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To use a model-based approach to estimate vaccination coverage of routinely recommended childhood and adolescent vaccines for the United States.We used a hierarchical model with retrospective cohort data from eleven IIS jurisdictions, which contains vaccination records submitted by providers. Numerators included data from 2014 to 2019 at the county level for 2.4 million children at age 24 months and 14.4 million adolescents aged 13-17. Age-appropriate Census populations were used as denominators. Covariates associated with childhood and adolescent vaccinations were included in the model. Model-based estimates for each county were generated and aggregated to the national level to produce national vaccination coverage estimates and compared to National Immunization Survey (NIS) estimates of vaccination coverage. Trends of estimated vaccination coverage were compared between the model-based approach and NIS.From 2014 to 18, model-based national vaccination coverage estimates were within ten percentage points of NIS-Child vaccination coverage estimates for most vaccines among children at age 24 months. One notable difference was higher model-based vaccination coverage estimates for hepatitis B birth dose compared to NIS-Child coverage estimates. From 2014 to 19, model-based national vaccination coverage estimates were within ten percentage points of NIS-Teen vaccination coverage estimates for most vaccines among adolescents aged 13-17 years. Model-based vaccination coverage estimates were notably lower for varicella, MMR, and Hepatitis B compared to NIS-Teen coverage estimates among adolescents. Trends in estimates of national vaccination coverage were similar between model-based estimates for children and adolescents as compared to NIS-Child and NIS-Teen, respectively.A hierarchical model applied to data from IIS may be used to estimate coverage for routinely recommended vaccines among children and adolescents and allows for timely analyses of childhood and adolescent vaccines to quickly assess trends in vaccination coverage across the United States. Monitoring real-time vaccination coverage can help promote immunizations to protect children and adolescents against vaccine-preventable diseases.

Although severe COVID-19 illness and hospitalization are more common among adults, these outcomes can occur in adolescents (1). Nearly one third of adolescents aged 12-17 years hospitalized with COVID-19 during March 2020-April 2021 required intensive care, and 5% of those hospitalized required endotracheal intubation and mechanical ventilation (2). On December 11, 2020, the Food and Drug Administration (FDA) issued Emergency Use Authorization (EUA) of the Pfizer-BioNTech COVID-19 vaccine for adolescents aged 16-17 years; on May 10, 2021, the EUA was expanded to include adolescents aged 12-15 years; and on August 23, 2021, FDA granted approval of the vaccine for persons aged ≥16 years. To assess progress in adolescent COVID-19 vaccination in the United States, CDC assessed coverage with ≥1 dose* and completion of the 2-dose vaccination series† among adolescents aged 12-17 years using vaccine administration data for 49 U.S. states (all except Idaho) and the District of Columbia (DC) during December 14, 2020-July 31, 2021. As of July 31, 2021, COVID-19 vaccination coverage among U.S. adolescents aged 12-17 years was 42.4% for ≥1 dose and 31.9% for series completion. Vaccination coverage with ≥1 dose varied by state (range = 20.2% [Mississippi] to 70.1% [Vermont]) and for series completion (range = 10.7% [Mississippi] to 60.3% [Vermont]). By age group, 36.0%, 40.9%, and 50.6% of adolescents aged 12-13, 14-15, and 16-17 years, respectively, received ≥1 dose; 25.4%, 30.5%, and 40.3%, respectively, completed the vaccine series. Improving vaccination coverage and implementing COVID-19 prevention strategies are crucial to reduce COVID-19-associated morbidity and mortality among adolescents and to facilitate safer reopening of schools for in-person learning.

After the March 2020 declaration of the COVID-19 pandemic in the United States, an analysis of provider ordering data from the federally funded Vaccines for Children program found a substantial decrease in routine pediatric vaccine ordering (1), and data from New York City and Michigan indicated sharp declines in routine childhood vaccine administration in these areas (2,3). In November 2020, CDC interim guidance stated that routine vaccination of children and adolescents should remain an essential preventive service during the COVID-19 pandemic (4,5). To further understand the impact of the pandemic on routine childhood and adolescent vaccination, vaccine administration data during March-September 2020 from 10 U.S. jurisdictions with high-performing* immunization information systems were assessed. Fewer administered doses of routine childhood and adolescent vaccines were recorded in all 10 jurisdictions during March-September 2020 compared with those recorded during the same period in 2018 and 2019. The number of vaccine doses administered substantially declined during March-May 2020, when many jurisdictions enacted stay-at-home orders. After many jurisdictions lifted these orders, the number of vaccine doses administered during June-September 2020 approached prepandemic baseline levels, but did not increase to the level that would have been necessary to catch up children who did not receive routine vaccinations on time. This lag in catch-up vaccination might pose a serious public health threat that would result in vaccine-preventable disease outbreaks, especially in schools that have reopened for in-person learning. During the past few decades, the United States has achieved a substantial reduction in the prevalence of vaccine-preventable diseases driven in large part to the ongoing administration of routinely recommended pediatric vaccines. These efforts need to continue even during the COVID-19 pandemic to reduce the morbidity and mortality from vaccine-preventable diseases. Health care providers should assess the vaccination status of all pediatric patients, including adolescents, and contact those who are behind schedule to ensure that all children are fully vaccinated.

In December 2020, two COVID-19 vaccines (Pfizer-BioNTech and Moderna) were authorized for emergency use in the United States for the prevention of coronavirus disease 2019 (COVID-19).* Because of limited initial vaccine supply, the Advisory Committee on Immunization Practices (ACIP) prioritized vaccination of health care personnel† and residents and staff members of long-term care facilities (LTCF) during the first phase of the U.S. COVID-19 vaccination program (1). Both vaccines require 2 doses to complete the series. Data on vaccines administered during December 14, 2020-January 14, 2021, and reported to CDC by January 26, 2021, were analyzed to describe demographic characteristics, including sex, age, and race/ethnicity, of persons who received ≥1 dose of COVID-19 vaccine (i.e., initiated vaccination). During this period, 12,928,749 persons in the United States in 64 jurisdictions and five federal entities§ initiated COVID-19 vaccination. Data on sex were reported for 97.0%, age for 99.9%, and race/ethnicity for 51.9% of vaccine recipients. Among persons who received the first vaccine dose and had reported demographic data, 63.0% were women, 55.0% were aged ≥50 years, and 60.4% were non-Hispanic White (White). More complete reporting of race and ethnicity data at the provider and jurisdictional levels is critical to ensure rapid detection of and response to potential disparities in COVID-19 vaccination. As the U.S. COVID-19 vaccination program expands, public health officials should ensure that vaccine is administered efficiently and equitably within each successive vaccination priority category, especially among those at highest risk for infection and severe adverse health outcomes, many of whom are non-Hispanic Black (Black), non-Hispanic American Indian/Alaska Native (AI/AN), and Hispanic persons (2,3).

Influenza causes considerable morbidity and mortality in the United States. Between 2010 and 2020, an estimated 9-41 million cases resulted in 140,000-710,000 hospitalizations and 12,000-52,000 deaths annually (1). As the United States enters the 2021-22 influenza season, the potential impact of influenza illnesses is of concern given that influenza season will again coincide with the ongoing COVID-19 pandemic, which could further strain overburdened health care systems. The Advisory Committee on Immunization Practices (ACIP) recommends routine annual influenza vaccination for the 2021-22 influenza season for all persons aged ≥6 months who have no contraindications (2). To assess the potential impact of the COVID-19 pandemic on influenza vaccination coverage, the percentage change between administration of at least 1 dose of influenza vaccine during September-December 2020 was compared with the average administered in the corresponding periods in 2018 and 2019. The data analyzed were reported from 11 U.S. jurisdictions with high-performing state immunization information systems.* Overall, influenza vaccine administration was 9.0% higher in 2020 compared with the average in 2018 and 2019, combined. However, in 2020, the number of influenza vaccine doses administered to children aged 6-23 months and children aged 2-4 years, was 13.9% and 11.9% lower, respectively than the average for each age group in 2018 and 2019. Strategic efforts are needed to ensure high influenza vaccination coverage among all age groups, especially children aged 6 months-4 years who are not yet eligible to receive a COVID-19 vaccine. Administration of influenza vaccine and a COVID-19 vaccine among eligible populations is especially important to reduce the potential strain that influenza and COVID-19 cases could place on health care systems already overburdened by COVID-19.

BackgroundAs of August 21, 2021, >60% of the U.S. population aged ≥18 years were fully vaccinated with vaccines highly effective in preventing hospitalization due to Coronavirus Disease-2019 (COVID-19). Infection despite full vaccination (vaccine breakthrough) has been reported, but characteristics of those with vaccine breakthrough resulting in hospitalization and relative rates of hospitalization in unvaccinated and vaccinated persons are not well described, including during late June and July 2021 when the highly transmissible Delta variant predominated.MethodsFrom January 1–June 30, 2021, cases defined as adults aged ≥18 years with laboratory-confirmed Severe Acute Respiratory Coronavirus-2 (SARS-CoV-2) infection were identified from >250 acute care hospitals in the population-based COVID-19-Associated Hospitalization Surveillance Network (COVID-NET). Through chart review for sampled cases, we examine characteristics associated with vaccination breakthrough. From January 24–July 24, 2021, state immunization information system data linked to both >37,000 cases representative cases and the defined surveillance catchment area population were used to compare weekly hospitalization rates in vaccinated and unvaccinated individuals. Unweighted case counts and weighted percentages are presented.ResultsFrom January 1 – June 30, 2021, fully vaccinated cases increased from 1 (0.01%) to 321 (16.1%) per month. Among 4,732 sampled cases, fully vaccinated persons admitted with COVID-19 were older compared with unvaccinated persons (median age 73 years [Interquartile Range (IQR) 65-80] v. 59 years [IQR 48-70]; pConclusionPopulation-based hospitalization rates show that unvaccinated adults aged ≥18 years are 17 times more likely to be hospitalized compared with vaccinated adults. Rates are far higher in unvaccinated persons in all adult age groups, including during a period when the Delta variant was the predominant strain of the SARS-CoV-2 virus. Vaccines continue to play a critical role in preventing serious COVID-19 illness and remain highly effective in preventing COVID-19 hospitalizations.

Clinical trials of COVID-19 vaccines currently authorized for emergency use in the United States (Pfizer-BioNTech, Moderna, and Janssen [Johnson & Johnson]) indicate that these vaccines have high efficacy against symptomatic disease, including moderate to severe illness (1-3). In addition to clinical trials, real-world assessments of COVID-19 vaccine effectiveness are critical in guiding vaccine policy and building vaccine confidence, particularly among populations at higher risk for more severe illness from COVID-19, including older adults. To determine the real-world effectiveness of the three currently authorized COVID-19 vaccines among persons aged ≥65 years during February 1-April 30, 2021, data on 7,280 patients from the COVID-19-Associated Hospitalization Surveillance Network (COVID-NET) were analyzed with vaccination coverage data from state immunization information systems (IISs) for the COVID-NET catchment area (approximately 4.8 million persons). Among adults aged 65-74 years, effectiveness of full vaccination in preventing COVID-19-associated hospitalization was 96% (95% confidence interval [CI]=94%-98%) for Pfizer-BioNTech, 96% (95% CI=95%-98%) for Moderna, and 84% (95% CI=64%-93%) for Janssen vaccine products. Effectiveness of full vaccination in preventing COVID-19-associated hospitalization among adults aged ≥75 years was 91% (95% CI=87%-94%) for Pfizer-BioNTech, 96% (95% CI=93%-98%) for Moderna, and 85% (95% CI=72%-92%) for Janssen vaccine products. COVID-19 vaccines currently authorized in the United States are highly effective in preventing COVID-19-associated hospitalizations in older adults. In light of real-world data demonstrating high effectiveness of COVID-19 vaccines among older adults, efforts to increase vaccination coverage in this age group are critical to reducing the risk for COVID-19-related hospitalization.

Approximately 60 million persons in the United States live in rural counties, representing almost one fifth (19.3%) of the population.* In September 2020, COVID-19 incidence (cases per 100,000 population) in rural counties surpassed that in urban counties (1). Rural communities often have a higher proportion of residents who lack health insurance, live with comorbidities or disabilities, are aged ≥65 years, and have limited access to health care facilities with intensive care capabilities, which places these residents at increased risk for COVID-19-associated morbidity and mortality (2,3). To better understand COVID-19 vaccination disparities across the urban-rural continuum, CDC analyzed county-level vaccine administration data among adults aged ≥18 years who received their first dose of either the Pfizer-BioNTech or Moderna COVID-19 vaccine, or a single dose of the Janssen COVID-19 vaccine (Johnson & Johnson) during December 14, 2020-April 10, 2021 in 50 U.S. jurisdictions (49 states and the District of Columbia [DC]). Adult COVID-19 vaccination coverage was lower in rural counties (38.9%) than in urban counties (45.7%) overall and among adults aged 18-64 years (29.1% rural, 37.7% urban), those aged ≥65 years (67.6% rural, 76.1% urban), women (41.7% rural, 48.4% urban), and men (35.3% rural, 41.9% urban). Vaccination coverage varied among jurisdictions: 36 jurisdictions had higher coverage in urban counties, five had higher coverage in rural counties, and five had similar coverage (i.e., within 1%) in urban and rural counties; in four jurisdictions with no rural counties, the urban-rural comparison could not be assessed. A larger proportion of persons in the most rural counties (14.6%) traveled for vaccination to nonadjacent counties (i.e., farther from their county of residence) compared with persons in the most urban counties (10.3%). As availability of COVID-19 vaccines expands, public health practitioners should continue collaborating with health care providers, pharmacies, employers, faith leaders, and other community partners to identify and address barriers to COVID-19 vaccination in rural areas (2).

To assess the impact of immunization with pneumococcal conjugate vaccines on all-cause pneumonia hospitalizations among children in Soweto, South Africa.We used data collected at the Chris Hani Baragwanath Hospital in Soweto between 2006 and 2014 - i.e. before and after April 2009, when a pneumococcal conjugate vaccine was first included in South Africa's routine immunization programme. Using a Bayesian generalized seasonal autoregressive moving-average model and the data collected in 2006-2008, we estimated the numbers of children that would have been hospitalized for pneumonia between 2010 and 2014 if no pneumococcal conjugate vaccines had been used. These estimates were then compared with the corresponding numbers of hospitalizations observed.Between 2006 and 2014, 26 778 children younger than five years - including 3388 known to be infected with human immunodeficiency virus (HIV) - were admitted to the study hospital for pneumonia. We estimated that, for the children known to be infected with HIV and for the other children, pneumococcal conjugate vaccines reduced the numbers of hospitalizations for pneumonia in 2014 by 33% (50% credible interval, CrI: 6 to 52) and 39% (50% CrI: 24 to 50), respectively. In the study hospital in 2012-2014, as a result of immunizations with these vaccines, there were an estimated 3100 fewer pneumonia hospitalizations of children younger than five years.In our study hospital, following the introduction of pneumococcal conjugate vaccines into the national immunization programme, there were significant reductions in pneumonia hospitalizations among children.Évaluer l'impact de l'immunisation à l'aide de vaccins antipneumococciques conjugués sur les hospitalisations d'enfants atteints de pneumonie, toutes causes confondues, à Soweto, en Afrique du Sud.Nous avons utilisé des données recueillies auprès de l'hôpital Chris Hani Baragwanath à Soweto entre 2006 et 2014, c'est-à-dire avant et après avril 2009, date à laquelle un vaccin antipneumococcique conjugué a été inclus pour la première fois dans le programme de vaccination systématique en l'Afrique du Sud. À l'aide d'un modèle bayésien généralisé saisonnier à moyenne mobile autorégressive et des données recueillies entre 2006 et 2008, nous avons estimé le nombre d'enfants qui auraient été hospitalisés pour une pneumonie entre 2010 et 2014 si aucun vaccin antipneumococcique conjugué n'avait été utilisé. Ces estimations ont ensuite été comparées au nombre d'hospitalisations observées correspondant.Entre 2006 et 2014, 26 778 enfants âgés de moins de cinq ans – parmi lesquels 3388 dont la séropositivité au virus de l'immunodéficience humaine (VIH) était connue – ont été admis au sein de l'hôpital d'étude pour une pneumonie. Nous avons estimé qu'en 2014, les vaccins antipneumococciques conjugués avaient permis de réduire le nombre d'hospitalisations pour une pneumonie de 33% (intervalle de crédibilité, ICr, à 50%: 6-52) dans le cas des enfants dont la séropositivité au VIH était connue, et de 39% (ICr à 50%: 24-50) dans le cas des autres enfants. D'après nos estimations, le nombre d'hospitalisations pour une pneumonie d'enfants âgés de moins de cinq ans a diminué de 3100 dans l'hôpital d'étude entre 2012 et 2014 grâce à ces vaccins.Suite à l'inclusion des vaccins antipneumococciques conjugués dans le programme de vaccination national, nous avons constaté une forte diminution du nombre d'enfants hospitalisés pour une pneumonie dans l'hôpital d'étude.Evaluar el impacto de la inmunización con vacunas antineumocócicas conjugadas en todos los casos de hospitalización por neumonía entre niños en Soweto, Sudáfrica.Se utilizaron datos recopilados en el Chris Hani Baragwanath Hospital en Soweto entre 2006 y 2014, es decir, antes y después de abril de 2009, cuando la vacuna antineumocócica conjugada se incluyó por primera vez en el programa de inmunización rutinaria de Sudáfrica. A través de un modelo bayesiano de promedio móvil, generalizado, temporal y autoagresivo y los datos recopilados entre 2006 y 2008, se estimó el número de niños que habrían sido hospitalizados por neumonía entre 2010 y 2014 si no se hubiera utilizado la vacuna antineumocócica conjugada. Estas estimaciones se compararon con los números correspondientes a las hospitalizaciones observadas.Entre 2006 y 2014, 26 778 niños menores de 5 años ingresaron por neumonía en el hospital del estudio, incluyendo 3 388 infectados por el virus de la inmunodeficiencia humana (VIH). Se estimó que, tanto para los niños infectados por el VIH como para el resto, las vacunas antineumocócias conjugadas redujeron el número de hospitalizaciones por neumonía en 2014 en un 33% (intervalo creíble, ICr, del 50%: de 6 a 52) y en un 39% (ICr del 50%: de 24 a 50), respectivamente. En el hospital del estudio entre 2012 y 2014, como resultado de las inmunizaciones con estas vacunas, hubo una reducción de cerca de 3 100 hospitalizaciones por neumonía de niños menores de 5 años.En nuestro hospital del estudio, después de la introducción de las vacunas antineumocócicas conjugadas en el programa nacional de inmunización, hubo reducciones significativas en las hospitalizaciones por neumonía entre los niños.تقييم أثر التمنيع باستخدام لقاحات المكورات الرئوية على جميع حالات علاج الأطفال بالمستشفيات من الالتهاب الرئوي في سويتو بجنوب أفريقيا.استخدمنا البيانات التي تم جمعها في مستشفى Chris Hani Baragwanath في سويتو بين عامي 2006 و2014؛ أي قبل وبعد أبريل/نيسان 2009، عندما تم إدراج لقاح المكورات الرئوية لأول مرة في برنامج التمنيع الروتيني في جنوب أفريقيا. وباستخدام نموذج "بايزي" متوسط المجاوزة في الانحدار الذاتي الموسمي والبيانات التي تم جمعها في الفترة ما بين عامي 2006 و2008، فقد قمنا بتقدير عدد الأطفال الذين كان من الممكن دخولهم المستشفى بسبب الالتهاب الرئوي بين عامي 2010 و2014 إذا لم يتم استخدام لقاحات المكورات الرئوية. وتمت مقارنة هذه التقديرات مع الأرقام المقابلة لعمليات الاستشفاء المسجلة في المستشفيات.في الفترة ما بين عامي 2006 و2014، تم إدخال 26778 طفلًا دون الخامسة من العمر – بمن فيهم 3388 طفلاً معروفًا أنهم مصابون بفيروس عوز المناعة البشري (HIV) – إلى المستشفى الخاضعة للدراسة بسبب الالتهاب الرئوي. وتشير تقديراتنا إلى أن لقاحات المكورات الرئوية – بالنسبة للأطفال المصابين بفيروس عوز المناعة البشري (HIV) والأطفال الآخرين – قد قللت عدد حالات الاستشفاء من الالتهاب الرئوي في عام 2014 بنسبة ‏33‏٪ (بهامش موثوقية يبلغ ‏50‏٪، ونسبة ثقة تتراوح ما بين: 6 إلى 52) و‏39‏% (بنسبة ثقة مقدارها ‏50‏%: 24 إلى 50)، على التوالي. في المستشفى الخاضعة للدراسة في الفترة ما بين عامي 2012 و2014، كان هناك تراجع مقداره 3100 حالة في عدد حالات الاستشفاء من الالتهاب الرئوي للأطفال دون سن الخامسة وذلك نتيجة للتطعيمات باستخدام هذه اللقاحات.في المستشفى الخاضعة لدراستنا، وبعد إدخال لقاحات المكورات الرئوية في برنامج التمنيع الوطني، حدثت انخفاضات كبيرة في حالات الاستشفاء من الالتهاب الرئوي بين الأطفال.为评估接种肺炎球菌结合疫苗对南非索韦托儿童全因肺炎住院治疗的影响。.我们使用 2006 年到 2014 年间——即，在 2009 年四月前后，肺炎球菌结合疫苗首次纳入南非常规免疫计划期间，在索韦托 Chris Hani Baragwanath 医院收集的数据。 我们使用贝叶斯综合季节性自回归滑动平均模型和 2006–2008 年间收集的数据，估算出 2010 年到 2014 年间不使用肺炎球菌结合疫苗的情况下因肺炎住院的儿童人数。 之后将估算值与观察到的相应住院治疗人数进行了比较。.在 2006 年到 2014 年间，26 778 名五岁以下儿童——包括 3388 名已知感染人类免疫缺陷病毒 (HIV) 的儿童——被收入肺炎研究医院接受治疗。 我们估计，在 2014 年，对于已知感染 HIV 的儿童和其他儿童，肺炎球菌结合疫苗分别将肺炎住院治疗人数降低了 33%（50% 置信区间，CrI： 6 至 52）和 39% (50% CrI: 24 至 50）。 在 2012-2014 年间，由于疫苗接种，研究医院五岁以下因肺炎住院治疗的儿童人数预计减少了 3100 人。.在我们的研究医院，在国家免疫计划中引入肺炎球菌结合疫苗之后，儿童肺炎住院治疗人数显著减少。.Оценить влияние иммунизации пневмококковыми конъюгированными вакцинами на общий показатель госпитализации при пневмонии среди детей в Соуэто, Южная Африка.Мы использовали данные, собранные в больнице Криса Хани Барагваната в Соуэто в период с 2006 по 2014 г., то есть до и после апреля 2009 г., когда пневмококковая конъюгированная вакцина впервые была включена в стандартную программу иммунизации в Южной Африке. Используя байесовскую обобщенную сезонную модель авторегрессии скользящего среднего и данные, собранные в 2006–2008 гг., мы подсчитали количество детей, которые были бы госпитализированы с пневмонией в период с 2010 по 2014 г., если бы не использовались пневмококковые конъюгированные вакцины. Затем было проведено сравнение этих оценок с соответствующим количеством госпитализаций.В период с 2006 по 2014 г. 26 778 детей в возрасте до пяти лет, включая 3388 детей, которые, как было известно, были инфицированы вирусом иммунодефицита человека (ВИЧ), были госпитализированы с пневмонией в стационар, участвующий в исследовании. Мы подсчитали, что среди детей, инфицированных ВИЧ, и среди остальных детей пневмококковые конъюгированные вакцины сократили число госпитализаций с пневмонией в 2014 г. на 33% (50% доверительный интервал, ДИ: от 6 до 52) и 39% (50% ДИ: от 24 до 50) соответственно. В стационаре, участвующем в исследовании, в 2012–2014 гг. в результате иммунизации этими вакцинами, по оценкам, насчитывалось на 3100 меньше случаев госпитализации при пневмонии у детей в возрасте младше пяти лет.В нашем стационаре, участвующем в исследовании, после введения пневмококковых конъюгированных вакцин в национальную программу иммунизации наблюдалось значительное сокращение случаев госпитализации при пневмонии среди детей.

BACKGROUND: The public health impact of rotavirus vaccination in African settings with a high human immunodeficiency virus (HIV) infection prevalence is yet to be established. We evaluated trends in all-cause diarrheal hospitalizations in Soweto Johannesburg before and after the introduction of rotavirus vaccine into South Africas national immunization program in August 2009. METHODS: Hospitalizations in children

Background Vaccinating pregnant women may prevent invasive Group B Streptococcus (GBS) disease in their young infants. In a low-middle income setting, we sought to determine an association between natural maternal antibody responses and the development of invasive GBS disease. Methods We undertook a matched case-control study in Johannesburg, South Africa. Maternal and infant antibody concentrations were compared between serotype-specific Ia and III GBS cases and well-baby controls in which the mother was colonized with the same serotype. Results The median maternal serotype Ia and III antibody concentrations (in μg/mL) were 0.05 (IQR: 0.02–0.24; n = 27) and 0.14 (IQR: 0.08–0.33; n = 29) in cases, and 0.29 (IQR: 0.06–1.60; n = 43) and 0.29 (IQR: 0.13–0.58; n = 31) in homotypic controls, respectively. A smaller proportion of cases as compared to homotypic controls had higher serotype Ia and III maternal antibody concentrations. Using Bayesian modeling, we demonstrated that the risk of invasive GBS disease was less than 10% with maternal antibody concentrations ≥6 μg/mL and ≥3 μg/mL for serotypes Ia and III, respectively. Conclusions Maternal capsular antibody concentrations are associated with the risk of invasive GBS disease in infants. In a low-middle income setting with a high burden of invasive disease, we have demonstrated a sero-correlate of protection for GBS serotypes Ia and III which could facilitate vaccine licensure.

Group B Streptococcus (GBS) surface-proteins have been shown to be immunogenic and potential vaccine candidates. We aim to determine the association between maternal IgG antibodies to select GBS surface-proteins and invasive GBS disease in their infants.Using a matched case-control study, maternal antibody levels for GBS-immunogenic bacterial adhesin, fibrinogen-binding protein A and pilus-island (PI) PI-1, PI-2a, PI-2b were compared between infants with invasive GBS disease and well-baby controls.The absolute risk of disease did not differ between cases and colonized controls with increasing antibody concentrations for these surface-proteins. There was, however, a relative risk reduction in invasive disease associated with fibrinogen-binding protein A, with an adjusted odds ratio of 0.04 (95% CI: 0.01-0.69) at antibody levels ≥10,000 AU/ml.We have not demonstrated an association between naturally occurring fibrinogen-binding protein A, GBS-immunogenic bacterial adhesin, and PI surface-protein antibodies and the risk of invasive disease in young infants. These surface-proteins may not be suitable GBS vaccine candidates.

Background In outbreak settings, mass vaccination strategies could maximize health protection of military personnel. Self-administration of live attenuated influenza vaccine (LAIV) may be a means to vaccinate large numbers of people and achieve deployment readiness while sparing the use of human resources. Methods A phase IV, open-label, randomized controlled trial evaluating the immunogenicity and acceptance of self-administered (SA) LAIV was conducted from 2012 to 2014. SA subjects were randomized to either individual self-administration or self-administration in a group setting. Control randomized subjects received healthcare worker-administered (HCWA) LAIV. Anti-hemagglutinin (HAI) antibody concentrations were measured pre- and post-vaccination. The primary endpoint was immunogenicity non-inferiority between SA and HCWA groups. Subjects were surveyed on preferred administration method. Results A total of 1077 subjects consented and were randomized (529 SA, 548 HCWA). Subject characteristics were very similar between groups, though SA subjects were younger, more likely to be white and on active duty. The per-protocol analysis included 1024 subjects (501 SA, 523 HCWA). Post-vaccination geometric mean titers by vaccine strain and by study group (HCWA vs. SA) were: A/H1N1 (45.8 vs. 48.7, respectively; p = 0.43), A/H3N2 (45.5 vs. 46.4; p = 0.80), B/Yamagata (17.2 vs. 17.8; p = 0.55). Seroresponses to A components were high (∼67%), while seroresponses to B components were lower (∼25%). Seroresponse did not differ by administration method. Baseline preference for administration method was similar between groups, with the majority in each group expressing no preference. At follow-up, the majority (64%) of SA subjects preferred SA vaccine. Conclusions LAIV immunogenicity was similar for HCWA and SA vaccines. SA was well-tolerated and preferred to HCWA among those who performed SA.

Introduction We evaluated pneumococcal conjugate vaccine (PCV) effectiveness against hospitalisation for presumed bacterial pneumonia (PBP) in HIV-uninfected South African children. 7-valent PCV was introduced in April 2009 using a 2+1 schedule (doses at age 6, 14 and 39 weeks), superseded with 13-valent PCV in May 2011. Methods A matched case–control study was conducted at three public hospitals (Soweto, Cape Town and KwaZulu-Natal) between April 2009 and August 2012. PBP cases had either WHO defined radiographically confirmed pneumonia or ‘other infiltrate’ on chest radiograph with C-reactive protein ≥40 mg/L. Hospitalised controls were children admitted with a disease unlikely to be pneumococcal and matched for case age, site and HIV infection status. Age-matched community controls were enrolled from Soweto. Adjusted vaccine effectiveness (aVE) was estimated using conditional logistic regression. Results Of 1444 HIV-uninfected enrolled PBP cases, 1326 had ≥1 hospital controls (n=2075). Overall, aVE of an up-to-date PCV schedule was 20.1% (95% CI −9.3% to 41.6%) in children aged ≥8 weeks and 39.2% (95% CI 8.46% to 59.6%) among children 16–103 weeks of age. There were 889 PBP cases in Soweto with hospital controls and ≥1 community control (n=2628). The aVE using community controls was similar compared with hospital controls in Soweto, including 32.1% (95% CI 4.6% to 51.6%) and 38.4% (95% CI 7.7% to 58.8%), respectively, in age group ≥8 weeks and 52.7% (95% CI 25.7% to 69.9%) and 53.8% (95% CI 19.5% to 73.5%), respectively, in age group 16–103 weeks. Conclusions PCV implemented using a 2+1 schedule in the routine infant immunisation programme was effective at preventing PBP in HIV-uninfected children. Effectiveness estimates were similar to efficacy measured by earlier randomised controlled trials using different vaccination schedules.

Case-control studies are commonly used to evaluate effectiveness of licensed vaccines after deployment in public health programs. Such studies can provide policy-relevant data on vaccine performance under ‘real world’ conditions, contributing to the evidence base to support and sustain introduction of new vaccines. However, case-control studies do not measure the impact of vaccine introduction on disease at a population level, and are subject to bias and confounding, which may lead to inaccurate results that can misinform policy decisions. In 2012, a group of experts met to review recent experience with case-control studies evaluating the effectiveness of several vaccines; here we summarize the recommendations of that group regarding best practices for planning, design and enrollment of cases and controls. Rigorous planning and preparation should focus on understanding the study context including healthcare-seeking and vaccination practices. Case-control vaccine effectiveness studies are best carried out soon after vaccine introduction because high coverage creates strong potential for confounding. Endpoints specific to the vaccine target are preferable to non-specific clinical syndromes since the proportion of non-specific outcomes preventable through vaccination may vary over time and place, leading to potentially confusing results. Controls should be representative of the source population from which cases arise, and are generally recruited from the community or health facilities where cases are enrolled. Matching of controls to cases for potential confounding factors is commonly used, although should be reserved for a limited number of key variables believed to be linked to both vaccination and disease. Case-control vaccine effectiveness studies can provide information useful to guide policy decisions and vaccine development, however rigorous preparation and design is essential. publishedVersion

BACKGROUND: Meningococcal conjugate vaccines were licensed beginning in 2005 on the basis of serologic end points and recommended for use in adolescents. A single dose at age 11 to 12 years was expected to provide protection through late adolescence. We conducted a case-control evaluation of vaccine effectiveness (VE) and duration of protection of a meningococcal (groups A, C, W, and Y) polysaccharide diphtheria toxoid conjugate vaccine (MenACWY-D). METHODS: Cases of culture- or polymerase chain reaction-confirmed serogroup A, C, W, and Y meningococcal disease among adolescents were identified through meningococcal disease surveillance sites in the United States from January 1, 2006, through August 31, 2013. Attempts were made to enroll 4 friend and school controls per case. VE was calculated using the generalized estimating equation, controlling for underlying medical conditions and smoking. RESULTS: Serogroup C accounted for 88 (49%), serogroup Y 80 (44%), and serogroup W 13 (7%) of enrolled cases. Thirty-six (20%) cases and 87 (44%) controls received MenACWY-D. The overall VE estimate 0 to 8 years postvaccination was 69% (51% to 80%); VE was 79% (49% to 91%) at CONCLUSIONS: MenACWY-D was effective in the first year after vaccination but effectiveness waned 3 to

The case-control methodology is frequently used to evaluate vaccine effectiveness post-licensure. The results of such studies provide important insight into the level of protection afforded by vaccines in a ‘real world’ context, and are commonly used to guide vaccine policy decisions. However, the potential for bias and confounding are important limitations to this method, and the results of a poorly conducted or incorrectly interpreted case-control study can mislead policies. In 2012, a group of experts met to review recent experience with case-control studies evaluating vaccine effectiveness; we summarize the recommendations of that group regarding best practices for data collection, analysis, and presentation of the results of case-control vaccine effectiveness studies. Vaccination status is the primary exposure of interest, but can be challenging to assess accurately and with minimal bias. Investigators should understand factors associated with vaccination as well as the availability of documented vaccination status in the study context; case-control studies may not be a valid method for evaluating vaccine effectiveness in settings where many children lack a documented immunization history. To avoid bias, it is essential to use the same methods and effort gathering vaccination data from cases and controls. Variables that may confound the association between illness and vaccination are also important to capture as completely as possible, and where relevant, adjust for in the analysis according to the analytic plan. In presenting results from case-control vaccine effectiveness studies, investigators should describe enrollment among eligible cases and controls as well as the proportion with no documented vaccine history. Emphasis should be placed on confidence intervals, rather than point estimates, of vaccine effectiveness. Case-control studies are a useful approach for evaluating vaccine effectiveness; however careful attention must be paid to the collection, analysis and presentation of the data in order to best inform evidence-based vaccine policies. publishedVersion

Summary Background The effectiveness of the rotavirus vaccine under conditions of routine use in an African setting with a high prevalence of HIV infection needs to be established. We assessed the vaccine effectiveness of monovalent human rotavirus vaccine in preventing admission to hospital for acute rotavirus diarrhoea, after its introduction at age 6 and 14 weeks into South Africa's national immunisation programme. Methods This case-control study was done at seven hospitals in South Africa between April 19, 2010, and Oct 31, 2012. The hospitals were located in a range of urban, peri-urban, and rural settings, with varying rates of population HIV infection. Cases were children aged from 18 weeks to 23 months who were age-eligible to have received at least one dose of the human rotavirus vaccine (ie, those born after June 14, 2009) admitted to hospital with laboratory-confirmed acute rotavirus diarrhoea, and the primary control group was children admitted to hospital with diarrhoea testing negative for rotavirus. A second control group comprised children admitted to a subset of three of the seven hospitals with respiratory illness. The primary endpoint was adjusted vaccine effectiveness (1 – adjusted odds ratio × 100%) in children aged from 18 weeks to 23 months and was calculated by unconditional logistic regression. This study is registered on the South African National Clinical Trial Register, number DOH-27-0512-3247. Findings Of 540 rotavirus-positive cases, 278 children (52%) received two doses, 126 (23%) one dose, and 136 (25%) no doses of human rotavirus vaccine, compared with 1434 rotavirus-negative controls of whom 856 (60%) received two doses, 334 (23%) one dose, and 244 (17%) no doses. Adjusted vaccine effectiveness using rotavirus-negative controls was 57% (95% CI 40–68) for two doses and 40% (16–57) for one dose; estimates were similar when respiratory controls were used as the control group. Adjusted vaccine effectiveness for two doses was similar between age groups 18 weeks–11 months (54%, 95% CI 32–68) and 12–23 months (61%, 35–77), and was similar in HIV-exposed-uninfected (64%, 95% CI 34–80) and HIV-unexposed-uninfected children (54%, 31–69). Interpretation Human rotavirus vaccine provided sustained protection against admission to hospital for acute rotavirus diarrhoea during the first and second years of life. This finding is encouraging and establishes the public health value of rotavirus vaccine in an African setting, especially as rotavirus vaccines are introduced into an increasing number of African countries. Funding GAVI Alliance (with support from PATH).

Multiple imputation (MI) has become a standard statistical technique for dealing with missing values. The CDC Anthrax Vaccine Research Program (AVRP) dataset created new challenges for MI due to the large number of variables of different types and the limited sample size. A common method for imputing missing data in such complex studies is to specify, for each of J variables with missing values, a univariate conditional distribution given all other variables, and then to draw imputations by iterating over the J conditional distributions. Such fully conditional imputation strategies have the theoretical drawback that the conditional distributions may be incompatible. When the missingness pattern is monotone, a theoretically valid approach is to specify, for each variable with missing values, a conditional distribution given the variables with fewer or the same number of missing values and sequentially draw from these distributions. In this article, we propose the “multiple imputation by ordered monotone bl...

Background. Before the introduction of 7-valent pneumococcal conjugate vaccine (PCV7), invasive pneumococcal disease (IPD) rates among blacks were twice the rates in whites. We measured the effects of trends in PCV7type and non-PCV7-type IPD rates on racial disparities in overall IPD and estimated the proportion of IPD caused by serotypes included in the 13-valent pneumococcal conjugate vaccine (PCV13). Methods. We analyzed data from the Active Bacterial Core surveillance system, which performs active, laboratory- and population-based surveillance for IPD for 29.2 million people in the United States, for the period 1998– 2009. For patients with unknown race, we multiplied imputed race to calculate age-, race-, and serotype-specific IPD incidence rates. Results. During 1998–2009, 47 449 IPD cases were identified; race was unknown for 5419 (11%). After multiple imputation, 31 981 (67%) patients were considered white and 13 750 (29%) black. PCV7-type IPD rates in all ages in both races decreased to

Pneumonia is a leading cause of child morbidity and death. Data on risk factors can guide prevention efforts. Within a study on pneumococcal conjugate vaccine effectiveness, we investigated risk factors for presumed bacterial pneumonia (PBP).PBP cases were human immunodeficiency virus (HIV) uninfected children with lower respiratory tract infection and consolidation on chest radiograph or nonconsolidated infiltrate with C-reactive protein ≥40 mg/L hospitalized at Chris Hani Baragwanath Academic Hospital (CHBAH) in Soweto. Age-matched community controls were identified using CHBAH birth records ±1 week of case birth date. Data were analyzed using conditional logistic regression.A total of 889 PBP cases (median age 9 months) were matched to 2628 controls. Crowding was a significant risk factor among well-nourished children (adjusted odds ratio [aOR]: 2.29, 95% confidence interval [CI]: 1.89-2.78), but not in those with low weight-for-age. Malnutrition was associated with PBP; strength of association was highest in the absence of crowding (aOR: 6.68, 95% CI: 4.74-9.42). Exclusive breastfeeding was protective only among HIV-unexposed children (aOR: 0.65, 95% CI: 0.54-0.78). Self-reported maternal HIV infection was a risk factor among children exclusively breastfeed up to 4 months (aOR: 2.33, 95% CI: 1.53-3.55). Having indoor tap water was protective (aOR: 0.65, 95% CI: 0.54-0.78), whereas a primary care giver who smoked was a risk factor (aOR: 5.15, 95% CI: 2.94-9.03).Our findings confirm several known pneumonia risk factors and highlight complex interactions between factors, including HIV exposure, breastfeeding, malnutrition and crowding. Improved housing, reduced secondhand smoke exposure and HIV prevention among women of reproductive age could lessen the child pneumonia burden.

Summary Background The 13-valent pneumococcal conjugate vaccine (PCV13) was designed to include disease-causing serotypes that are important in low-income and middle-income countries. Vaccine effectiveness estimates are scarce in these settings. South Africa replaced PCV7 with PCV13 in 2011 using a 2 + 1 schedule. We aimed to assess the effectiveness of two or more doses of PCV13 against invasive pneumococcal disease in children with HIV infection and in those not infected with HIV. Methods Cases of invasive pneumococcal disease in children aged 5 years or younger were identified through national laboratory-based surveillance. Isolates were serotyped with the Quellung reaction or PCR. We sought in-hospital controls for every case, matched for age, HIV status, and study site. We aimed to enrol four controls for every case not infected with HIV and six controls for every case with HIV infection (case-control sets). With conditional logistic regression, we calculated vaccine effectiveness as a percentage, with the equation 1 – [adjusted odds ratio for vaccination] × 100. We included data from an earlier investigation of PCV7 to assess vaccine effectiveness in children exposed to but not infected with HIV and in malnourished children not infected with HIV. Findings Between January, 2012, and December, 2014, we enrolled children aged 16 weeks or older to our study: 240 were cases not infected with HIV, 75 were cases with HIV infection, 1118 were controls not infected with HIV, and 283 were controls with HIV infection. The effectiveness of two or more doses of PCV13 against PCV13-serotype invasive pneumococcal disease was 85% (95% CI 37 to 96) among 11 case-control sets of children not infected with HIV and 91% (−35 to 100) among three case-control sets of children with HIV infection. PCV13 effectiveness among 26 case-control sets of children not infected with HIV was 52% (95% CI −12 to 79) against all-serotype invasive pneumococcal disease and 94% (44 to 100) for serotype 19A. Vaccine effectiveness against PCV7-serotype invasive pneumococcal disease was 87% (95% CI 38 to 97) in children exposed to HIV but uninfected and 90% (53 to 98) in malnourished children not infected with HIV. Interpretation Our results indicate that PCV13 in a 2 + 1 schedule is effective for preventing vaccine-type pneumococcal infections in young children not infected with HIV, including those who are malnourished or who have been exposed to HIV. Although the point estimate for PCV13 vaccine effectiveness in children infected with HIV was high, it did not reach significance, possibly because of the small sample size. These findings support recommendations for widespread use of pneumococcal conjugate vaccine in low-income and middle-income countries. Funding Gavi, The Vaccine Alliance.

Background Although human immunodeficiency virus (HIV) infection is an established risk factor for several bacterial infections, the association between HIV infection and meningococcal disease remains unclear. Methods Expanded chart reviews were completed on persons with meningococcal disease and HIV infection reported from 2000 through 2008 from 9 US sites participating in an active population-based surveillance system for meningococcal disease. The incidence of meningococcal disease among patients meeting Centers for Disease Control and Prevention acquired immune deficiency syndrome (AIDS) surveillance criteria was estimated using data from the National HIV Surveillance System for the participating sites. Results Thirty-three cases of meningococcal disease in individuals with HIV infection were reported from participating sites, representing 2.0% of all reported meningococcal disease cases. Most (75.8%) persons with HIV infection were adult males aged 25 to 64 years old. Among all meningococcal disease cases aged 25 to 64 years old, case fatality ratios were similar among HIV-infected and HIV-uninfected persons (13.3% vs 10.6%; P = .6). The cumulative, mean incidence of meningococcal disease among patients aged 25 to 64 years old with HIV infection ever classified as AIDS was 3.5 cases per 100000 person years (95% confidence interval [CI], 2.1–5.6), compared with 0.3 cases per 100000 person years (95% CI, 0.3–0.3) for persons of the same age group not reported to have AIDS (relative risk = 12.9; 95% CI, 7.9–20.9). Conclusions Individuals with HIV infection meeting the AIDS surveillance case definition have a higher incidence of meningococcal disease compared with the general adult population.

Background. Certain chronic diseases increase risk for invasive pneumococcal disease (IPD) and are indications for receipt of 23-valent pneumococcal polysaccharide vaccine (PPV23). Since the pediatric introduction of 7-valent pneumococcal conjugate vaccine (PCV7) in 2000, incidence of IPD among adults has declined. The relative magnitude of these indirect effects among persons with and without PPV23 indications is unknown. Methods. We evaluated IPD incidence among adults with and without PPV23 indications using populationand laboratory-based data collected during 1998–2009 and estimates of the denominator populations with PPV23 indications from the National Health Interview Survey. We compared rates before and after PCV7 use by age, race, PPV23 indication, and serotype. Results. The proportion of adult IPD cases with PPV23 indications increased from 51% before to 61% after PCV7 introduction (P< .0001). PCV7-serotype IPD declined among all race, age, and PPV23 indication strata, ranging from 82% to 97%. Overall IPD rates declined in most strata, by up to 65%. However, incidence remained highest among adults with PPV23 indications compared with those without (34.9 vs 8.8 cases per 100 000 population, respectively). Apart from age ≥65 years, diabetes is now the most common indication for PPV23 (20% of all cases vs 10% of cases in 1998–1999). Conclusions. Although IPD rates have declined among adults, adults with underlying conditions remain at increased risk of IPD and comprise a larger proportion of adult IPD cases in 2009 compared with 2000. A continued increase in the prevalence of diabetes among US adults could lead to increased burden of pneumococcal disease.

Factors associated with neonatal sepsis, an important cause of child mortality, are poorly described in Africa. We characterized factors associated with early-onset (days 0-2 of life) and late-onset (days 3-28) -sepsis and perinatal death among infants enrolled in the Prevention of Perinatal Sepsis Trial (NCT00136370 at ClinicalTrials.gov), Soweto, South Africa.Secondary analysis of 8011 enrolled mothers and their neonates. Prenatal and labor records were abstracted and neonatal wards were monitored for hospitalized Prevention of Perinatal Sepsis-enrolled neonates. Endpoint definitions required clinical and laboratory signs. All univariate factors associated with endpoints at P0.15 were evaluated using multivariable logistic regression.About 10.5% (837/8011) of women received intrapartum antibiotic prophylaxis; 3.8% of enrolled versus 15% of hospital births were preterm. Among 8129 infants, 289 had early-onset sepsis, 34 had late-onset sepsis, 49 had culture-confirmed neonatal sepsis and 71 died in the perinatal period. Factors associated with early-onset sepsis included preterm delivery [adjusted relative risk (aRR) = 2.6; 95% confidence interval (CI): 1.4-4.8]; low birth weight (1500 g: aRR = 6.5, 95% CI: 2.4-17.3); meconium-stained amniotic fluid (MSAF) (aRR = 2.8, 95% CI: 2.2-3.7) and first birth (aRR = 1.8; 95% CI: 1.4-2.3). Preterm, low birth weight, MSAF and first birth were similarly associated with perinatal death and culture-confirmed sepsis. MSAF (aRR = 2.4, 95% CI: 1.1-5.0) was associated with late-onset sepsis.Preterm and low birth weight were important sepsis risk factors. MSAF and first birth were also associated with sepsis and death, warranting further exploration. Intrapartum antibiotic prophylaxis did not protect against all-cause sepsis or death, underscoring the need for alternate prevention strategies.

Background. Streptococcus pneumoniae (pneumococcus) caused approximately 44000 US invasive pneumo-coccal disease (IPD) cases in 2008. Antibiotic nonsusceptibility complicates IPD treatment. Using penicillinsusceptibility breakpoints adopted in 2008, we evaluated antibiotic-nonsusceptible IPD trends in light of theintroductions of a 7-valent pneumococcal conjugate vaccine (PCV7) in 2000 and a 13-valent pneumococcalconjugate vaccine (PCV13) in 2010.Methods. IPD cases were defined by isolation of pneumococcus from a normally sterile site in individualsresiding in Active Bacterial Core surveillance (ABCs) areas during 1998–2008. Pneumococci were serotyped andtested for antibiotic susceptibility using broth microdilution.Results. During 1998–2008, ABCs identified 43198 IPD cases. Penicillin-nonsusceptible strains caused 6%–14%of IPD cases, depending on age. Between 1998–1999 and 2008, penicillin-nonsusceptible IPD rates declined 64% forchildrenaged,5years(12.1–4.4casesper100000),and45%foradultsaged$65(4.8–2.6casesper100000).RatesofIPD nonsusceptible to multiple antibiotics mirrored these trends. During 2007–2008, serotypes in PCV13 but notPCV7 caused 78%–97% of penicillin-nonsusceptible IPD, depending on age.Conclusions. Antibiotic-nonsusceptible IPD rates remain below pre-PCV7 rates for children ,5 and adults$65 years old. PCV13 vaccines hold promise for further nonsusceptibility reductions.Streptococcus pneumoniae (pneumococcus) caused ap-proximately 63000 invasive pneumococcal disease(IPD)casesannuallyinthelate1990sintheUnitedStates,leading to about 6100 deaths [1]. During the first7 years after the introduction in the United States of a7-valent pneumococcal conjugate vaccine (PCV7) forchildren, an estimated 211000 fewer cases of IPD oc-curredamongallagesthanwouldhaveoccurredwithoutthe vaccine [2]; however, approximately 44000 IPDcasescontinuetooccurannually[3].Antibioticresistanceand intermediate susceptibility, together termed non-susceptibility,complicatemanagementofpneumococcaldisease [4–6]. Despite increasing during the 1990s [7],the incidence of antibiotic-nonsusceptible IPD in theUnited States fell following the introduction of PCV7[8, 9]. The 7 serotypes covered by PCV7 accounted for78% of nonsusceptible serotypes in 1998 [7], and theincidence rate of these serotypes decreased 78% amongchildren aged ,2 years by 2001 [9]. However, by 2003,the incidence of antibiotic-nonsusceptible IPD in chil-dren aged ,5 years was increasing again [8], coincidingwith the emergence of serotypes not included in PCV7

With the introduction of Haemophilus influenzae serotype b (Hib) conjugate vaccines, there has been a dramatic reduction of Hib disease in young children and the epidemiological trends of invasive H. influenzae have shifted.Data were collected from active surveillance for invasive H. influenzae disease conducted through Active Bacterial Core surveillance sites during 1989-2008.During 1999-2008, the estimated mean annual incidence of H. influenzae infection was 1.62 cases per 100 000 population; 15.3% of cases were fatal. Incidence was higher among adults aged ≥65 years, compared with other age groups. The largest burden of disease among children aged5 years was in infants aged1 year; many of these cases occurred during the first month of life in preterm or low-birth weight infants. An estimated 10% of the total burden of disease among children aged5 years occurred in American Indian and Alaska Native children. During 1989-2008, 7559 cases of H. influenzae disease were reported from Active Bacterial Core surveillance sites. Small increases in the incidence of serotypes a, e, and f were observed during 1989-2008. The largest of these increases was in serotype f and was primarily among adults aged ≥18 years.Since the introduction of Hib conjugate vaccines, the incidence of invasive disease caused by H. influenzae in the United States has decreased dramatically; however, a considerable burden of non-Hib disease is still present in the oldest and youngest age groups. There is no evidence of substantial replacement disease with non-b serotypes in young children in the United States.

Randomization of treatment assignment in experiments generates treatment groups with approximately balanced baseline covariates. However, in observational studies, where treatment assignment is not random, patients in the active treatment and control groups often differ on crucial covariates that are related to outcomes. These covariate imbalances can lead to biased treatment effect estimates. The propensity score is the probability that a patient with particular baseline characteristics is assigned to active treatment rather than control. Though propensity scores are unknown in observational studies, by matching or subclassifying patients on estimated propensity scores, we can design observational studies that parallel randomized experiments, with approximate balance on observed covariates. Observational study designs based on estimated propensity scores can generate approximately unbiased treatment effect estimates. Critically, propensity score designs should be created without access to outcomes, mirroring the separation of study design and outcome analysis in randomized experiments. This paper describes the potential outcomes framework for causal inference and best practices for designing observational studies with propensity scores. We discuss the use of propensity scores in two studies assessing the effectiveness and risks of antifibrinolytic drugs during cardiac surgery.

Resumen La asignacion aleatoria del tratamiento en los experimentos divide a los pacientes en grupos de tratamiento que estan aproximadamente equilibrados en cuanto a las covariables basales. Sin embargo, en los estudios observacionales, en los que la asignacion del tratamiento no es aleatoria, los pacientes de los grupos de tratamiento activo y de control difieren a menudo en covariables cruciales que estan relacionadas con las variables de respuesta. Estos desequilibrios en las covariables pueden conducir a estimaciones sesgadas del efecto del tratamiento. La puntuacion de propension (propensity score) es la probabilidad de que a un paciente con unas caracteristicas basales especificas se le asigne el tratamiento activo, y no el control. Aunque las puntuaciones de propension son desconocidas en los estudios observacionales, al parear o subclasificar a los pacientes segun las puntuaciones de propension estimadas, podemos disenar estudios observacionales que sean analogos a los experimentos aleatorios, con un equilibrio aproximado entre pacientes en cuanto a las covariables observadas. Los disenos de estudios observacionales basados en puntuaciones de propension estimadas pueden producir estimaciones aproximadamente insesgadas del efecto del tratamiento. Una cuestion crucial es que los disenos de puntuacion de propension deben crearse sin tener acceso a las respuestas, imitando la separacion entre el diseno del estudio y el analisis de las respuestas que es propia de los experimentos aleatorios. En este articulo se describen el marco conceptual de las respuestas potenciales para la inferencia causal y las mejores practicas para el diseno de estudios observacionales con puntuaciones de propension. Comentamos el uso de puntuaciones de propension en dos estudios en los que se evaluaron la efectividad y los riesgos de los farmacos antifibrinoliticos durante las cirugias cardiacas.

In January 2005, a quadrivalent meningococcal conjugate vaccine (MenACWYD) was licensed for use in the United States. The Advisory Committee on Immunization Practices recommends MenACWYD for all adolescents 11 to 18 years of age and others at increased risk for meningococcal disease.Reports of breakthrough meningococcal disease after vaccination with MenACWYD were collected. A simulation approach was used to estimate the expected number of cases in vaccinated persons.Between 2005 and 2008, 14 breakthrough cases, including 3 deaths occurred. At a vaccine effectiveness (VE) of 90%, 7 breakthrough cases would be expected (range, 1-17); at VE of 85%, 11 cases (range, 2-30); at VE of 80%, 15 cases (range, 5-28); and at VE of 75%, 18 cases (range, 7-32) would be expected. The probability of the ≥14 observed cases occurring was 2.9% at VE of 90%, 29.3% at VE of 85%, 66.1% at VE of 80%, and 83.0% at VE of 75%.This report provides an early estimate of MenACWYD effectiveness within 3 to 4 years after vaccination, and suggests that MenACWYD effectiveness is 80% to 85%, similar to the VE reported for meningococcal polysaccharide vaccine.

The rate of bacterial meningitis declined by 55% in the United States in the early 1990s, when the Haemophilus influenzae type b (Hib) conjugate vaccine for infants was introduced. More recent prevention measures such as the pneumococcal conjugate vaccine and universal screening of pregnant women for group B streptococcus (GBS) have further changed the epidemiology of bacterial meningitis.We analyzed data on cases of bacterial meningitis reported among residents in eight surveillance areas of the Emerging Infections Programs Network, consisting of approximately 17.4 million persons, during 1998-2007. We defined bacterial meningitis as the presence of H. influenzae, Streptococcus pneumoniae, GBS, Listeria monocytogenes, or Neisseria meningitidis in cerebrospinal fluid or other normally sterile site in association with a clinical diagnosis of meningitis.We identified 3188 patients with bacterial meningitis; of 3155 patients for whom outcome data were available, 466 (14.8%) died. The incidence of meningitis changed by -31% (95% confidence interval [CI], -33 to -29) during the surveillance period, from 2.00 cases per 100,000 population (95% CI, 1.85 to 2.15) in 1998-1999 to 1.38 cases per 100,000 population (95% CI 1.27 to 1.50) in 2006-2007. The median age of patients increased from 30.3 years in 1998-1999 to 41.9 years in 2006-2007 (P0.001 by the Wilcoxon rank-sum test). The case fatality rate did not change significantly: it was 15.7% in 1998-1999 and 14.3% in 2006-2007 (P=0.50). Of the 1670 cases reported during 2003-2007, S. pneumoniae was the predominant infective species (58.0%), followed by GBS (18.1%), N. meningitidis (13.9%), H. influenzae (6.7%), and L. monocytogenes (3.4%). An estimated 4100 cases and 500 deaths from bacterial meningitis occurred annually in the United States during 2003-2007.The rates of bacterial meningitis have decreased since 1998, but the disease still often results in death. With the success of pneumococcal and Hib conjugate vaccines in reducing the risk of meningitis among young children, the burden of bacterial meningitis is now borne more by older adults. (Funded by the Emerging Infections Programs, Centers for Disease Control and Prevention.).

OBJECTIVE: We conducted a case-control study to evaluate risk factors for invasive pneumococcal disease (IPD) among children who were aged 3 to 59 months in the era of pneumococcal conjugate vaccine (PCV7). METHODS: IPD cases were identified through routine surveillance during 2001–2004. We matched a median of 3 control subjects to each case patient by age and zip code. We calculated odds ratios for potential risk factors for vaccine-type and non–vaccine-type IPD by using multivariable conditional logistic regression. RESULTS: We enrolled 782 case patients (45% vaccine-type IPD) and 2512 matched control subjects. Among children who received any PCV7, children were at increased risk for vaccine-type IPD when they had underlying illnesses, were male, or had no health care coverage. Vaccination with PCV7 did not influence the risk for non–vaccine-type IPD. Presence of underlying illnesses increased the risk for non–vaccine-type IPD, particularly among children who were not exposed to household smoking. Non–vaccine-type case patients were more likely than control subjects to attend group child care, be male, live in low-income households, or have asthma; case patients were less likely than control subjects to live in households with other children. CONCLUSIONS: Vaccination with PCV7 has reduced the risk for vaccine-type IPD that is associated with race and group child care attendance. Because these factors are still associated with non–vaccine-type IPD risk, additional reductions in disparities should be expected with new, higher valency conjugate vaccines.

The success of interventions designed to address important issues in social and medical science is best addressed by randomized experiments. With human beings there are often complications, however, such as noncompliance and missing data. Such complications are often addressed by statistically invalid methods of analysis, in particular, intention-to-treat and per-protocol analyses. Here we address these two complications using a statistically valid approach based on principal stratification with a fully Bayesian analysis. This analysis is applied to a randomized trial of a potentially important intervention designed to reduce the transmission of bacterial colonization between mothers and their infants through vaginal delivery in South Africa: the Prevention of Perinatal Sepsis (PoPs).

Background. In January 2005, a quadrivalent (serogroups A, C , Y, and W-135) meningococcal conjugate vaccine was licensed for use in adolescents. This report describes the epidemiologic features of meningococcal disease in the United States from January 1998 through December 2007, before and during implementation of adolescent quadrivalent meningococcal conjugate vaccination. Methods. Data were collected from active surveillance for invasive Neisseria meningitidis conducted through the Active Bacterial Core surveillance (ABCs) sites during 1998-2007. Isolates from cases were serogrouped at the ABCs site and confirmed at the Centers for Disease Control and Prevention. Estimates of the incidence and number of cases in the 50 states were calculated, standardizing for race and age group. Results. In the period 1998-2007, a total of 2262 cases of meningococcal disease were reported from ABCs sites; 11.3% of these cases were fatal. The estimated United States average annual incidence of meningococcal disease was 0.53 cases per 100,000 population (95% confidence interval, 0.51-0.55), and an estimated 1525 (95% confidence interval, 1470-1598) cases occurred annually. The annual incidence decreased 64.1%, from 0.92 cases per 100,000 population in 1998 to 0.33 cases per 100,000 population in 2007. Infants aged

Summary Background About 500 000 sepsis-related deaths per year arise in the first 3 days of life. On the basis of results from non-randomised studies, use of vaginal chlorhexidine wipes during labour has been proposed as an intervention for the prevention of early-onset neonatal sepsis in developing countries. We therefore assessed the efficacy of chlorhexidine in early-onset neonatal sepsis and vertical transmission of group B streptococcus. Methods In a trial in Soweto, South Africa, 8011 women (aged 12–51 years) were randomly assigned in a 1:1 ratio to chlorhexidine vaginal wipes or external genitalia water wipes during active labour, and their 8129 newborn babies were assigned to full-body (intervention group) or foot (control group) washes with chlorhexidine at birth, respectively. In a subset of mothers (n=5144), we gathered maternal lower vaginal swabs and neonatal skin swabs after delivery to assess colonisation with potentially pathogenic bacteria. Primary outcomes were neonatal sepsis in the first 3 days of life and vertical transmission of group B streptococcus. Analysis was by intention to treat. The trial is registered with ClinicalTrials.gov, number NCT00136370. Findings Rates of neonatal sepsis did not differ between the groups (chlorhexidine 141 [3%] of 4072 vs control 148 [4%] of 4057; p=0·6518). Rates of colonisation with group B streptococcus in newborn babies born to mothers in the chlorhexidine (217 [54%] of 401) and control groups (234 [55%] of 429] did not differ (efficacy −0·05%, 95% CI −9·5 to 7·9). Interpretation Because chlorhexidine intravaginal and neonatal wipes did not prevent neonatal sepsis or the vertical acquisition of potentially pathogenic bacteria among neonates, we need other interventions to reduce childhood mortality. Funding US Agency for International Development, National Vaccine Program Office and Centers for Disease Control's Antimicrobial Resistance Working Group, and Bill & Melinda Gates Foundation.

We evaluated the potential effects of a hypothetical vaccine in preventing invasive methicillin-resistant Staphylococcus aureus (MRSA) disease in the United States. Using an active, population-based surveillance program, we estimated baseline disease rates in the United States and compared three distinct vaccination strategies which targeted adults > or =65 years of age, persons at risk for recurrent invasive infection, and patients at hospital discharge. The strategies were projected to reduce the burden of invasive MRSA disease by 12.1%, 13.9% and 17.6%, respectively; with the strategy of vaccinating both adults > or =65 years of age and all adults at hospital discharge having the greatest impact per dose. Our data suggest that availability of an effective S. aureus vaccine could result in substantial reductions in invasive MRSA disease incidence. As candidate vaccines are evaluated, these data will be important in determining the optimal vaccination strategy.

Group B streptococcal disease is one of the most common infections in the first week after birth. In 2002, national guidelines recommended universal late antenatal screening of pregnant women for colonization with group B streptococcus to identify candidates for intrapartum chemoprophylaxis.We evaluated the implementation of the guidelines in a multistate, retrospective cohort selected from the Active Bacterial Core surveillance, a 10-state, population-based system that monitors invasive group B streptococcal disease. We abstracted data from the labor and delivery records of a stratified random sample of live births and of all cases in which the newborn had early-onset group B streptococcal disease (i.e., disease in infants7 days of age) in 2003 and 2004. We compared our results with those from a study with a similar design that evaluated screening practices in 1998 and 1999.We abstracted records of 254 births in which the infant had group B streptococcal disease and 7437 births in which the infant did not. The rate of screening for group B streptococcus before delivery increased from 48.1% in 1998-1999 to 85.0% in 2003-2004; the percentage of infants exposed to intrapartum antibiotics increased from 26.8% to 31.7%. Chemoprophylaxis was administered in 87.0% of the women who were positive for group B streptococcus and who delivered at term, but in only 63.4% of women with unknown colonization status who delivered preterm. The overall incidence of early-onset group B streptococcal disease was 0.32 cases per 1000 live births. Preterm infants had a higher incidence of early-onset group B streptococcal disease than did term infants (0.73 vs. 0.26 cases per 1000 live births); however, 74.4% of the cases of group B streptococcal disease (189 of 254) occurred in term infants. Missed screening among mothers who delivered at term accounted for 34 of the 254 cases of group B streptococcal disease (13.4%). A total of 61.4% of the term infants with group B streptococcal disease were born to women who had tested negative for group B streptococcus before delivery.Recommendations for universal screening were rapidly adopted. Improved management of preterm deliveries and improved collection, processing, and reporting of culture results may prevent additional cases of early-onset group B streptococcal disease.

Background In June 2005, the Advisory Committee on Immunization Practices recommended the newly licensed quadrivalent meningococcal conjugate vaccine for routine use among all US children aged 11 years. A 1-time catch-up vaccination campaign for children and adolescents aged 11-17 years, followed by routine annual immunization of each child aged 11 years, could generate immediate herd immunity benefits. The objective of our study was to analyze the cost-effectiveness of a catch-up vaccination campaign with quadrivalent meningococcal conjugate vaccine for children and adolescents aged 11-17 years. Methods We built a probabilistic model of disease burden and economic impacts for a 10-year period with and without a program of adolescent catch-up meningococcal vaccination, followed by 9 years of routine immunization of children aged 11 years. We used US age- and serogroup-specific surveillance data on incidence and mortality. Assumptions related to the impact of herd immunity were drawn from experience with routine meningococcal vaccination in the United Kingdom. We estimated costs per case, deaths prevented, life-years saved, and quality-adjusted life-years saved. Results With herd immunity, the catch-up and routine vaccination program for adolescents would prevent 8251 cases of meningococcal disease in a 10-year period (a 48% decrease). Excluding program costs, this catch-up and routine vaccination program would save US$551 million in direct costs and $920 million in indirect costs, including costs associated with permanent disability and premature death. At $83 per vaccinee, the catch-up vaccination would cost society approximately $223,000 per case averted, approximately $2.6 million per death prevented, approximately $127,000 per life-year saved, and approximately $88,000 per quality-adjusted life-year saved. Targeting counties with a high incidence of disease decreased the cost per life-year saved by two-thirds. Conclusions Although costly, catch-up and routine vaccination of adolescents can have a substantial impact on meningococcal disease burden. Because of herd immunity, catch-up and routine vaccination cost per life-year saved could be up to one-third less than that previously assessed for routine vaccination of children aged 11 years.

Invasive pneumococcal disease (IPD) is 3-5 times more common among Navajo adults than in the general US population. The authors conducted a case-control study to identify risk factors for IPD among Navajo adults. Navajos agedor =18 years with IPD were identified through prospective, population-based active laboratory surveillance (December 1999-February 2002). Controls matched to cases on age, gender, and neighborhood were selected. Risk factors were identified through structured interviews and medical record reviews. The authors conducted a matched analysis based on 118 cases and 353 controls. Risk factors included in the final multivariable analysis were chronic renal failure (odds ratio (OR) = 2.6, 95% confidence interval (CI): 0.9, 7.7), congestive heart failure (OR = 5.6, 95% CI: 2.2, 14.5), self-reported alcohol use or alcoholism (OR = 2.9, 95% CI: 1.5, 5.4), body mass index (weight (kg)/height (m)(2))5th (OR = 3.2, 95% CI: 1.0, 10.6) or95th (OR = 2.8, 95% CI: 1.0, 8.0) percentile, and unemployment (OR = 2.6, 95% CI: 1.2, 5.5). The population attributable fractions were 10% for chronic renal failure, 18% for congestive heart failure, 30% for self-reported alcohol use or alcoholism, 6% for body mass index, and 20% for unemployment. Several modifiable risk factors for IPD in Navajos were identified. The high prevalence of renal failure, alcoholism, and unemployment among Navajo adults compared with the general US population may explain some of their increased risk of IPD.

Summary Background In 2000, seven-valent pneumococcal conjugate vaccine (PCV7) was introduced in the USA and resulted in dramatic reductions in invasive pneumococcal disease (IPD) and moderate increases in non-PCV7 type IPD. In 2010, PCV13 replaced PCV7 in the US immunisation schedule. We aimed to assess the effect of use of PCV13 in children on IPD in children and adults in the USA. Methods We used laboratory-based and population-based data on incidence of IPD from the Active Bacterial Core surveillance (part of the Centers for Disease Control and Prevention's Emerging Infections Program) in a time-series model to compare rates of IPD before and after the introduction of PCV13. Cases of IPD between July 1, 2004, and June 30, 2013, were classified as being caused by the PCV13 serotypes against which PCV7 has no effect (PCV13 minus PCV7). In a time-series model, we used an expected outcomes approach to compare the reported incidence of IPD to that which would have been expected if PCV13 had not replaced PCV7. Findings Compared with incidence expected among children younger than 5 years if PCV7 alone had been continued, incidence of IPD overall declined by 64% (95% interval estimate [95% IE] 59–68) and IPD caused by PCV13 minus PCV7 serotypes declined by 93% (91–94), by July, 2012, to June, 2013. Among adults, incidence of IPD overall also declined by 12–32% and IPD caused by PCV13 minus PCV7 type IPD declined by 58–72%, depending on age. We estimated that over 30 000 cases of IPD and 3000 deaths were averted in the first 3 years after the introduction of PCV13. Interpretation PCV13 reduced IPD across all age groups when used routinely in children in the USA. These findings provide reassurance that, similar to PCV7, PCVs with additional serotypes can also prevent transmission to unvaccinated populations. Funding Centers for Disease Control and Prevention.

Summary Background When seven-valent pneumococcal conjugate vaccine was introduced in the USA, many children were vaccinated on schedules that differed from those tested in clinical trials. Our aim was to assess the effectiveness of the vaccine against various pneumococcal serotypes, and to measure the effectiveness of the recommended dose schedule and of catch-up and incomplete schedules. Methods Invasive disease, defined as isolation of pneumococcus from a sterile site, was identified in children aged 3–59 months through the US Centers for Disease Control and Prevention's Active Bacterial Core surveillance. We tested isolates for serotype and antimicrobial susceptibility. Three controls, matched for age and zip code were selected for each case. We calculated the matched odds ratio for vaccination using conditional logistic regression, controlling for underlying conditions. Vaccine effectiveness was calculated as one minus the adjusted matched odds ratio times 100%. Findings We enrolled 782 cases and 2512 controls. Effectiveness of one or more doses against vaccine serotypes was 96% (95% CI 93–98) in healthy children and 81% (57–92) in those with coexisting disorders. It was 76% (63–85) against infections that were not susceptible to penicillin. Vaccination prevented disease caused by all seven vaccine serotypes, and by vaccine-related serotype 6A. Several schedules were more protective than no vaccination; three infant doses with a booster were more protective against vaccine-type disease than were three infant doses alone (p=0·0323). Interpretation The seven-valent pneumococcal conjugate vaccine prevents invasive disease in both healthy and chronically ill children. The vaccine is effective when used with various non-standard schedules.