Contribution of vaccination to improved survival and health: modelling 50 years of the Expanded Programme on Immunization.

BACKGROUND: WHO, as requested by its member states, launched the Expanded Programme on Immunization (EPI) in 1974 to make life-saving vaccines available to all globally. To mark the 50-year anniversary of EPI, we sought to quantify the public health impact of vaccination globally since the programme's inception. METHODS: In this modelling study, we used a suite of mathematical and statistical models to estimate the global and regional public health impact of 50 years of vaccination against 14 pathogens in EPI. For the modelled pathogens, we considered coverage of all routine and supplementary vaccines delivered since 1974 and estimated the mortality and morbidity averted for each age cohort relative to a hypothetical scenario of no historical vaccination. We then used these modelled outcomes to estimate the contribution of vaccination to globally declining infant and child mortality rates over this period. FINDINGS: Since 1974, vaccination has averted 154 million deaths, including 146 million among children younger than 5 years of whom 101 million were infants younger than 1 year. For every death averted, 66 years of full health were gained on average, translating to 10·2 billion years of full health gained. We estimate that vaccination has accounted for 40% of the observed decline in global infant mortality, 52% in the African region. In 2024, a child younger than 10 years is 40% more likely to survive to their next birthday relative to a hypothetical scenario of no historical vaccination. Increased survival probability is observed even well into late adulthood. INTERPRETATION: Since 1974 substantial gains in childhood survival have occurred in every global region. We estimate that EPI has provided the single greatest contribution to improved infant survival over the past 50 years. In the context of strengthening primary health care, our results show that equitable universal access to immunisation remains crucial to sustain health gains and continue to save future lives from preventable infectious mortality. FUNDING: WHO.

Immunization: vital progress, unfinished agenda.

Vaccination against infectious diseases has changed the future of the human species, saving millions of lives every year, both children and adults, and providing major benefits to society as a whole. Here we show, however, that national and sub-national coverage of vaccination varies greatly and major unmet needs persist. Although scientific progress opens exciting perspectives in terms of new vaccines, the pathway from discovery to sustainable implementation can be long and difficult, from the financing, development and licensing to programme implementation and public acceptance. Immunization is one of the best investments in health and should remain a priority for research, industry, public health and society.

Changing Landscape of Routine Pediatric Surgery for Rural and Urban Children: A Report From the Child Health Evaluation of Surgical Services (CHESS) Group.

OBJECTIVE: To describe the changes to routine pediatric surgical care over the past 2 decades for children living in urban and rural environments. BACKGROUND: A knowledge gaps exists regarding trends in the location where routine pediatric surgical care is provided to children from urban and rural environments over time. METHODS: Children (age 0-18) undergoing 7 common surgeries were identified using State Inpatient Databases (SID, 2002-2017). Rural-Urban Commuting Area codes were used to classify patient and hospital zip codes. Multivariable regression models for distance traveled >60 miles and transfer status were used to compare rural and urban populations, adjusting for year, age, sex, race, and insurance status. RESULTS: Among 143,467 children, 13% lived in rural zip codes. The distance traveled for care increased for both rural and urban children for all procedures but significantly more for the rural cohort (eg, 102% vs 30%, P <0.001, cholecystectomy). Transfers also increased for rural children (eg, transfers for appendectomy increased from 1% in 2002 to 23% in 2017, P <0.001). Factors associated with the need to travel >60 miles included year [adjusted odds ratio (aOR)=2.18, 95% CI: 1.94-2.46: 2017 vs 2002], rural residence (aOR=6.55, 95% CI: 6.11-7.01), age less than 5 years (aOR=2.17, 95% CI: 1.92-2.46), and Medicaid insurance (aOR=1.35, 95% CI: 1.26-1.45). Factors associated with transfer included year (aOR=5.77, 95% CI: 5.26-6.33: 2017 vs 2002), rural residence (aOR=1.47, 95% CI: 1.39-1.56), age less than 10 years (aOR=2.34, 95% CI: 2.15-2.54), and Medicaid insurance (aOR=1.49, 95% CI: 1.42-1.46). CONCLUSION: Rural children, younger age, and those on Medicaid disproportionately traveled greater distances and were more frequently transferred for common pediatric surgical procedures.

Duration of effectiveness of vaccines against SARS-CoV-2 infection and COVID-19 disease: results of a systematic review and meta-regression.

BACKGROUND: Knowing whether COVID-19 vaccine effectiveness wanes is crucial for informing vaccine policy, such as the need for and timing of booster doses. We aimed to systematically review the evidence for the duration of protection of COVID-19 vaccines against various clinical outcomes, and to assess changes in the rates of breakthrough infection caused by the delta variant with increasing time since vaccination. METHODS: This study was designed as a systematic review and meta-regression. We did a systematic review of preprint and peer-reviewed published article databases from June 17, 2021, to Dec 2, 2021. Randomised controlled trials of COVID-19 vaccine efficacy and observational studies of COVID-19 vaccine effectiveness were eligible. Studies with vaccine efficacy or effectiveness estimates at discrete time intervals of people who had received full vaccination and that met predefined screening criteria underwent full-text review. We used random-effects meta-regression to estimate the average change in vaccine efficacy or effectiveness 1-6 months after full vaccination. FINDINGS: Of 13 744 studies screened, 310 underwent full-text review, and 18 studies were included (all studies were carried out before the omicron variant began to circulate widely). Risk of bias, established using the risk of bias 2 tool for randomised controlled trials or the risk of bias in non-randomised studies of interventions tool was low for three studies, moderate for eight studies, and serious for seven studies. We included 78 vaccine-specific vaccine efficacy or effectiveness evaluations (Pfizer-BioNTech-Comirnaty, n=38; Moderna-mRNA-1273, n=23; Janssen-Ad26.COV2.S, n=9; and AstraZeneca-Vaxzevria, n=8). On average, vaccine efficacy or effectiveness against SARS-CoV-2 infection decreased from 1 month to 6 months after full vaccination by 21·0 percentage points (95% CI 13·9-29·8) among people of all ages and 20·7 percentage points (10·2-36·6) among older people (as defined by each study, who were at least 50 years old). For symptomatic COVID-19 disease, vaccine efficacy or effectiveness decreased by 24·9 percentage points (95% CI 13·4-41·6) in people of all ages and 32·0 percentage points (11·0-69·0) in older people. For severe COVID-19 disease, vaccine efficacy or effectiveness decreased by 10·0 percentage points (95% CI 6·1-15·4) in people of all ages and 9·5 percentage points (5·7-14·6) in older people. Most (81%) vaccine efficacy or effectiveness estimates against severe disease remained greater than 70% over time. INTERPRETATION: COVID-19 vaccine efficacy or effectiveness against severe disease remained high, although it did decrease somewhat by 6 months after full vaccination. By contrast, vaccine efficacy or effectiveness against infection and symptomatic disease decreased approximately 20-30 percentage points by 6 months. The decrease in vaccine efficacy or effectiveness is likely caused by, at least in part, waning immunity, although an effect of bias cannot be ruled out. Evaluating vaccine efficacy or effectiveness beyond 6 months will be crucial for updating COVID-19 vaccine policy. FUNDING: Coalition for Epidemic Preparedness Innovations.

Frequency-dependent selection can forecast evolution in Streptococcus pneumoniae.

Predicting how pathogen populations will change over time is challenging. Such has been the case with Streptococcus pneumoniae, an important human pathogen, and the pneumococcal conjugate vaccines (PCVs), which target only a fraction of the strains in the population. Here, we use the frequencies of accessory genes to predict changes in the pneumococcal population after vaccination, hypothesizing that these frequencies reflect negative frequency-dependent selection (NFDS) on the gene products. We find that the standardized predicted fitness of a strain, estimated by an NFDS-based model at the time the vaccine is introduced, enables us to predict whether the strain increases or decreases in prevalence following vaccination. Further, we are able to forecast the equilibrium post-vaccine population composition and assess the invasion capacity of emerging lineages. Overall, we provide a method for predicting the impact of an intervention on pneumococcal populations with potential application to other bacterial pathogens in which NFDS is a driving force.

COVID-19 Mortality and Progress Toward Vaccinating Older Adults - World Health Organization, Worldwide, 2020-2022.

After the emergence of SARS-CoV-2 in late 2019, transmission expanded globally, and on January 30, 2020, COVID-19 was declared a public health emergency of international concern.* Analysis of the early Wuhan, China outbreak (1), subsequently confirmed by multiple other studies (2,3), found that 80% of deaths occurred among persons aged ≥60 years. In anticipation of the time needed for the global vaccine supply to meet all needs, the World Health Organization (WHO) published the Strategic Advisory Group of Experts on Immunization (SAGE) Values Framework and a roadmap for prioritizing use of COVID-19 vaccines in late 2020 (4,5), followed by a strategy brief to outline urgent actions in October 2021.† WHO described the general principles, objectives, and priorities needed to support country planning of vaccine rollout to minimize severe disease and death. A July 2022 update to the strategy brief§ prioritized vaccination of populations at increased risk, including older adults,¶ with the goal of 100% coverage with a complete COVID-19 vaccination series** for at-risk populations. Using available public data on COVID-19 mortality (reported deaths and model estimates) for 2020 and 2021 and the most recent reported COVID-19 vaccination coverage data from WHO, investigators performed descriptive analyses to examine age-specific mortality and global vaccination rollout among older adults (as defined by each country), stratified by country World Bank income status. Data quality and COVID-19 death reporting frequency varied by data source; however, persons aged ≥60 years accounted for >80% of the overall COVID-19 mortality across all income groups, with upper- and lower-middle-income countries accounting for 80% of the overall estimated excess mortality. Effective COVID-19 vaccines were authorized for use in December 2020, with global supply scaled up sufficiently to meet country needs by late 2021 (6). COVID-19 vaccines are safe and highly effective in reducing severe COVID-19, hospitalizations, and mortality (7,8); nevertheless, country-reported median completed primary series coverage among adults aged ≥60 years only reached 76% by the end of 2022, substantially below the WHO goal, especially in middle- and low-income countries. Increased efforts are needed to increase primary series and booster dose coverage among all older adults as recommended by WHO and national health authorities.

Pediatric Injury Transfer Patterns During the COVID-19 Pandemic: An Interrupted time Series Analysis.

INTRODUCTION: With the expected surge of adult patients with COVID-19, the Children's Hospital Association recommended a tiered approach to divert children to pediatric centers. Our objective was understanding changes in interfacility transfer to Pediatric Trauma Centers (PTCs) during the first 6 mo of the pandemic. METHODS: Children aged < 18 y injured between January 1, 2016 and September 30, 2020, who met National Trauma Databank inclusion criteria from 9 PTCs were included. An interrupted time-series analysis was used to estimate an expected number of transferred patients compared to observed volume. The "COVID" cohort was compared to a historical cohort (historical average [HA]), using an average across 2016-2019. Site-based differences in transfer volume, demographics, injury characteristics, and hospital-based outcomes were compared between cohorts. RESULTS: Twenty seven thousand thirty one/47,382 injured patients (57.05%) were transferred to a participating PTC during the study period. Of the COVID cohort, 65.4% (4620/7067) were transferred, compared to 55.7% (3281/5888) of the HA (P < 0.001). There was a decrease in 15-y-old to 17-y-old patients (10.43% COVID versus 12.64% HA, P = 0.003). More patients in the COVID cohort had injury severity scores ≤ 15 (93.25% COVID versus 87.63% HA, P < 0.001). More patients were discharged home after transfer (31.80% COVID versus 21.83% HA, P < 0.001). CONCLUSIONS: Transferred trauma patients to Level I PTC increased during the COVID-19 pandemic. The proportion of transferred patients discharged from emergency departments increased. Pediatric trauma transfers may be a surrogate for referring emergency department capacity and resources and a measure of pediatric trauma triage capability.

Evaluating the Regional Differences in Pediatric Injury Patterns During the COVID-19 Pandemic.

INTRODUCTION: Reports of pediatric injury patterns during the COVID-19 pandemic are conflicting and lack the granularity to explore differences across regions. We hypothesized there would be considerable variation in injury patterns across pediatric trauma centers in the United States. MATERIALS AND METHODS: A multicenter, retrospective study evaluating patients <18 y old with traumatic injuries meeting National Trauma Data Bank criteria was performed. Patients injured after stay-at-home orders through September 2020 ("COVID" cohort) were compared to "Historical" controls from an averaged period of equivalent dates in 2016-2019. Differences in injury type, intent, and mechanism were explored at the site level. RESULTS: 47,385 pediatric trauma patients were included. Overall trauma volume increased during the COVID cohort compared to the Historical (COVID 7068 patients versus Historical 5891 patients); however, some sites demonstrated a decrease in overall trauma of 25% while others had an increase of over 33%. Bicycle injuries increased at every site, with a range in percent change from 24% to 135% increase. Although the greatest net increase was due to blunt injuries, there was a greater relative increase in penetrating injuries at 7/9 sites, with a range in percent change from a 110% increase to a 69% decrease. CONCLUSIONS: There was considerable discrepancy in pediatric injury patterns at the individual site level, perhaps suggesting a variable impact of the specific sociopolitical climate and pandemic policies of each catchment area. Investigation of the unique response of the community during times of stress at pediatric trauma centers is warranted to be better prepared for future environmental stressors.

Common Data Elements for Disorders of Consciousness: Recommendations from the Working Group on Behavioral Phenotyping.

BACKGROUND: The recent publication of practice guidelines for management of patients with disorders of consciousness (DoC) in the United States and Europe was a major step forward in improving the accuracy and consistency of terminology, diagnostic criteria, and prognostication in this population. There remains a pressing need for a more precise brain injury classification system that combines clinical semiology with neuroimaging, electrophysiologic, and other biomarker data. To address this need, the National Institute of Neurological Disorders and Stroke launched the Common Data Elements (CDEs) initiative to facilitate systematic collection of high-quality research data in studies involving patients with neurological disease. The Neurocritical Care Society's Curing Coma Campaign expanded this effort in 2018 to develop CDEs for DoC. Herein, we present CDE recommendations for behavioral phenotyping of patients with DoC. METHODS: The Behavioral Phenotyping Workgroup used a preestablished, five-step process to identify and select candidate CDEs that included review of existing National Institute of Neurological Disorders and Stroke CDEs, nomination and systematic vetting of new CDEs, CDE classification, iterative review, and approval of panel recommendations and development of corresponding case review forms. RESULTS: We identified a slate of existing and newly proposed basic, supplemental, and exploratory CDEs that can be used for behavioral phenotyping of adult and pediatric patients with DoC. CONCLUSIONS: The proposed behavioral phenotyping CDEs will assist with international harmonization of DoC studies and allow for more precise characterization of study cohorts, favorably impacting observational studies and clinical trials aimed at improving outcome in this population.

Acetolysis modifications to process small pollen samples swabbed from live bees.

Understanding the resources bees use is essential because we depend greatly on their ecosystem services, and this information could help guide conservation efforts. One way to identify the flowers that bees visit is to collect pollen directly from the bee and then identify the pollen with plant taxa. However, the current method for processing such pollen samples, acetolysis, is designed for samples such as those collected across individuals (e.g., pollen trap), bee nests, or, at the very least, from pollen pellets collected from live bees or from the exhaustive removal of pollen from lethally collected individuals. Smaller samples, including those down to just a few pollen grains sampled from live bees, could facilitate additional opportunities for bee-pollen research, if they can be processed effectively. We present a revised acetolysis methodology designed specifically for processing small pollen samples, so that they can then be used for more accurate identification. Using pollen samples from cotton swabs directly applied to live bees in the field, we demonstrate the effectiveness of our methodology for processing small pollen samples, including samples too small to be visually detected. This methodology can permit nonlethal collections in the field from a greater number of bee species.

Factors Associated with Hospital Readmission One Year Post-Discharge in Infants with Gastroschisis.

INTRODUCTION: Gastroschisis is the most common congenital abdominal wall defect with a rising prevalence. Infants with gastroschisis are at risk for multiple complications, leading to a potential increased risk for hospital readmission after discharge. We aimed to find the frequency and factors associated with an increased risk of readmission. METHODS: A retrospective analysis of infants born with gastroschisis between 2013 and 2019 who received initial surgical intervention and follow-up care in the Children's Wisconsin health system was performed. The primary outcome was the frequency of hospital readmission within 1 year of discharge. We also compared maternal and infant clinical and demographic variables between those readmitted for reasons related to gastroschisis, and those readmitted for other reasons or not readmitted. RESULTS: Forty of 90 (44%) infants born with gastroschisis were readmitted within 1-year of the initial discharge date, with 33 (37%) of the 90 infants being readmitted due to reasons directly related to gastroschisis. The presence of a feeding tube (p < 0.0001), a central line at discharge (p = 0.007), complex gastroschisis (p = 0.045), conjugated hyperbilirubinemia (p = 0.035), and the number of operations during the initial hospitalization (p = 0.044) were associated with readmission. Maternal race/ethnicity was the only maternal variable associated with readmission, with Black race being less likely to be readmitted (p = 0.003). Those who were readmitted were also more likely to be seen in outpatient clinics and utilize emergency healthcare resources. There was no statistically significant difference in readmission based on socioeconomic factors (all p > 0.084). CONCLUSION: Infants with gastroschisis have a high hospital readmission rate, which is associated with a variety of risk factors including complex gastroschisis, multiple operations, and the presence of a feeding tube or central line at discharge. Improved awareness of these risk factors may help stratify patients in need of increased parental counseling and additional follow-up.

A mastery learning approach to education about fall risk and gait assessment.

Mastery learning is a form of competency-based education in which learning time varies but outcomes are uniform. Trainees must meet a minimum passing standard (MPS) before completing a mastery learning curriculum. The objective of this study was to establish a curriculum for fall risk and gait assessment for medical students, determine an MPS for a fall risk and gait assessment clinical skills examination (CSE), and apply the MPS to a sample of medical students completing a fall risk and gait assessment CSE. Medical students completed an interactive session about fall risk and gait assessment including the Timed Up and Go (TUG) test and completed deliberate practice with 3 patients. Skills were evaluated using an 18-item skills checklist. A panel of clinical experts set the MPS at 82%. Eighty-seven medical students participated. The average score on the checklist was 14.7 of 18 (81.4%.) Although almost all performed the TUG correctly, only 61% met the MPS for the checklist. Our results suggest that a mastery learning approach may better prepare the 39% of students that did not meet MPS to complete a fall risk and gait assessment.

Development and evaluation of a simulation-based mastery learning maintenance of certification course.

BACKGROUND/OBJECTIVES: To develop and evaluate a post-acute care simulation-based mastery learning (SBML) continuing medical education (CME)/maintenance of certification (MOC) procedure course. DESIGN: Pretest-posttest study of the SBML intervention. SETTING: A 2-day post-acute care procedures course. PARTICIPANTS: Sixteen practicing clinicians (5 physicians,11 advanced practice providers). Participants engaged in a skills pretest on knee aspiration/injection, gastrostomy tube removal/replacement, tracheostomy tube exchange, and basic suturing using a checklist created for each procedure. Participants received a didactic on each procedure followed by deliberate practice with feedback. Using the same checklists, participants completed a skills posttest and were required to meet a minimum passing standard (MPS) to obtain CME/MOC credit. MEASUREMENTS: The MPS for each skills checklist was determined by a multidisciplinary panel of 11 experts. Participants completed surveys on procedure self-confidence and a course evaluation. RESULTS: There was statistically significant improvement between pre- and posttests for all four procedures (p < .001). All participants were able to meet or exceed the MPS for each skill during the 2-day course. Participants' self-confidence regarding each procedure improved significantly (p < .001). CONCLUSION: An SBML training course granting CME/MOC credit for post-acute care providers significantly improves performance of knee aspiration/injection, gastrostomy tube removal/replacement, tracheostomy tube exchange, and basic suturing.

The World of Immunization: Achievements, Challenges, and Strategic Vision for the Next Decade.

Immunization is among the most cost-effective public health interventions available and is estimated to have averted at least 37 million deaths between 2000 and 2019. Since the establishment of the Expanded Programme on Immunization in 1974, global vaccination coverage increased and the coverage gap between rich and poor countries decreased. Creation of Gavi, the Vaccine Alliance, in 2000 allowed the poorest countries in the world to benefit from new, life-saving vaccines and expand the breadth of protection against an increasing number of vaccine-preventable diseases. Despite this progress, inequities in access to and uptake of vaccines persist. Opportunities to realize the full potential of vaccines are within reach but require focused, tailored and committed action by Governments and immunization stakeholders. The Immunization Agenda 2030 provides a framework for action during the next decade to attain a world where everyone, everywhere, at every age fully benefits from vaccines for good health and well-being.

The Etiology of Pneumonia From Analysis of Lung Aspirate and Pleural Fluid Samples: Findings From the Pneumonia Etiology Research for Child Health (PERCH) Study.

BACKGROUND: An improved understanding of childhood pneumonia etiology is required to inform prevention and treatment strategies. Lung aspiration is the gold standard specimen for pneumonia diagnostics. We report findings from analyses of lung and pleural aspirates collected in the Pneumonia Etiology Research for Child Health (PERCH) study. METHODS: The PERCH study enrolled children aged 1-59 months hospitalized with World Health Organization-defined severe or very severe pneumonia in 7 countries in Africa and Asia. Percutaneous transthoracic lung aspiration (LA) and pleural fluid (PF) aspiration was performed on a sample of pneumonia cases with radiological consolidation and/or PF in 4 countries. Venous blood and nasopharyngeal/oropharyngeal swabs were collected from all cases. Multiplex quantitative polymerase chain reaction (PCR) and routine microbiologic culture were applied to clinical specimens. RESULTS: Of 44 LAs performed within 3 days of admission on 622 eligible cases, 13 (30%) had a pathogen identified by either culture (5/44) or by PCR (11/29). A pathogen was identified in 12/14 (86%) PF specimens tested by either culture (9/14) or PCR (9/11). Bacterial pathogens were identified more frequently than viruses. All but 1 of the cases with a virus identified were coinfected with bacterial pathogens. Streptococcus pneumoniae (9/44 [20%]) and Staphylococcus aureus (7/14 [50%]) were the predominant pathogens identified in LA and PF, respectively. CONCLUSIONS: Bacterial pathogens predominated in this selected subgroup of PERCH participants drawn from those with radiological consolidation or PF, with S. pneumoniae and S. aureus the leading pathogens identified.

Urinary arsenic is associated with wasting and underweight status in young children in rural Bangladesh.

BACKGROUND: Deficits in child growth are associated with poor cognitive outcomes and an increased risk for infection and mortality globally. One hundred forty million people are chronically exposed to arsenic from contaminated drinking water worldwide. While arsenic exposure has been associated with cognitive developmental delays in children, there is limited research on the association between arsenic exposure and growth deficits in young children. PURPOSE: The objective of this study was to assess the association between chronic arsenic exposure and deficits in growth among children under 5 years in a rural setting in Bangladesh. METHODS: Urinary arsenic measurements were collected from 465 children between the ages of 28 days-59 months in rural Matlab, Bangladesh, and analyzed by graphite furnace atomic absorption. Height and weight measurements were collected from children according to World Health Organization child growth standards. A z-score cutoff2 standard deviations below the mean was used to define stunting (height-for-age z-score), underweight (weight-for-age z-score), and wasting (weight-for-height z-score). RESULTS: Children under 5 years with urinary arsenic concentrations in the third tertile (greater than 31 µg per liter (µg/L)) had a two times higher odds of being underweight after adjustment for age, creatinine, paternal education, breastfeeding, number of individuals using the same sleeping room, and physician-diagnosed pneumonia (Odds Ratio (OR): 2.29 (95% Confidence Interval (CI): 1.16, 4.52)). Children under 2 years of age had a two times higher odds of being wasted after adjustment for age, creatinine, paternal education, breastfeeding, number of individuals using the same sleeping room, and physician-diagnosed pneumonia (OR: 2.85 (95% CI: 1.18, 6.89)). CONCLUSIONS: These findings suggest that arsenic exposure is associated with an increased odds of being wasted and underweight among young children in rural Bangladesh.

The Predictive Performance of a Pneumonia Severity Score in Human Immunodeficiency Virus-negative Children Presenting to Hospital in 7 Low- and Middle-income Countries.

BACKGROUND: In 2015, pneumonia remained the leading cause of mortality in children aged 1-59 months. METHODS: Data from 1802 human immunodeficiency virus (HIV)-negative children aged 1-59 months enrolled in the Pneumonia Etiology Research for Child Health (PERCH) study with severe or very severe pneumonia during 2011-2014 were used to build a parsimonious multivariable model predicting mortality using backwards stepwise logistic regression. The PERCH severity score, derived from model coefficients, was validated on a second, temporally discrete dataset of a further 1819 cases and compared to other available scores using the C statistic. RESULTS: Predictors of mortality, across 7 low- and middle-income countries, were age <1 year, female sex, ≥3 days of illness prior to presentation to hospital, low weight for height, unresponsiveness, deep breathing, hypoxemia, grunting, and the absence of cough. The model discriminated well between those who died and those who survived (C statistic = 0.84), but the predictive capacity of the PERCH 5-stratum score derived from the coefficients was moderate (C statistic = 0.76). The performance of the Respiratory Index of Severity in Children score was similar (C statistic = 0.76). The number of World Health Organization (WHO) danger signs demonstrated the highest discrimination (C statistic = 0.82; 1.5% died if no danger signs, 10% if 1 danger sign, and 33% if ≥2 danger signs). CONCLUSIONS: The PERCH severity score could be used to interpret geographic variations in pneumonia mortality and etiology. The number of WHO danger signs on presentation to hospital could be the most useful of the currently available tools to aid clinical management of pneumonia.

The impact of serotype-specific vaccination on phylodynamic parameters of Streptococcus pneumoniae and the pneumococcal pan-genome.

In the United States, the introduction of the heptavalent pneumococcal conjugate vaccine (PCV) largely eliminated vaccine serotypes (VT); non-vaccine serotypes (NVT) subsequently increased in carriage and disease. Vaccination also disrupts the composition of the pneumococcal pangenome, which includes mobile genetic elements and polymorphic non-capsular antigens important for virulence, transmission, and pneumococcal ecology. Antigenic proteins are of interest for future vaccines; yet, little is known about how the they are affected by PCV use. To investigate the evolutionary impact of vaccination, we assessed recombination, evolution, and pathogen demographic history of 937 pneumococci collected from 1998-2012 among Navajo and White Mountain Apache Native American communities. We analyzed changes in the pneumococcal pangenome, focusing on metabolic loci and 19 polymorphic protein antigens. We found the impact of PCV on the pneumococcal population could be observed in reduced diversity, a smaller pangenome, and changing frequencies of accessory clusters of orthologous groups (COGs). Post-PCV7, diversity rebounded through clonal expansion of NVT lineages and inferred in-migration of two previously unobserved lineages. Accessory COGs frequencies trended toward pre-PCV7 values with increasing time since vaccine introduction. Contemporary frequencies of protein antigen variants are better predicted by pre-PCV7 values (1998-2000) than the preceding period (2006-2008), suggesting balancing selection may have acted in maintaining variant frequencies in this population. Overall, we present the largest genomic analysis of pneumococcal carriage in the United States to date, which includes a snapshot of a true vaccine-naïve community prior to the introduction of PCV7. These data improve our understanding of pneumococcal evolution and emphasize the need to consider pangenome composition when inferring the impact of vaccination and developing future protein-based pneumococcal vaccines.

Global emergence and population dynamics of divergent serotype 3 CC180 pneumococci.

Streptococcus pneumoniae serotype 3 remains a significant cause of morbidity and mortality worldwide, despite inclusion in the 13-valent pneumococcal conjugate vaccine (PCV13). Serotype 3 increased in carriage since the implementation of PCV13 in the USA, while invasive disease rates remain unchanged. We investigated the persistence of serotype 3 in carriage and disease, through genomic analyses of a global sample of 301 serotype 3 isolates of the Netherlands3-31 (PMEN31) clone CC180, combined with associated patient data and PCV utilization among countries of isolate collection. We assessed phenotypic variation between dominant clades in capsule charge (zeta potential), capsular polysaccharide shedding, and susceptibility to opsonophagocytic killing, which have previously been associated with carriage duration, invasiveness, and vaccine escape. We identified a recent shift in the CC180 population attributed to a lineage termed Clade II, which was estimated by Bayesian coalescent analysis to have first appeared in 1968 [95% HPD: 1939-1989] and increased in prevalence and effective population size thereafter. Clade II isolates are divergent from the pre-PCV13 serotype 3 population in non-capsular antigenic composition, competence, and antibiotic susceptibility, the last of which resulting from the acquisition of a Tn916-like conjugative transposon. Differences in recombination rates among clades correlated with variations in the ATP-binding subunit of Clp protease, as well as amino acid substitutions in the comCDE operon. Opsonophagocytic killing assays elucidated the low observed efficacy of PCV13 against serotype 3. Variation in PCV13 use among sampled countries was not independently correlated with the CC180 population shift; therefore, genotypic and phenotypic differences in protein antigens and, in particular, antibiotic resistance may have contributed to the increase of Clade II. Our analysis emphasizes the need for routine, representative sampling of isolates from disperse geographic regions, including historically under-sampled areas. We also highlight the value of genomics in resolving antigenic and epidemiological variations within a serotype, which may have implications for future vaccine development.