IMPORTANCE: Routine vaccinations are key to prevent outbreaks of vaccine-preventable diseases. However, there have been documented declines in routine childhood vaccinations in the U.S. and worldwide during the COVID-19 pandemic. OBJECTIVE: Assess how the COVID-19 pandemic impacted routine childhood vaccinations by evaluating vaccination coverage for routine childhood vaccinations for children born in 2016-2021. METHODS: Data on routine childhood vaccinations reported to CDC by nine U.S. jurisdictions via the immunization information systems (IISs) by December 31, 2022, were available for analyses. Population size for each age group was obtained from the National Center for Health Statistics' Bridging Population Estimates. MAIN OUTCOMES AND MEASURES: Vaccination coverage for routine childhood vaccinations at age three months, five months, seven months, one year, and two years was calculated by vaccine type and overall, for 4:3:1:3:3:1:4 series (≥4 doses DTaP, ≥3 doses Polio, ≥1 dose MMR, ≥3 doses Hib, ≥3 doses Hepatitis B, ≥1 dose Varicella, and ≥ 4 doses pneumococcal conjugate), for each birth cohort year and by jurisdiction. RESULTS: Overall, there was a 10.4 percentage point decrease in the 4:3:1:3:3:1:4 series in those children born in 2020 compared to those children born in 2016. As of December 31, 2022, 71.0% and 71.3% of children born in 2016 and 2017, respectively, were up to date on their routine childhood vaccinations by two years of age compared to 69.1%, 64.7% and 60.6% for children born in 2018, 2019, and 2020, respectively. CONCLUSIONS AND RELEVANCE: The decline in vaccination coverage for routine childhood vaccines is concerning. In order to protect population health, strategic efforts are needed by health care providers, schools, parents, as well as state, local, and federal governments to work together to address these declines in vaccination coverage during the COVID-19 pandemic to prevent outbreaks of vaccine preventable diseases by maintaining high levels of population immunity.

OBJECTIVE: To use a model-based approach to estimate vaccination coverage of routinely recommended childhood and adolescent vaccines for the United States. METHODS: 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 2 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. RESULTS: 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. CONCLUSIONS: 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.

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.

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).

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.

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.

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] x 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: 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 <1 year, 69% (44% to 83%) at 1 to <3 years, and 61% (25% to 79%) at 3 to <8 years. VE was 77% (57% to 88%) against serogroup C and 51% (1% to 76%) against serogroup Y. CONCLUSIONS: MenACWY-D was effective in the first year after vaccination but effectiveness waned 3 to <8 years postvaccination. The estimates of VE from this evaluation informed the Advisory Committee on Immunization Practices in its decision to add a booster dose of MenACWY.

BACKGROUND: 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). METHODS: PBP cases were HIV-uninfected children with lower respiratory tract infection and consolidation on chest radiograph or non-consolidated 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. RESULTS: A total of 889 PBP cases (median age 9 months) were matched to 2,628 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), while a primary care giver who smoked was a risk factor (aOR 5.15, 95%CI 2.94-9.03). CONCLUSIONS: 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.

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 Africa's national immunization program in August 2009. METHODS: Hospitalizations in children <5 years of age with a diagnosis of diarrhea, defined byInternational Classification of Diseases, Tenth Revisioncodes A00-A05, A06.0-A06.3, A06.9, A07.0-A07.2, A07.9, and A08-A09, were identified at the Chris Hani Baragwanath Academic Hospital from 1 January 2006 to 31 December 2014. The median annual prevaccine (2006-2008) hospitalization incidence was compared to that of the vaccine era (2010-2014), and stratified by age group and HIV infection status. RESULTS: Incidence reductions (per 1000 population) were greatest in children aged <12 months: 54.4 in the prevaccine era vs 30.0, 23.6, 20.0, 18.8, and 18.9 in the postvaccine years 2010-2014, respectively (a 44.9%-65.4% reduction). Lower incidence reductions (39.8%-49.4%) were observed among children aged 12-24 months from the second year post-vaccine introduction onward. Reductions were observed in both HIV-infected and HIV-uninfected children. There was a change in the seasonal pattern of diarrheal hospitalizations post-vaccine introduction, with flattening of the autumn-winter peaks seen in the prevaccine years. CONCLUSIONS: An accelerated and sustained decline in all-cause diarrheal hospitalizations, temporally associated with rotavirus vaccine introduction, was observed in children <2 years of age. However, the impact of other interventions such as improved sanitation and changes in HIV management cannot be discounted.

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.

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.

BACKGROUND: In South Africa, a 7-valent pneumococcal conjugate vaccine (PCV7) was introduced in 2009 with a three-dose schedule for infants at 6, 14, and 36 weeks of age; a 13-valent vaccine (PCV13) replaced PCV7 in 2011. In 2012, it was estimated that 81% of 12-month-old children had received three doses of vaccine. We assessed the effect of vaccination on invasive pneumococcal disease. METHODS: We conducted national, active, laboratory-based surveillance for invasive pneumococcal disease. We calculated the change in the incidence of the disease from a prevaccine (baseline) period (2005 through 2008) to postvaccine years 2011 and 2012, with a focus on high-risk age groups. RESULTS: Surveillance identified 35,192 cases of invasive pneumococcal disease. The rates among children younger than 2 years of age declined from 54.8 to 17.0 cases per 100,000 person-years from the baseline period to 2012, including a decline from 32.1 to 3.4 cases per 100,000 person-years in disease caused by PCV7 serotypes (-89%; 95% confidence interval [CI], -92 to -86). Among children not infected with the human immunodeficiency virus (HIV), the estimated incidence of invasive pneumococcal disease caused by PCV7 serotypes decreased by 85% (95% CI, -89 to -79), whereas disease caused by nonvaccine serotypes increased by 33% (95% CI, 15 to 48). Among adults 25 to 44 years of age, the rate of PCV7-serotype disease declined by 57% (95% CI, -63 to -50), from 3.7 to 1.6 cases per 100,000 person-years. CONCLUSIONS: Rates of invasive pneumococcal disease among children in South Africa fell substantially by 2012. Reductions in the rates of disease caused by PCV7 serotypes among both children and adults most likely reflect the direct and indirect effects of vaccination. (Funded by the National Institute for Communicable Diseases of the National Health Laboratory Service and others.).

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 x 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 blocks" approach, which combines these two basic approaches by decomposing any missingness pattern into a collection of smaller "constructed" monotone missingness patterns, and iterating. We apply this strategy to impute the missing data in the AVRP interim data. Supplemental materials, including all source code and a synthetic example dataset, are available online.

INTRODUCTION: Invasive pneumococcal disease (IPD) causes significant disease burden, especially in developing countries, even in the era of pneumococcal conjugate vaccine (PCV) and maternal-to-child HIV transmission prevention programs. We evaluated factors that might increase IPD risk in young children in a high HIV prevalence setting. METHODS: We conducted a case-control study using IPD cases identified at 24 Group for Enteric, Respiratory and Meningeal disease Surveillance - South Africa (GERMS-SA) program sites (2010-2012). At least four controls were matched by age, HIV status and hospital to each case. Potential risk factors were evaluated using multivariable conditional logistic regression. RESULTS: In total 486 age-eligible cases were enrolled. Factors associated with IPD in HIV-uninfected children (237 cases, 928 controls) included: siblings <5 years (adjusted odds ratio [aOR]=1.68, 95% confidence interval [CI] 1.16-2.46), underlying medical conditions (aOR=1.99, CI 1.22-3.22), preceding upper respiratory tract infection (URTI) (aOR=1.79, CI 1.19-2.69), daycare attendance (aOR=1.58, CI 1.01-2.47), perinatal HIV exposure (aOR=1.62, CI 1.10-2.37), household car ownership (aOR=0.45, CI 0.25-0.83) and ≥2 PCV-7 doses (aOR=0.67, CI 0.46-0.99). Amongst HIV-infected children (124 cases, 394 controls), IPD-associated factors included malnutrition (aOR=2.68, CI 1.40-5.14), URTI (aOR=3.49, CI 1.73-7.03), tuberculosis in last 3 months (aOR=5.12, CI 1.69-15.50), and current antiretroviral treatment (ART) (aOR=0.13, CI 0.05-0.38). CONCLUSION: Previously-identified factors related to poverty, poor health, and intense exposure continue to be risk factors for IPD in children. Ensuring delivery of PCV and ART are important for improving disease prevention.

BACKGROUND: South Africa introduced seven-valent pneumococcal conjugate vaccine (PCV-7) in April 2009 using a 2+1 schedule (six and fourteen weeks and nine months). We estimated the effectiveness of ≥2 PCV-7 doses against invasive pneumococcal disease (IPD) in HIV-infected and -uninfected children. METHODS: IPD (pneumococcus identified from a normally sterile site) cases were identified through national laboratory-based surveillance. Specimens were serotyped by Quellung or polymerase chain reaction. Four controls, matched for age, HIV status and hospital were sought for each case. Using conditional logistic regression, we calculated vaccine effectiveness (VE) as one minus the adjusted odds ratio for vaccination. RESULTS: From March 2010 through November 2012, we enrolled 187 HIV-uninfected (48 [26%] vaccine-serotype) and 109 HIV-infected (43 [39%] vaccine-serotype) cases and 752 HIV-uninfected and 347 HIV-infected controls aged ≥16 weeks. Effectiveness of ≥2 PCV-7 doses against vaccine-serotype IPD was 74% (95% CI: 25, 91) among HIV-uninfected and -12% (95% CI: -449, 77) among HIV-infected children. Effectiveness of ≥3 doses against vaccine-serotype IPD was 90% (95% CI: 14, 99) among HIV-uninfected and 57% (95% CI: -371, 96) among HIV-infected children. Among HIV-exposed-uninfected children effectiveness of ≥2 doses was 92% (95% CI: 47, 99) against vaccine-serotype IPD. Effectiveness of ≥2 doses against all-serotype multidrug-resistant IPD was 96% (95% CI: 62, 100) among HIV-uninfected children. CONCLUSIONS: A 2+1 PCV-7 schedule was effective in preventing vaccine-serotype IPD in HIV-uninfected and HIV-exposed-uninfected children. This finding supports the World Health Organization recommendation for this schedule as an alternative to a three-dose primary series among HIV-uninfected individuals.

OBJECTIVE: To estimate the effectiveness against early-onset group B streptococcal (GBS) disease of intrapartum antibiotic prophylaxis among term and preterm deliveries, deliveries with fewer than 4 hours of antibiotics, and deliveries receiving clindamycin regimens. METHODS: We performed a secondary analysis of the Birthnet cohort, a survey of 7,691 births to residents of the Active Bacterial Core surveillance system from 2003 to 2004. We used propensity score matching on covariates associated with prophylaxis and early-onset GBS disease to evaluate the effectiveness (1-risk ratio) of specific intrapartum antibiotic prophylaxis regimens against the disease end point. RESULTS: The effectiveness of 4 or more hours of prophylaxis with penicillin or ampicillin was high among term (91%, 95% confidence interval [CI] +63% to +98%) and preterm (86%, 95% CI +38% to +97%) neonates. Effectiveness was significantly lower for clindamycin (22%, 95% CI -53% to +60%). The effectiveness of 2 or fewer to fewer than 4 hours of prophylaxis with penicillin or ampicillin before delivery (47%, 95% CI -16% to +76%) and the effectiveness of prophylaxis with penicillin or ampicillin fewer than 2 hours before delivery (38%, 95% CI -17% to +67%) were both lower than the effectiveness of prophylaxis durations at 4 or more hours. CONCLUSION: Beta-lactam prophylaxis given 4 or more hours before delivery is highly effective for prevention of early-onset GBS disease. Prophylaxis of shorter durations or with clindamycin is less effective, reinforcing the need for health care providers to adhere to prevention recommendations, particularly for preterm deliveries, penicillin-allergic women, and neonates exposed to fewer than 4 hours of prophylaxis. LEVEL OF EVIDENCE: II.

BACKGROUND: HIV-exposed newborns may be at higher risk of sepsis because of immune system aberrations, impaired maternal antibody transfer and altered exposure to pathogenic bacteria. METHODS: We performed a secondary analysis of a study (clinicaltrials.gov, number NCT00136370) conducted between April 2004 and October 2007 in South Africa. We used propensity score matching to evaluate the association between maternal HIV infection and (1) vaginal colonization with bacterial pathogens; (2) vertical transmission of pathogens to the newborn; and (3) sepsis within 3 days of birth (EOS) or between 4-28 days of life (LOS). RESULTS: Colonization with group B Streptococcus (17% vs 23%, P = .0002), Escherichia coli (47% vs 45%, P = .374), and Klebsiella pneumoniae (7% vs 10%, P = .008) differed modestly between HIV-infected and uninfected women, as did vertical transmission rates. Maternal HIV infection was not associated with increased risk of neonatal EOS or LOS, although culture-confirmed EOS was >3 times higher among HIV-exposed infants (P = .05). When compared with HIV-unexposed, neonates, HIV-exposed, uninfected neonates (HEU) had a lower risk of EOS (20.6 vs 33.7 per 1000 births; P = .046) and similar rate of LOS (5.8 vs 4.1; P = .563). HIV-infected newborns had a higher risk than HEU of EOS (134 vs 21.5; P < .0001) and LOS (26.8 vs 5.6; P = .042). CONCLUSIONS: Maternal HIV infection was not associated with increased risk of maternal bacterial colonization, vertical transmission, EOS, or LOS. HIV-infected neonates, however, were at increased risk of EOS and LOS.

OBJECTIVE: To compare sentinel and population-based surveillance of the effect of seven-valent pneumococcal conjugate vaccine (PCV7), introduced in 2000, on the hospitalization of children aged under 5 years with invasive pneumococcal disease (IPD) in the United States of America. METHODS: Population surveillance data were used to identify children hospitalized between 1998 and 2006 with IPD caused by Streptococcus pneumoniae serotypes. The change from 1998 and 1999 (baseline) to 2006 in the number of hospitalized IPD cases recorded by sentinel surveillance systems involving single hospitals or groups of hospitals was compared with the change in the incidence of hospitalized IPD cases measured by population-based surveillance. FINDINGS: The change in incidence in the eight surveillance areas varied from -37 to -82% for IPD caused by any serotype and from -96 to -100% for IPD caused by serotypes contained in PCV7. All individual sentinel hospitals with more than three cases annually at baseline reported a decrease in cases by 2006. In addition, over 95% of sentinel systems with an average of more than 30 cases annually at baseline recorded a change by 2006 in the number of cases caused by any serotype that fell within the 95% confidence interval for the change in the incidence of hospitalized cases in the corresponding population surveillance area. The change in cases caused by PCV7 serotypes was accurately measured by 93% and 100% of sentinel systems with ≤ 20 and > 20 cases annually at baseline, respectively. CONCLUSION: Sentinel surveillance can accurately measure the effect of PCV7 on the number of children hospitalized with IPD, provided sufficient cases are detected at baseline. Serotyping increases accuracy.

BACKGROUND: 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. METHODS: 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 P < 0.15 were evaluated using multivariable logistic regression. RESULTS: 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. CONCLUSIONS: 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 44,000 US invasive pneumococcal disease (IPD) cases in 2008. Antibiotic nonsusceptibility complicates IPD treatment. Using penicillin susceptibility breakpoints adopted in 2008, we evaluated antibiotic-nonsusceptible IPD trends in light of the introductions of a 7-valent pneumococcal conjugate vaccine (PCV7) in 2000 and a 13-valent pneumococcal conjugate vaccine (PCV13) in 2010. METHODS: IPD cases were defined by isolation of pneumococcus from a normally sterile site in individuals residing in Active Bacterial Core surveillance (ABCs) areas during 1998-2008. Pneumococci were serotyped and tested for antibiotic susceptibility using broth microdilution. RESULTS: During 1998-2008, ABCs identified 43,198 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% for children aged <5 years (12.1-4.4 cases per 100,000), and 45% for adults aged ≥65 (4.8-2.6 cases per 100,000). Rates of IPD nonsusceptible to multiple antibiotics mirrored these trends. During 2007-2008, serotypes in PCV13 but not PCV7 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.

BACKGROUND: 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. METHODS: Data were collected from active surveillance for invasive H. influenzae disease conducted through Active Bacterial Core surveillance sites during 1989-2008. RESULTS: 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 aged <5 years was in infants aged <1 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 aged <5 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. CONCLUSIONS: 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.

BACKGROUND: The Region of the Americas eliminated measles in 2002 through high first-dose routine measles vaccine coverage and vaccination campaigns every 4-6 years; a second routine dose at school entry was added in some countries. The impact of this second routine dose on measles elimination was evaluated. METHODS: Data on socioeconomic factors, demographic characteristics, vaccination coverage, and the estimated proportion of children (<15 years of age) susceptible to measles were compiled. Countries were grouped using propensity score methods, and Kaplan-Meier curves were used to compare time to measles elimination between countries with a 1-dose schedule and those with a 2-dose schedule. RESULTS: One-dose (n = 14) and 2-dose (n = 7) countries did not differ with respect to median routine first-dose measles vaccine coverage, median coverage for 3 measles campaigns, or estimated percentage of susceptible children after routine first vaccination dose and campaigns. Compared with 1-dose countries, 2-dose countries had higher median gross national income per capita (P =.002), percentage of population living in urban areas (P =.04), and female literacy (P =.01), as well as lower infant mortality (P = .007); however, no differences in time to elimination were found. CONCLUSIONS: One-dose and 2-dose countries had similar times to measles elimination despite socioeconomic differences between their populations. A second routine dose might not have hastened measles elimination, because threshold immunity needed to eliminate measles was achieved with high first routine dose coverage and vaccination campaigns. Further research will be needed to determine the applicability of these findings to other regions.

BACKGROUND: The epidemiology of streptococcal infection in pregnant and postpartum women is poorly described in recent literature. We used data from multistate surveillance for invasive Streptococcus pneumoniae, group A Streptococcus (GAS), and group B Streptococcus (GBS) infections to estimate disease incidence and severity in these populations. METHODS: Cases were reported through the Centers for Disease Control and Prevention Active Bacterial Core surveillance, an active population- and laboratory-based system. A case was defined as illness in a woman aged 15-44 years with streptococcus isolated from a normally sterile body site during 2007-2009. Pregnant or postpartum status was recorded at the time of culture. Incidence was calculated as cases per 1000 woman-years with use of national Census data; 95% confidence intervals were calculated on the basis of lambda distribution. We used multivariable logistic regression to explore associations between pregnant or postpartum status and hospital length of stay, a marker of disease severity. RESULTS: We identified 1848 cases in women; 6.0% of women were pregnant, and 7.5% were postpartum. Pregnant women had a higher mean incidence of GBS disease, compared with nonpregnant women (0.04 cases per 1000 woman-years [range, 0.03-0.05 cases per 1000 woman-years] vs 0.02 cases per 1000 woman-years [range, 0.02-0.02 cases per 1000 woman-years]). Postpartum women had elevated mean incidence of all 3 pathogens, compared with nonpregnant women (S. pneumoniae: 0.15 cases per 1000 woman-years [range, 0.09-0.25 cases per 1000 woman-years] vs 0.052 cases per 1000 woman-years [range, 0.049-0.056 cases per 1000 woman-years]; GAS: 0.56 cases per 1000 woman-years [range, 0.42-0.70 cases per 1000 woman-years] vs 0.019 cases per 1000 woman-years [range, 0.017-0.021 cases per 1000 woman-years]; GBS: 0.49 cases per 1000 woman-years [range, 0.36-0.64 cases per 1000 woman-years] vs 0.018 [range, 0.016-0.020 cases per 1000 woman-years]). Neither pregnancy nor postpartum status was associated with longer length of stay among women infected with any of the 3 pathogens. CONCLUSIONS: Although invasive streptococcal infections do not appear to be more severe in pregnant or postpartum women, postpartum women have a 20-fold increased incidence of GAS and GBS, compared with nonpregnant women.

BACKGROUND: 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. METHODS: 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. RESULTS: 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 (P<0.001 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. CONCLUSIONS: 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.).

BACKGROUND: Streptococcus pneumoniae continues to cause a variety of common clinical syndromes, despite vaccination programs for both adults and children. The total U.S. burden of pneumococcal disease is unknown. METHODS: We constructed a decision tree-based model to estimate U.S. healthcare utilization and costs of pneumococcal disease in 2004. Data were obtained from the 2004-2005 National (Hospital) Ambulatory Medical Care Surveys (outpatient visits, antibiotics) and the National Hospital Discharge Survey (hospitalization rates), and CDC surveillance data. Other assumptions regarding the incidence of each syndrome due to pneumococcus, expected health outcomes, and healthcare utilization were derived from literature and expert opinion. Healthcare and time costs used 2007 dollars. RESULTS: We estimate that, in 2004, pneumococcal disease caused 4.0 million illness episodes, 22,000 deaths, 445,000 hospitalizations, 774,000 emergency department visits, 5.0 million outpatient visits, and 4.1 million outpatient antibiotic prescriptions. Direct medical costs totaled $3.5 billion. Pneumonia (866,000 cases) accounted for 22% of all cases and 72% of pneumococcal costs. In contrast, acute otitis media and sinusitis (1.5 million cases each) comprised 75% of cases but only 16% of direct medical costs. Patients ≥65 years old, accounted for most serious cases and the majority of direct medical costs ($1.8 billion in healthcare costs annually). In this age group, pneumonia caused 242,000 hospitalizations, 1.4 million hospital days, 194,000 emergency department visits, 374,000 outpatient visits, and 16,000 deaths. However, if work loss and productivity are considered, the cost of pneumococcal disease among younger working adults (18-<50) nearly equaled those ≥65. CONCLUSIONS: Pneumococcal disease remains a substantial cause of morbidity and mortality even in the era of routine pediatric and adult vaccination. Continued efforts are warranted to reduce serious pneumococcal disease, especially adult pneumonia.

BACKGROUND: 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 aged 11 to 18 years and others at increased risk for meningococcal disease. METHODS: 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. RESULTS: 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%. CONCLUSIONS: 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.

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.