Inequality in Immunization: Holding on to Equity as We 'Catch Up'.

Immunization, hailed as one of the most successful public health interventions in the world, has contributed to major advancements in health as well as social and economic development [...].

Estimating the health impact of vaccination against ten pathogens in 98 low-income and middle-income countries from 2000 to 2030: a modelling study.

BACKGROUND: The past two decades have seen expansion of childhood vaccination programmes in low-income and middle-income countries (LMICs). We quantify the health impact of these programmes by estimating the deaths and disability-adjusted life-years (DALYs) averted by vaccination against ten pathogens in 98 LMICs between 2000 and 2030. METHODS: 16 independent research groups provided model-based disease burden estimates under a range of vaccination coverage scenarios for ten pathogens: hepatitis B virus, Haemophilus influenzae type B, human papillomavirus, Japanese encephalitis, measles, Neisseria meningitidis serogroup A, Streptococcus pneumoniae, rotavirus, rubella, and yellow fever. Using standardised demographic data and vaccine coverage, the impact of vaccination programmes was determined by comparing model estimates from a no-vaccination counterfactual scenario with those from a reported and projected vaccination scenario. We present deaths and DALYs averted between 2000 and 2030 by calendar year and by annual birth cohort. FINDINGS: We estimate that vaccination of the ten selected pathogens will have averted 69 million (95% credible interval 52-88) deaths between 2000 and 2030, of which 37 million (30-48) were averted between 2000 and 2019. From 2000 to 2019, this represents a 45% (36-58) reduction in deaths compared with the counterfactual scenario of no vaccination. Most of this impact is concentrated in a reduction in mortality among children younger than 5 years (57% reduction [52-66]), most notably from measles. Over the lifetime of birth cohorts born between 2000 and 2030, we predict that 120 million (93-150) deaths will be averted by vaccination, of which 58 million (39-76) are due to measles vaccination and 38 million (25-52) are due to hepatitis B vaccination. We estimate that increases in vaccine coverage and introductions of additional vaccines will result in a 72% (59-81) reduction in lifetime mortality in the 2019 birth cohort. INTERPRETATION: Increases in vaccine coverage and the introduction of new vaccines into LMICs have had a major impact in reducing mortality. These public health gains are predicted to increase in coming decades if progress in increasing coverage is sustained. FUNDING: Gavi, the Vaccine Alliance and the Bill & Melinda Gates Foundation.

Estimated economic impact of vaccinations in 73 low- and middle-income countries, 2001-2020.

OBJECTIVE: To estimate the economic impact likely to be achieved by efforts to vaccinate against 10 vaccine-preventable diseases between 2001 and 2020 in 73 low- and middle-income countries largely supported by Gavi, the Vaccine Alliance. METHODS: We used health impact models to estimate the economic impact of achieving forecasted coverages for vaccination against Haemophilus influenzae type b, hepatitis B, human papillomavirus, Japanese encephalitis, measles, Neisseria meningitidis serogroup A, rotavirus, rubella, Streptococcus pneumoniae and yellow fever. In comparison with no vaccination, we modelled the costs - expressed in 2010 United States dollars (US$) - of averted treatment, transportation costs, productivity losses of caregivers and productivity losses due to disability and death. We used the value-of-a-life-year method to estimate the broader economic and social value of living longer, in better health, as a result of immunization. FINDINGS: We estimated that, in the 73 countries, vaccinations given between 2001 and 2020 will avert over 20 million deaths and save US$ 350 billion in cost of illness. The deaths and disability prevented by vaccinations given during the two decades will result in estimated lifelong productivity gains totalling US$ 330 billion and US$ 9 billion, respectively. Over the lifetimes of the vaccinated cohorts, the same vaccinations will save an estimated US$ 5 billion in treatment costs. The broader economic and social value of these vaccinations is estimated at US$ 820 billion. CONCLUSION: By preventing significant costs and potentially increasing economic productivity among some of the world's poorest countries, the impact of immunization goes well beyond health.

Case-control vaccine effectiveness studies: Data collection, analysis and reporting results.

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 vaccine effectiveness studies: Preparation, design, and enrollment of cases and controls.

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.

Inequalities in full immunization coverage: trends in low- and middle-income countries.

OBJECTIVE: To investigate disparities in full immunization coverage across and within 86 low- and middle-income countries. METHODS: In May 2015, using data from the most recent Demographic and Health Surveys and Multiple Indicator Cluster Surveys, we investigated inequalities in full immunization coverage - i.e. one dose of bacille Calmette-Guérin vaccine, one dose of measles vaccine, three doses of vaccine against diphtheria, pertussis and tetanus and three doses of polio vaccine - in 86 low- or middle-income countries. We then investigated temporal trends in the level and inequality of such coverage in eight of the countries. FINDINGS: In each of the World Health Organization's regions, it appeared that about 56-69% of eligible children in the low- and middle-income countries had received full immunization. However, within each region, the mean recorded level of such coverage varied greatly. In the African Region, for example, it varied from 11.4% in Chad to 90.3% in Rwanda. We detected pro-rich inequality in such coverage in 45 of the 83 countries for which the relevant data were available and pro-urban inequality in 35 of the 86 study countries. Among the countries in which we investigated coverage trends, Madagascar and Mozambique appeared to have made the greatest progress in improving levels of full immunization coverage over the last two decades, particularly among the poorest quintiles of their populations. CONCLUSION: Most low- and middle-income countries are affected by pro-rich and pro-urban inequalities in full immunization coverage that are not apparent when only national mean values of such coverage are reported.

Missed opportunities in full immunization coverage: findings from low- and lower-middle-income countries.

BACKGROUND: An estimated 23 million infants are still not being benefitted from routine immunization services. We assessed how many children failed to be fully immunized even though they or their mothers were in contact with health services to receive other interventions. DESIGN: Fourteen countries with Demographic and Health Surveys and Multiple Indicator Cluster Surveys carried out after 2000 and with coverage for DPT (Diphtheria-tetanus-pertussis) vaccine below 70% were selected. We defined full immunization coverage (FIC) as having received one dose of BCG (bacille Calmette-Guérin), one dose of measles, three doses of polio, and three doses of DPT vaccines. We tabulated FIC against: antenatal care (ANC), skilled birth attendance (SBA), postnatal care for the mother (PNC), vitamin A supplementation (VitA) for the child, and sleeping under an insecticide-treated bed-net (ITN). Missed opportunities were defined as the percentage of children who failed to be fully immunized among those receiving one or more other interventions. RESULTS: Children who received other health interventions were also more likely to be fully immunized. In nearly all countries, FIC was lowest among children born to mothers who failed to attend ANC, and highest when the mother had four or more ANC visits Côte d'Ivoire presented the largest difference in FIC: 54 percentage points (pp) between having four or more ANC visits and lack of ANC. SBA was also related with higher FIC. For instance, the coverage in children without SBA was 36 pp lower than for those with SBA in Nigeria. The largest absolute difference on FIC in relation to PNC was observed for Ethiopia: 31 pp between those without and with PNC. FIC was also positively related with having received VitA. The largest absolute difference was observed in DR Congo: 41 pp. The differences in FIC among whether or not children slept under ITN were much smaller than for other interventions. Haiti presented the largest absolute difference: 16 pp. CONCLUSIONS: Our results show the need to develop and implement strategies to vaccinate all children who contact health services in order to receive other interventions.

Estimating the burden of pneumococcal pneumonia among adults: a systematic review and meta-analysis of diagnostic techniques.

BACKGROUND: Pneumococcal pneumonia causes significant morbidity and mortality among adults. Given limitations of diagnostic tests for non-bacteremic pneumococcal pneumonia, most studies report the incidence of bacteremic or invasive pneumococcal disease (IPD), and thus, grossly underestimate the pneumococcal pneumonia burden. We aimed to develop a conceptual and quantitative strategy to estimate the non-bacteremic disease burden among adults with community-acquired pneumonia (CAP) using systematic study methods and the availability of a urine antigen assay. METHODS AND FINDINGS: We performed a systematic literature review of studies providing information on the relative yield of various diagnostic assays (BinaxNOW® S. pneumoniae urine antigen test (UAT) with blood and/or sputum culture) in diagnosing pneumococcal pneumonia. We estimated the proportion of pneumococcal pneumonia that is bacteremic, the proportion of CAP attributable to pneumococcus, and the additional contribution of the Binax UAT beyond conventional diagnostic techniques, using random effects meta-analytic methods and bootstrapping. We included 35 studies in the analysis, predominantly from developed countries. The estimated proportion of pneumococcal pneumonia that is bacteremic was 24.8% (95% CI: 21.3%, 28.9%). The estimated proportion of CAP attributable to pneumococcus was 27.3% (95% CI: 23.9%, 31.1%). The Binax UAT diagnosed an additional 11.4% (95% CI: 9.6, 13.6%) of CAP beyond conventional techniques. We were limited by the fact that not all patients underwent all diagnostic tests and by the sensitivity and specificity of the diagnostic tests themselves. We address these resulting biases and provide a range of plausible values in order to estimate the burden of pneumococcal pneumonia among adults. CONCLUSIONS: Estimating the adult burden of pneumococcal disease from bacteremic pneumococcal pneumonia data alone significantly underestimates the true burden of disease in adults. For every case of bacteremic pneumococcal pneumonia, we estimate that there are at least 3 additional cases of non-bacteremic pneumococcal pneumonia.

The effect of Haemophilus influenzae type B and pneumococcal conjugate vaccines on childhood meningitis mortality: a systematic review.

BACKGROUND: Two of the most prevalent causes of severe bacterial meningitis in children, Haemophilus influenzae type B (Hib) and Streptococcus pneumoniae, are preventable by existing vaccines increasingly available in developing countries. Our objective was to estimate the dose-specific effect of Hib and pneumococcal conjugate vaccines (PCV) on childhood meningitis mortality in low-income countries for use in the Lives Saved Tool (LiST). METHODS: We systematically searched and reviewed published vaccine efficacy trials and observational studies reporting the effect of Hib or PCV vaccines on organism-specific meningitis, bacterial meningitis and all-cause meningitis incidence and mortality among children less than five years old in low- and middle-income countries. Data collection and quality assessments were performed using standardized guidelines. For outcomes available across multiple studies (≥ 2) and approximating meningitis mortality, we pooled estimates reporting dose-specific effects using random effects meta-analytic methods, then combined these with meningitis etiology data to determine the preventable fraction of childhood meningitis mortality for inclusion in LiST. RESULTS: We identified 18 studies of Hib conjugate vaccines reporting relevant meningitis morbidity and mortality outcomes (2 randomized controlled trials [RCTs], 16 observational studies) but few provided dose-specific effects. A meta-analysis of four case-control studies examined the dose-specific effect of Hib conjugate vaccines on Hib meningitis morbidity (1 dose: RR=0.64, 95% CI 0.38-1.06; 2 doses: RR=0.09, 95% CI 0.03-0.27; 3 doses: RR=0.06, 95% CI 0.02-0.22), consistent with results from single RCTs. Pooled estimates of two RCTs provided evidence for the effect of three doses of PCV on vaccine-serotype meningitis morbidity (RR=0.16, 95% CI 0.02-1.20). We considered these outcomes of severe disease as proxy estimates for meningitis mortality and combined the estimates of protective effects with meningitis etiology data to provide an estimate of the preventable fraction of childhood meningitis mortality with three doses of Hib (38-43%) and pneumococcal conjugate vaccines (28-35%) for use in LiST. CONCLUSIONS: Few RCTs or vaccine effectiveness studies evaluated the dose-specific impact of Hib and PCV vaccines on childhood meningitis mortality, necessitating use of proxy measures to estimate population impact in LiST. Our analysis indicates that approximately three-quarters of meningitis deaths are preventable with existing Hib and PCV vaccines.

Global, regional, and national causes of child mortality: an updated systematic analysis for 2010 with time trends since 2000.

BACKGROUND: Information about the distribution of causes of and time trends for child mortality should be periodically updated. We report the latest estimates of causes of child mortality in 2010 with time trends since 2000. METHODS: Updated total numbers of deaths in children aged 0-27 days and 1-59 months were applied to the corresponding country-specific distribution of deaths by cause. We did the following to derive the number of deaths in children aged 1-59 months: we used vital registration data for countries with an adequate vital registration system; we applied a multinomial logistic regression model to vital registration data for low-mortality countries without adequate vital registration; we used a similar multinomial logistic regression with verbal autopsy data for high-mortality countries; for India and China, we developed national models. We aggregated country results to generate regional and global estimates. FINDINGS: Of 7·6 million deaths in children younger than 5 years in 2010, 64·0% (4·879 million) were attributable to infectious causes and 40·3% (3·072 million) occurred in neonates. Preterm birth complications (14·1%; 1·078 million, uncertainty range [UR] 0·916-1·325), intrapartum-related complications (9·4%; 0·717 million, 0·610-0·876), and sepsis or meningitis (5·2%; 0·393 million, 0·252-0·552) were the leading causes of neonatal death. In older children, pneumonia (14·1%; 1·071 million, 0·977-1·176), diarrhoea (9·9%; 0·751 million, 0·538-1·031), and malaria (7·4%; 0·564 million, 0·432-0·709) claimed the most lives. Despite tremendous efforts to identify relevant data, the causes of only 2·7% (0·205 million) of deaths in children younger than 5 years were medically certified in 2010. Between 2000 and 2010, the global burden of deaths in children younger than 5 years decreased by 2 million, of which pneumonia, measles, and diarrhoea contributed the most to the overall reduction (0·451 million [0·339-0·547], 0·363 million [0·283-0·419], and 0·359 million [0·215-0·476], respectively). However, only tetanus, measles, AIDS, and malaria (in Africa) decreased at an annual rate sufficient to attain the Millennium Development Goal 4. INTERPRETATION: Child survival strategies should direct resources toward the leading causes of child mortality, with attention focusing on infectious and neonatal causes. More rapid decreases from 2010-15 will need accelerated reduction for the most common causes of death, notably pneumonia and preterm birth complications. Continued efforts to gather high-quality data and enhance estimation methods are essential for the improvement of future estimates. FUNDING: The Bill & Melinda Gates Foundation.

Patient safety: break the silence.

A culture of patient safety requires commitment and full participation from all staff members. In 2008, results of a culture of patient safety survey conducted in the perioperative division of the Lehigh Valley Health Network in Pennsylvania revealed a lack of patient-centered focus, teamwork, and positive communication. As a result, perioperative leaders assembled a multidisciplinary team that designed a safety training program focusing on Crew Resource Management, TeamSTEPPS, and communication techniques. The team used video vignettes and an audience response system to engage learners and promote participation. Topics included using preprocedural briefings and postprocedural debriefings, conflict resolution, and assertiveness techniques. Postcourse evaluations showed that the majority of respondents believed they were better able to question the decisions or actions of someone with more authority. The facility has experienced a marked decrease in the number of incidents requiring a root cause analysis since the program was conducted.

Evaluation of risk factors for severe pneumonia in children: the Pneumonia Etiology Research for Child Health study.

As a case-control study of etiology, the Pneumonia Etiology Research for Child Health (PERCH) project also provides an opportunity to assess the risk factors for severe pneumonia in hospitalized children at 7 sites. We identified relevant risk factors by literature review and iterative expert consultation. Decisions for inclusion in PERCH were based on comparability to published data, analytic plans, data collection costs and logistic feasibility, including interviewer time and subject fatigue. We aimed to standardize questions at all sites, but significant variation in the economic, cultural, and geographic characteristics of sites made it difficult to obtain this objective. Despite these challenges, the depth of the evaluation of multiple risk factors across the breadth of the PERCH sites should furnish new and valuable information about the major risk factors for childhood severe and very severe pneumonia, including risk factors for pneumonia caused by specific etiologies, in developing countries.

The worldwide impact of the seven-valent pneumococcal conjugate vaccine.

BACKGROUND: Pneumococcal conjugate vaccines (PCV) are emerging as one of the most promising means to prevent pediatric disease. The 7-valent PCV (PCV-7) has been extensively evaluated in clinical trials, and recent evidence from the introduction of PCV-7 through national immunization programs has demonstrated impact on pneumococcal disease. METHODS: Clinical trials have shown PCV-7 to be effective against the more severe forms of pneumococcal infections: pneumonia and invasive pneumococcal disease (IPD), as well as overall child mortality. A review shows the tremendous impact PCV-7 has had to date, and the potential further benefits of the emerging multi-valent vaccines. RESULTS: Since its introduction, the PCV-7 has substantially reduced the incidence of IPD, hospital admissions due to pneumonia and acute otitis media in numerous, mostly high income, low-disease burden countries. The reductions in IPD and pneumonia have also been observed among unvaccinated age groups in countries with routine use of PCV-7, demonstrating that PCV-7 provides herd immunity. Some settings observed an increase in rate of nonvaccine serotype IPD, yet rates of overall and vaccine-serotype IPD show marked reductions post-PCV-7 introduction. Limited data are available on the impact of PCV-7 in lower income countries. The available data from efficacy trials from The Gambia and South Africa suggest that PCV-7 will have substantial impact on reducing pneumococcal disease. CONCLUSION: PCV-7 has shown dramatic reduction in disease and mortality rates in the countries in which it has been introduced. The newly introduced 10-valent and 13-valent pneumococcal vaccines are expected to have substantial disease impact, but monitoring is essential to determine their true impact and sustain further introduction of pneumococcal conjugate vaccines.