preserved in STGG and nasal (NS) swabs preserved in VTM. STUDY DESIGN: Paired samples of NP and NS swabs were collected between December 2020 and March 2021 from a prospective longitudinal cohort study of 44 households and 132 participants from a peri-urban community (Lima, Peru). NP and NS swabs were taken from all participants once and twice per week, respectively, independent of respiratory symptoms. STGG medium was used for NP samples and VTM for NS samples. Samples were analyzed for SARS-CoV-2 by RT-PCR for N, S and ORF1ab targets. We calculated the concordance in detections between sample types and compared the RT-PCR cycle thresholds (Ct). RESULTS: Among the 148 paired samples, we observed a high concordance in detections between NP and NS samples (agreement = 94.59%; Kappa = 0.79). Median Ct values were statistically similar between sample types for each RT-PCR target: N, S and ORF1ab (p = 0.11, p = 0.71 and p = 0.11, respectively). CONCLUSIONS: NP swabs collected in STGG medium are reliable alternatives to nasal swabs collected in VTM for the study of SARS-CoV-2.

Assessing the Impact of Acute Respiratory Illnesses on the Risk of Subsequent Respiratory Illness.

BACKGROUND: Whether acute respiratory illnesses (ARIs), often associated with virus detection, are associated with lower risk for subsequent ARI remains unclear. We assessed the association between symptomatic ARI and subsequent ARI in young children. METHODS: In a prospective cohort of Peruvian children <3 years, we examined the impact of index ARI on subsequent ARI risk. Index ARI were matched with ≤3 asymptomatic observations and followed over 28 days. We compared risk of subsequent ARI between groups using conditional logistic regression adjusting for several covariates, accounting for repeat observations from individual children. RESULTS: Among 983 index ARI, 339 (34%) had an ARI event during follow-up, compared with 876/2826 (31%) matched asymptomatic observations. We found no significant association of index ARI and subsequent ARI risk during follow-up overall (adjusted odds ratio [aOR], 1.10; 95% confidence interval [CI], .98-1.23) or when limited to index ARI with respiratory viruses detected (aOR, 1.03; 95% CI, .86-1.24). Similarly, when the outcome was limited to ARI in which viruses were detected, no significant association was seen (aOR, 1.05; 95% CI, .87-1.27). CONCLUSIONS: ARIs were not associated with short-term protection against subsequent ARI in these children. Additional longitudinal studies are needed to understand drivers of recurrent ARI in young children.

SARS-CoV-2 infections in households in a peri-urban community of Lima, Peru: A prospective cohort study.

BACKGROUND: We assessed the prevalence and incidence of SARS-CoV-2 infections in a prospective study of households in Lima, Peru. METHODS: Households with a child, a young adult 18-50 years, and an adult age >50 years in peri-urban Lima were followed with twice-a-week household visits during a 2-month period. Nasal swabs and saliva specimens were collected twice weekly, and nasopharyngeal swabs were collected weekly from each participant, regardless of symptoms. Laboratory-confirmed SARS-CoV-2 infection was defined by two RT-PCR tests from any of the collected specimens within a week. Blood samples collected at enrollment and end of follow-up were tested with rapid serological tests. We calculated the prevalence and incidence of laboratory-confirmed SARS-CoV-2 infections. RESULTS: We enrolled 132 participants from 44 households: 44 children, 44 young adults, and 44 older adults. A total of 13 SARS-CoV-2 infections were detected in eight households, for an overall period prevalence of 9.85% (95% confidence interval [CI]: 5.35-16.25). Most (61.54%) infections were symptomatic. Eight of 11 (72.73%) SARS-CoV-2 detections corresponded to the Lambda variant. During 218.79 person-months at risk of follow-up, there were six new SARS-CoV-2 infections detected (2.74 per 100 person-month, 95% CI: 1.25-6.04). At enrollment, 59 of 128 participants tested had positive SARS-CoV-2 IgG serology (46.09%, 95% CI: 37.25-55.12). Five of six new infections occurred among participants with negative baseline serology. CONCLUSIONS: We demonstrated high incidence of SARS-CoV-2 infections in households, especially among subjects without evidence of prior infection, most of them not detected by the Ministry of Health system.

Efficacy and safety of the CVnCoV SARS-CoV-2 mRNA vaccine candidate in ten countries in Europe and Latin America (HERALD): a randomised, observer-blinded, placebo-controlled, phase 2b/3 trial.

BACKGROUND: Additional safe and efficacious vaccines are needed to control the COVID-19 pandemic. We aimed to analyse the efficacy and safety of the CVnCoV SARS-CoV-2 mRNA vaccine candidate. METHODS: HERALD is a randomised, observer-blinded, placebo-controlled, phase 2b/3 clinical trial conducted in 47 centres in ten countries in Europe and Latin America. By use of an interactive web response system and stratification by country and age group (18-60 years and ≥61 years), adults with no history of virologically confirmed COVID-19 were randomly assigned (1:1) to receive intramuscularly either two 0·6 mL doses of CVnCoV containing 12 µg of mRNA or two 0·6 mL doses of 0·9% NaCl (placebo) on days 1 and 29. The primary efficacy endpoint was the occurrence of a first episode of virologically confirmed symptomatic COVID-19 of any severity and caused by any strain from 15 days after the second dose. For the primary endpoint, the trial was considered successful if the lower limit of the CI was greater than 30%. Key secondary endpoints were the occurrence of a first episode of virologically confirmed moderate-to-severe COVID-19, severe COVID-19, and COVID-19 of any severity by age group. Primary safety outcomes were solicited local and systemic adverse events within 7 days after each dose and unsolicited adverse events within 28 days after each dose in phase 2b participants, and serious adverse events and adverse events of special interest up to 1 year after the second dose in phase 2b and phase 3 participants. Here, we report data up to June 18, 2021. The study is registered at ClinicalTrials.gov, NCT04652102, and EudraCT, 2020-003998-22, and is ongoing. FINDINGS: Between Dec 11, 2020, and April 12, 2021, 39 680 participants were enrolled and randomly assigned to receive either CVnCoV (n=19 846) or placebo (n=19 834), of whom 19 783 received at least one dose of CVnCoV and 19 746 received at least one dose of placebo. After a mean observation period of 48·2 days (SE 0·2), 83 cases of COVID-19 occurred in the CVnCoV group (n=12 851) in 1735·29 person-years and 145 cases occurred in the placebo group (n=12 211) in 1569·87 person-years, resulting in an overall vaccine efficacy against symptomatic COVID-19 of 48·2% (95·826% CI 31·0-61·4; p=0·016). Vaccine efficacy against moderate-to-severe COVID-19 was 70·7% (95% CI 42·5-86·1; CVnCoV 12 cases in 1735·29 person-years, placebo 37 cases in 1569·87 person-years). In participants aged 18-60 years, vaccine efficacy against symptomatic disease was 52·5% (95% CI 36·2-64·8; CVnCoV 71 cases in 1591·47 person-years, placebo, 136 cases in 1449·23 person-years). Too few cases occurred in participants aged 61 years or older (CVnCoV 12, placebo nine) to allow meaningful assessment of vaccine efficacy. Solicited adverse events, which were mostly systemic, were more common in CVnCoV recipients (1933 [96·5%] of 2003) than in placebo recipients (1344 [67·9%] of 1978), with 542 (27·1%) CVnCoV recipients and 61 (3·1%) placebo recipients reporting grade 3 solicited adverse events. The most frequently reported local reaction after any dose in the CVnCoV group was injection-site pain (1678 [83·6%] of 2007), with 22 grade 3 reactions, and the most frequently reported systematic reactions were fatigue (1603 [80·0%] of 2003) and headache (1541 [76·9%] of 2003). 82 (0·4%) of 19 783 CVnCoV recipients reported 100 serious adverse events and 66 (0·3%) of 19 746 placebo recipients reported 76 serious adverse events. Eight serious adverse events in five CVnCoV recipients and two serious adverse events in two placebo recipients were considered vaccination-related. None of the fatal serious adverse events reported (eight in the CVnCoV group and six in the placebo group) were considered to be related to study vaccination. Adverse events of special interest were reported for 38 (0·2%) participants in the CVnCoV group and 31 (0·2%) participants in the placebo group. These events were considered to be related to the trial vaccine for 14 (<0·1%) participants in the CVnCoV group and for five (<0·1%) participants in the placebo group. INTERPRETATION: CVnCoV was efficacious in the prevention of COVID-19 of any severity and had an acceptable safety profile. Taking into account the changing environment, including the emergence of SARS-CoV-2 variants, and timelines for further development, the decision has been made to cease activities on the CVnCoV candidate and to focus efforts on the development of next-generation vaccine candidates. FUNDING: German Federal Ministry of Education and Research and CureVac.

World Health Organization Expert Working Group: Recommendations for assessing morbidity associated with enteric pathogens.

BACKGROUND: Diarrhoeal infections are one of the leading causes of child's mortality and morbidity. Vaccines against Shigella, enterotoxigenic E. coli (ETEC), norovirus and invasive non-typhoidal Salmonella are in clinical development, however, their full value in terms of short and long-term health and socio-economic burden needs to be evaluated and communicated, to rationalise investment in vaccine development, and deployment. While estimates of mortality of enteric infections exist, the long-term morbidity estimates are scarce and have not been systematically collected. METHODS: The World Health Organization (WHO) has convened a Burden of Enteric Diseases Morbidity Working Group (BoED MWG) who identified key workstreams needed to characterise the morbidity burden of enteric infections. The group also identified four criteria for the prioritisation of pathogens of which impact on long-term morbidity needs to be assessed. RESULTS: The BoED MWG suggested to identify and analyse the individual level data from historical datasets to estimate the impact of enteric infections and confounders on long-term morbidity, including growth faltering and cognitive impairment in children (workstream 1); to conduct a systematic review of evidence on the association of aetiology specific diarrhoea with short- and long- term impact on growth, including stunting, and possibly cognitive impairment in children, while accounting for potential confounders (workstream 2); and to conduct a systematic review of evidence on the association of aetiology specific diarrhoea with short- and long- term impact on health outcomes in adults. The experts prioritised four pathogens for this work: Campylobacter jejuni, ETEC (LT or ST), norovirus (G1 or G2), and Shigella (dysenteriae, flexneri, sonnei). CONCLUSIONS: The proposed work will contribute to improving the understanding of the impact of enteric pathogens on long-term morbidity. The timing of this work is critical as all four pathogens have vaccine candidates in the clinical pipeline and decisions about investments in development, manufacturing or vaccine procurement and use are expected to be made soon.

Social contact patterns and implications for infectious disease transmission - a systematic review and meta-analysis of contact surveys.

Background: Transmission of respiratory pathogens such as SARS-CoV-2 depends on patterns of contact and mixing across populations. Understanding this is crucial to predict pathogen spread and the effectiveness of control efforts. Most analyses of contact patterns to date have focused on high-income settings. Methods: Here, we conduct a systematic review and individual-participant meta-analysis of surveys carried out in low- and middle-income countries and compare patterns of contact in these settings to surveys previously carried out in high-income countries. Using individual-level data from 28,503 participants and 413,069 contacts across 27 surveys, we explored how contact characteristics (number, location, duration, and whether physical) vary across income settings. Results: Contact rates declined with age in high- and upper-middle-income settings, but not in low-income settings, where adults aged 65+ made similar numbers of contacts as younger individuals and mixed with all age groups. Across all settings, increasing household size was a key determinant of contact frequency and characteristics, with low-income settings characterised by the largest, most intergenerational households. A higher proportion of contacts were made at home in low-income settings, and work/school contacts were more frequent in high-income strata. We also observed contrasting effects of gender across income strata on the frequency, duration, and type of contacts individuals made. Conclusions: These differences in contact patterns between settings have material consequences for both spread of respiratory pathogens and the effectiveness of different non-pharmaceutical interventions. Funding: This work is primarily being funded by joint Centre funding from the UK Medical Research Council and DFID (MR/R015600/1).

Infectious diseases, particularly those caused by airborne pathogens like SARS-CoV-2, spread by social contact, and understanding how people mix is critical in controlling outbreaks. To explore these patterns, researchers typically carry out large contact surveys. Participants are asked for personal information (such as gender, age and occupation), as well as details of recent social contacts, usually those that happened in the last 24 hours. This information includes, the age and gender of the contact, where the interaction happened, how long it lasted, and whether it involved physical touch. These kinds of surveys help scientists to predict how infectious diseases might spread. But there is a problem: most of the data come from high-income countries, and there is evidence to suggest that social contact patterns differ between places. Therefore, data from these countries might not be useful for predicting how infections spread in lower-income regions. Here, Mousa et al. have collected and combined data from 27 contact surveys carried out before the COVID-19 pandemic to see how baseline social interactions vary between high- and lower-income settings. The comparison revealed that, in higher-income countries, the number of daily contacts people made decreased with age. But, in lower-income countries, younger and older individuals made similar numbers of contacts and mixed with all age groups. In higher-income countries, more contacts happened at work or school, while in low-income settings, more interactions happened at home and people were also more likely to live in larger, intergenerational households. Mousa et al. also found that gender affected how long contacts lasted and whether they involved physical contact, both of which are key risk factors for transmitting airborne pathogens. These findings can help researchers to predict how infectious diseases might spread in different settings. They can also be used to assess how effective non-medical restrictions, like shielding of the elderly and workplace closures, will be at reducing transmissions in different parts of the world.

Evaluation of post-introduction COVID-19 vaccine effectiveness: Summary of interim guidance of the World Health Organization.

Phase 3 randomized-controlled trials have provided promising results of COVID-19 vaccine efficacy, ranging from 50 to 95% against symptomatic disease as the primary endpoints, resulting in emergency use authorization/listing for several vaccines. However, given the short duration of follow-up during the clinical trials, strict eligibility criteria, emerging variants of concern, and the changing epidemiology of the pandemic, many questions still remain unanswered regarding vaccine performance. Post-introduction vaccine effectiveness evaluations can help us to understand the vaccine's effect on reducing infection and disease when used in real-world conditions. They can also address important questions that were either not studied or were incompletely studied in the trials and that will inform evolving vaccine policy, including assessment of the duration of effectiveness; effectiveness in key subpopulations, such as the very old or immunocompromised; against severe disease and death due to COVID-19; against emerging SARS-CoV-2 variants of concern; and with different vaccination schedules, such as number of doses and varying dosing intervals. WHO convened an expert panel to develop interim best practice guidance for COVID-19 vaccine effectiveness evaluations. We present a summary of the interim guidance, including discussion of different study designs, priority outcomes to evaluate, potential biases, existing surveillance platforms that can be used, and recommendations for reporting results.

Social Contact Patterns and Implications for Infectious Disease Transmission: A Systematic Review and Meta-Analysis of Contact Surveys.

BACKGROUND: Transmission of respiratory pathogens such as SARS-CoV-2 depends on patterns of contact and mixing across populations. Understanding this is crucial to predict pathogen spread and the effectiveness of control efforts. Most analyses of contact patterns to date have focussed on high-income settings. METHODS: Here, we conduct a systematic review and individual-participant meta-analysis of surveys carried out in low- and middle-income countries and compare patterns of contact in these settings to surveys previously carried out in high-income countries. Using individual-level data from 28,503 participants and 413,069 contacts across 27 surveys we explored how contact characteristics (number, location, duration and whether physical) vary across income settings. RESULTS: Contact rates declined with age in high- and upper-middle-income settings, but not in low-income settings, where adults aged 65+ made similar numbers of contacts as younger individuals and mixed with all age-groups. Across all settings, increasing household size was a key determinant of contact frequency and characteristics, but low-income settings were characterised by the largest, most intergenerational households. A higher proportion of contacts were made at home in low-income settings, and work/school contacts were more frequent in high-income strata. We also observed contrasting effects of gender across income-strata on the frequency, duration and type of contacts individuals made. CONCLUSIONS: These differences in contact patterns between settings have material consequences for both spread of respiratory pathogens, as well as the effectiveness of different non-pharmaceutical interventions. FUNDING: This work is primarily being funded by joint Centre funding from the UK Medical Research Council and DFID (MR/R015600/1).

Global diarrhoea-associated mortality estimates and models in children: Recommendations for dataset and study selection.

BACKGROUND: Multiple factors contribute to variation in disease burden, including the type and quality of data, and inherent properties of the models used. Understanding how these factors affect mortality estimates is crucial, especially in the context of public health decision making. We examine how the quality of the studies selected to provide mortality data, influence estimates of burden and provide recommendations about the inclusion of studies and datasets to calculate mortality estimates. METHODS: To determine how mortality estimates are affected by the data used to generate model outputs, we compared the studies used by The Institute of Health Metrics and Evaluation (IHME) and Maternal and Child Epidemiology Estimation (MCEE) modelling groups to generate enterotoxigenic Escherichia coli (ETEC) and Shigella-associated mortality estimates for 2016. Guided by an expert WHO Working Group, we applied a modified Newcastle-Ottawa Scale (NOS) to evaluate the quality of studies used by both modelling groups. RESULTS: IHME and MCEE used different sets of ETEC and Shigella studies in their models and the majority of studies were high quality. The distribution of the NOS scores was similar between the two modelling groups. We observed an overrepresentation of studies from some countries in SEAR, AFR and WPR compared to other WHO regions. CONCLUSION: We identified key differences in study inclusion and exclusion criteria used by IHME and MCEE and discuss their impact on datasets used to generate diarrhoea-associated mortality estimates. Based on these observations, we provide a set of recommendations for future estimates of mortality associated with enteric diseases.

Challenges in the diagnosis of paediatric pneumonia in intervention field trials: recommendations from a pneumonia field trial working group.

Pneumonia is a leading killer of children younger than 5 years despite high vaccination coverage, improved nutrition, and widespread implementation of the Integrated Management of Childhood Illnesses algorithm. Assessing the effect of interventions on childhood pneumonia is challenging because the choice of case definition and surveillance approach can affect the identification of pneumonia substantially. In anticipation of an intervention trial aimed to reduce childhood pneumonia by lowering household air pollution, we created a working group to provide recommendations regarding study design and implementation. We suggest to, first, select a standard case definition that combines acute (≤14 days) respiratory symptoms and signs and general danger signs with ancillary tests (such as chest imaging and pulse oximetry) to improve pneumonia identification; second, to prioritise active hospital-based pneumonia surveillance over passive case finding or home-based surveillance to reduce the risk of non-differential misclassification of pneumonia and, as a result, a reduced effect size in a randomised trial; and, lastly, to consider longitudinal follow-up of children younger than 1 year, as this age group has the highest incidence of severe pneumonia.

Nasopharyngeal Pneumococcal Density during Asymptomatic Respiratory Virus Infection and Risk for Subsequent Acute Respiratory Illness.

Increased nasopharyngeal pneumococcal (Streptococcus pneumoniae) colonization density has been associated with invasive pneumococcal disease, but factors that increase pneumococcal density are poorly understood. We evaluated pneumococcal densities in nasopharyngeal samples from asymptomatic young children from Peru and their association with subsequent acute respiratory illness (ARI). Total pneumococcal densities (encompassing all present serotypes) during asymptomatic periods were significantly higher when a respiratory virus was detected versus when no virus was detected (p<0.001). In adjusted analyses, increased pneumococcal density was significantly associated with the risk for a subsequent ARI (p<0.001), whereas asymptomatic viral detection alone was associated with lower risk for subsequent ARI. These findings suggest that interactions between viruses and pneumococci in the nasopharynx during asymptomatic periods might have a role in onset of subsequent ARI. The mechanisms for these interactions, along with other potentially associated host and environmental factors, and their role in ARI pathogenesis and pneumococcal transmission require further elucidation.