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Objectives: We estimated the global impact of rotavirus vaccines on deaths among children under five years old by year., Methods: We used a proportionate outcomes model with a finely disaggregated age structure to estimate rotavirus deaths prevented by vaccination over the period 2006-2019 in 186 countries. We ran deterministic and probabilistic uncertainty analyses and compared our estimates to surveillance-based estimates in 20 countries., Results: We estimate that rotavirus vaccines prevented 139,000 under-five rotavirus deaths (95% uncertainty interval 98,000-201,000) in the period 2006-2019. In 2019 alone, rotavirus vaccines prevented 15% (95% uncertainty interval 11-21%) of under-five rotavirus deaths (0.5% of child mortality). Assuming global use of rotavirus vaccines and coverage equivalent to other co-administered vaccines could prevent 37% of under-five rotavirus deaths (1.2% of child mortality). Our estimates were sensitive to the choice of rotavirus mortality burden data and several vaccine impact modeling assumptions. The World Health Organization's recommendation to remove age restrictions in 2012 could have prevented up to 17,000 rotavirus deaths in the period 2013-2019. Our modeled estimates of rotavirus vaccine impact were broadly consistent with estimates from post-vaccination surveillance sites., Conclusion: Rotavirus vaccines have made a valuable contribution to global public health. Enhanced rotavirus mortality prevention strategies are needed in countries with high mortality in under-5-year-old children., Competing Interests: Declarations of competing interest The authors have no competing interests to declare., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Premature unblinding of individual participants is rarely reported in publications, but such unblinding can disrupt vaccine trials by causing worry and drop-out of other participants or "pseudo unblinding," in which participants or investigators over-interpret certain symptoms as being related to receiving an investigational product. This review summarizes appropriate reasons for unblinding in vaccine trials. Regulatory guidance could be improved by distinguishing guidance for vaccine trials from drug trials, with the recognition that unblinding individual participants in vaccine studies is rarely needed for management of adverse events following immunization., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: All authors received support from the Coalition for Epidemic Preparedness Innovations(CEPI) either directly or through a grant administered by the Task Force for Child Survival. NH reports ongoing support from Hillevax and Takeda, and past support from Pfizer, Valneva, and Inovio for service on safety reviews or DSMBs, and support from ILiAD Biotechnologies for an advisory board. CD reports a relationship with Dynavax Technologies Corporation that includes equity or stocks and service on a Scientific Advisory Board for Medicago. MD reports current research support from Merck and previous research support from Walgreens. CW reports suppoort from Moderna Inc that includes consulting or advisory. UH reports support from Pfizer Inc, Sanofi Aventis France, InfectoPharm Medicines and Advice GmbH that includes: speaking and lecture fees, from Takeda Switzerland and HilleVax that includes consulting or advisory. KE reports support from Pfizer, Moderna, GSK, Seqirus, Merck; Roche, Sanofi for sevice on advisory committees or DSMBs and consulting fees from Bionet and X-4 Pharma.WO serves as an uncompensated member of the Moderna Scientific Advisory Board. CW reports support from Moderna. MS reports consulting, advisory, or speaking and lecture fees with Pfizer, GlaxoSmithKline, Sanofi, Merck & Co Inc, AstraZeneca Pharmaceuticals LP, Janssen Pharmaceuticals Inc and board membership with Janssen. AH, RC, JB, SE, JE, NKA,SO,YJ, NB and PP report no conflicts., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Objectives: We determined the pulse oximetry benefit in pediatric pneumonia mortality risk stratification and chest-indrawing pneumonia in-hospital mortality risk factors., Methods: We report the characteristics and in-hospital pneumonia-related mortality of children aged 2-59 months who were included in the Pneumonia Research Partnership to Assess WHO Recommendations dataset. We developed multivariable logistic regression models of chest-indrawing pneumonia to identify mortality risk factors., Results: Among 285,839 children, 164,244 (57.5%) from hospital-based studies were included. Pneumonia case fatality risk (CFR) without pulse oximetry measurement was higher than with measurement (5.8%, 95% confidence interval [CI] 5.6-5.9% vs 2.1%, 95% CI 1.9-2.4%). One in five children with chest-indrawing pneumonia was hypoxemic (19.7%, 95% CI 19.0-20.4%), and the hypoxemic CFR was 10.3% (95% CI 9.1-11.5%). Other mortality risk factors were younger age (either 2-5 months [adjusted odds ratio (aOR) 9.94, 95% CI 6.67-14.84] or 6-11 months [aOR 2.67, 95% CI 1.71-4.16]), moderate malnutrition (aOR 2.41, 95% CI 1.87-3.09), and female sex (aOR 1.82, 95% CI 1.43-2.32)., Conclusion: Children with a pulse oximetry measurement had a lower CFR. Many children hospitalized with chest-indrawing pneumonia were hypoxemic and one in 10 died. Young age and moderate malnutrition were risk factors for in-hospital chest-indrawing pneumonia-related mortality. Pulse oximetry should be integrated in pneumonia hospital care for children under 5 years., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

In 2017, to reduce the burden of measles and rubella, a nation-wide measles-rubella campaign was launched in India. Despite detailed planning efforts that involved many stakeholders, vaccine refusal arose in several communities during the campaign. As strategic health communication and promotion is critical in any vaccine campaign, we sought to document lessons learned from the 2017 MR campaign from a strategic health communication and promotion perspective to capture lessons learned. To inform future campaigns, we conducted in-depth interviews through a perspective that is not usually captured, that of government and civil society stakeholders that had experience in vaccine campaign implementation (n = 21). We interviewed stakeholders at the national level and within three states that had diverse experiences with the campaign. Three key themes related to strategic health communication and promotion emerged: the importance of sensitizing communities at all levels through relevant and timely information about the vaccine and the vaccine campaign, leveraging key influencers to deliver tailored messaging about the importance of vaccines and mitigating vaccine misinformation rapidly. Our study findings have important implications for health communication and promotion research related to vaccine campaigns. The field must continue to enhance vaccine campaign efforts by identifying important health communication and promotion factors, including the importance of sensitization, trusted messengers that use tailored messaging and mitigating misinformation, as vaccine campaigns are crucial in improving vaccine acceptance., (© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Australian First Nations children are at very high risk of early, recurrent, and persistent bacterial otitis media and respiratory tract infection. With the PREVIX randomised controlled trials, we aimed to evaluate the immunogenicity of novel pneumococcal conjugate vaccine (PCV) schedules., Methods: PREVIX_BOOST was a parallel, open-label, outcome-assessor-blinded, randomised controlled trial. Aboriginal children living in remote communities of the Northern Territory of Australia were eligible if they had previously completed the three-arm PREVIX_COMBO randomised controlled trial of the following vaccine schedules: three doses of a 13-valent PCV (PCV13; PPP) or a ten-valent pneumococcal Haemophilus influenzae protein D conjugate vaccine (PHiD-CV10; SSS) given at 2, 4, and 6 months, or SSS given at 1, 2, and 4 months followed by PCV13 at 6 months (SSSP). At age 12 months, eligible children were randomly assigned by a computer-generated random sequence (1:1, stratified by primary group allocation) to receive either a PCV13 booster or a PHiD-CV10 booster. Analyses used intention-to-treat principles. Co-primary outcomes were immunogenicity against protein D and serotypes 3, 6A, and 19A. Immunogenicity measures were geometric mean concentrations (GMC) and proportion of children with IgG concentrations of 0·35 μg/mL or higher (threshold for invasive pneumococcal disease), and GMCs and proportion of children with antibody levels of 100 EU/mL or higher against protein D. Standardised assessments of otitis media, hearing impairment, nasopharyngeal carriage, and developmental outcomes are reported. These trials are registered with ClinicalTrials.gov (NCT01735084 and NCT01174849)., Findings: Between April 10, 2013, and Sept 4, 2018, 261 children were randomly allocated to receive a PCV13 booster (n=131) or PHiD-CV10 booster (n=130). Adequate serum samples for pneumococcal serology were obtained from 127 (95%) children in the PCV13 booster group and 126 (97%) in the PHiD-CV10 booster group; for protein D, adequate samples were obtained from 126 (96%) children in the PCV13 booster group and 123 (95%) in the PHiD-CV10 booster group. The proportions of children with IgG concentrations above standard thresholds in PCV13 booster versus PHiD-CV10 booster groups were the following: 71 (56%) of 126 versus 81 (66%) of 123 against protein D (difference 10%, 95% CI -2 to 22), 85 (67%) of 127 versus 59 (47%) of 126 against serotype 3 (-20%, -32 to -8), 119 (94%) of 127 versus 91 (72%) of 126 against serotype 6A (-22%, -31 to -13), and 116 (91%) of 127 versus 108 (86%) of 126 against serotype 19A (-5%, -13 to 3). Infant PCV13 priming mitigated differences between PCV13 and PHiD-CV10 boosters. In both groups, we observed a high prevalence of otitis media (about 90%), hearing impairment (about 75%), nasopharyngeal carriage of pneumococcus (about 66%), and non-typeable H influenzae (about 57%). Of 66 serious adverse events, none were vaccine related., Interpretation: Low antibody concentrations 6 months post-booster might indicate increased risk of pneumococcal infection. The preferred booster was PCV13 if priming did not have PCV13, otherwise either PCV13 or PHiD-CV10 boosters provided similar immunogenicity. Mixed schedules offer flexibility to regional priorities. Non-PCV13 serotypes and non-typeable H influenzae continue to cause substantial disease and disability in Australian First Nation's children., Funding: National Health and Medical Research Council (NHMRC)., Competing Interests: Declaration of interests ABC served as advisor on an unlicensed vaccine (GlaxoSmithKline) and an unlicensed monoclonal antibody (AstraZeneca), was an adviser on an unlicensed molecule for chronic cough (Merck); and has various project grants and a Centre of Research Excellence relating to various aspects of bronchiectasis in children from the National Health and Medical Research Council. PM served on a data safety and monitoring board for the Novavax COVID-19 vaccine. JB provided a report to MSD Australia. All other authors declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: Bangladesh introduced the 10-valent pneumococcal conjugate vaccine (PCV10) for children aged < 1 year in March 2015. Previous vaccine effectiveness (VE) studies for pneumonia have used invasive pneumococcal disease or chest X-rays. None have used ultrasound. We sought to determine the VE of PCV10 against sonographically-confirmed pneumonia in three subdistrict health complexes in Bangladesh., Methods: We conducted a matched case-control study between July 2015 and September 2017 in three subdistricts of Sylhet, Bangladesh. Cases were vaccine-eligible children aged 3-35 months with sonographically-confirmed pneumonia, who were matched with two types of controls by age, sex, week of diagnosis, subdistrict health complex (clinic controls) or distance from subdistrict health complex (community controls) and had an illness unlikely due to Streptococcus pneumoniae (clinic controls) or were healthy (community controls). VE was measured using multivariable conditional logistic regression., Results: We evaluated 8926 children (average age 13.3 months, 58% boys) with clinical pneumonia by ultrasound; 2470 had pneumonia with consolidations ≥ 1 cm; 1893 pneumonia cases were matched with 4238 clinic controls; and 1832 were matched with 3636 community controls. VE increased with the threshold used for consolidation size on ultrasound: the adjusted VE of ≥ 2 doses vs. non-recipients of PCV10 against pneumonia increased from 15.8% (95% CI 1.6-28.0%) for consolidations ≥ 1 cm to 29.6% (12.8-43.2%) for consolidations ≥ 1.5 cm using clinic controls and from 2.7% (- 14.2-17.2%) to 23.5% (4.4-38.8%) using community controls, respectively., Conclusions: PCV10 was effective at reducing sonographically-confirmed pneumonia in children aged 3-35 months of age when compared to unvaccinated children. VE increased with the threshold used for consolidation size on ultrasound in clinic and community controls alike. This study provides evidence that lung ultrasound is a useful alternative to chest X-ray for case-control studies evaluating the effectiveness of vaccines against pneumonia., (© 2022. The Author(s).)

Background: Indoor air pollution is associated with adverse health effects; however, few studies exist studying indoor air pollution on the Navajo Nation in the southwest U.S., a community with high rates of respiratory disease., Methods: Indoor PM 2.5 concentration was evaluated in 26 homes on the Navajo Nation using real-time PM 2.5 monitors. Household risk factors and daily activities were evaluated with three metrics of indoor PM 2.5 : time-weighted average (TWA), 90th percentile of concentration, and daily minutes exceeding 100 μg/m 3 . A questionnaire and recall sheet were used to record baseline household characteristics and daily activities., Results: The median TWA, 90th percentile, and daily minutes exceeding 100 μg/m 3 were 7.9 μg/m 3 , 14.0 μg/m 3 , and 17 min, respectively. TWAs tended to be higher in autumn and in houses that used fuel the previous day. Other characteristics associated with elevated PM exposure in all metrics included overcrowded houses, nonmobile houses, and houses with current smokers, pets, and longer cooking time., Conclusions: Some residents of the Navajo Nation have higher risk of exposure to indoor air pollution by Environmental Protection Agency (EPA) standards. Efforts to identify the causes and associations with adverse health effects are needed to ensure that exposure to risks and possible health impacts are mitigated., (© 2021. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Introduction: Few studies have described the drivers of vaccine hesitancy and acceptance in India from the perspective of those involved in the design and implementation of vaccine campaigns-such as government officials and civil society stakeholders-a prerequisite to developing approaches to address this barrier to high immunization coverage and further child health improvements., Methods: We conducted a qualitative study to understand government officials and civil society stakeholders' perceptions of the drivers of vaccine hesitancy in India. We conducted in-depth phone interviews using a structured guide of open-ended questions with 21 participants from international and national non-governmental organizations, professional associations, and universities, and state and national government-six national-level stakeholders in New Delhi, six state-level stakeholders in Uttar Pradesh, six in Kerala, and three in Gujarat-from July 2020 to October 2020. We analyzed data through a multi-stage process following Grounded Theory. We present findings on individual-level, contextual, and vaccine/vaccination program-specific factors influencing vaccine hesitancy., Results: We identified multiple drivers and complex ways they influence vaccine beliefs, attitudes, and behaviors from the perspective of government officials and civil society stakeholders involved in vaccine campaigns. Important individual-level influences were low awareness of the benefits of vaccination, safety concerns, especially related to mild adverse events following immunization, and mistrust in government and health service quality. Contextual-level factors included communications, the media environment, and social media, which serves as a major conduit of misinformation and driver of hesitancy, as well as sociodemographic factors-specific drivers varied widely by income, education, urban/rural setting, and across religious and cultural groups. Among vaccine/vaccination-level issues, vaccine program design and delivery and the role of health care professionals emerged as the strongest determinants of hesitancy., Conclusions: Drivers of vaccine hesitancy in India, as elsewhere, vary widely by local context; successful interventions should address individual, contextual, and vaccine-specific factors. While previous studies focused on individual-level factors, our study demonstrates the equal importance of contextual and vaccine-specific influences, especially the communication and media environment, influential leaders, sociodemographic factors, and frontline health workers., Competing Interests: The authors have declared that no competing interests exist.

Introduction: Existing risk assessment tools to identify children at risk of hospitalised pneumonia-related mortality have shown suboptimal discriminatory value during external validation. Our objective was to derive and validate a novel risk assessment tool to identify children aged 2-59 months at risk of hospitalised pneumonia-related mortality across various settings., Methods: We used primary, baseline, patient-level data from 11 studies, including children evaluated for pneumonia in 20 low-income and middle-income countries. Patients with complete data were included in a logistic regression model to assess the association of candidate variables with the outcome hospitalised pneumonia-related mortality. Adjusted log coefficients were calculated for each candidate variable and assigned weighted points to derive the Pneumonia Research Partnership to Assess WHO Recommendations (PREPARE) risk assessment tool. We used bootstrapped selection with 200 repetitions to internally validate the PREPARE risk assessment tool., Results: A total of 27 388 children were included in the analysis (mean age 14.0 months, pneumonia-related case fatality ratio 3.1%). The PREPARE risk assessment tool included patient age, sex, weight-for-age z-score, body temperature, respiratory rate, unconsciousness or decreased level of consciousness, convulsions, cyanosis and hypoxaemia at baseline. The PREPARE risk assessment tool had good discriminatory value when internally validated (area under the curve 0.83, 95% CI 0.81 to 0.84)., Conclusions: The PREPARE risk assessment tool had good discriminatory ability for identifying children at risk of hospitalised pneumonia-related mortality in a large, geographically diverse dataset. After external validation, this tool may be implemented in various settings to identify children at risk of hospitalised pneumonia-related mortality., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Puerperal sepsis (PP sepsis) is a leading cause of maternal mortality globally. The majority of maternal sepsis cases and deaths occur at home and remain undiagnosed and under-reported. In this paper, we present findings from a nested case-control study in Bangladesh and Pakistan which sought to assess the validity of community health worker (CHW) identification of PP sepsis using a clinical diagnostic algorithm with physician assessment and classification used as the gold standard., Methods: Up to 300 postpartum women were enrolled in each of the 3 sites 1) Sylhet, Bangladesh (n = 278), 2) Karachi, Pakistan (n = 278) and 3) Matiari, Pakistan (n = 300). Index cases were women with suspected PP Sepsis as diagnosed by CHWs clinical assessment of one or more of the following signs and symptoms: temperature (recorded fever ≥38.1°C, reported history of fever, lower abdominal or pelvic pain, and abnormal or foul-smelling discharge. Each case was matched with 3 control women who were diagnosed by CHWs to have no infection. Cases and controls were assessed by trained physicians using the same algorithm implemented by the CHWs. Using physician assessment as the gold standard, Kappa statistics for reliability and diagnostic validity (sensitivity and specificity) are presented with 95% CI. Sensitivity and specificity were adjusted for verification bias., Results: The adjusted sensitivity and specificity of CHW identification of PP sepsis across all sites was 82% (Karachi: 78%, Matiari: 78%, Sylhet: 95%) and 90% (Karachi: 95%, Matiari: 85%, Sylhet: 90%) respectively. CHW-Physician agreement was highest for moderate and high fever (range across sites: K = 0.84-0.97) and lowest for lower abdominal pain (K = 0.30-0.34). The clinical signs and symptoms for other conditions were reported infrequently, however, the CHW-physician agreement was high for all symptoms except severe headache/ blurred vision (K = 0.13-0.38) and reported "lower abdominal pain without fever" (K = 0.39-0.57)., Conclusion: In all sites, CHWs with limited training were able to identify signs and symptoms and to classify cases of PP sepsis with high validity. Integrating postpartum infection screening into existing community-based platforms and post-natal visits is a promising strategy to monitor women for PP sepsis - improving delivery of cohesive maternal and child health care in low resource settings., Competing Interests: Competing interests: The authors completed the ICMJE Declaration of Interest Form (available upon request from the corresponding author), and declare no conflicts of interest., (Copyright © 2021 by the Journal of Global Health. All rights reserved.)

Background: Existing scores to identify children at risk of hospitalized pneumonia-related mortality lack broad external validation. Our objective was to externally validate three such risk scores., Methods: We applied the Respiratory Index of Severity in Children (RISC) for HIV-negative children, the RISC-Malawi, and the Pneumonia Etiology Research for Child Health (PERCH) scores to hospitalized children in the Pneumonia REsearch Partnerships to Assess WHO REcommendations (PREPARE) data set. The PREPARE data set includes pooled data from 41 studies on pediatric pneumonia from across the world. We calculated test characteristics and the area under the curve (AUC) for each of these clinical prediction rules., Results: The RISC score for HIV-negative children was applied to 3574 children 0-24 months and demonstrated poor discriminatory ability (AUC = 0.66, 95% confidence interval (CI) = 0.58-0.73) in the identification of children at risk of hospitalized pneumonia-related mortality. The RISC-Malawi score had fair discriminatory value (AUC = 0.75, 95% CI = 0.74-0.77) among 17 864 children 2-59 months. The PERCH score was applied to 732 children 1-59 months and also demonstrated poor discriminatory value (AUC = 0.55, 95% CI = 0.37-0.73)., Conclusions: In a large external application of the RISC, RISC-Malawi, and PERCH scores, a substantial number of children were misclassified for their risk of hospitalized pneumonia-related mortality. Although pneumonia risk scores have performed well among the cohorts in which they were derived, their performance diminished when externally applied. A generalizable risk assessment tool with higher sensitivity and specificity to identify children at risk of hospitalized pneumonia-related mortality may be needed. Such a generalizable risk assessment tool would need context-specific validation prior to implementation in that setting., Competing Interests: Competing interests: The authors have completed the ICMJE Declaration of Interest Form (available upon request from the corresponding author), and declare no conflicts of interest. YBN is staff member of the World Health Organization., (Copyright © 2021 by the Journal of Global Health. All rights reserved.)

Background: Bangladesh introduced the ten-valent pneumococcal conjugate vaccine (PCV10) into its national immunization program in March 2015 creating an opportunity to assess the real-world impact of PCV on invasive pneumococcal disease (IPD)., Methods: Between January 2014 and June 2018, children aged 3-35 months in three rural sub-districts of Sylhet district of Bangladesh were visited every two months to collect morbidity and care-seeking data. Children attending sub-district hospitals with pneumonia, meningitis, or sepsis were assessed for IPD after obtaining informed consent. Blood and cerebrospinal fluid were collected from enrolled children to isolate pneumococcus using culture and molecular test. Children who were age-eligible to receive the PCV and had pneumococcus isolated were enrolled as cases. Four age and sex-matched clinic and community controls were selected for each case within one to two weeks of case identification. Data on immunization status and confounders were collected. PCV coverage was estimated using vaccine coverage surveys. Case-control and incidence trend analyses were conducted to assess the impact of PCV on IPD., Results: The community cohort yielded 217,605 child years of observations and 154,773 sick child-visits to study hospitals. Pneumococcus was isolated from 44 children who were age-eligible to receive PCV; these children were enrolled as cases. The cases were matched with 166 community- and 150 clinic-controls. The matched case-control analyses using community-controls showed 83% effectiveness (95% CI: 1.57-97.1%) and clinic controls showed 90% effectiveness (95% CI: -26.0% to 99.1%) of PCV in preventing IPD. Incidence trend analysis estimated vaccine effectiveness at 80.1% (95% CI: 38.4, 93.6)., Conclusion: PCV in this pediatric population in Bangladesh was highly effective in preventing IPD., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021. Published by Elsevier Ltd.)

Background: India has made substantial progress in improving child health in recent years. However, the country continues to account for a large number of vaccine preventable child deaths. We estimated wealth-related full immunization inequalities in India. We also calculated the degree to which predisposing, reinforcing, and enabling factors contribute to these inequalities., Methods: We used data from the two rounds of a large nationally representative survey done in all states in India in 2005-06 (n = 9582) and 2015-16 (n = 49,284). Full immunization status was defined as three doses of diphtheria-tetanus-pertussis vaccine, three doses of polio vaccine, one dose of Bacillus Calmette-Guérin vaccine, and one dose of measles vaccine in children 12-23 months. We compared full immunization coverage by wealth quintiles using descriptive statistics. We calculated concentration indices for full immunization coverage at the national and state levels. Using predisposing, reinforcing, and enabling factors associated with full immunization status identified from the literature, we applied a generalized linear model (GLM) framework with a binomial distribution and an identity link to decompose the concentration index., Results: National full immunization coverage increased from 43.65% in 2005-06 to 62.46% in 2015-16. Overall, full immunization coverage in both 2005-06 and 2015-16 in all states was lowest in children from poorer households and improved with increasing socioeconomic status. The national concentration index decreased from 0.36 to 0.13 between the two study periods, indicating a reduction in poor-rich inequality. Similar reductions were observed for most states, except in states where inequalities were already minimal (i.e., Tamil Nadu) and in some northeastern states (i.e., Meghalaya and Manipur). In 2005-06, the contributors to wealth-related full immunization inequality were antenatal care, maternal education, and socioeconomic status. The same factors contributed to full immunization inequality in 2015-16 in addition to difficulty reaching a health facility., Conclusions: Immunization coverage and wealth-related equality have improved nationally and in most states over the last decade in India. Targeted, context-specific interventions could help address overall wealth-related full immunization inequalities. Intensified government efforts could help in this regard, particularly in high-focus states where child mortality remains high.

Rotavirus is the leading cause of severe dehydrating gastroenteritis and death due to diarrhea among children under 5, causing over 180,000 under-5 deaths annually. Safe, effective rotavirus vaccines have been available for over a decade and are used in over 98 countries. In addition to the globally available, WHO-prequalified ROTARIX (GSK) and RotaTeq (Merck), several new rotavirus vaccines have attained national licensure - ROTAVAC (Bharat Biotech) and ROTASIIL (Serum Institute of India), licensed and manufactured in India and now WHO-prequalified, and Rotavin-M1 (PolyVac), licensed and manufactured in Vietnam. In this review, we summarize the available clinical trial and post-introduction evidence for these three new orally administered rotavirus vaccines. All three vaccines have demonstrated safety and efficacy against rotavirus diarrhea, although publicly available preclinical data are limited in some cases. This expanding product landscape presents a range of options to optimize immunization programs, and new presentations of each vaccine are currently under development.

Background: Aboriginal children living in Australian remote communities are at high risk of early and persistent otitis media, hearing loss, and social disadvantage. Streptococcus pneumoniae and non-typeable Haemophilus influenzae (NTHi) are the primary pathogens. We compared otitis media outcomes in infants randomised to either a combination of Synflorix™ (PHiD-CV10, with protein D of NTHi) and Prevenar13™ (PCV13, with 3, 6A, and 19A), with recommended schedules for each vaccine alone. We previously reported superior broader overall immunogenicity of the combination schedule at 7 months, and early superiority of PHiD-CV10 compared to PCV13 at 4 months., Methods: In an open-label superiority trial, we randomised (1:1:1) Aboriginal infants at 28 to 38 days of age, to either Prevenar13™ (P) at 2-4-6 months (&#95;PPP), Synflorix™ (S) at 2-4-6 months (&#95;SSS), or Synflorix™ at 1-2-4 months plus Prevenar13™ at 6 months (SSSP). Ears were assessed using tympanometry at 1 and 2 months, combined with otoscopy at 4, 6, and 7 months. A worst ear diagnosis was made for each child visit according to a severity hierarchy of normal, otitis media with effusion (OME), acute otitis media without perforation (AOMwoP), AOM with perforation (AOMwiP), and chronic suppurative otitis media (CSOM)., Results: Between September 2011 and September 2017, 425 infants were allocated to &#95;PPP(143), &#95;SSS(141) or SSSP(141). Ear assessments were successful in 96% scheduled visits. At 7 months prevalence of any OM was 91, 86, and 90% in the &#95;PPP, &#95;SSS, and SSSP groups, respectively. There were no significant differences in prevalence of any form of otitis media between vaccine groups at any age. Combined group prevalence of any OM was 43, 57, 82, 87, and 89% at 1, 2, 4, 6, and 7 months of age, respectively. Of 388 infants with ear assessments at 4, 6 and 7 months, 277 (71.4%) had OM that met criteria for specialist referral; rAOM, pOME, or CSOM., Conclusions: Despite superior broader overall immunogenicity of the combination schedule at 7 months, and early superiority of PHiD-CV10 compared to PCV13 at 4 months, there were no significant differences in prevalence of otitis media nor healthy ears throughout the first months of life., Trial Registration: ACTRN12610000544077 registered 06/07/2010 and ClinicalTrials.gov NCT01174849 registered 04/08/2010.

Background: Aboriginal children living in remote communities are at high risk of early and persistent otitis media. Streptococcus pneumoniae and non-typeable Haemophilus influenzae (NTHi) are primary pathogens. Vaccines with potential to prevent early OM have not been evaluated in this population. We compared immunogenicity (ELISA and opsonophagocytic activity) of a combination of Synflorix™ (PHiD-CV10, 10 serotypes and protein D of NTHi) and Prevenar13™ (PCV13, 10 serotypes plus 3, 6A, and 19A), with recommended schedules., Methods: This open-label superiority trial randomised (1:1:1) Aboriginal infants at 28 to 38 days of age, to PCV13 (P) at 2-4-6 months (&#95;PPP), PHiD-CV10 (S) at 2-4-6 months (&#95;SSS), or PHiD-CV10 at 1-2-4 plus PCV13 at -6 months (SSSP). Primary outcomes (blinded) were immunogenicity against PCV13-only serotypes 3, 6A, 19A, and PHiD-CV10-only protein D at 7 months. Secondary outcomes include immunogenicity against all serotypes at 2, 4 and 7 months., Findings: Between 2011 and 2017, 425 infants were allocated to &#95;PPP(143), &#95;SSS(141) or SSSP(1 4 1). An intention to treat approach including all available data was used. The SSSP group had superior immunogenicity against serotypes 3, 6A, and 19A compared to &#95;SSS (OPA GMT ratios 8.1 to 59.5, p < 0.001), and against protein D compared to &#95;PPP (GMC ratio 11.9 (95%CI 9.7 to 14.6)). Immune responses to protein D and 3, 6A, and 19A in SSSP were not significantly lower (i.e. no harm) than either &#95;SSS or &#95;PPP. For ten common serotypes responses at 2, 4 and 7 months were superior for SSSP (following 1-, 2-, and 4- doses) than &#95;SSS and &#95;PPP (following 0-, 1-, and 3- doses). At 4 months, &#95;SSS was superior to &#95;PPP. Reactogenicity and hospitalisations were rare and unrelated to the intervention., Interpretation: From two months, the 1-2-4-6-month combined schedule (SSSP) was safe and significantly more immunogenic than 2-4-6-month schedules. The earlier responses may be beneficial in high-risk populations., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2021 The Author(s).)

Objectives: While India has made substantial progress in introducing new vaccines and scaling up immunization coverage, inequities persist sub-nationally. This study was performed to investigate the risk of under-immunization based on class membership and to identify heterogeneous classes based on sociodemographic characteristics in pediatric and maternal populations in India through latent class analysis., Methods: Data from the most recent National Family Health Survey conducted in 2015-2016 were used. Latent class analysis was used to model immunization coverage in children aged 12-23 months and mothers, and to identify subgroups to characterize those at risk of not being immunized., Results: Patterns of sociodemographic characteristics were found to contribute to non-immunization or under-immunization among pediatric and maternal populations in India. Individuals who fit into one of three categories were identified in both populations: those at high, medium, and lower risk of not being immunized. Lower socioeconomic status, lack of antenatal care, and lower maternal education put individuals at higher risk of not being immunized with routine childhood vaccines and maternal tetanus toxoid., Conclusions: Predisposing risk factors can persistently impact immunization status despite improvements in immunization access in India. Tailored programmatic interventions should be developed to improve immunization coverage among those children and mothers who are at highest risk of being under-immunized or not immunized., (Copyright © 2020 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

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., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests. ML has consulted for Pfizer, Affinivax, and Merck and has received grant support not related to this paper from Pfizer and PATH Vaccine Solutions. WPH, ML, and NJC have consulted for Antigen Discovery Inc. The authors have declared that no competing interests exist. KLOB has received grant support for pneumococcal work not related to this paper from Pfizer, GSK, and Gavi. KLOB has consulted for Merck and Sanofi Pasteur. LRG, LLH, and RCW have received grant support not related to this paper from Pfizer, Merck, and GSK.

Background: Pneumococcal conjugate vaccine (PCV) effectiveness against radiographic pneumonia in South Asia is unknown. Bangladesh introduced PCV10 in 2015 using a three dose primary series (3 + 0). We sought to measure PCV10 effectiveness for two or more vaccine doses on radiographic pneumonia among vaccine-eligible children in rural Bangladesh., Methods: We conducted a matched case-control study over two years from 2015 to 2017 using clinic and community controls in three subdistricts of Sylhet, Bangladesh. Cases were vaccine eligible 3-35 month olds at Upazila Health Complex outpatient clinics with World Health Organization-defined radiographic primary endpoint pneumonia (radiographic pneumonia). Clinic controls were matched to cases within a one week time window by age, sex, and clinic and had an illness unlikely to be Streptococcus pneumoniae; community controls were healthy and similarly matched within a one week time window by age and sex, and distance from the clinic. We estimated adjusted vaccine effectiveness (aVE) using conditional logistic regression., Results: We matched 1262 cases with 2707 clinic and 2461 community controls. Overall, aVE using clinic controls was 21.4% (95% confidence interval, -0.2%, 38.4%) for ≥2 PCV10 doses and among 3-11 month olds was 47.3% (10.5%, 69.0%) for three doses. aVE increased with higher numbers of doses in clinic control sets (p = 0.007). In contrast, aVE using community controls was 7.6% (95% confidence interval, -22.2%, 30.0%) for ≥2 doses. We found vaccine introduction in the study area faster and less variable than expected with 75% coverage on average, which reduced power. Information bias may also have affected community controls., Conclusions: Clinic control analyses show PCV10 prevented radiographic pneumonia in Bangladesh, especially among younger children receiving three doses. While both analyses were underpowered, community control enrollment - compared to clinic controls - was more difficult in a complex, pluralistic healthcare system. Future studies in comparable settings may consider alternative study designs., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: [EDM, SA, NHC, SJR, AMK, ADR, AAMH, FP, NS, MER, MH, HBS, AQ, NB, MS, LHM, WC, and AHB reports grants from Bill and Melinda Gates Foundation, grants from GlaxoSmithKline, during the conduct of the study.]., (Copyright © 2020 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: The absolute number of pneumonia deaths in India has declined substantially since 2000. However, pneumonia remains a major cause of morbidity in children in the country. We used a risk factor-based model to estimate pneumonia and severe pneumonia morbidity in Indian states in 2000 and 2015., Methods: In this modelling study, we estimated the burden of pneumonia and severe pneumonia in children younger than 5 years using a risk factor-based model. We did a systematic literature review to identify published data on the incidence of pneumonia from community-based longitudinal studies and calculated summary estimates. We estimated state-specific incidence rates for WHO-defined clinical pneumonia between 2000 and 2015 using Poisson regression and the prevalence of risk factors in each state was obtained from National Family Health Surveys. From clinical pneumonia studies, we identified studies reporting the proportion of clinical pneumonia cases with lower chest wall indrawing to estimate WHO-defined severe pneumonia cases. We used the estimate of the proportion of cases with lower chest wall indrawing to estimate WHO-defined severe pneumonia cases for each state., Findings: Between 2000 and 2015, the estimated number of pneumonia cases in Indian HIV-uninfected children younger than 5 years decreased from 83·8 million cases (95% uncertainty interval [UI] 14·0-300·8) to 49·8 million cases (9·1-174·2), representing a 41% reduction in pneumonia cases. The incidence of pneumonia in children younger than 5 years in India was 657 cases per 1000 children (95% UI 110-2357) in 2000 and 403 cases per 1000 children (74-1408) in 2015. The estimated national pneumonia case fatality rate in 2015 was 0·38% (95% UI 0·11-2·10). In 2015, the estimated number of severe pneumonia cases was 8·4 million (95% UI 1·2-31·7), with an incidence of 68 cases per 1000 children (9-257) and a case fatality ratio of 2·26% (0·60-16·30). In 2015, the estimated number of pneumonia cases in HIV-uninfected children was highest in Uttar Pradesh (12·4 million [95% UI 2·1-45·0]), Bihar (7·3 million [1·3-26·1]), and Madhya Pradesh (4·6 million [0·7-17·0]). Between 2000 and 2015, the greatest reduction in pneumonia cases was observed in Kerala (82% reduction). In 2015, pneumonia incidence was greater than 500 cases per 1000 children in two states: Uttar Pradesh (565 cases per 1000 children [95% UI 94-2047]) and Madhya Pradesh (563 cases per 1000 children [88-2084])., Interpretation: The estimated number of pneumonia and severe pneumonia cases among children younger than 5 years in India decreased between 2000 and 2015. Improvements in socioeconomic indicators and specific government initiatives are likely to have contributed to declines in the prevalence of pneumonia risk factors in many states. However, pneumonia incidence in many states remains high. The introduction of new vaccines that target pneumonia pathogens and reduce risk factors will help further reduce the burden of pneumonia in the country., Funding: Bill & Melinda Gates Foundation., (Copyright © 2020 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

In the early months of the pandemic, most reported cases and deaths due to COVID-19 occurred in high-income countries. However, insufficient testing could have led to an underestimation of true infections in many low- and middle-income countries. As confirmed cases increase, the ultimate impact of the pandemic on individuals and communities in low- and middle-income countries is uncertain. We therefore propose research in three broad areas as urgently needed to inform responses in low- and middle-income countries: transmission patterns of SARS-CoV-2, the clinical characteristics of the disease, and the impact of pandemic prevention and response measures. Answering these questions will require a multidisciplinary approach led by local investigators and in some cases additional resources. Targeted research activities should be done to help mitigate the potential burden of COVID-19 in low- and middle-income countries without diverting the limited human resources, funding, or medical supplies from response activities., Competing Interests: Competing interestsAll authors declare no competing interests., (© The Author(s) 2020.)

Introduction: Streptococcus pneumoniae and non-typeable Haemophilus influenzae (NTHi) are major otitis media pathogens that densely co-colonise the nasopharynx and infect the middle ear of Australian Aboriginal infants from very early in life. Our co-primary hypotheses are that at 18 months of age infants receiving 10-valent pneumococcal Haemophilus influenzae protein D conjugate vaccine (PHiD-CV10) compared with those receiving 13-valent pneumococcal conjugate vaccine (PCV13) as a booster at 12 months of age will have higher antibody levels to Haemophilus influenzae protein D and that infants receiving PCV13 will have higher antibody levels to PCV13-only serotypes 3, 6A and 19A., Methods and Analyses: Our randomised controlled trial will enrol 270 Aboriginal children at 12 months of age to a booster dose of either PHiD-CV10 or PCV13. Children who completed the three-dose primary course schedules of PHiD-CV10 at 2, 4, 6 months of age; PCV13 at 2, 4, 6 months of age; or a combination schedule of PHiD-CV10 at 1, 2, 4 months of age plus PCV13 at 6 months of age are eligible. The co-primary assessor-blinded outcomes when the infants are 18 months of age are as follows: (a) IgG geometric mean concentration (GMC) and proportion with IgG ≥100 EU/mL for protein D, and (b) IgG GMC and the proportion with IgG ≥0.35 µg/mL for pneumococcal serotypes 3, 6A and 19A. Secondary immunogenicity comparisons of six primary and booster dose schedules of 10 shared serotypes at 18 months of age, nasopharyngeal carriage, all forms of otitis media, hearing loss and developmental milestones at 18, 24, 30 and 36 months of age will be reported., Ethics and Dissemination: Ethics committees of NT Department of Health, Menzies, WA Department of Health and WA Aboriginal Health approved the study. Results will be presented to communities, at conferences and published in peer-reviewed journals., Trial Registration Number: NCT01735084., Competing Interests: Competing interests: In the last 5 years, AJL and PM have served on an OM Advisory Board for GSK and have received GSK support for the clinical outreach training program. KM has served on Advisory Boards for GSK who provided in kind support for the Vietnam Pneumococcal trial, of which he is the PI. His group is involved in a collaborative research project with Pfizer on adult pneumonia in Mongolia, and they have received a small grant to support research capacity building in the paediatric hospitals in Ho Chi Minh City, Vietnam. MS has served on the Advisory Board of GSK and Pfizer. He is also co-investigator on projects funded by GSK and Pfizer. ABC serves on an independent data safety monitoring board for two unlicensed GSK vaccines studies currently under evaluation. DL has received support from Pfizer Australia to attend conferences and is an investigator on an investigator-initiated research grant that was funded by Pfizer Australia., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: This study was done to determine the burden of invasive Staphylococcus aureus on the White Mountain Apache Tribal lands., Methods: Active population and laboratory-based surveillance for invasive S aureus infections was conducted from May 2016 to April 2018. A case was defined as a Native American individual living on or around the White Mountain Apache Tribal lands with S aureus isolated from a normally sterile body site., Results: Fifty-three cases were identified. Most cases were adults (90.6%) and had ≥1 underlying medical condition (86.8%), the most common of which were diabetes (49.1%) and obesity (41.5%). A total of 26.4% cases were categorized as community acquired. Most infections were methicillin-resistant (75.5%). A total of 7.5% of cases required amputation, and 7.7% of cases died within 30 days of initial culture. The incidence of invasive S aureus was 156.3 per 100 000 persons. The age-adjusted incidence of invasive methicillin-resistant S aureus was 138.2 per 100 000 persons., Conclusions: This community has a disproportionately high burden of invasive methicillin-resistant S aureus compared with the general US population. Interventions are urgently needed to reduce the morbidity and mortality associated with these infections., (© The Author(s) 2020. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Background: Bangladesh introduced the 10-valent pneumococcal conjugate vaccine (PCV-10) in 2015. We measured population-based incidence of invasive pneumococcal disease (IPD) prior to introduction of PCV-10 to provide a benchmark against which the impact of PCV-10 can be assessed., Methods: We conducted population, facility and laboratory-based surveillance in children 0-59 months of age in three rural sub-districts of Sylhet district of Bangladesh from January 2014 to June 2015. All children received two-monthly home visits with one week recall for morbidity and care seeking. Children attending the three Upazilla Health Complexes (UHC, sub-district hospitals) in the surveillance area were screened for suspected IPD. Blood samples were collected from suspected IPD cases for culture and additionally, cerebrospinal fluid (CSF) was collected from suspected meningitis cases for culture and molecular testing. Pneumococcal isolates were serotyped by Quellung. Serotyping of cases detected by molecular testing was done by sequential multiplex polymerase chain reaction., Results: Children under surveillance contributed to 126,657 child years of observations. Sixty-three thousand three hundred eighty-four illness episodes were assessed in the UHCs. Blood specimens were collected from 8,668 suspected IPD cases and CSF from 177 suspected meningitis cases. Streptococcus pneumoniae was isolated from 46 cases; 32 (70%) were vaccine serotype. The population-based incidence of IPD was 36.3/100,000 child years of observations. About 80% of the cases occurred in children below two years of age., Discussion: IPD was common in rural Bangladesh suggesting the potential benefit of an effective vaccine. Measurement of the burden of IPD requires multiple surveillance modalities., Competing Interests: The authors have declared that no competing interests exist.

Culture-based methods for detecting Streptococcus pneumoniae in the nasopharynx lack sensitivity. In this study, we aimed to compare the performance of culture and molecular methods in detecting pneumococcus in the nasopharynx of healthy individuals and to evaluate the associations of age and colonization density with detection. Between 2010 and 2012, nasopharyngeal specimens were collected from healthy individuals living on Navajo Nation and White Mountain Apache Tribal lands in the United States. Pneumococci were detected by means of broth-enrichment culture and autolysin-encoding gene (lytA) quantitative polymerase chain reaction (qPCR). Among 982 persons evaluated (median age, 18.7 years; 47% male), 35% were culture-positive and an additional 27% were qPCR-positive. Agreement between culture and qPCR was 70.9% but was higher among children (age <18 years) (75.9%-84.4%) than among adults (age ≥18 years) (61.0%-74.6%). The mean density of colonization was lower for culture-negative samples (3.14 log10 copies/mL) than for culture-positive samples (5.02 log10 copies/mL), overall and for all age groups. The percent culture-positive increased with increasing density, exceeding 80% at densities of ≥10,000 copies/mL. Mean colonization density decreased with age. Use of qPCR improved detection of pneumococcus in the nasopharynx of healthy individuals. This finding was most notable among adults, probably because of improved detection of low-density colonization., (© The Author(s) 2019. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Native American populations experience a substantial burden of pneumococcal disease despite use of highly effective pneumococcal conjugate vaccines (PCVs). Protein-based pneumococcal vaccines may extend protection beyond the serotype-specific protection elicited by PCVs., Methods: In this phase IIb, double-blind, controlled trial, 6-12 weeks-old Native American infants randomized 1:1, received either a protein-based pneumococcal vaccine (dPly/PhtD) containing pneumolysin toxoid (dPly, 10 µg) and pneumococcal histidine triad protein D (PhtD, 10 µg) or placebo, administered along with 13-valent PCV (PCV13) at ages 2, 4, 6 and 12-15 months. Other pediatric vaccines were given per the routine immunization schedule. We assessed vaccine efficacy (VE) against acute otitis media (AOM) and acute lower respiratory tract infection (ALRI) endpoints. Immunogenicity, reactogenicity and unsolicited adverse events were assessed in a sub-cohort and serious adverse events were assessed in all children., Results: 1803 infants were randomized (900 dPly/PhtD; 903 Control). VE against all episodes of American Academy of Pediatrics (AAP)-defined AOM was 3.8% (95% confidence interval: -11.4, 16.9). Point estimates of VE against other AOM outcomes ranged between 2.9% (-9.5, 14.0) and 5.2% (-8.0, 16.8). Point estimates of VE against ALRI outcomes ranged between -4.4% (-39.2, 21.8) and 2.0% (-18.3, 18.8). Point estimates of VE tended to be higher against first than all episodes but the confidence intervals included zero. dPly/PhtD vaccine was immunogenic and had an acceptable reactogenicity and safety profile after primary and booster vaccination in Native American infants., Conclusions: The dPly/PhtD vaccine was immunogenic and well tolerated, however, incremental efficacy in preventing AAP-AOM over PCV13 was not demonstrated., Clinical Trials Registration: NCT01545375 (www.clinicaltrials.gov)., (Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: With the rise in fluoroquinolone-resistant Salmonella Typhi and the recent emergence of ceftriaxone resistance, azithromycin is one of the last oral drugs available against typhoid for which resistance is uncommon. Its increasing use, specifically in light of the ongoing outbreak of extensively drug-resistant (XDR) Salmonella Typhi (resistant to chloramphenicol, ampicillin, cotrimoxazole, streptomycin, fluoroquinolones and third-generation cephalosporins) in Pakistan, places selective pressure for the emergence and spread of azithromycin-resistant isolates. However, little is known about azithromycin resistance in Salmonella, and no molecular data are available on its mechanism., Methods and Findings: We conducted typhoid surveillance in the two largest pediatric hospitals of Bangladesh from 2009-2016. All typhoidal Salmonella strains were screened for azithromycin resistance using disc diffusion and resistance was confirmed using E-tests. In total, we identified 1,082 Salmonella Typhi and Paratyphi A strains; among these, 13 strains (12 Typhi, 1 Paratyphi A) were azithromycin-resistant (MIC range: 32-64 μg/ml) with the first case observed in 2013. We sequenced the resistant strains, but no molecular basis of macrolide resistance was identified by the currently available antimicrobial resistance prediction tools. A whole genome SNP tree, made using RAxML, showed that the 12 Typhi resistant strains clustered together within the 4.3.1.1 sub-clade (H58 lineage 1). We found a non-synonymous single-point mutation exclusively in these 12 strains in the gene encoding AcrB, an efflux pump that removes small molecules from bacterial cells. The mutation changed the conserved amino acid arginine (R) at position 717 to a glutamine (Q). To test the role of R717Q present in azithromycin-resistant strains, we cloned acrB from azithromycin-resistant and sensitive strains, expressed them in E. coli, Typhi and Paratyphi A strains and tested their azithromycin susceptibility. Expression of AcrB-R717Q in E. coli and Typhi strains increased the minimum inhibitory concentration (MIC) for azithromycin by 11- and 3-fold respectively. The azithromycin-resistant Paratyphi A strain also contained a mutation at R717 (R717L), whose introduction in E. coli and Paratyphi A strains increased MIC by 7- and 3-fold respectively, confirming the role of R717 mutations in conferring azithromycin resistance., Conclusions: This report confirms 12 azithromycin-resistant Salmonella Typhi strains and one Paratyphi A strain. The molecular basis of this resistance is one mutation in the AcrB protein at position 717. This is the first report demonstrating the impact of this non-synonymous mutation in conferring macrolide resistance in a clinical setting. With increasing azithromycin use, strains with R717 mutations may spread and be acquired by XDR strains. An azithromycin-resistant XDR strain would shift enteric fever treatment from outpatient departments, where patients are currently treated with oral azithromycin, to inpatient departments to be treated with injectable antibiotics like carbapenems, thereby further burdening already struggling health systems in endemic regions. Moreover, with the dearth of novel antimicrobials in the horizon, we risk losing our primary defense against widespread mortality from typhoid. In addition to rolling out the WHO prequalified typhoid conjugate vaccine in endemic areas to decrease the risk of pan-resistant Salmonella Typhi strains, it is also imperative to implement antimicrobial stewardship and water sanitation and hygiene intervention to decrease the overall burden of enteric fever., Competing Interests: The authors have declared that no competing interests exist.

Background: Pneumonia is a leading cause of death in children of low-resource settings. Barriers to care include an early and accurate diagnosis. Lung ultrasound is a novel tool for the identification of pediatric pneumonia; however, there is currently no standardized approach to train in image acquisition and interpretation of findings in epidemiological studies. We developed a training program for physicians with limited ultrasound experience on how to use ultrasound for the diagnosis of pediatric pneumonia and how to standardize image interpretation using a panel of readers., Methods: Twenty-five physicians participating in the training program conducted lung ultrasounds in all children with suspected pneumonia, aged 3 to 35 months, presenting to three subdistrict hospitals in Sylhet, Bangladesh, between June 2015 and September 2017., Results: A total of 9051 pediatric lung ultrasound assessments were conducted through 27 months of data collection. Study physicians underwent training and all were successfully standardized, achieving 91% agreement and maintained a sensitivity and specificity of 88% and 92%, respectively, when their diagnosis was compared with experts. Overall kappa between two readers was high (0.86, 95% confidence interval [CI], 0.84-0.87), and remained high when a third expert reader was included (0.80, 95% CI, 0.79-0.81). Agreement and kappa statistics were similarly high when stratified by age, sex, presence of danger signs, or hypoxemia., Conclusions: Lung ultrasound is a novel tool for the diagnosis of pediatric pneumonia with evidence supporting its validity and feasibility of implementation. Here we introduced a training program that resulted in a high level of inter-sonographer agreement., (© 2019 The Authors. Pediatric Pulmonology published by Wiley Periodicals, Inc.)

Background: In 2016, India became one of the first countries in Asia to introduce an indigenously manufactured rotavirus vaccine. However, any new vaccine introduction needs to be meticulously planned to allow for strengthening of the existing immunization systems instead of burdening them., Methods: The process of rotavirus vaccine introduction in India started with the establishment of National Rotavirus Surveillance Network in 2005 which generated relevant evidence to inform policy level decisions to introduce the vaccine. The preparatory activities started with assessment of health systems and closing any gaps. This was followed by development of vaccine specific training packages and cascade training for programme managers and health workers. The introduction was complemented with strong communications systems and media involvement to allow for good acceptability of the vaccine on the ground. Each step of introduction was led by the government and technically supported by development partners., Results: India introduced rotavirus vaccine in a phased wise manner. In the first two phases the vaccine has been introduced in nine states of the country accounting for nearly 35% of the annual birth cohort of the country. From March 2016 to November 2017, approximately 13,260,000 rotavirus vaccine doses were administered in the country. The vaccine was well accepted by both the health workers and parents/caregivers., Conclusion: Rotavirus vaccine introduction in India is an excellent example of how government stewardship with well-defined roles for development partners can allow a new vaccine introduction to be used as a system strengthening activity., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Importance: The BCG vaccine is currently the only approved tuberculosis vaccine and is widely administered worldwide, usually during infancy. Previous studies found increased rates of lymphoma and leukemia in BCG-vaccinated populations., Objective: To determine whether BCG vaccination was associated with cancer rates in a secondary analysis of a BCG vaccine trial., Design, Setting, and Participants: Retrospective review (60-year follow-up) of a clinical trial in which participants were assigned to the vaccine group by systematic stratification by school district, age, and sex, then randomized by alternation. The original study was conducted at 9 sites in 5 US states between December 1935 and December 1998. Participants were 2963 American Indian and Alaska Native schoolchildren younger than 20 years with no evidence of previous tuberculosis infection. Statistical analysis was conducted between August 2018 and July 2019., Interventions: Single intradermal injection of either BCG vaccine or saline placebo., Main Outcomes and Measures: The primary outcome was diagnosis of cancer after BCG vaccination. Data on participant interval health and risk factors, including smoking, tuberculosis infection, isoniazid use, and other basic demographic information, were also collected., Results: A total of 2963 participants, including 1540 in the BCG vaccine group and 1423 in the placebo group, remained after exclusions. Vaccination occurred at a median (interquartile range) age of 8 (5-11) years; 805 participants (52%) in the BCG group and 710 (50%) in the placebo group were female. At the time of follow-up, 97 participants (7%) in the placebo group and 106 participants (7%) in the BCG vaccine group could not be located; total mortality was 633 participants (44%) in the placebo group and 632 participants (41%) in the BCG group. The overall rate of cancer diagnosis was not significantly different in BCG vaccine vs placebo recipients (hazard ratio, 0.82; 95% CI, 0.66-1.02), including for lymphoma and leukemia. The rate of lung cancer was significantly lower in BCG vs placebo recipients (18.2 vs 45.4 cases per 100 000 person-years; hazard ratio, 0.38; 95% CI, 0.20-0.74; P = .005), controlling for sex, region, alcohol overuse, smoking, and tuberculosis., Conclusions and Relevance: Childhood BCG vaccination was associated with a lower risk of lung cancer development in American Indian and Alaska Native populations. This finding has potentially important health implications given the high mortality rate associated with lung cancer and the availability of low-cost BCG vaccines.

Introduction: Children with nephrotic syndrome are susceptible to invasive bacterial infections. In this study, we aimed to: (1) determine the pathogens associated with infections in children with nephrotic syndrome and (2) describe antimicrobial susceptibility and serotype distribution of Streptococcus pneumoniae to guide evidence-based treatment and prevention policies., Methods: From June 2013 to March 2015, we collected blood and/or ascitic fluid from children hospitalized with nephrotic syndrome and suspected bacterial disease in the largest pediatric hospital of Bangladesh. We cultured all samples and performed polymerase chain reaction (PCR) and immunochromatographic test on ascitic fluid for detection of S. pneumoniae. Pneumococcal isolates were tested for antibiotic susceptibility using disc diffusion and serotyped using Quellung reaction and PCR., Results: We identified 1342 children hospitalized with nephrotic syndrome. Among them, 608 children had suspected bacterial disease from whom blood and/or ascitic fluid were collected. A pathogen was identified in 8% (48/608) of cases, 94% (45/48) of which were S. pneumoniae. Most (73%, 33/45) pneumococcal infections were identified through culture of blood and ascitic fluid and 27% (12/45) through immunochromatographic test and PCR of ascitic fluid. In total, 24 different pneumococcal serotypes were detected; 51% are covered by PCV10 (+6A), 53% by PCV13 and 60% by PPSV23. All pneumococcal isolates were susceptible to penicillin., Conclusions: Because S. pneumoniae was the primary cause of invasive infections, pneumococcal vaccines may be considered as a preventive intervention in children with nephrotic syndrome. Additionally, penicillin can be used to prevent and treat pneumococcal infections in children with nephrotic syndrome in Bangladesh.

Background: Streptococcus pneumoniae is a major cause of pneumonia, meningitis, and other serious infections among children in India. India introduced the 13-valent pneumococcal conjugate vaccine (PCV) in several states in 2017, and is expected to expand to nationwide coverage in the near future. To establish a baseline for measuring the impact of PCV in India, we assessed overall and serotype-specific nasopharyngeal carriage in two pediatric populations., Methods: A cross-sectional study was conducted in Palwal District, Haryana, from December 2016 to July 2017, prior to vaccine introduction. Children 2-59 months of age with clinical pneumonia seeking healthcare and those in the community with no clear illness were targeted for enrollment. A nasopharyngeal swab was collected and tested for pneumococcus using conventional culture and sequential multiplex PCR. Isolates were tested for antimicrobial resistance using an E test. Children were considered colonized if pneumococcus was isolated by culture or PCR. The prevalence of pneumococcal and serotype-specific colonization was compared between groups of children using log-binomial regression., Results: Among 601 children enrolled, 91 had clinical pneumonia and 510 were community children. The proportion colonized with S. pneumoniae was 74.7 and 54.5% among children with clinical pneumonia and community children, respectively (adjusted prevalence ratio: 1.38; 95% confidence interval: 1.19, 1.60). The prevalence of PCV13 vaccine-type colonization was similar between children with clinical pneumonia (31.9%) and community children (28.0%; p = 0.46). The most common colonizing serotypes were 6A, 6B, 14, 19A, 19F, and 23F, all of which are included in the PCV13 vaccine product. Antimicrobial resistance to at least one drug was similar between isolates from children with clinical pneumonia (66.1%) and community children (61.5%; p = 0.49); while resistance to at least two drugs was more common among isolates from children with clinical pneumonia (25.8% vs. 16.4%; p = 0.08). Resistance for all drugs was consistently higher for PCV13 vaccine-type serotypes compared to non-vaccine serotypes in both groups., Conclusion: This study provides baseline information on the prevalence of serotype-specific pneumococcal colonization among children prior to the introduction of PCV in India. Our results suggest a role for pneumococcal vaccines in reducing pneumococcal colonization and antimicrobial resistant isolates circulating in India.

Background: India accounts for a disproportionate burden of global childhood illnesses. To inform policies and measure progress towards achieving child health targets, we estimated the annual national and state-specific childhood mortality and morbidity attributable to Streptococcus pneumoniae and Haemophilus influenzae type b (Hib) between 2000 and 2015., Methods: In this modelling study, we used vaccine clinical trial data to estimate the proportion of pneumonia deaths attributable to pneumococcus and Hib. The proportion of meningitis deaths attributable to each pathogen was derived from pathogen-specific meningitis case fatality and bacterial meningitis case data from surveillance studies. We applied these proportions to modelled state-specific pneumonia and meningitis deaths from 2000 to 2015 prepared by the WHO Maternal and Child Epidemiology Estimation collaboration (WHO/MCEE) on the basis of verbal autopsy studies from India. The burden of clinical and severe pneumonia cases attributable to pneumococcus and Hib was ascertained with vaccine clinical trial data and state-specific all-cause pneumonia case estimates prepared by WHO/MCEE by use of risk factor prevalence data from India. Pathogen-specific meningitis cases were derived from state-level modelled pathogen-specific meningitis deaths and state-level meningitis case fatality estimates. Pneumococcal and Hib morbidity due to non-pneumonia, non-meningitis (NPNM) invasive syndromes were derived by applying the ratio of pathogen-specific NPNM cases to pathogen-specific meningitis cases to the state-level pathogen-specific meningitis cases. Mortality due to pathogen-specific NPNM was calculated with the ratio of pneumococcal and Hib meningitis case fatality to pneumococcal and Hib meningitis NPNM case fatality. Census data from India provided the population at risk., Findings: Between 2000 and 2015, estimates of pneumococcal deaths in Indian children aged 1-59 months fell from 166 000 (uncertainty range [UR] 110 000-198 000) to 68 700 (44 600-86 000), while Hib deaths fell from 82 600 (52 300-112 000) to 15 600 (9800-21 500), representing a 58% (UR 22-78) decline in pneumococcal deaths and an 81% (59-91) decline in Hib deaths. In 2015, national mortality rates in children aged 1-59 months were 56 (UR 37-71) per 100 000 for pneumococcal infection and 13 (UR 8-18) per 100 000 for Hib. Uttar Pradesh (18 900 [UR 12 300-23 600]) and Bihar (8600 [5600-10 700]) had the highest numbers of pneumococcal deaths in 2015. Uttar Pradesh (9300 [UR 5900-12 700]) and Odisha (1100 [700-1500]) had the highest numbers of Hib deaths in 2015. Less conservative assumptions related to the proportion of pneumonia deaths attributable to pneumococcus indicate that as many as 118 000 (UR 69 000-140 000) total pneumococcal deaths could have occurred in 2015 in India., Interpretation: Pneumococcal and Hib mortality have declined in children aged 1-59 months in India since 2000, even before nationwide implementation of conjugate vaccines. Introduction of the Hib vaccine in several states corresponded with a more rapid reduction in morbidity and mortality associated with Hib infection. Rapid scale-up and widespread use of the pneumococcal conjugate vaccine and sustained use of the Hib vaccine could help accelerate achievement of child survival targets in India., Funding: Bill & Melinda Gates Foundation., (Copyright © 2019 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Introduction: To evaluate WHO chest radiograph interpretation processes during a pneumococcal vaccine effectiveness study of children aged 3-35 months with suspected pneumonia in Sylhet, Bangladesh., Methods: Eight physicians masked to all data were standardised to WHO methodology and interpreted chest radiographs between 2015 and 2017. Each radiograph was randomly assigned to two primary readers. If the primary readers were discordant for image interpretability or the presence or absence of primary endpoint pneumonia (PEP), then another randomly selected, masked reader adjudicated the image (arbitrator). If the arbitrator disagreed with both primary readers, or concluded no PEP, then a masked expert reader finalised the interpretation. The expert reader also conducted blinded quality control (QC) for 20% of randomly selected images. We evaluated agreement between primary readers and between the expert QC reading and the final panel interpretation using per cent agreement, unadjusted Cohen's kappa, and a prevalence and bias-adjusted kappa., Results: Among 9723 images, the panel classified 21.3% as PEP, 77.6% no PEP and 1.1% uninterpretable. Two primary readers agreed on interpretability for 98% of images (kappa, 0.25; prevalence and bias-adjusted kappa, 0.97). Among interpretable radiographs, primary readers agreed on the presence or absence of PEP in 79% of images (kappa, 0.35; adjusted kappa, 0.57). Expert QC readings agreed with final panel conclusions on the presence or absence of PEP for 92.9% of 1652 interpretable images (kappa, 0.75; adjusted kappa, 0.85)., Conclusion: Primary reader performance and QC results suggest the panel effectively applied the WHO chest radiograph criteria for pneumonia., Competing Interests: Competing interests: None declared.

Introduction: Haemophilus influenzae type b was the leading cause of bacterial meningitis in infants and children below the age of two years prior to the introduction of H. influenzae type b conjugate vaccines. In December 2011, the Indian government introduced H. influenzae b vaccine in the state of Tamilnadu. A prospective surveillance for bacterial meningitis was established at the Institute of Child Health in Chennai to evaluate the etiology of meningitis and impact of the vaccine., Material and Methods: Infants aged one to 23 months who were admitted to the hospital with symptoms of suspected bacterial meningitis were enrolled and lumbar puncture was performed. Cerebrospinal fluid samples were analyzed for white blood cells, protein, and glucose. Bacterial culture and a latex agglutination test for common bacterial pathogens were performed., Results: Between January 2009 and March 2014, 4,770 children with suspected bacterial meningitis were enrolled. Prior to the introduction of the vaccine, an average of 11.7 cases of H. influenzae b meningitis and 31.1 cases of probable meningitis with no etiology were identified each year. After introduction, the number of cases were reduced by 79% and 44% respectively. The average H. influenzae b vaccine coverage after introduction was 69% among all children with clinically suspected meningitis. In contrast, the mean number of aseptic meningitis and pneumococcal meningitis cases remained stable throughout the pre and post vaccination period; 28.2 and 4.8 per year, respectively., Conclusions: H. influenzae b conjugate vaccine reduced the number of cases of H. influenzae b meningitis and probable meningitis within the first two years of its introduction. The impact against meningitis was higher than the vaccination rate, indicating indirect effects of the vaccine. India has recently scaled up the use of Hib conjugate vaccine throughout the country which should substantially reduce childhood meningitis rates further in the country., (Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Introduction: Native Americans in the southwestern United States have a higher risk for many infectious diseases and may be at higher risk for Staphylococcus aureus due to the high prevalence of risk factors for S. aureus. Recent data on invasive S. aureus infections among Native Americans are limited., Methods: Active population- and laboratory-based surveillance was conducted in 2016-2017 on the Navajo Nation to document the rate of invasive S. aureus. A case of invasive S.aureus infection was defined as a Native American individual with S. aureus isolated from a normally sterile body site whose reported community of residence was on or around the Navajo Nation., Results: One hundred and fifty-nine cases of invasive S. aureus from 152 individuals were identified. The median age of cases was 56.3 years and 35% were female. Thirty-five percent of cases had community-acquired infections. Ninety-three percent of cases had underlying medical conditions, including diabetes (60%) and obesity (42%), 28% of cases had a documented prior S. aureus infection, and 33% were infected with methicillin-resistant S. aureus. The annual incidence of invasive S. aureus and of invasive methicillin-resistant S. aureus was 64.9/100,000 persons and 21.2/100,000 persons, respectively., Conclusions: This community has a high burden of invasive S. aureus infections. Further research is needed to identify prevention strategies and opportunities for intervention., Competing Interests: CGS, LRG, AR, GD, RCW, RR, KLO, LLH received an institutional research grant from Pfizer Inc. to conduct this work. MS received institutional research grants from Pfizer Inc. to conduct this and other work. RH and AQ are employees of Pfizer Inc. DY has no conflicts to report. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Background: In 2013, the US Advisory Committee on Immunization Practices (ACIP) opted against adding meningococcal vaccines to the infant schedule due to poor cost-effectiveness. This raises a policy question: if meningococcal disease is too rare to justify routine vaccination, are there other vaccine-preventable causes of US infant deaths that could be supported?, Methods: We tabulated US infant deaths from 2009-2013 using the CDC WONDER database. These causes of death were then categorized into one of 3 categories: 1) vaccine-preventable using currently available interventions; 2) potentially vaccine-preventable within the next 10 years; and 3) not preventable., Results: From 19.8 million births (3.9 million/year), ∼122,000 infants died (0.62%). Of these, 181 (0.15% of all deaths) were preventable using currently available vaccines, while an additional 779 were categorized as potentially preventable in the next 10 y. By exclusion, 121,040 (99.2%) were judged 'not vaccine-preventable'. Meningococcal deaths contributed at most 0.03% of all infant deaths, but accounted for 17-34% of current vaccine-preventable deaths., Conclusions: The low number of vaccine-preventable deaths in the US makes it increasingly difficult to justify the introduction of any new infant vaccines.

Background: Of the 215,000 global deaths from rotavirus estimated in 2013, 41% occur in Asian countries. However, despite a recommendation for global rotavirus vaccination since 2009, only eight countries in Asia have introduced the rotavirus vaccine into their national immunization program as of September 2017. To help policy makers assess the potential value of vaccination, we projected the reduction in rotavirus hospitalizations and deaths following a hypothetical national introduction of rotavirus vaccines in all countries in Asia using data on national-level rotavirus mortality, <5 population, rotavirus hospitalizations rates, routine vaccination coverage, and vaccine effectiveness., Methods: To quantify uncertainty, we generated 1,000 simulations of these inputs., Results: Our model predicted 710,000 fewer rotavirus hospitalizations, a 49% decrease from the 1,452,000 baseline hospitalizations and 35,000 fewer rotavirus deaths, a 40% decrease from the 88,000 baseline deaths if all 43 Asian countries had introduced rotavirus vaccine. Similar reductions were projected in subanalyses by vaccine introduction status, subregion, and birth cohort size., Conclusion: Rotavirus vaccines will substantially reduce morbidity and mortality due to rotavirus infections in Asia.

The study examines the impact of the introduction of 10-valent Pneumococcal Conjugate Vaccine (PCV10) into Bangladesh's national vaccine program. PCV10 is administered to children under 1 year-old; the scheduled ages of administration are at 6, 10, and 18 weeks. The study is conducted in ~770,000 population containing ~90,000 <5 children in Sylhet, Bangladesh and has five objectives: 1) To collect data on community-based pre-PCV incidence rates of invasive pneumococcal diseases (IPD) in 0-59 month-old children in Sylhet, Bangladesh; 2) To evaluate the effectiveness of PCV10 introduction on Vaccine Type (VT) IPD in 3-59 month-old children using an incident case-control study design. Secondary aims include measuring the effects of PCV10 introduction on all IPD in 3-59 month-old children using case-control study design, and quantifying the emergence of Non Vaccine Type IPD; 3) To evaluate the effectiveness of PCV10 introduction on chest radiograph-confirmed pneumonia in children 3-35 months old using incident case-control study design. We will estimate the incidence trend of clinical and radiologically-confirmed pneumonia in 3-35 month-old children in the study area before and after introduction of PCV10; 4) To determine the feasibility and utility of lung ultrasound for the diagnosis of pediatric pneumonia in a large sample of children in a resource-limited setting. We will also evaluate the effectiveness of PCV10 introduction on ultrasound-confirmed pneumonia in 3-35 month-old children using an incident case-control design and to examine the incidence trend of ultrasound-confirmed pneumonia in 3-35 month-old children in the study area before and after PCV10 introduction; and 5) To determine the direct and indirect effects of vaccination status on nasopharyngeal colonization on VT pneumococci among children with pneumonia .  This paper presents the methodology. The study will allow us to conduct a comprehensive and robust assessment of the impact of national introduction of PCV10 on pneumococcal disease in Bangladesh., Competing Interests: No competing interests were disclosed.

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.

Objective: To evaluate the effect of zinc as an adjuvant therapy in radiologically confirmed pneumonia in children 2-24 months of age., Patients and Methods: We analyzed data of 212 children with pneumonia for whom chest X-ray films were available at enrollment and at least two radiologists agreed on the diagnosis of pneumonia. We compared the time to recovery in the two groups (n = 121, zinc group and n = 91, placebo group) using a Cox proportional hazards regression model., Results: Time to recovery was similar in both groups [median interquartile range: zinc, 84 h (64, 140 h); placebo, 85 h (65, 140 h)]. The absolute risk reduction for treatment failure was 5.2% (95% confidence interval: -4.8, 15.1) with zinc supplementation., Conclusion: There was no significant beneficial effect of zinc on the duration of recovery or risk of treatment failure in children with radiologically confirmed pneumonia.

Despite the high burden of rotavirus diarrhea, uptake of rotavirus vaccines in Asia remains low. This primarily stems from a perception of rotavirus as a non-life-threatening pathogen amidst a background of competing health priorities and limited resources. In the largest pediatric hospital of Bangladesh, where there is a fierce competition for beds, we found that between November 2015 and October 2016, 12% of 23,064 admissions were due to gastrointestinal infections, 54% of which were caused by rotavirus. One in four cases requiring hospitalization, or 5,879 cases, was refused because of unavailability of beds. Most refused cases were of pneumonia (22%), severe perinatal asphyxia (17%), preterm birth complications (7%), and meningitis (2%), all of which bear high risks of death or disability, if not treated timely. When determining vaccine policies and conducting vaccine impact studies, it would be shortsighted to not consider the impact on morbidity and mortality of cases that are refused admission because of the hospitalization of children with a preventable disease as rotavirus diarrhea. In our hospital, routine use of a rotavirus vaccine with 41% efficacy will release 629 beds per year to accommodate previously refused cases. Based on evidence, we make the case that introduction of this vaccine in Bangladesh and the surrounding region will prevent morbidity and mortality, both directly and indirectly, and help us ensure survival and well-being of all children.

An estimated 215,000 children died of rotavirus infections in 2013, accounting for 37% of diarrhea-related deaths worldwide, 92% of which occurred in low and lower-middle income countries. Since 2009 the World Health Organization (WHO) recommends the use of rotavirus vaccines in all national immunization programs. This review compares rotavirus vaccine (RV) introductions and vaccine coverage by region, country income status and Gavi-eligibility from 2006-2016. Gross National Income data from the World Bank and surviving infant population from United Nations Population Division was obtained for 2016. Data from WHO were collected on rotavirus vaccine coverage, national immunization schedules, and new vaccine introductions for 2016 while estimated rotavirus deaths were collected for 2013, the last year of available WHO data. As of December 2016, the majority of countries (57%, 110/194) had not introduced universal rotavirus vaccine despite WHO's 2009 recommendation to do so. Countries in the WHO African region had the greatest proportion of introductions (37%, 31/84) by December 2016 and a great majority of these (77%, 24/31) were supported by new vaccine introduction (NVI) grants from Gavi. Almost half (48%) of global introductions were in low and lower-middle income Gavi-eligible and Gavi-graduating countries. Conversely, countries in the Southeast Asia WHO region and those not eligible for Gavi NVI support have been slow to introduce rotavirus vaccine. High-income countries, on average, had poorer rotavirus vaccine coverage compared to low and lower-middle income countries. The over-representation of African countries within the Gavi subset and high estimated rotavirus deaths in these African countries, likely explains why introduction efforts have been focused in this region. While much progress has been made with the integration and implementation of rotavirus vaccine into national immunization programs, 110 countries representing 69% of the global birth cohort had yet to introduce the vaccine by December 2016.

Background: Few trials have evaluated influenza vaccine efficacy (VE) in young children, a group particularly vulnerable to influenza complications. We aimed to estimate VE against influenza in children aged <2 years in Bangladesh; a subtropical setting, where influenza circulation can be irregular., Methods: Children aged 6-23 months were enrolled 1:1 in a parallel, double-blind, randomized controlled trial of trivalent inactivated influenza vaccine (IIV3) versus inactivated polio vaccine (IPV); conducted August 2010-March 2014 in Dhaka, Bangladesh. Children received two pediatric doses of vaccine, one month apart, and were followed for one year for febrile and respiratory illness. Field assistants conducted weekly home-based, active surveillance and ill children were referred to the study clinic for clinical evaluation and nasopharyngeal wash specimen collection. Analysis included all children who received a first vaccine dose and compared yearly incidence of reverse transcription polymerase chain reaction (RT-PCR)-confirmed influenza between trial arms. The VE was estimated as 1-(rate ratio of illness) × 100%, using unadjusted Poisson regression. The trial was registered with ClinicalTrials.gov, number NCT01319955., Results: Across four vaccination rounds, 4081 children were enrolled and randomized, contributing 2576 child-years of observation to the IIV3 arm and 2593 child-years to the IPV arm. Influenza incidence was 10 episodes/100 child-years in the IIV3 arm and 15 episodes/100 child-years in the IPV arm. Overall, the VE was 31% (95% confidence interval 18, 42%) against any RT-PCR-confirmed influenza. The VE varied by season, but was similar by influenza type/subtype and participant age and sex., Conclusions: Vaccination of young children with IIV3 provided a significant reduction in laboratory-confirmed influenza; however, exploration of additional influenza vaccine strategies, such as adjuvanted vaccines or standard adult vaccine doses, is warranted to find more effective influenza vaccines for young children in low-income countries., (Published by Elsevier Ltd.)

Background: Lack of surveillance systems and accurate data impede evidence-based decisions on treatment and prevention of enteric fever, caused by Salmonella Typhi/Paratyphi. The WHO coordinates a global Invasive Bacterial-Vaccine Preventable Diseases (IB-VPD) surveillance network but does not monitor enteric fever. We evaluated the feasibility and sustainability of integrating enteric fever surveillance into the ongoing IB-VPD platform., Methodologies: The IB-VPD surveillance system uses WHO definitions to enroll 2-59 month children hospitalized with possible pneumonia, sepsis or meningitis. We expanded this surveillance system to additionally capture suspect enteric fever cases during 2012-2016, in two WHO sentinel hospitals of Bangladesh, by adding inclusion criteria of fever ≥102°F for ≥3 days, irrespective of other manifestations. Culture-positive enteric fever cases from in-patient departments (IPD) detected in the hospital laboratories but missed by the expanded surveillance, were also enrolled to assess completion. Costs for this integration were calculated for the additional personnel and resources required., Principal Findings: In the IB-VPD surveillance, 5,185 cases were enrolled; 3% (N = 171/5185) were positive for microbiological growth, of which 55% (94/171) were culture-confirmed cases of enteric fever (85 Typhi and 9 Paratyphi A). The added inclusion criteria for enteric fever enrolled an additional 1,699 cases; 22% (358/1699) were positive, of which 85% (349/358) were enteric fever cases (305 Typhi and 44 Paratyphi A). Laboratory surveillance of in-patients of all ages enrolled 311 additional enteric fever cases (263 Typhi and 48 Paratyphi A); 9% (28/311) were 2-59 m and 91% (283/311) >59 m. Altogether, 754 (94+349+311) culture-confirmed enteric fever cases were found, of which 471 were 2-59 m. Of these 471 cases, 94% (443/471) were identified through the hospital surveillances and 6% (28/471) through laboratory results. Twenty-three percent (170/754) of all cases were children <2 years. Additional cost for the integration was USD 44,974/year, a 27% increase to the IB-VPD annual expenditure., Conclusion: In a setting where enteric disease is a substantial public health problem, we could integrate enteric fever surveillance into the standard IB-VPD surveillance platform at a modest cost.

Background: Undernutrition below two years of age remains a major public health problem in India. We conducted an evaluation of an integrated nutrition and health program that aimed to improve nutritional status of young children by improving breast and complementary feeding practices over that offered by the Government of India's standard nutrition and health care program., Methods: In Uttar Pradesh state, through multi-stage cluster random sampling, 81 villages in an intervention district and 84 villages in a comparison district were selected. A cohort of 957 third trimester pregnant women identified during house-to-house surveys was enrolled and, following childbirth, mother-child dyads were followed every three months from birth to 18 months of age. The primary outcomes were improvements in weight-for-age and length-for-age z scores, with improved breastfeeding and complementary feeding practices as intermediate outcomes., Findings: Optimal breastfeeding practices were higher among women in intervention than comparison areas, including initiating breastfeeding within one hour of delivery (17.4% vs. 2.7%, p<0.001), feeding colostrum (34.7% vs. 8.4%, p<0.001), avoiding pre-lacteals (19.6% vs. 2.1%, p<0.001) and exclusively breastfeeding up to 6 months (24.1% vs. 15.3%, p = 0.001). However, differences were few and mixed between study arms with respect to complementary feeding practices. The mean weight-for-age z-score was higher at 9 months (-2.1 vs. -2.4, p = 0.0026) and the prevalence of underweight status was lower at 12 months (58.5% vs. 69.3%, p = 0.047) among intervention children. The prevalence of stunting was similar between study arms at all ages. Coefficients to show the differences between the intervention and comparison districts (0.13 cm/mo) suggested significant faster linear growth among intervention district infants at earlier ages (0-5 months)., Interpretation: Mothers participating in the intervention district were more likely to follow optimal breast, although not complementary feeding practices. The program modestly improved linear growth in earlier age and weight gain in late infancy. Comprehensive nutrition and health interventions are complex; the implementation strategies need careful examination to improve feeding practices and thus impact growth., Trial Registration: The trial was registered with ClinicalTrials.gov, NCT00198835.