Comparison of measles IgG enzyme immunoassays (EIA) versus plaque reduction neutralization test (PRNT) for measuring measles serostatus: a systematic review of head-to-head analyses of measles IgG EIA and PRNT.

BACKGROUND: As countries move towards or achieve measles elimination status, serosurveillance is an important public health tool. However, a major challenge of serosurveillance is finding a feasible, accurate, cost-effective, and high throughput assay to measure measles antibody concentrations and estimate susceptibility in a population. We conducted a systematic review to assess, characterize, and - to the extent possible - quantify the performance of measles IgG enzyme-linked assays (EIAs) compared to the gold standard, plaque reduction neutralization tests (PRNT). METHODS: We followed the PRISMA statement for a systematic literature search and methods for conducting and reporting systematic reviews and meta-analyses recommended by the Cochrane Screening and Diagnostic Tests Methods Group. We identified studies through PubMed and Embase electronic databases and included serologic studies detecting measles virus IgG antibodies among participants of any age from the same source population that reported an index (any EIA or multiple bead-based assays, MBA) and reference test (PRNT) using sera, whole blood, or plasma. Measures of diagnostic accuracy with 95% confidence intervals (CI) were abstracted for each study result, where reported. RESULTS: We identified 550 unique publications and identified 36 eligible studies for analysis. We classified studies as high, medium, or low quality; results from high quality studies are reported. Because most high quality studies used the Siemens Enzygnost EIA kit, we generate individual and pooled diagnostic accuracy estimates for this assay separately. Median sensitivity of the Enzygnost EIA was 92.1% [IQR = 82.3, 95.7]; median specificity was 96.9 [93.0, 100.0]. Pooled sensitivity and specificity from studies using the Enzygnost kit were 91.6 (95%CI: 80.7,96.6) and 96.0 (95%CI: 90.9,98.3), respectively. The sensitivity of all other EIA kits across high quality studies ranged from 0% to 98.9% with median (IQR) = 90.6 [86.6, 95.2]; specificity ranged from 58.8% to 100.0% with median (IQR) = 100.0 [88.7, 100.0]. CONCLUSIONS: Evidence on the diagnostic accuracy of currently available measles IgG EIAs is variable, insufficient, and may not be fit for purpose for serosurveillance goals. Additional studies evaluating the diagnostic accuracy of measles EIAs, including MBAs, should be conducted among diverse populations and settings (e.g., vaccination status, elimination/endemic status, age groups).

Benefits and Challenges in Using Seroprevalence Data to Inform Models for Measles and Rubella Elimination.

Background: Control efforts for measles and rubella are intensifying globally. It becomes increasingly important to identify and reach remaining susceptible populations as elimination is approached. Methods: Serological surveys for measles and rubella can potentially measure susceptibility directly, but their use remains rare. In this study, using simulations, we outline key subtleties in interpretation associated with the dynamic context of age-specific immunity, highlighting how the patterns of immunity predicted from disease surveillance and vaccination coverage data may be misleading. Results: High-quality representative serosurveys could provide a more accurate assessment of immunity if challenges of conducting, analyzing, and interpreting them are overcome. We frame the core disease control and elimination questions that could be addressed by improved serological tools, discussing challenges and suggesting approaches to increase the feasibility and sustainability of the tool. Conclusions: Accounting for the dynamical context, serosurveys could play a key role in efforts to achieve and sustain elimination.

Impact on Epidemic Measles of Vaccination Campaigns Triggered by Disease Outbreaks or Serosurveys: A Modeling Study.

BACKGROUND: Routine vaccination supplemented by planned campaigns occurring at 2-5 y intervals is the core of current measles control and elimination efforts. Yet, large, unexpected outbreaks still occur, even when control measures appear effective. Supplementing these activities with mass vaccination campaigns triggered when low levels of measles immunity are observed in a sample of the population (i.e., serosurveys) or incident measles cases occur may provide a way to limit the size of outbreaks. METHODS AND FINDINGS: Measles incidence was simulated using stochastic age-structured epidemic models in settings conducive to high or low measles incidence, roughly reflecting demographic contexts and measles vaccination coverage of four heterogeneous countries: Nepal, Niger, Yemen, and Zambia. Uncertainty in underlying vaccination rates was modeled. Scenarios with case- or serosurvey-triggered campaigns reaching 20% of the susceptible population were compared to scenarios without triggered campaigns. The best performing of the tested case-triggered campaigns prevent an average of 28,613 (95% CI 25,722-31,505) cases over 15 y in our highest incidence setting and 599 (95% CI 464-735) cases in the lowest incidence setting. Serosurvey-triggered campaigns can prevent 89,173 (95% CI, 86,768-91,577) and 744 (612-876) cases, respectively, but are triggered yearly in high-incidence settings. Triggered campaigns reduce the highest cumulative incidence seen in simulations by up to 80%. While the scenarios considered in this strategic modeling exercise are reflective of real populations, the exact quantitative interpretation of the results is limited by the simplifications in country structure, vaccination policy, and surveillance system performance. Careful investigation into the cost-effectiveness in different contexts would be essential before moving forward with implementation. CONCLUSIONS: Serologically triggered campaigns could help prevent severe epidemics in the face of epidemiological and vaccination uncertainty. Hence, small-scale serology may serve as the basis for effective adaptive public health strategies, although, in high-incidence settings, case-triggered approaches are likely more efficient.

Seroepidemiology: an underused tool for designing and monitoring vaccination programmes in low- and middle-income countries.

Seroepidemiology, the use of data on the prevalence of bio-markers of infection or vaccination, is a potentially powerful tool to understand the epidemiology of infection before vaccination and to monitor the effectiveness of vaccination programmes. Global and national burden of disease estimates for hepatitis B and rubella are based almost exclusively on serological data. Seroepidemiology has helped in the design of measles, poliomyelitis and rubella elimination programmes, by informing estimates of the required population immunity thresholds for elimination. It contributes to monitoring of these programmes by identifying population immunity gaps and evaluating the effectiveness of vaccination campaigns. Seroepidemiological data have also helped to identify contributing factors to resurgences of diphtheria, Haemophilus Influenzae type B and pertussis. When there is no confounding by antibodies induced by natural infection (as is the case for tetanus and hepatitis B vaccines), seroprevalence data provide a composite picture of vaccination coverage and effectiveness, although they cannot reliably indicate the number of doses of vaccine received. Despite these potential uses, technological, time and cost constraints have limited the widespread application of this tool in low-income countries. The use of venous blood samples makes it difficult to obtain high participation rates in surveys, but the performance of assays based on less invasive samples such as dried blood spots or oral fluid has varied greatly. Waning antibody levels after vaccination may mean that seroprevalence underestimates immunity. This, together with variation in assay sensitivity and specificity and the common need to take account of antibody induced by natural infection, means that relatively sophisticated statistical analysis of data is required. Nonetheless, advances in assays on minimally invasive samples may enhance the feasibility of including serology in large survey programmes in low-income countries. In this paper, we review the potential uses of seroepidemiology to improve vaccination policymaking and programme monitoring and discuss what is needed to broaden the use of this tool in low- and middle-income countries.

Evaluating Scope and Bias of Population-Level Measles Serosurveys: A Systematized Review and Bias Assessment.

BACKGROUND: Measles seroprevalence data have potential to be a useful tool for understanding transmission dynamics and for decision making efforts to strengthen immunization programs. In this study, we conducted a systematized review and bias assessment of all primary data on measles seroprevalence in low- and middle-income countries (as defined by World Bank 2021 income classifications) published from 1962 to 2021. METHODS: On 9 March 2022, we searched PubMed for all available data. We included studies containing primary data on measles seroprevalence and excluded studies if they were clinical trials or brief reports, from only health-care workers, suspected measles cases, or only vaccinated persons. We extracted all available information on measles seroprevalence, study design, and seroassay protocol. We conducted a bias assessment based on multiple categories and classified each study as having low, moderate, severe, or critical bias. This review was registered with PROSPERO (CRD42022326075). RESULTS: We identified 221 relevant studies across all World Health Organization regions, decades, and unique age ranges. The overall crude mean seroprevalence across all studies was 78.0% (SD: 19.3%), and the median seroprevalence was 84.0% (IQR: 72.8-91.7%). We classified 80 (36.2%) studies as having severe or critical overall bias. Studies from country-years with lower measles vaccine coverage or higher measles incidence had higher overall bias. CONCLUSIONS: While many studies have substantial underlying bias, many studies still provide some insights or data that could be used to inform modelling efforts to examine measles dynamics and programmatic decisions to reduce measles susceptibility.

Measuring coverage in MNCH: design, implementation, and interpretation challenges associated with tracking vaccination coverage using household surveys.

Vaccination coverage is an important public health indicator that is measured using administrative reports and/or surveys. The measurement of vaccination coverage in low- and middle-income countries using surveys is susceptible to numerous challenges. These challenges include selection bias and information bias, which cannot be solved by increasing the sample size, and the precision of the coverage estimate, which is determined by the survey sample size and sampling method. Selection bias can result from an inaccurate sampling frame or inappropriate field procedures and, since populations likely to be missed in a vaccination coverage survey are also likely to be missed by vaccination teams, most often inflates coverage estimates. Importantly, the large multi-purpose household surveys that are often used to measure vaccination coverage have invested substantial effort to reduce selection bias. Information bias occurs when a child's vaccination status is misclassified due to mistakes on his or her vaccination record, in data transcription, in the way survey questions are presented, or in the guardian's recall of vaccination for children without a written record. There has been substantial reliance on the guardian's recall in recent surveys, and, worryingly, information bias may become more likely in the future as immunization schedules become more complex and variable. Finally, some surveys assess immunity directly using serological assays. Sero-surveys are important for assessing public health risk, but currently are unable to validate coverage estimates directly. To improve vaccination coverage estimates based on surveys, we recommend that recording tools and practices should be improved and that surveys should incorporate best practices for design, implementation, and analysis.

Measuring coverage in MNCH: total survey error and the interpretation of intervention coverage estimates from household surveys.

Nationally representative household surveys are increasingly relied upon to measure maternal, newborn, and child health (MNCH) intervention coverage at the population level in low- and middle-income countries. Surveys are the best tool we have for this purpose and are central to national and global decision making. However, all survey point estimates have a certain level of error (total survey error) comprising sampling and non-sampling error, both of which must be considered when interpreting survey results for decision making. In this review, we discuss the importance of considering these errors when interpreting MNCH intervention coverage estimates derived from household surveys, using relevant examples from national surveys to provide context. Sampling error is usually thought of as the precision of a point estimate and is represented by 95% confidence intervals, which are measurable. Confidence intervals can inform judgments about whether estimated parameters are likely to be different from the real value of a parameter. We recommend, therefore, that confidence intervals for key coverage indicators should always be provided in survey reports. By contrast, the direction and magnitude of non-sampling error is almost always unmeasurable, and therefore unknown. Information error and bias are the most common sources of non-sampling error in household survey estimates and we recommend that they should always be carefully considered when interpreting MNCH intervention coverage based on survey data. Overall, we recommend that future research on measuring MNCH intervention coverage should focus on refining and improving survey-based coverage estimates to develop a better understanding of how results should be interpreted and used.

Health effects of routine measles vaccination and supplementary immunisation activities in 14 high-burden countries: a Dynamic Measles Immunization Calculation Engine (DynaMICE) modelling study.

BACKGROUND: WHO recommends at least 95% population coverage with two doses of measles-containing vaccine (MCV). Most countries worldwide use routine services to offer a first dose of measles-containing vaccine (MCV1) and later, a second dose of measles-containing vaccine (MCV2). Many countries worldwide conduct supplementary immunisation activities (SIAs), offering vaccination to all people in a specific age range irrespective of previous vaccination history. We aimed to estimate the relative effects of each dose and delivery route in 14 countries with high measles burden. METHODS: We used an age-structured compartmental dynamic model, the Dynamic Measles Immunization Calculation Engine (DynaMICE), to assess the effects of different vaccination strategies on measles susceptibility and burden during 2000-20 in 14 countries with high measles incidence (containing 53% of the global birth cohort and 78% of the global measles burden). Country-specific routine MCV1 and MCV2 coverage data during 1980-2020 were obtained from the WHO and UNICEF Estimates of National Immunization Coverage database for all modelled countries and SIA data were obtained from the WHO summary of measles and rubella SIAs. We estimated the incremental health effects of different vaccination strategies using prevented cases of measles and deaths from measles and their efficiency using the incremental number needed to vaccinate (NNV) to prevent an additional measles case. FINDINGS: Compared with no vaccination, MCV1 implementation was estimated to have prevented 824 million cases of measles and 9·6 million deaths from measles, with a median NNV of 1·41 (IQR 1·35-1·44). Adding routine MCV2 to MCV1 was estimated to have prevented 108 million cases and 404 270 deaths, whereas adding SIAs to MCV1 was estimated to have prevented 256 million cases and 4·4 million deaths. Despite larger incremental effects, adding SIAs to MCV1 (median incremental NNV 6·02, 5·30-7·68) showed reduced efficiency compared with adding routine MCV2 (5·41, 4·76-6·11). INTERPRETATION: Vaccination strategies, including non-selective SIAs, reach a greater proportion of children who are unvaccinated and reduce measles burden more than MCV2 alone, but efficiency is lower because of the wide age range targeted by SIAs. This analysis provides information to help improve the health effects and efficiency of measles vaccination strategies. The interplay between MCV1, MCV2, and SIAs should be considered when planning future measles vaccination strategies. FUNDING: Gavi, the Vaccine Alliance and the Bill & Melinda Gates Foundation.

Estimates of the global burden of Congenital Rubella Syndrome, 1996-2019.

OBJECTIVES: Many countries introduced rubella-containing vaccination (RCV) after 2011, following changes in recommended World Health Organization (WHO) vaccination strategies and external support. We evaluated the impact of these introductions. METHODS: We estimated the country-specific, region-specific, and global Congenital Rubella Syndrome (CRS) incidence during 1996-2019 using mathematical modeling, including routine and campaign vaccination coverage and seroprevalence data. RESULTS: In 2019, WHO African and Eastern Mediterranean regions had the highest estimated CRS incidence (64 [95% confidence intervals (CI): 24-123] and 27 [95% CI: 4-67] per 100,000 live births respectively), where nearly half of births occur in countries that have introduced RCV. Other regions, where >95% of births occurred in countries that had introduced RCV, had a low estimated CRS incidence (<1 [95% CI: <1 to 8] and <1 [95% CI: <1 to 12] per 100,000 live births in South-East Asia [SEAR] and the Western Pacific [WPR] respectively, and similarly in Europe and the Americas). The estimated number of CRS births globally declined by approximately two-thirds during 2010-2019, from 100,000 (95% CI: 54,000-166,000) to 32,000 (95% CI: 13,000-60,000), representing a 73% reduction since 1996, largely following RCV introductions in WPR and SEAR, where the greatest reductions occurred. CONCLUSIONS: Further reductions can occur by introducing RCV in remaining countries and maintaining high RCV coverage.

Population-Level Risk Factors Related to Measles Case Fatality: A Conceptual Framework Based on Expert Consultation and Literature Review.

A better understanding of population-level factors related to measles case fatality is needed to estimate measles mortality burden and impact of interventions such as vaccination. This study aimed to develop a conceptual framework of mechanisms associated with measles case fatality ratios (CFRs) and assess the scope of evidence available for related indicators. Using expert consultation, we developed a conceptual framework of mechanisms associated with measles CFR and identified population-level indicators potentially associated with each mechanism. We conducted a literature review by searching PubMed on 31 October 2021 to determine the scope of evidence for the expert-identified indicators. Studies were included if they contained evidence of an association between an indicator and CFR and were excluded if they were from non-human studies or reported non-original data. Included studies were assessed for study quality. Expert consultation identified five mechanisms in a conceptual framework of factors related to measles CFR. We identified 3772 studies for review and found 49 studies showing at least one significant association with CFR for 15 indicators (average household size, educational attainment, first- and second-dose coverage of measles-containing vaccine, human immunodeficiency virus prevalence, level of health care available, stunting prevalence, surrounding conflict, travel time to major city or settlement, travel time to nearest health care facility, under-five mortality rate, underweight prevalence, vitamin A deficiency prevalence, vitamin A treatment, and general malnutrition) and only non-significant associations for five indicators (antibiotic use for measles-related pneumonia, malaria prevalence, percent living in urban settings, pneumococcal conjugate vaccination coverage, vitamin A supplementation). Our study used expert consultation and a literature review to provide additional insights and a summary of the available evidence of these underlying mechanisms and indicators that could inform future measles CFR estimations.

Mapping the distribution of zero-dose children to assess the performance of vaccine delivery strategies and their relationships with measles incidence in Nigeria.

Geographically precise identification and targeting of populations at risk of vaccine-preventable diseases has gained renewed attention within the global health community over the last few years. District level estimates of vaccination coverage and corresponding zero-dose prevalence constitute a potentially useful evidence base to evaluate the performance of vaccination strategies. These estimates are also valuable for identifying missed communities, hence enabling targeted interventions and better resource allocation. Here, we fit Bayesian geostatistical models to map the routine coverage of the first doses of diphtheria-tetanus-pertussis vaccine (DTP1) and measles-containing vaccine (MCV1) and corresponding zero-dose estimates in Nigeria at 1x1 km resolution and the district level using geospatial data sets. We also map MCV1 coverage before and after the 2019 measles vaccination campaign in the northern states to further explore variations in routine vaccine coverage and to evaluate the effectiveness of both routine immunization (RI) and campaigns in reaching zero-dose children. Additionally, we map the spatial distributions of reported measles cases during 2018 to 2020 and explore their relationships with MCV zero-dose prevalence to highlight the public health implications of varying performance of vaccination strategies across the country. Our analysis revealed strong similarities between the spatial distributions of DTP and MCV zero dose prevalence, with districts with the highest prevalence concentrated mostly in the northwest and the northeast, but also in other areas such as Lagos state and the Federal Capital Territory. Although the 2019 campaign reduced MCV zero-dose prevalence substantially in the north, pockets of vulnerabilities remained in areas that had among the highest prevalence prior to the campaign. Importantly, we found strong correlations between measles case counts and MCV RI zero-dose estimates, which provides a strong indication that measles incidence in the country is mostly affected by RI coverage. Our analyses reveal an urgent and highly significant need to strengthen the country's RI program as a longer-term measure for disease control, whilst ensuring effective campaigns in the short term.

A Practical Guide to Pilot Testing Community-Based Vaccination Coverage Surveys.

Pilot testing is crucial when preparing any community-based vaccination coverage survey. In this paper, we use the term pilot test to mean informative work conducted before a survey protocol has been finalized for the purpose of guiding decisions about how the work will be conducted. We summarize findings from seven pilot tests and provide practical guidance for piloting similar studies. We selected these particular pilots because they are excellent models of preliminary efforts that informed the refinement of data collection protocols and instruments. We recommend survey coordinators devote time and budget to identify aspects of the protocol where testing could mitigate project risk and ensure timely assessment yields, credible estimates of vaccination coverage and related indicators. We list specific items that may benefit from pilot work and provide guidance on how to prioritize what to pilot test when resources are limited.

Persistence of vaccine-induced measles antibody beyond age 12 months: a comparison of response to one and two doses of Edmonston-Zagreb measles vaccine among HIV-infected and uninfected children in Malawi.

BACKGROUND: Previously, we demonstrated that measles antibody prevalence was lower at age 12 months among children infected with human immunodeficiency virus (HIV) than uninfected children following measles vaccination (MV) at ages 6 and 9 months. Among HIV-uninfected children, measles antibody prevalence was lower among 1- than 2-dose MV recipients. Here, we report results through age 24 months. METHODS: Children born to HIV-infected mothers received MV at 6 and 9 months, and children of HIV-uninfected mothers were randomized to MV at 6 and 9 months or MV at 9 months. We followed children through age 24 months. The child's HIV status was determined and measles immunoglobulin G (IgG) level was measured by enzyme immunoassay (EIA) and by plaque reduction neutralization (PRN) on a subset. RESULTS: Among HIV-uninfected children, the difference in measles antibody prevalence at age 12 months between one- and two-dose recipients reported previously by EIA was shown to be smaller by PRN. By age 24 months, 84% and 87% of HIV-uninfected children receiving 1 or 2 doses, respectively, were seroprotected. Only 41% of 22 HIV-infected children were measles seroprotected at age 20 months. DISCUSSION: Measles seroprotection persisted through age 24 months among HIV-uninfected children who received 1 or 2 doses of MV. HIV-infected children demonstrated seroprotection through age 12 months, but this was not sustained.

Multilevel analysis of predictors of multiple indicators of childhood vaccination in Nigeria.

BACKGROUND: Substantial inequalities exist in childhood vaccination coverage levels. To increase vaccine uptake, factors that predict vaccination coverage in children should be identified and addressed. METHODS: Using data from the 2018 Nigeria Demographic and Health Survey and geospatial data sets, we fitted Bayesian multilevel binomial and multinomial logistic regression models to analyse independent predictors of three vaccination outcomes: receipt of the first dose of Pentavalent vaccine (containing diphtheria-tetanus-pertussis, Hemophilus influenzae type B and Hepatitis B vaccines) (PENTA1) (n = 6059) and receipt of the third dose having received the first (PENTA3/1) (n = 3937) in children aged 12-23 months, and receipt of measles vaccine (MV) (n = 11839) among children aged 12-35 months. RESULTS: Factors associated with vaccination were broadly similar for documented versus recall evidence of vaccination. Based on any evidence of vaccination, we found that health card/document ownership, receipt of vitamin A and maternal educational level were significantly associated with each outcome. Although the coverage of each vaccine dose was higher in urban than rural areas, urban residence was not significant in multivariable analyses that included travel time. Indicators relating to socio-economic status, as well as ethnic group, skilled birth attendance, lower travel time to the nearest health facility and problems seeking health care were significantly associated with both PENTA1 and MV. Maternal religion was related to PENTA1 and PENTA3/1 and maternal age related to MV and PENTA3/1; other significant variables were associated with one outcome each. Substantial residual community level variances in different strata were observed in the fitted models for each outcome. CONCLUSION: Our analysis has highlighted socio-demographic and health care access factors that affect not only beginning but completing the vaccination series in Nigeria. Other factors not measured by the DHS such as health service quality and community attitudes should also be investigated and addressed to tackle inequities in coverage.

Using Household Surveys to Assess Missed Opportunities for Simultaneous Vaccination: Longitudinal Examples from Colombia and Nigeria.

One important strategy to increase vaccination coverage is to minimize missed opportunities for vaccination. Missed opportunities for simultaneous vaccination (MOSV) occur when a child receives one or more vaccines but not all those for which they are eligible at a given visit. Household surveys that record children's vaccination dates can be used to quantify occurrence of MOSVs and their impact on achievable vaccination coverage. We recently automated some MOSV analyses in the World Health Organization's freely available software: Vaccination Coverage Quality Indicators (VCQI) making it straightforward to study MOSVs for any Demographic & Health Survey (DHS), Multi-Indicator Cluster Survey (MICS), or Expanded Programme on Immunization (EPI) survey. This paper uses VCQI to analyze MOSVs for basic vaccine doses among children aged 12-23 months in four rounds of DHS in Colombia (1995, 2000, 2005, and 2010) and five rounds of DHS in Nigeria (1999, 2003, 2008, 2013, and 2018). Outcomes include percent of vaccination visits MOSVs occurred, percent of children who experienced MOSVs, percent of MOSVs that remained uncorrected (that is, the missed vaccine had still not been received at the time of the survey), and the distribution of time-to-correction for children who received the MOSV dose at a later visit.

Correction: Implementing WHO guidance on conducting and analysing vaccination coverage cluster surveys: Two examples from Nigeria.

[This corrects the article DOI: 10.1371/journal.pone.0247415.].

Implementing WHO guidance on conducting and analysing vaccination coverage cluster surveys: Two examples from Nigeria.

In 2015, the World Health Organization substantially revised its guidance for vaccination coverage cluster surveys (revisions were finalized in 2018) and has since developed a set of accompanying resources, including definitions for standardized coverage indicators and software (named the Vaccination Coverage Quality Indicators-VCQI) to calculate them.-The current WHO vaccination coverage survey manual was used to design and conduct two nationally representative vaccination coverage surveys in Nigeria-one to assess routine immunization and one to measure post-measles campaign coverage. The primary analysis for both surveys was conducted using VCQI. In this paper, we describe those surveys and highlight some of the analyses that are facilitated by the new resources. In addition to calculating coverage of each vaccine-dose by age group, VCQI analyses provide insight into several indicators of program quality such as crude coverage versus valid doses, vaccination timeliness, missed opportunities for simultaneous vaccination, and, where relevant, vaccination campaign coverage stratified by several parameters, including the number of previous doses received. The VCQI software furnishes several helpful ways to visualize survey results. We show that routine coverage of all vaccines is far below targets in Nigeria and especially low in northeast and northwest zones, which also have highest rates of dropout and missed opportunities for vaccination. Coverage in the 2017 measles campaign was higher and showed less geospatial variation than routine coverage. Nonetheless, substantial improvement in both routine program performance and campaign implementation will be needed to achieve disease control goals.

Association of serotype with risk of death due to pneumococcal pneumonia: a meta-analysis.

BACKGROUND: The 92 capsular serotypes of Streptococcus pneumoniae differ greatly in nasopharyngeal carriage prevalence, invasiveness, and disease incidence. There has been some debate, though, regarding whether serotype independently affects the outcome of invasive pneumococcal disease (IPD). Published studies have shown variable results with regard to case-fatality ratios for specific serotypes and the role of host factors in affecting these relationships. We evaluated whether risk of death due to IPD is a stable serotype-associated property across studies and then compared the pooled effect estimates with epidemiologic and biological correlates. METHODS: We performed a systematic review and meta-analysis of serotype-specific disease outcomes for patients with pneumonia and meningitis. Study-specific estimates of risk of death (risk ratio [RR]) were pooled from 9 studies that provided serotype-specific data on pneumonia and meningitis using a random-effects method with serotype 14 as the reference. Pooled RRs were compared with RRs from adults with low comorbidity scores to evaluate potential confounding by host factors. RESULTS: Significant differences were found in the RR estimates among serotypes in patients with bacteremic pneumonia. Overall, serotypes 1, 7F, and 8 were associated with decreased RRs, and serotypes 3, 6A, 6B, 9N, and 19F were associated with increased RRs. Outcomes among meningitis patients did not differ significantly among serotypes. Serotypes with increased RRs had a high carriage prevalence, had low invasiveness, and were more heavily encapsulated in vitro. CONCLUSIONS: These results suggest that IPD outcome, like other epidemiologic measures, is a stable serotype-associated property.

Estimation of intervention effects using first or multiple episodes in clinical trials: The Andersen-Gill model re-examined.

Randomized trials of interventions against infectious diseases are often analyzed using data on first or only episodes of disease, even when subsequent episodes have been recorded. It is often said that the Andersen-Gill (AG) model gives a biased estimate of intervention effect if there is event dependency over time. We demonstrate that, in the presence of event dependency, an effective intervention may have an indirect effect on disease risk at time t(j) via its direct effect on disease risk at time t(i), i