Impact of Supplementary Immunization Activities using Novel Oral Polio Vaccine Type 2 during a Large outbreak of Circulating Vaccine-Derived Poliovirus in Nigeria.

BACKGROUND: Novel oral poliovirus vaccine (OPV) type 2 (nOPV2) has been made available for outbreak response under an emergency use listing authorization based on supportive clinical trial data. Since 2021 more than 350 million doses of nOPV2 were used for control of a large outbreak of circulating vaccine-derived poliovirus type 2 (cVDPV2) in Nigeria. METHODS: Using a bayesian time-series susceptible-infectious-recovered model, we evaluate the field effectiveness of nOPV2 immunization campaigns in Nigeria compared with campaigns using monovalent OPV type 2 (mOPV2). RESULTS: We found that both nOPV2 and mOPV2 campaigns were highly effective in reducing transmission of cVDPV2, on average reducing the susceptible population by 42% (95% confidence interval, 28-54%) and 38% (20-51%) per campaign, respectively, which were indistinguishable from each other in this analysis (relative effect, 1.1 [.7-1.9]). Impact was found to vary across areas and between immunization campaigns. CONCLUSIONS: These results are consistent with the comparable individual immunogenicity of nOPV2 and mOPV2 found in clinical trials but also suggest that outbreak response campaigns may have small impacts in some areas requiring more campaigns than are suggested in current outbreak response procedures.

Mapping for Health in Cameroon: Polio Legacy and Beyond.

During the poliovirus outbreak in Cameroon from October 2013 to April 2015, the Ministry of Public Health's Expanded Program on Immunization requested technical support to improve mapping of health district boundaries and health facility locations for more effective planning and analysis of polio program data. In December 2015, teams collected data on settlements, health facilities, and other features using smartphones. These data, combined with high-resolution satellite imagery, were used to create new health area and health district boundaries, providing the most accurate health sector administrative boundaries to date for Cameroon. The new maps are useful to and used by the polio program as well as other public health programs within Cameroon such as the District Health Information System and the Emergency Operations Center, demonstrating the value of the Global Polio Eradication Initiative's legacy.

Association of low-frequency and rare coding-sequence variants with blood lipids and coronary heart disease in 56,000 whites and blacks.

Low-frequency coding DNA sequence variants in the proprotein convertase subtilisin/kexin type 9 gene (PCSK9) lower plasma low-density lipoprotein cholesterol (LDL-C), protect against risk of coronary heart disease (CHD), and have prompted the development of a new class of therapeutics. It is uncertain whether the PCSK9 example represents a paradigm or an isolated exception. We used the "Exome Array" to genotype >200,000 low-frequency and rare coding sequence variants across the genome in 56,538 individuals (42,208 European ancestry [EA] and 14,330 African ancestry [AA]) and tested these variants for association with LDL-C, high-density lipoprotein cholesterol (HDL-C), and triglycerides. Although we did not identify new genes associated with LDL-C, we did identify four low-frequency (frequencies between 0.1% and 2%) variants (ANGPTL8 rs145464906 [c.361C>T; p.Gln121*], PAFAH1B2 rs186808413 [c.482C>T; p.Ser161Leu], COL18A1 rs114139997 [c.331G>A; p.Gly111Arg], and PCSK7 rs142953140 [c.1511G>A; p.Arg504His]) with large effects on HDL-C and/or triglycerides. None of these four variants was associated with risk for CHD, suggesting that examples of low-frequency coding variants with robust effects on both lipids and CHD will be limited.

Analysis of vaccination campaign effectiveness and population immunity to support and sustain polio elimination in Nigeria.

BACKGROUND: The world is closer than ever to a polio-free Africa. In this end-stage, it is important to ensure high levels of population immunity to prevent polio outbreaks. Here, we introduce a new method of assessing vaccination campaign effectiveness and estimating immunity at the district-level. We demonstrate how this approach can be used to plan the vaccination campaigns prospectively to better manage population immunity in Northern Nigeria. METHODS: Using Nigerian acute flaccid paralysis surveillance data from 2004-2014, we developed a Bayesian hierarchical model of campaign effectiveness and compared it to lot-quality assurance sampling data. We then used reconstructed sero-specific population immunity based on campaign history and compared district estimates of immunity to the occurrence of confirmed poliovirus cases. RESULTS: Estimated campaign effectiveness has improved across northern Nigeria since 2004, with Kano state experiencing an increase of 40 % (95 % CI, 26-54 %) in effectiveness from 2013 to 2014. Immunity to type 1 poliovirus has increased steadily. On the other hand, type 2 immunity was low and variable until the recent use of trivalent oral polio vaccine. We find that immunity estimates are related to the occurrence of both wild and vaccine-derived poliovirus cases and that campaign effectiveness correlates with direct measurements using lot-quality assurance sampling. Future campaign schedules highlight the trade-offs involved with using different vaccine types. CONCLUSIONS: The model in this study provides a novel method for assessing vaccination campaign performance and epidemiologically-relevant estimates of population immunity. Small-area estimates of campaign effectiveness can then be used to evaluate prospective campaign plans. This modeling approach could be applied to other countries as well as other vaccine preventable diseases.

Resequencing and clinical associations of the 9p21.3 region: a comprehensive investigation in the Framingham heart study.

BACKGROUND: 9p21.3 is among the most strongly replicated regions for cardiovascular disease. There are few reports of sequencing the associated 9p21.3 interval. We set out to sequence the 9p21.3 region followed by a comprehensive study of genetic associations with clinical and subclinical cardiovascular disease and its risk factors, as well as with copy number variation and gene expression, in the Framingham Heart Study (FHS). METHODS AND RESULTS: We sequenced 281 individuals (94 with myocardial infarction, 94 with high coronary artery calcium levels, and 93 control subjects free of elevated coronary artery calcium or myocardial infarction), followed by genotyping and association in >7000 additional FHS individuals. We assessed genetic associations with clinical and subclinical cardiovascular disease, risk factor phenotypes, and gene expression levels of the protein-coding genes CDKN2A and CDKN2B and the noncoding gene ANRIL in freshly harvested leukocytes and platelets. Within this large sample, we found strong associations of 9p21.3 variants with increased risk for myocardial infarction, higher coronary artery calcium levels, and larger abdominal aorta diameters and no evidence for association with traditional cardiovascular disease risk factors. No common protein-coding variation, variants in splice donor or acceptor sites, or copy number variation events were observed. By contrast, strong associations were observed between genetic variants and gene expression, particularly for a short isoform of ANRIL and for CDKN2B. CONCLUSIONS: Our thorough genomic characterization of 9p21.3 suggests common variants likely account for observed disease associations and provides further support for the hypothesis that complex regulatory variation affecting ANRIL and CDKN2B gene expression may contribute to increased risk for clinically apparent and subclinical coronary artery disease and aortic disease.

Fast computation for genome-wide association studies using boosted one-step statistics.

MOTIVATION: Statistical analyses of genome-wide association studies (GWAS) require fitting large numbers of very similar regression models, each with low statistical power. Taking advantage of repeated observations or correlated phenotypes can increase this statistical power, but fitting the more complicated models required can make computation impractical. RESULTS: In this article, we present simple methods that capitalize on the structure inherent in GWAS studies to dramatically speed up computation for a wide variety of problems, with a special focus on methods for correlated phenotypes. AVAILABILITY: The R package 'boss' is available on the Comprehensive R Archive Network (CRAN) at http://cran.r-project.org/web/packages/boss/

Real-time prediction model of cVDPV2 outbreaks to aid outbreak response vaccination strategies.

BACKGROUND: Circulating vaccine-derived poliovirus outbreaks are spreading more widely than anticipated, which has generated a crisis for the global polio eradication initiative. Effectively responding with vaccination activities requires a rapid risk assessment. This assessment is made difficult by the low case-to-infection ratio of type 2 poliovirus, variable transmissibility, changing population immunity, surveillance delays, and limited vaccine supply from the global stockpile. The geographical extent of responses have been highly variable between countries. METHODS: We develop a statistical spatio-temporal model of short-term, district-level poliovirus spread that incorporates known risk factors, including historical wild poliovirus transmission risk, routine immunization coverage, population immunity, and exposure to the outbreak virus. RESULTS: We find that proximity to recent cVDPV2 cases is the strongest risk factor for spread of an outbreak, and find significant associations between population immunity, historical risk, routine immunization, and environmental surveillance (p < 0.05). We examine the fit of the model to type 2 vaccine derived poliovirus spread since 2016 and find that our model predicts the location of cVDPV2 cases well (AUC = 0.96). We demonstrate use of the model to estimate appropriate scope of outbreak response activities to current outbreaks. CONCLUSION: As type 2 immunity continues to decline following the cessation of tOPV in 2016, outbreak responses to new cVDPV2 detections will need to be faster and larger in scope. We provide a framework that can be used to support decisions on the appropriate size of a vaccination response when new detections are identified. While the model does not account for all relevant local factors that must be considered in the overall vaccination response, it enables a quantitative basis for outbreak response size.

Analysis of population immunity to poliovirus following cessation of trivalent oral polio vaccine.

BACKGROUND: The global withdrawal of trivalent oral poliovirus vaccine (OPV) (tOPV, containing Sabin poliovirus strains serotypes 1, 2 and 3) from routine immunization, and the introduction of bivalent OPV (bOPV, containing Sabin poliovirus strains serotypes 1 and 3) and trivalent inactivated poliovirus vaccine (IPV) into routine immunization was expected to improve population serologic and mucosal immunity to types 1 and 3 poliovirus, while population mucosal immunity to type 2 poliovirus would decline. However, over the period since tOPV withdrawal, the implementation of preventive bOPV supplementary immunization activities (SIAs) has decreased, while outbreaks of type 2 circulating vaccine derived poliovirus (cVDPV2) have required targeted use of monovalent type 2 OPV (mOPV2). METHODS: We develop a dynamic model of OPV-induced immunity to estimate serotype-specific, district-level immunity for countries in priority regions and characterize changes in immunity since 2016. We account for the changes in routine immunization schedules and varying implementation of preventive and outbreak response SIAs, assuming homogenous coverages of 50% and 80% for SIAs. RESULTS: In areas with strong routine immunization, the switch from tOPV to bOPV has likely resulted in gains in population immunity to types 1 and 3 poliovirus. However, we estimate that improved immunogenicity of new schedules has not compensated for declines in preventive SIAs in areas with weak routine immunization. For type 2 poliovirus, without tOPV in routine immunization or SIAs, mucosal immunity has declined nearly everywhere, while use of mOPV2 has created highly heterogeneous population immunity for which it is important to take into account when responding to cVDPV2 outbreaks. CONCLUSIONS: The withdrawal of tOPV and declining allocations of resources for preventive bOPV SIAs have resulted in reduced immunity in vulnerable areas to types 1 and 3 poliovirus and generally reduced immunity to type 2 poliovirus in the regions studied, assuming homogeneous coverages of 50% and 80% for SIAs. The very low mucosal immunity to type 2 poliovirus generates substantially greater risk for further spread of cVDPV2 outbreaks. Emerging gaps in immunity to all serotypes will require judicious targeting of limited resources to the most vulnerable populations by the Global Polio Eradication Initiative (GPEI).

The impact of disruptions caused by the COVID-19 pandemic on global polio eradication.

In early 2020, the COVID-19 pandemic led to substantial disruptions in global activities. The disruptions also included intentional and unintentional reductions in health services, including immunization campaigns against the transmission of wild poliovirus (WPV) and persistent serotype 2 circulating vaccine-derived poliovirus (cVDPV2). Building on a recently updated global poliovirus transmission and Sabin-strain oral poliovirus vaccine (OPV) evolution model, we explored the implications of immunization disruption and restrictions of human interactions (i.e., population mixing) on the expected incidence of polio and on the resulting challenges faced by the Global Polio Eradication Initiative (GPEI). We demonstrate that with some resumption of activities in the fall of 2020 to respond to cVDPV2 outbreaks and full resumption on January 1, 2021 of all polio immunization activities to pre-COVID-19 levels, the GPEI could largely mitigate the impact of COVID-19 to the delays incurred. The relative importance of reduced mixing (leading to potentially decreased incidence) and reduced immunization (leading to potentially increased expected incidence) depends on the timing of the effects. Following resumption of immunization activities, the GPEI will likely face similar barriers to eradication of WPV and elimination of cVDPV2 as before COVID-19. The disruptions from the COVID-19 pandemic may further delay polio eradication due to indirect effects on vaccine and financial resources.

New analytic approaches for analyzing and presenting polio surveillance data to supplement standard performance indicators.

BACKGROUND: Sensitive surveillance for acute flaccid paralysis (AFP) allows for rapid detection of polio outbreaks and provides essential evidence to support certification of the eradication of polio. However, accurately assessing the sensitivity of surveillance systems can be difficult due to limitations in the reliability of available performance indicators, including the rate of detection of non-polio AFP and the proportion of adequate stool sample collection. Recent field reviews have found evidence of surveillance gaps despite indicators meeting expected targets. METHODS: We propose two simple new approaches for AFP surveillance performance indicator analysis to supplement standard indicator analysis approaches commonly used by the Global Polio Eradication Initiative (GPEI): (1) using alternative groupings of low population districts in the country (spatial binning) and (2) flagging unusual patterns in surveillance data (surveillance flags analysis). Using GPEI data, we systematically compare AFP surveillance performance using standard indicator analysis and these new approaches. RESULTS: Applying spatial binning highlights areas meeting surveillance indicator targets that do not when analyzing performance of low population districts. Applying the surveillance flags we find several countries with unusual data patterns, in particular age groups which are not well-covered by the surveillance system, and countries with implausible rates of adequate stool specimen collection. CONCLUSIONS: Analyzing alternate groupings of administrative units is a simple method to find areas where traditional AFP surveillance indicator targets are not reliably met. For areas where AFP surveillance indicator targets are met, systematic assessment of unusual patterns ('flags') can be a useful prompt for further investigation and field review.

Violence, insecurity, and the risk of polio: A systematic analysis.

BACKGROUND: Since the introduction of polio vaccines in the 1950's and 60's, eradication of poliovirus from the world has been technically feasible. Progress towards this goal, however, has been uneven and influenced by social and political factors that challenge the implementation of robust immunization programs. While violence and insecurity are often cited as barriers to eradication, current global risk models are largely based on virologic and immunologic indicators measured at national levels. In this manuscript, we quantify the relevance of indicators of violence and insecurity on the risk of polio spread. METHODS AND FINDINGS: Using logistic regression models and public data sources, we evaluate the relationship between measures of violence and instability and the location of poliomyelitis cases between 2006 and 2015 at the country-level, both individually and after controlling for more proximal determinants of disease, such as nearby circulating poliovirus and vaccination rates. We found that increases in a country's Fragile States Index (FSI) and Global Peace Index (GPI), aggregate indicators of violence and instability, were associated with the occurrence of poliovirus cases in the subsequent year (p< 0.01), even after controlling for established risk factors. These effects of violence and insecurity must be mediated through immunity and exposure to poliovirus, coarse measures of which are included in our model. This also implies that in our study, and in risk models in general, the interpretation depends on the quality and granularity of available data. CONCLUSION: National virologic and immunologic indicators understate the risk of poliovirus spread in areas with violence and insecurity, and the inclusion of such factors improves precision. In addition, the link between violence and incidence of disease highlights the broader challenge of implementing health interventions in conflict areas. We discuss practical implications of this work in understanding and measuring the risks to polio eradication and other global health initiatives, and the policy implications of the need to reach vulnerable populations in conflict zones.

Polio immunity and the impact of mass immunization campaigns in the Democratic Republic of the Congo.

BACKGROUND: In order to prevent outbreaks from wild and vaccine-derived poliovirus, maintenance of population immunity in non-endemic countries is critical. METHODS: We estimated population seroprevalence using dried blood spots collected from 4893 children 6-59months olds in the 2013-2014 Demographic and Health Survey in the Democratic Republic of the Congo (DRC). RESULTS: Population immunity was 81%, 90%, and 70% for poliovirus types 1, 2, and 3, respectively. Among 6-59-month-old children, 78% reported at least one dose of polio in routine immunization, while only 15% had three doses documented on vaccination cards. All children in the study had been eligible for at least two trivalent oral polio vaccine campaigns at the time of enrollment; additional immunization campaigns seroconverted 5.0%, 14%, and 5.5% of non-immune children per-campaign for types 1, 2, and 3, respectively, averaged over relevant campaigns for each serotype. CONCLUSIONS: Overall polio immunity was high at the time of the study, though pockets of low immunity cannot be ruled out. The DRC still relies on supplementary immunization campaigns, and this report stresses the importance of the quality and coverage of those campaigns over their quantity, as well as the importance of routine immunization.

Measuring polio immunity to plan immunization activities.

The Global Polio Eradication Initiative is closer than ever to achieving a polio-free world. Immunization activities must still be carried out in non-endemic countries to maintain population immunity at levels which will stop poliovirus from spreading if it is re-introduced from still-infected areas. In areas where there is no active transmission of poliovirus, programs must rely on surrogate indicators of population immunity to determine the appropriate immunization activities, typically caregiver-reported vaccination history obtained from non-polio acute flaccid paralysis patients identified through polio surveillance. We used regression models to examine the relationship between polio vaccination campaigns and caregiver-reported polio vaccination history. We find that in many countries, vaccination campaigns have a surprisingly weak impact on these commonly used indicators. We conclude that alternative criteria and data, such as routine immunization indicators from vaccination records or household surveys, should be considered for planning polio vaccination campaigns, and that validation of such surrogate indicators is necessary if they are to be used as the basis for program planning and risk assessment. We recommend that the GPEI and similar organizations consider or continue devoting additional resources to rigorously study population immunity and campaign effectiveness in at-risk countries.

Meta-analysis identifies common and rare variants influencing blood pressure and overlapping with metabolic trait loci.

Meta-analyses of association results for blood pressure using exome-centric single-variant and gene-based tests identified 31 new loci in a discovery stage among 146,562 individuals, with follow-up and meta-analysis in 180,726 additional individuals (total n = 327,288). These blood pressure-associated loci are enriched for known variants for cardiometabolic traits. Associations were also observed for the aggregation of rare and low-frequency missense variants in three genes, NPR1, DBH, and PTPMT1. In addition, blood pressure associations at 39 previously reported loci were confirmed. The identified variants implicate biological pathways related to cardiometabolic traits, vascular function, and development. Several new variants are inferred to have roles in transcription or as hubs in protein-protein interaction networks. Genetic risk scores constructed from the identified variants were strongly associated with coronary disease and myocardial infarction. This large collection of blood pressure-associated loci suggests new therapeutic strategies for hypertension, emphasizing a link with cardiometabolic risk.

Graph Estimation with Joint Additive Models.

In recent years, there has been considerable interest in estimating conditional independence graphs in high dimensions. Most previous work has assumed that the variables are multivariate Gaussian, or that the conditional means of the variables are linear; in fact, these two assumptions are nearly equivalent. Unfortunately, if these assumptions are violated, the resulting conditional independence estimates can be inaccurate. We propose a semi-parametric method, graph estimation with joint additive models, which allows the conditional means of the features to take on an arbitrary additive form. We present an efficient algorithm for our estimator's computation, and prove that it is consistent. We extend our method to estimation of directed graphs with known causal ordering. Using simulated data, we show that our method performs better than existing methods when there are non-linear relationships among the features, and is comparable to methods that assume multivariate normality when the conditional means are linear. We illustrate our method on a cell-signaling data set.

Whole-genome sequence-based analysis of high-density lipoprotein cholesterol.

We describe initial steps for interrogating whole-genome sequence data to characterize the genetic architecture of a complex trait, levels of high-density lipoprotein cholesterol (HDL-C). We report whole-genome sequencing and analysis of 962 individuals from the Cohorts for Heart and Aging Research in Genetic Epidemiology (CHARGE) studies. From this analysis, we estimate that common variation contributes more to heritability of HDL-C levels than rare variation, and screening for mendelian variants for dyslipidemia identified individuals with extreme HDL-C levels. Whole-genome sequencing analyses highlight the value of regulatory and non-protein-coding regions of the genome in addition to protein-coding regions.

Behavior of QQ-plots and genomic control in studies of gene-environment interaction.

Genome-wide association studies of gene-environment interaction (GxE GWAS) are becoming popular. As with main effects GWAS, quantile-quantile plots (QQ-plots) and Genomic Control are being used to assess and correct for population substructure. However, in G x E work these approaches can be seriously misleading, as we illustrate; QQ-plots may give strong indications of substructure when absolutely none is present. Using simulation and theory, we show how and why spurious QQ-plot inflation occurs in G x E GWAS, and how this differs from main-effects analyses. We also explain how simple adjustments to standard regression-based methods used in G x E GWAS can alleviate this problem.