Modeling the Cost-Effectiveness of the Integrated Disease Surveillance and Response (IDSR) System: Meningitis in Burkina Faso

Background: Effective surveillance for infectious diseases is an essential component of public health. There are few studies estimating the cost-effectiveness of starting or improving disease surveillance. We present a cost-effectiveness analysis the Integrated Disease Surveillance and Response (IDSR) strategy in Africa. Methodology/Principal Findings: To assess the impact of the IDSR in Africa, we used pre- and post- IDSR meningococcal meningitis surveillance data from Burkina Faso (1996–2002 and 2003–2007). IDSR implementation was correlated with a median reduction of 2 weeks to peak of outbreaks (25 th percentile 1 week; 75 th percentile 4 weeks). IDSR was also correlated with a reduction of 43 meningitis cases per 100,000 (25 th –40: 75 th-129). Assuming the correlations between reductions in time to peak of outbreaks and cases are related, the cost-effectiveness of IDSR was $23 per case averted (25 th-$30; 75 th- cost saving), and $98 per meningitis-related death averted (25 th-$140: 75 th – cost saving). Conclusions/Significance: We cannot absolutely claim that the measured differences were due to IDSR. We believe, however, that it is reasonable to claim that IDSR can improve the cost-effectiveness of public health surveillance

Identifying Host Genetic Risk Factors in the Context of Public Health Surveillance for Invasive Pneumococcal Disease

Host genetic factors that modify risk of pneumococcal disease may help target future public health interventions to individuals at highest risk of disease. We linked data from population-based surveillance for invasive pneumococcal disease (IPD) with state-based newborn dried bloodspot repositories to identify biological samples from individuals who developed invasive pneumococcal disease. Genomic DNA was extracted from 366 case and 732 anonymous control samples. TagSNPs were selected in 34 candidate genes thought to be associated with host response to invasive pneumococcal disease, and a total of 326 variants were successfully genotyped. Among 543 European Americans (EA) (182 cases and 361 controls), and 166 African Americans (AA) (53 cases and 113 controls), common variants in surfactant protein D (SFTPD) are consistently underrepresented in IPD. SFTPD variants with the strongest association for IPD are intronic rs17886286 (allelic OR 0.45, 95% confidence interval (CI) [0.25, 0.82], with p = 0.007) in EA and 5′ flanking rs12219080 (allelic OR 0.32, 95%CI [0.13, 0.78], with p = 0.009) in AA. Variants in CD46 and IL1R1 are also associated with IPD in both EA and AA, but with effects in different directions; FAS, IL1B, IL4, IL10, IL12B, SFTPA1, SFTPB, and PTAFR variants are associated (p≤0.05) with IPD in EA or AA. We conclude that variants in SFTPD may protect against IPD in EA and AA and genetic variation in other host response pathways may also contribute to risk of IPD. While our associations are not corrected for multiple comparisons and therefore must be replicated in additional cohorts, this pilot study underscores the feasibility of integrating public health surveillance with existing, prospectively collected, newborn dried blood spot repositories to identify host genetic factors associated with infectious diseases

Whole genome sequencing to investigate the emergence of clonal complex 23 Neisseria meningitidis serogroup Y disease in the United States

In the United States, serogroup Y, ST-23 clonal complex Neisseria meningitidis was responsible for an increase in meningococcal disease incidence during the 1990s. This increase was accompanied by antigenic shift of three outer membrane proteins, with a decrease in the population that predominated in the early 1990s as a different population emerged later in that decade. To understand factors that may have been responsible for the emergence of serogroup Y disease, we used whole genome pyrosequencing to investigate genetic differences between isolates from early and late N. meningitidis populations, obtained from meningococcal disease cases in Maryland in the 1990s. The genomes of isolates from the early and late populations were highly similar, with 1231 of 1776 shared genes exhibiting 100% amino acid identity and an average πN = 0.0033 and average πS = 0.0216. However, differences were found in predicted proteins that affect pilin structure and antigen profile and in predicted proteins involved in iron acquisition and uptake. The observed changes are consistent with acquisition of new alleles through horizontal gene transfer. Changes in antigen profile due to the genetic differences found in this study likely allowed the late population to emerge due to escape from population immunity. These findings may predict which antigenic factors are important in the cyclic epidemiology of meningococcal disease

sodC-Based Real-Time PCR for Detection of Neisseria meningitidis

Real-time PCR (rt-PCR) is a widely used molecular method for detection of Neisseria meningitidis (Nm). Several rt-PCR assays for Nm target the capsule transport gene, ctrA. However, over 16% of meningococcal carriage isolates lack ctrA, rendering this target gene ineffective at identification of this sub-population of meningococcal isolates. The Cu-Zn superoxide dismutase gene, sodC, is found in Nm but not in other Neisseria species. To better identify Nm, regardless of capsule genotype or expression status, a sodC-based TaqMan rt-PCR assay was developed and validated. Standard curves revealed an average lower limit of detection of 73 genomes per reaction at cycle threshold (Ct) value of 35, with 100% average reaction efficiency and an average R2 of 0.9925. 99.7% (624/626) of Nm isolates tested were sodC-positive, with a range of average Ct values from 13.0 to 29.5. The mean sodC Ct value of these Nm isolates was 17.6±2.2 (±SD). Of the 626 Nm tested, 178 were nongroupable (NG) ctrA-negative Nm isolates, and 98.9% (176/178) of these were detected by sodC rt-PCR. The assay was 100% specific, with all 244 non-Nm isolates testing negative. Of 157 clinical specimens tested, sodC detected 25/157 Nm or 4 additional specimens compared to ctrA and 24 more than culture. Among 582 carriage specimens, sodC detected Nm in 1 more than ctrA and in 4 more than culture. This sodC rt-PCR assay is a highly sensitive and specific method for detection of Nm, especially in carriage studies where many meningococcal isolates lack capsule genes

Effectiveness and Duration of Protection of One Dose of a Meningococcal Conjugate Vaccine

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). 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. 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. 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

NeighborNet tree of genetic relatedness of early strain type, late strain type and 20 available sequenced meningococcal genomes using aligned sequence of regions common to all genomes.

<p>Tree produced using SplitsTree. Other genomes include: GB013, 053442, 961–5945, NZ05/33, CU385, M01-240355, M01-240149, M13399, M04-240196, H44/76, N1568, M6190, Z2491, G2136, M0579, FAM18, MC58, OX99-30304, alpha14, and ES14902.</p

General Features of Sequenced Genomes.

1<p>Large Contig, contig at least 500 bases in length.</p>2<p>Contig N50, length such that 50% of the assembled genome lies in contigs of N50 size or longer.</p>3<p>ORF, open reading frame.</p>4<p>Q40+ Bases, all the bases in the assembled contigs that carry a phred-equivalent quality score of 40 and above. A score of 40 is equivalent to an accuracy of 99.99%.</p

Genes found in a majority of sequenced genomes but absent from NM220 and NM233.

<p>Genes found in a majority of sequenced genomes but absent from NM220 and NM233.</p

Circular representation of similarity of late strain type genome to early strain type genome.

<p>Ordered from outermost to innermost, the rims show: rim 1 (plus strand) and rim 2 (minus strand), predicted coding regions, colored by role category; rim 3, SNP density; rim 4, π_N, plotted from 0 (base of rim) to 0.1; rim 5, π_S, plotted 0 (base of rim) to 0.5. Role category colors are: amino acid biosynthesis, violet; biosynthesis of cofactors, prosthetic groups and carriers, light blue; cell envelope, light green; cellular processes, red; central intermediary metabolism, brown; disrupted reading frame, black; DNA metabolism, gold; energy metabolism, light gray; fatty acid and phospholipid metabolism, magenta; hypothetical proteins, black; mobile and extrachromosomal element functions, cyan; protein fate, pink; protein synthesis, pink; purines, pyrimidines, nucleosides and nucleotides, orange; regulatory functions, olive; signal transduction, olive; transcription, dark green; transport and binding proteins, blue-green; unknown function, gray; viral functions, gray. SNP density: pink, 0 SNPs per kbp; yellow, 1–25 SNPs per kbp; red, 26–50 SNPs per kbp; green, 51–75 SNPs per kbp; blue, 76–155 SNPs per kbp.</p