Streptococcus pneumoniae serotype 3 population structure in the era of conjugate vaccines, 2001-2018.

Background. Despite use of highly effective conjugate vaccines, invasive pneumococcal disease (IPD) remains a leading cause of morbidity and mortality and disproportionately affects Indigenous populations. Although included in the 13-valent pneumococcal conjugate vaccine (PCV13), which was introduced in 2010, serotype 3 continues to cause disease among Indigenous communities in the Southwest USA. In the Navajo Nation, serotype 3 IPD incidence increased among adults (3.8/100 000 in 2001-2009 and 6.2/100 000 in 2011-2019); in children the disease persisted although the rates dropped from 5.8/100 000 to 2.3/100 000.Methods. We analysed the genomic epidemiology of serotype 3 isolates collected from 129 adults and 63 children with pneumococcal carriage (n=61) or IPD (n=131) from 2001 to 2018 of the Navajo Nation. Using whole-genome sequencing data, we determined clade membership and assessed changes in serotype 3 population structure over time.Results. The serotype 3 population structure was characterized by three dominant subpopulations: clade II (n=90, 46.9 %) and clade Iα (n=59, 30.7 %), which fall into Clonal Complex (CC) 180, and a non-CC180 clade (n=43, 22.4 %). The proportion of clade II-associated IPD cases increased significantly from 2001 to 2010 to 2011-2018 among adults (23.1-71.8 %; P<0.001) but not in children (27.3-33.3 %; P=0.84). Over the same period, the proportion of clade II-associated carriage increased; this was statistically significant among children (23.3-52.6 %; P=0.04) but not adults (0-50.0 %, P=0.08).Conclusions. In this setting with persistent serotype 3 IPD and carriage, clade II has increased since 2010. Genomic changes may be contributing to the observed trends in serotype 3 carriage and disease over time.

Supporting evidence-based rotavirus vaccine introduction decision-making and implementation: Lessons from 8 Gavi-eligible countries.

Despite the 2009 World Health Organization recommendation that all countries introduce rotavirus vaccines (RVV) into their national immunization programs, just 81 countries had introduced RVV by the end of 2015, leaving millions of children at risk for rotavirus morbidity and mortality. In response, the Rotavirus Accelerated Vaccine Introduction Network (RAVIN) was established in 2016 to provide support to eight Gavi-eligible countries that had yet to make an RVV introduction decision and/or had requested technical assistance with RVV preparations: Afghanistan, Bangladesh, Benin, Cambodia, Democratic Republic of Congo, Lao People's Democratic Republic, Myanmar, and Nepal. During 2016-2020, RAVIN worked with country governments and partners to support evidence-based immunization decision-making, RVV introduction preparation and implementation, and multilateral coordination. By the September 2020 program close-out, five of the eight RAVIN focus countries successfully introduced RVV into their routine childhood immunization programs. We report on the RAVIN approach, describe how the project responded collectively to an evolving RVV product landscape, synthesize common characteristics of the RAVIN country experiences, highlight key lessons learned, and outline the unfinished agenda to inform future new vaccine introduction efforts by countries and global partners.

Estimating the global impact of rotavirus vaccines on child mortality.

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.

Considerations for unblinding individual study participants during vaccine trials.

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.

In-hospital mortality risk stratification in children aged under 5 years with pneumonia with or without pulse oximetry: A secondary analysis of the Pneumonia REsearch Partnership to Assess WHO REcommendations (PREPARE) dataset.

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.

Communication lessons learned from the 2017 measles-rubella campaign in India: perspectives from vaccine decision-makers.

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.

Measles and rubella are diseases that cause sickness and death. Both are preventable as there are safe and effective vaccines available. Measles and rubella are significant in India. These vaccines are generally delivered to the public through vaccine campaigns. A measles­rubella vaccine campaign was implemented in 2017. In this study, we interviewed 21 government and civil society stakeholders that are involved in vaccine campaigns in India to capture lessons learned. We were interested in understanding how vaccine campaigns could be improved through health communication and promotion efforts. Stakeholders suggested to use trusted community members to inform people about the vaccine campaign, and that it was important for trusted community leaders to dispel rumors about vaccines quickly. To increase vaccine acceptance, it is critical that health communication and promotion efforts target concerns that people may have about the vaccine as well as the vaccine campaign.

Effectiveness of the 10-valent pneumococcal conjugate vaccine on pediatric pneumonia confirmed by ultrasound: a matched case-control study.

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.

Understanding determinants of vaccine hesitancy and acceptance in India: A qualitative study of government officials and civil society stakeholders.

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.

Immunogenicity, otitis media, hearing impairment, and nasopharyngeal carriage 6-months after 13-valent or ten-valent booster pneumococcal conjugate vaccines, stratified by mixed priming schedules: PREVIX_COMBO and PREVIX_BOOST randomised controlled trials.

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).

Derivation and validation of a novel risk assessment tool to identify children aged 2-59 months at risk of hospitalised pneumonia-related mortality in 20 countries.

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.

Evaluation of indoor PM2.5 concentrations in a Native American Community: a pilot study.

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 PM2.5 concentration was evaluated in 26 homes on the Navajo Nation using real-time PM2.5 monitors. Household risk factors and daily activities were evaluated with three metrics of indoor PM2.5: time-weighted average (TWA), 90th percentile of concentration, and daily minutes exceeding 100 µg/m3. 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/m3 were 7.9 µg/m3, 14.0 µg/m3, 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.

Validation of community health worker identification of maternal puerperal sepsis using a clinical diagnostic algorithm in Bangladesh and Pakistan.

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.

External validation of the RISC, RISC-Malawi, and PERCH clinical prediction rules to identify risk of death in children hospitalized with pneumonia.

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.

Impact of national introduction of ten-valent pneumococcal conjugate vaccine on invasive pneumococcal disease in Bangladesh: Case-control and time-trend studies.

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.

Change in full immunization inequalities in Indian children 12-23 months: an analysis of household survey data.

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.

Interchangeability, immunogenicity and safety of a combined 10-valent pneumococcal Haemophilus influenzae protein D conjugate vaccine (Synflorix) and 13-valent-PCV (Prevenar13) schedule at 1-2-4-6 months: PREVIX_COMBO, a 3-arm randomised controlled trial.

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 (_PPP), PHiD-CV10 (S) at 2-4-6 months (_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 _PPP(143), _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 _SSS (OPA GMT ratios 8.1 to 59.5, p < 0.001), and against protein D compared to _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 _SSS or _PPP. For ten common serotypes responses at 2, 4 and 7 months were superior for SSSP (following 1-, 2-, and 4- doses) than _SSS and _PPP (following 0-, 1-, and 3- doses). At 4 months, _SSS was superior to _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.

Otitis media outcomes of a combined 10-valent pneumococcal Haemophilus influenzae protein D conjugate vaccine and 13-valent pneumococcal conjugate vaccine schedule at 1-2-4-6 months: PREVIX_COMBO, a 3-arm randomised controlled trial.

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 (_PPP), Synflorix™ (S) at 2-4-6 months (_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 _PPP(143), _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 _PPP, _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.

Product review of the rotavirus vaccines ROTASIIL, ROTAVAC, and Rotavin-M1.

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.

Frequency-dependent selection can forecast evolution in Streptococcus pneumoniae.

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