[Show abstract][Hide abstract] ABSTRACT: The success of 7-valent pneumococcal conjugate vaccination (PCV-7) introduced to the US childhood immunization schedule in 2000 was partially offset by increases in invasive pneumococcal disease (IPD) and pneumococcal carriage due to non-vaccine serotypes, in particular 19A, in the years that followed. A 13-valent conjugate vaccine (PCV-13) was introduced in 2010. As part of an ongoing study of the response of the Massachusetts pneumococcal population to conjugate vaccination, we report the findings from the samples collected in 2011, as PCV-13 was introduced.
We used multilocus sequence typing (MLST) to analyze 367 pneumococcal isolates carried by Massachusetts children (aged 3 months-7 years) collected during the winter of 2010-11 and used eBURST software to compare the pneumococcal population structure with that found in previous years.
One hundred and four distinct sequence types (STs) were found, including 24 that had not been previously recorded. Comparison with a similar sample collected in 2009 revealed no significant overall difference in the ST composition (p = 0.39, classification index). However, we describe clonal dynamics within the important replacement serotypes 19A, 15B/C, and 6C, and clonal expansion of ST 433 and ST 432, which are respectively serotype 22F and 21 clones.
While little overall change in serotypes or STs was evident, multiple changes in the frequency of individual STs and or serotypes may plausibly be ascribed to the introduction of PCV-13. This 2011 sample documents the initial impact of PCV-13 and will be important for comparison with future studies of the evolution of the pneumococcal population in Massachusetts.
[Show abstract][Hide abstract] ABSTRACT: Using data from 3 private healthcare claims repositories, we evaluated the incidence of pneumococcal disease among adults
with US Advisory Committee on Immunization Practices (ACIP) defined at-risk conditions or rheumatoid arthritis, lupus, Crohn's
disease, and neuromuscular disorder/seizures and those with traditional high-risk conditions. We observed that adults with
≥2 concurrent comorbid conditions had pneumococcal disease incidence rates that were as high as or higher than rates observed
in those with traditional high-risk conditions.
[Show abstract][Hide abstract] ABSTRACT: We evaluated prospectively laboratory surveillance data from Massachusetts to investigate whether seasonal variation in invasive pneumococcal disease is associated with the proportion of penicillin susceptible isolates. The proportion of penicillin susceptible isolates associated with invasive pneumococcal disease varied by season, with proportions highest in the winter and lowest in the summer, and rates of invasive disease were highest in the autumn and winter seasons and lowest in the summer.
[Show abstract][Hide abstract] ABSTRACT: Background: Despite widespread vaccination, Streptococcus pneumoniae (SPN) continues to cause invasive pneumococcal disease (IPD), particularly in the immunocompromised. Current recommendations in the United States target the immunocompromised for use of the 13-valent conjugate vaccine. We examined the impact of chronic kidney disease on the development of invasive pneumococcal disease (IPD).
Methods: Kaiser Permanente Northern California (KPNC) is an integrated health care plan serving approximately 3.3 million members. IPD cases (defined as cultured from a normally sterile body site) were identified from the KPNC Lab system from May 2005 - April 2013. We used diagnostic codes from the electronic medical record to identify chronic kidney disease(CKD) as CKD3 (Glomerular filtration rate [GFR]30-59 ml/min), CKD4 (GFR 15-29 ml/min) and CKD5,6 (GFR <15 or on dialysis). We estimated rates of IPD in KPNC members with CKD and compared to rates of IPD in the general membership. We used KPNC registries to identify members with asthma, coronary artery disease (CAD), diabetes (DM), stroke, heart failure (HF), and HIV infection for the analysis. We ran a single multivariate poisson regression model to estimate the incidence of IPD, and included age, race and each condition as predictor variables.
Results: The unadjusted relative risk of IPD in members of all ages with CKD compared to the general membership was 4.1 for CKD3; 5.7 for CKD4; and 15.1 for CKD5,6. After controlling for multiple underlying factors in the multivariate analysis, CKD3 was associated with a 2.29 (95% CI 1.63-3.19) RR for IPD; and CKD 4,5 with a 7.10 RR (3.95-12.23) (preliminary analysis).
Conclusion: In adults, chronic kidney disease is strongly associated with an increased risk of IPD. This has important implications for recommendations on who should receive conjugated pneumococcal vaccines.
IDWeek 2014 Meeting of the Infectious Diseases Society of America; 10/2014
[Show abstract][Hide abstract] ABSTRACT: Background:
The impact of the 7-valent pneumococcal conjugate vaccine (PCV7) on pneumococcal disease in children and adults has been substantial. In 2010, PCV13, a second generation pneumococcal conjugate vaccine was introduced for infants with catch up dosing. A decline in IPD and specifically vaccine serotypes in children < 5 years of age has already been reported. We present data on the incidence and serotype distribution of IPD in adults over 18 years of age for the 6 years before and after introduction of PCV13.
Kaiser Permanente Northern California (KPNC) is an integrated health care plan serving approximately 3.3 million members. IPD cases were identified from the KPNC Lab system, and defined as S.pneumoniae from a normally sterile body site, from May 2008 through April 2014, in members age 18 and over. Serotyping was done at the Boston University Schools of Medicine. Age and race were derived from KPNC membership databases. Rates were calculated as Annual Incidence of IPD = (IPD cases / (Membership / 105). Study years begin in May and end in April of the following year, to coincide with the introduction of PCV13.
The rate of IPD in the adult population declined coinciding with the introduction of PCV13 (5.10-4.11 per 100,000) and continued through the year ending April 2013 (table 1). In 2014 an increase in incidence, mainly in non-PCV13 serotypes, was observed. The greatest increase from 2013 to 2014 was in individuals of Black race (10.38 per 100,000 in 2012 to 20.64 per 100,000 in 2013). In this group, the increase was observed in PCV7, PCV13, and non-PCV13 serotypes.
We observed increased IPD in adults in 2013-2014 after 2 consecutive years of decline following PCV13 introduction. Much of this increase was seen in individuals of Black race. Racial differences should be considered in policy decisions regarding use of the conjugated vaccine in adults.
Table. Rates of IPD in KPNC, 2008-2014, per 100,000. Serotype categories contain serotypes specific to the vaccines.
Year of PCV13 Introduction 5/10-4/11
IDWeek 2014 Meeting of the Infectious Diseases Society of America; 10/2014
[Show abstract][Hide abstract] ABSTRACT: Background: The identification of site specific genes and functions essential for virulence may provide further understanding of the pathogenesis of pneumococcal disease and potentially reveal novel targets for treatment and prevention.
Methods: We screened more than 10 selected serotypes of Streptococus pneumoniae in our chinchilla model of experimental otitis media (EOM), initially using nasopharyngeal inoculation followed by barotrauma and subsequently with direct intrabullar challenge. Genomic DNA of these isolates was extracted by standard methods and sequenced using the HiSeq Illumina platform. De novo assembled sequences were annotated with RAST (Rapid Annotation by Subsystem Technology). Functional comparative genomic analysis was performed in SEED viewer; genes of subsystems identified as uniquely absent in 33F strains underwent detailed analysis in SEED, BRIG and BLAST.
Results: The serotype 33F isolates colonized the nasopharynx comparable to all other serotypes but failed to produce either clinically apparent or culture-positive middle ear disease. The lack of virulence was confirmed by the failure to develop middle ear disease following direct intrabullar challenge as well as with 2 additional 33F isolates. Functional genomic comparison against OM producing strains as well as ~50 invasive strains revealed that all three 33F strains lack the pneumococcal serine-rich repeat protein (PsrP) pathogenicity island. The PsrP island appeared to be present in the sequenced IPD strains.
Conclusion: Serotype 33F failed to produce EOM using either NP colonization and barotrauma or direct inoculation. Comparative genomic analysis revealed the absence of the PsrP pathogenicity island in these strains. PsrP is a representative of serine-rich repeat proteins found in many pathogenic streptococci and Staphylococcus aureus. Although non-essential for survival, it plays an important role in the formation of biofilms and adhesion to host cells. Further characterization of the function of this island in S. pneumoniae is necessary to define its role in virulence both for middle ear infection as well as invasive disease and pneumonia.
IDWeek 2014 Meeting of the Infectious Diseases Society of America; 10/2014
[Show abstract][Hide abstract] ABSTRACT: Objective:
To examine whether there is a different clinical profile and severity of invasive pneumococcal disease (IPD) in children caused by nonvaccine types in the era of 13-valent pneumococcal conjugate vaccine (PCV13).
Observational study of childhood IPD in Massachusetts based on state public health surveillance data comparing pre-PCV13 (2007-2009) and post-PCV13 (2010-2012) eras.
There were 168 pre-PCV13 cases of IPD and 85 post-PCV13 cases of IPD in Massachusetts children ≤5 years of age. PCV13 serotypes declined by 18% in the first 2 years after PCV13 use (P = .011). In the post-PCV13 phase, a higher proportion of children were hospitalized (57.6% vs. 50.6%), and a higher proportion of children had comorbidity (23.5% vs. 19.6%). Neither difference was statistically significant, nor were comparisons of IPD caused by vaccine and nonvaccine types. Children with comorbidities had higher rates of IPD caused by a nonvaccine type (27.6% vs. 17.2%; P = .085), were more likely to be hospitalized (80.4% vs. 50%; P < .0001), and were more likely to have a longer hospital stay (median of 3 days vs. 0.5 days; P = .0001).
Initial data suggest that nonvaccine serotypes are more common in children with underlying conditions, who have greater morbidity from disease. In the post-PCV13 era, a larger proportion of patients are hospitalized, but mortality rates are unchanged. Routine vaccination with PCV13 may not be enough to reduce the risk in patients with comorbidity.
[Show abstract][Hide abstract] ABSTRACT: In the current era of universal immunization of young children with pneumococcal conjugate vaccine, it is unclear whether the high risk ratios for pneumococcal disease previously attributed to specified chronic conditions have persisted. In addition, further analysis of pneumococcal disease risk may clarify whether certain chronic conditions that currently are not specified as significantly increasing the risk of pneumococcal disease, should be so considered.
We conducted a retrospective cohort analysis utilizing healthcare claims data from 2007 - 2010 to compare rates of pneumococcal disease among children <5 and 5-17 years of age with high-risk and at-risk conditions to rates among children without these conditions in the same age group. Risk profiles and manifestations of pneumococcal infection were ascertained from diagnosis, procedure, and drug codes.
Among at-risk children, rate ratios for invasive pneumococcal disease (vs. children without at/high-risk conditions) were 1·8 (95% CI 1·4-2·3) in children <5 years of age and 3·3 (2·4-4·4) in children 5-17 years of age. Corresponding rate ratios for high-risk children were 11·2 (7·0-17·9) and 40·1 (28·8-56·0). Rate ratios increased in asthmatic children with increasing disease severity and in all at-risk children by the number of concurrent at-risk conditions. Rate ratios for pneumococcal pneumonia and all-cause pneumonia demonstrated similar patterns.
Children with high-risk and at-risk conditions continue to demonstrate an increased burden of pneumococcal disease. Pneumococcal disease rates are high among asthmatic children with moderate and severe disease and children with multiple at-risk conditions.
[Show abstract][Hide abstract] ABSTRACT: The direct impact of PCV13 on colonization with unique PCV13 serotypes and the uptake of vaccine necessary to create indirect protection in non-immunized children was assessed.
Carriage surveillance among children < 60 months began in July 2010 at a pediatric practice in Boston, MA. Children had NP cultures and parents completed questionnaires detailing demographics and health status. Concurrently, we monitored uptake of PCV13 in children in the community. Children were classified as 'presumed immune' or 'presumed non-immune' based on age and PCV13 immunizations received. We assessed trends using adjusted prevalence rates calculated within rolling, 25-week, consecutive intervals.
Between July 2010 and June 2012, 1050 SP were recovered from 1042 children. Eighty-nine isolates (8.5%) were one of 6 unique PCV13 serotypes. The expected fall/winter peak in PCV13 carriage was observed in non-immune children, but was blunted in immune children. There was a 74% reduction in PCV13 colonization in immune compared with non-immune children. We document a 50% or more decline in the PCV13 carriage in non-immune children, at the time when the approximately 75% or more of the community children had received PCV13 and were considered immune. During the study, the difference in PCV13 serotype colonization prevalence in non-immune and immune children disappeared. No evidence of replacement has been observed to date.
The direct impact of PCV13 on colonization was demonstrated. Evidence of indirect protection in unimmunized (non-immune) children was observed as vaccine uptake reached 75% in the target community.
[Show abstract][Hide abstract] ABSTRACT: Although it is widely accepted that adults with immunocompromising conditions are at greatly increased risk of pneumococcal infection, the extent of risk among immunocompetent adults with chronic medical conditions is less certain, particularly in the current era of universal vaccination of children with pneumococcal conjugate vaccines.
We conducted a retrospective cohort study using data from 3 healthcare claims repositories (2006-2010) to compare rates of pneumococcal disease in immunocompetent adults with chronic medical conditions ("at-risk") and immunocompromised adults ("high-risk"), with rates in adults without these conditions ("healthy"). Risk profiles and episodes of pneumococcal disease-all-cause pneumonia, pneumococcal pneumonia, and invasive pneumococcal disease (IPD)-were ascertained from diagnosis, procedure, and drug codes.
Rates of all-cause pneumonia among at-risk persons aged 18-49 years, 50-64 years, and ≥65 years were 3.2 (95% confidence interval [CI], 3.1-3.2), 3.1 (95% CI, 3.1-3.1), and 3.0 (95% CI, 3.0-3.0) times the rates in age-matched healthy counterparts, respectively. We identified rheumatoid arthritis, systemic lupus erythematosus, Crohn's disease, and neuromuscular or seizure disorders as additional at-risk conditions for pneumococcal disease. Among persons with at-risk conditions, the rate of all-cause pneumonia substantially increased with the accumulation of concurrent at-risk conditions (risk stacking): among persons 18-49 years, rate ratios increased from 2.5 (95% CI, 2.5-2.5) in those with 1 at-risk condition to 6.2 (95% CI, 6.1-6.3) in those with 2 conditions, and to 15.6 (95% CI, 15.3-16.0) in those with ≥3 conditions. Findings for pneumococcal pneumonia and IPD were similar.
Despite widespread use of pneumococcal conjugate vaccines, rates of pneumonia and IPD remain disproportionately high in adults with at-risk conditions, including those with conditions not currently included in the Advisory Committee on Immunization Practices' guidelines for prevention and those with multiple at-risk conditions.
[Show abstract][Hide abstract] ABSTRACT: In April 2010, a 13-valent pneumococcal conjugate vaccine (PCV13) replaced PCV7 for use in the United States. We evaluated rates of pneumococcal colonization, by serotype and antibiotic resistance, in Massachusetts communities where serial cross-sectional surveillance has been conducted for the past decade.
Nasopharyngeal swabs were obtained from children 0 to <7 years of age and seen by primary care providers for well child or acute illness visits in 2001, 2004, 2007, 2009, and 2011. Pneumococcal isolates were serotyped by Quellung reaction and classified as PCV7 serotypes (4, 6B, 9V, 14, 18C, 19F, 23F), additional PCV13 serotypes (1, 3, 5, 6A, 7F, 19A), or non-PCV13 serotypes. Changes in colonization and impact of PCV13 were assessed using generalized linear mixed models, adjusting for known risk factors and accounting for clustering by community.
Introduction of PCV13 did not affect the rate of overall pneumococcal colonization (31% in 2011). Colonization with non-PCV13 serotypes increased between 2001 and 2011 for all children (odds ratio [OR] per year, 1.12; 95% confidence interval [CI], 1.10, 1.15; P < .0001). 19A remained the second most common serotype in 2011, although a decline from 2009 was observed. Penicillin (7%), erythromycin (28%), ceftriaxone (10%), and clindamycin (10%) nonsusceptibility were commonly identified, concentrated among a small number of serotypes (including 19A, 35B, 15B/C, and 15A). Among healthy children 6-23 months old, colonization with PCV13 serotypes was lower among recipients of PCV13 vaccine (adjusted OR, 0.30; 95% CI, 0.11, 0.78). This effect was not observed in 6- to 23-month-old children with a concomitant respiratory tract infection (adjusted OR 1.36; 95% CI, 0.66, 2.77) or children 2 to <7 years old (adjusted OR, 1.17; 95% CI, 0.58, 2.34).
13-Valent pneumococcal conjugate vaccine reduced the prevalence of colonization with PCV13 serotypes among children 6-23 months old, but its efficacy was not shown among older children.
[Show abstract][Hide abstract] ABSTRACT: In February 2012, the Advisory Committee on Immunization Practices (ACIP) advised that all adults aged ≥65 years receive a single dose of reduced-antigen-content tetanus, diphtheria, and acellular pertussis (Tdap), expanding on a 2010 recommendation for adults >65 that was limited to those with close contact with infants. We evaluated clinical and economic outcomes of adding Tdap booster of adults aged ≥65 to "baseline" practice [full-strength DTaP administered from 2 months to 4-6 years, and one dose of Tdap at 11-64 years replacing decennial Td booster], using a dynamic model.
We constructed a population-level disease transmission model to evaluate the cost-effectiveness of supplementing baseline practice by vaccinating 10% of eligible adults aged ≥65 with Tdap replacing the decennial Td booster. US population effects, including indirect benefits accrued by unvaccinated persons, were estimated during a 1-year period after disease incidence reached a new steady state, with consequences of deaths and long-term pertussis sequelae projected over remaining lifetimes. Model outputs include: cases by severity, encephalopathy, deaths, costs (of vaccination and pertussis care) and quality-adjusted life-years (QALYs) associated with each strategy. Results in terms of incremental cost/QALY gained are presented from payer and societal perspectives. Sensitivity analyses vary key parameters within plausible ranges.
For the US population, the intervention is expected to prevent >97,000 cases (>4,000 severe and >5,000 among infants) of pertussis annually at steady state. Additional vaccination costs are $4.7 million. Net cost savings, including vaccination costs, are $47.7 million (societal perspective) and $44.8 million (payer perspective). From both perspectives, the intervention strategy is dominant (less costly, and more effective by >3,000 QALYs) versus baseline. Results are robust to sensitivity analyses and alternative scenarios.
Immunization of eligible adults aged ≥65, consistent with the current ACIP recommendation, is cost saving from both payer and societal perspectives.
PLoS ONE 01/2014; 9(1):e72723. DOI:10.1371/journal.pone.0072723 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The pneumococcal Pilus-1 enhances attachment to epithelial cells in the respiratory tract and subsequent invasion. Pilus-1 expression is bi-stable and positively regulated by the RlrA transcriptional regulator. To delineate the role of pilus-1 in Experimental Otitis Media (EOM), we evaluated colonization and disease due to a Streptococcus pneumoniae (SP) wild type strain (Taiwan19F-14 wt) and its otherwise isogenic pilus-1 and pilus-2 deficient mutant (Taiwan19F-14 ΔPI-1/PI-2-) as well as potential for a chimeric protein (RrgB321) vaccine candidate for prevention of middle ear (ME) disease.
Chinchillas were challenged intranasally with either Taiwan19F-14 wt or Taiwan19F-14PI-1/PI-2 deficient mutant. ME status was assessed and direct cultures performed. New cohorts of animals were immunized with RrgB321 or alum. Intranasal challenge with Taiwan19F-14 wt [erythromycin susceptible E(S)] was performed. Subsequently, a second cohort of animals was immunized and challenged with either Taiwan19F-14 wt or a Pilus-1 over-expressing mutant [Taiwan19F-14+pMU1328_Pc-rlrA mutant; E resistant (R)] strain. Pilus-1 expression was analyzed in SP isolated from nasopharynx (NP) and ME fluids by flow cytometry.
Culture positive EOM developed following challenge with either wild type SP (Taiwan19F-14) or its pilus-1 deficient mutant. Culture positive EOM developed following challenge with wild type in both RrgB321 immunized and control animals. Pilus-1 expression in ME fluids was significantly higher in controls compared to immunized chinchillas. In second cohort of immunized and control animals challenged with the over-expressing Pilus-1 mutant, delayed development of EOM in the immunized animals was observed. Pneumococci recovered from ME fluid of immunized animals were no longer E(R) signifying the loss of the pMU1328_Pc-rlrA plasmid.
Pneumococcal pilus-1 was not essential for EOM. Regulation of Pilus-1 expression in ME fluids in the presence of anti RrgB321 antibody was essential for survival of S. pneumoniae. Pneumococci have evolved mechanisms of regulation of non-essential surface proteins to evade host defenses.
PLoS ONE 01/2014; 9(1):e83798. DOI:10.1371/journal.pone.0083798 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: We hypothesized that capsular switch event, in which pneumococcus acquires a new capsule operon by horizontal gene transfer, may result in emergence of strains with increased virulence in acute otitis media. Using serotype 6A strain from a patient with invasive pneumococcal disease and clonally distant serotype 6C strain isolated from asymptomatic carrier we created 6A:6C (6A background with 6C capsule) capsular transformants and applied whole genome macro-restriction analysis to assess conservation of the 6A chassis. Next, we assessed complement (C3) and antibodies deposition on surface of peumococcal cells and tested capsule recipient, capsule donor and two 6A:6C transformants for virulence in chinchilla experimental otitis media model. Both 6A:6C(1or2) transformants bound less C3 compared to 6C capsule-donor strain but more compared to serotype 6A capsule-recipient strain. Pneumococci were present in significantly higher proportion of ears among animals challenged with either of two 6A:6C(1 or 2) transformants compared to chinchillas infected with 6C capsule-donor strain [p<0.001] whereas a significantly decreased proportion of ears were infected with 6A:6C(1or 2) transformants as compared to 6A capsule-recipient strain. Our observations though limited to two serotypes demonstrate that capsular switch events can result in S. pneumoniae strains of enhanced virulence for respiratory tract infection.
Microbes and Infection 12/2013; 16(4). DOI:10.1016/j.micinf.2013.12.002 · 2.86 Impact Factor