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1.  Stability of the pneumococcal population structure in Massachusetts as PCV13 was introduced 
Background
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.
Methods
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.
Results
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.
Conclusions
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.
Electronic supplementary material
The online version of this article (doi:10.1186/s12879-015-0797-z) contains supplementary material, which is available to authorized users.
doi:10.1186/s12879-015-0797-z
PMCID: PMC4336693
Pneumococcal conjugate vaccine; Streptococcus pneumoniae; Colonization; Molecular epidemiology; MLST
2.  Panel 6: Vaccines 
Objective
To update progress on the effectiveness of vaccine for prevention of acute otitis media (AOM) and identification of promising candidate antigens against Streptococcus pneumoniae, nontypeable Haemophilus influenzae, and Moraxella catarrhalis.
Review Methods
Literature searches were performed in OvidSP and PubMed restricted to articles published between June 2007 and September 2011. Search terms included otitis media, vaccines, vaccine antigens, and each of the otitis pathogens and candidate antigens identified in the ninth conference report.
Conclusions
The current report provides further evidence for the effectiveness of pneumococcal conjugate vaccines (PCVs) in the prevention of otitis media. Observational studies demonstrate a greater decline in AOM episodes than reported in clinical efficacy trials. Unmet challenges include extending protection to additional serotypes and additional pathogens, the need to prevent early episodes, the development of correlates of protection for protein antigens, and the need to define where an otitis media vaccine strategy fits with priorities for child health.
Implications for Practice
Acute otitis media continues to be a burden on children and families, especially those who suffer from frequent recurrences. The 7-valent PCV (PCV7) has reduced the burden of disease as well as shifted the pneumococcal serotypes and the distribution of otopathogens currently reported in children with AOM. Antibiotic resistance remains an ongoing challenge. Multiple candidate antigens have demonstrated the necessary requirements of conservation, surface exposure, immunogenicity, and protection in animal models. Further research on the role of each antigen in pathogenesis, in the development of correlates of protection in animal models, and in new adjuvants to elicit responses in the youngest infants is likely to be productive and permit more antigens to move into human clinical trials.
doi:10.1177/0194599812466535
PMCID: PMC4029613  PMID: 23536534
otitis media; vaccines; vaccine antigens; otitis pathogens; candidate antigens
3.  Using Pneumococcal Carriage Data to Monitor Postvaccination Changes in Invasive Disease 
American Journal of Epidemiology  2013;178(9):1488-1495.
Pneumococcal conjugate vaccines (PCVs) have been introduced worldwide. However, few developing countries have high-quality surveillance systems available for monitoring vaccine impact. We evaluated whether data from nasopharyngeal carriage studies can be used to accurately monitor post-PCV changes in the incidence of invasive pneumococcal disease (IPD) among children under 5 years of age. For various dates during 1991–2010, data on nasopharyngeal pneumococcal carriage and on IPD before and after administration of 7-valent PCV (PCV7) were available from England and Wales, the Netherlands, the Navajo and White Mountain Apache American Indian populations, and the US states of Massachusetts and Alaska. We estimated the change in carriage prevalence for each serotype in each study and then either calculated the average change (inverse variance-weighted) among vaccine and nonvaccine serotypes (model 1) or used mixed-effects models to estimate the change for each serotype individually, pooling serotype data within or between studies (models 2 and 3). We then multiplied these values by the proportion of IPD caused by each serotype during the pre-PCV7 period to obtain an estimate of post-PCV7 disease incidence. Model 1 accurately captured overall changes in IPD incidence following PCV7 introduction for most studies, while the more detailed models, models 2 and 3, were less accurate. Carriage data can be used in this simple model to estimate post-PCV changes in IPD incidence.
doi:10.1093/aje/kwt156
PMCID: PMC3813314  PMID: 24013204
carriage; conjugate vaccine, pneumococcal; pneumococcus; surveillance; vaccine effectiveness; vaccines
4.  Antibody Persistence and Immunologic Memory after Sequential Pneumococcal Conjugate and Polysaccharide Vaccination in HIV-Infected Children on Highly Active Antiretroviral Therapy 
Vaccine  2013;31(42):10.1016/j.vaccine.2013.08.002.
Background
The capacity of pneumococcal vaccination to confer memory in HIV-infected children is critical for durable protection.
Methods
HIV-infected children 2–<19 years administered two doses of pneumococcal conjugate vaccine (PCV7) and one dose of polysaccharide vaccine (PPV) on HAART were randomized four-five years later to receive a PCV7 or PPV booster. Total and high avidity antibodies to serotypes 1 (PPV) and 6B and 14 (PCV7 and PPV) were determined by ELISA. Memory was defined as persistence of ≥0.5 mcg/mL of serotype-specific antibody on day 0 or change from <0.5 mcg/mL to ≥0.5 mcg/mL between day 0 and week 1, or, ≥4-fold antibody rise between day 0 and week 1.
Results
Prior to boosting, four to five years after the previous PCV7-PCV7-PPV series, geometric mean concentrations (GMCs) were 0.46 mcg/mL (serotype 1), 1.31 mcg/mL (serotype 6B), and 1.47 mcg/mL (serotype 14), with concentrations ≥0.5 mcg/mL in 41% (serotype 1) to 82% (serotypes 6B and 14). Memory based on antibody concentration ≥0.5 mcg/mL before or 1 week after boosting with PCV7 or PPV was demonstrated in 42–61% for serotype 1 and 87–94% for serotypes 6B and 14, with lower rates based on day 0 to week 1 ≥4-fold antibody rise (serotype 1, 3–13%; serotype 6B, 13–31%; serotype 14, 29–53%). Antibody concentrations post-boosting were greater following PCV7 than PPV for serotypes 6B and 14. Ratios of highly avid to total antibody pre- and post-boosting were 0.5–0.8. Predictors of memory included higher CD4% (nadir before HAART and at P1024 and P1061s entry), CD19% (at P1024 and P1061s entry), and antibody response after the PCV7-PCV7-PPV primary series and lower viral load (at P1024 and P1061s entry) and age.
Conclusions
Protective antibody concentrations, high avidity, and booster responses to PCV7 or PPV indicative of memory were present four-five years after PCV7-PCV7-PPV in HIV-infected children on HAART.
doi:10.1016/j.vaccine.2013.08.002
PMCID: PMC3825555  PMID: 23954381
pneumococcal; vaccine; memory; HIV; children
5.  Differential Effects of Pneumococcal Vaccines against Serotypes 6A and 6C 
The Journal of infectious diseases  2008;198(12):1818-1822.
Background
Because classical pneumococcal serotyping cannot distinguish between serotypes 6A and 6C, the effects of pneumococcal vaccines against serotype 6C are unknown. Pneumococcal vaccines contain 6B, but do not contain 6A and 6C.
Methods
We used a phagocytic killing assay to estimate the immunogenicity of 7-valent conjugate vaccine (PCV7) in children and 23-valent polysaccharide vaccine (PPV23) in adults against serotypes 6A and 6C. We evaluated trends in invasive pneumococcal disease (IPD) caused by serotypes 6A and 6C using active surveillance in the U.S.
Results
Sera from PCV7-immunized children had median opsonization indices of 150 and <20 for serotypes 6A and 6C, respectively. Similarly, only 52% (25/48) of adults vaccinated with PPV23 showed opsonic indices greater than 20 against serotype 6C. During 1999–2006, the incidence (cases per 100,000) of serotype 6A IPD declined from 4.9 to 0.46 (−91%, P<0.05) among children aged <5 years, and from 0.86 to 0.36 (−58%, P<0.05) among persons aged ≥5 years. Although incidence of 6C IPD showed no consistent trend (range 0–0.6) among <5 year-olds, it increased from 0.25 to 0.62 (P<0.05) among persons aged ≥5 years.
Conclusions
PCV7 introduction has led to reductions in serotype 6A IPD, but not serotype 6C IPD in the U.S.
doi:10.1086/593339
PMCID: PMC4159939  PMID: 18983249
Pneumococcus; vaccine; cross-protection; serotype; herd immunity
6.  Regulation of bacterial trafficking in the nasopharynx 
Paediatric Respiratory Reviews  2012;13(3):150-153.
Summary
Bacterial ‘colonisation’ of the nasopharynx by potential bacterial pathogens in early childhood is a normal, important series of events. They are part of a dynamic process in which the microbiota of the upper airways becomes established and evolves in early childhood. The potential pathogens ‘colonising’ the upper airways interact with resident, apparently non-pathogenic, bacteria; other potential pathogens including those from their own species; viruses and the hosts immune response. Environmental factors such as family dynamics, child care, antibiotic usage, smoking and indeed vaccines all have an impact. Understanding the significant of potential beneficial interactions as well as those factors that are detrimental to the host will be important in disease prevention in the future.
doi:10.1016/j.prrv.2012.04.001
PMCID: PMC3383606  PMID: 22726870
Streptococcus pneumoniae; Haemophilus influenzae; Microbial populations; Bacterial interference; Bacterial competition; commensals
7.  A Second Generation Pneumococcal Conjugate Vaccine for Prevention of Pneumococcal Diseases in Children 
Current Opinion in Pediatrics  2011;23(1):98-104.
Purpose
A second generation 13 valent pneumococcal conjugate vaccine (PCV13) was licensed and recommended for universal immunization of children through age five years in 2010. Its introduction is intended to address the residual burden of pneumococcal diseases that persists a decade after the introduction of PCV7.
Recent Findings
Immunization with PCV7 has resulted in a substantial decline in pneumococcal diseases caused by vaccine serotypes in both vaccinated and unvaccinated persons in the US. However an increase in disease due to non vaccine serotypes, including empyema; the emergence of multidrug, including ceftriaxone, resistant serotype 19A strains; and the need for broader serotype coverage to address the global disease burden provides a rationale for a second generation conjugate vaccine that includes serotypes 1, 3, 5, 6A, 7F and 19A.
Summary
This article reviews the lessons learned from a decade of experience with PCV7, the increasing problem of disease due to non-vaccine serotypes, and the likelihood of PCV13 to impact the residual disease burden. We contrast the potential differences in prevention of invasive pneumococcal disease (IPD) compared to nonbacteremic pneumonia and acute otitis media. We conclude with the current recommendations for PCV13 providing a rationale for immunization through age 5 years to create both direct and indirect protection in the population.
doi:10.1097/MOP.0b013e328341d1f5
PMCID: PMC3357900  PMID: 21191300
Pneumococcal disease; Conjugate vaccine; Nonvaccine serotypes; AAP recommendations; Catch up regimen
8.  Cost-Effectiveness of Tdap Vaccination of Adults Aged ≥65 Years in the Prevention of Pertussis in the US: A Dynamic Model of Disease Transmission 
PLoS ONE  2014;9(1):e72723.
Objectives
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.
Methods
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.
Results
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.
Conclusions
Immunization of eligible adults aged ≥65, consistent with the current ACIP recommendation, is cost saving from both payer and societal perspectives.
doi:10.1371/journal.pone.0072723
PMCID: PMC3886978  PMID: 24416118
9.  Variation of Pneumococcal Pilus-1 Expression Results in Vaccine Escape during Experimental Otitis Media [EOM] 
PLoS ONE  2014;9(1):e83798.
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.
Methods
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.
Results
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.
Conclusion
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.
doi:10.1371/journal.pone.0083798
PMCID: PMC3885439  PMID: 24421906
11.  Population genomics of post-vaccine changes in pneumococcal epidemiology 
Nature genetics  2013;45(6):10.1038/ng.2625.
Whole genome sequencing of 616 asymptomatically carried pneumococci was used to study the impact of the 7-valent pneumococcal conjugate vaccine. Comparison of closely related isolates revealed the role of transformation in facilitating capsule switching to non-vaccine serotypes and the emergence of drug resistance. However, such recombination was found to occur at significantly different rates across the species, and the evolution of the population was primarily driven by changes in the frequency of distinct genotypes extant pre-vaccine. These alterations resulted in little overall effect on accessory genome composition at the population level, contrasting with the fall in pneumococcal disease rates after the vaccine’s introduction.
doi:10.1038/ng.2625
PMCID: PMC3725542  PMID: 23644493
12.  Population genomics of post-vaccine changes in pneumococcal epidemiology 
Nature genetics  2013;45(6):10.1038/ng.2625.
Whole genome sequencing of 616 asymptomatically carried pneumococci was used to study the impact of the 7-valent pneumococcal conjugate vaccine. Comparison of closely related isolates revealed the role of transformation in facilitating capsule switching to non-vaccine serotypes and the emergence of drug resistance. However, such recombination was found to occur at significantly different rates across the species, and the evolution of the population was primarily driven by changes in the frequency of distinct genotypes extant pre-vaccine. These alterations resulted in little overall effect on accessory genome composition at the population level, contrasting with the fall in pneumococcal disease rates after the vaccine’s introduction.
doi:10.1038/ng.2625
PMCID: PMC3725542  PMID: 23644493
13.  Cost-Effectiveness Analysis of Tdap in the Prevention of Pertussis in the Elderly 
PLoS ONE  2013;8(9):e67260.
Objectives
Health benefits and costs of combined reduced-antigen-content tetanus, diphtheria, and pertussis (Tdap) immunization among adults ≥65 years have not been evaluated. In February 2012, the Advisory Committee on Immunization Practices (ACIP) recommended expanding Tdap vaccination (one single dose) to include adults ≥65 years not previously vaccinated with Tdap. Our study estimated the health and economic outcomes of one-time replacement of the decennial tetanus and diphtheria (Td) booster with Tdap in the 10% of individuals aged 65 years assumed eligible each year compared with a baseline scenario of continued Td vaccination.
Methods
We constructed a model evaluating the cost-effectiveness of vaccinating a cohort of adults aged 65 with Tdap, by calculating pertussis cases averted due to direct vaccine effects only. Results are presented from societal and payer perspectives for a range of pertussis incidences (25–200 cases per 100,000), due to the uncertainty in estimating true annual incidence. Cases averted were accrued throughout the patient 's lifetime, and a probability tree used to estimate the clinical outcomes and costs (US$ 2010) for each case. Quality-adjusted life-years (QALYs) lost to acute disease were calculated by multiplying cases of mild/moderate/severe pertussis by the associated health-state disutility; QALY losses due to death and long-term sequelae were also considered. Incremental costs and QALYs were summed over the cohort to derive incremental cost-effectiveness ratios. Scenario analyses evaluated the effect of alternative plausible parameter estimates on results.
Results
At incidence levels of 25, 100, 200 cases/100,000, vaccinating adults aged 65 years costs an additional $336,000, $63,000 and $17,000/QALY gained, respectively. Vaccination has a cost-effectiveness ratio less than $50,000/QALY if pertussis incidence is >116 cases/100,000 from societal and payer perspectives. Results were robust to scenario analyses.
Conclusions
Tdap immunization of adults aged 65 years according to current ACIP recommendations is a cost-effective health-care intervention at plausible incidence assumptions.
doi:10.1371/journal.pone.0067260
PMCID: PMC3760878  PMID: 24019859
14.  Immunogenicity, Immunologic Memory, and Safety Following Measles Revaccination in HIV-Infected Children Receiving Highly Active Antiretroviral Therapy 
The Journal of Infectious Diseases  2012;206(4):512-522.
Background. Response rates and immunologic memory following measles vaccination are reduced in human immunodeficiency virus (HIV)–infected children in the absence of highly active antiretroviral therapy (HAART).
Methods. HIV-infected children 2 to <19 years old receiving HAART and with HIV loads <30 000 copies/mL, CD4% ≥15, and ≥1 prior measles-mumps-rubella vaccination (MMR) were given another MMR. Measles antibody concentrations before and 8, 32, and 80 weeks postvaccination were determined by plaque reduction neutralization (PRN). A subset was given another MMR 4–5 years later, and PRN antibody was measured before and 7 and 28 days later.
Results. At entry, 52% of 193 subjects were seroprotected (PRN ≥120 mIU/mL). Seroprotection increased to 89% 8 weeks postvaccination, and remained at 80% 80 weeks postvaccination. Of 65 subjects revaccinated 4–5 years later, 85% demonstrated memory based on seroprotection before or 7 days after vaccination. HIV load ≤400 copies/mL at initial study vaccination was associated with higher seroprotection rates, greater antibody concentrations, and memory. Grade 3 fever or fatigue occurred in 2% of subjects.
Conclusions. Measles revaccination induced high rates of seroprotection and memory in children receiving HAART. Both endpoints were associated with HIV viral load suppression.
Clinical Trials Registration: NCT00013871 (www.clinicaltrials.gov).
doi:10.1093/infdis/jis386
PMCID: PMC3491735  PMID: 22693229
15.  Virulence of Streptococcus pneumoniae serotype 6C in experimental otitis media 
Increases in colonization with serotypes of Streptococcus pneumoniae not contained within the 7-valent pneumococcal conjugate vaccine (PCV) have been reported among children following introduction. Serotype 6C has emerged as prevalent in nasopharyngeal colonization and acute otitis media (AOM), though it is uncommonly recovered from children with invasive pneumococcal disease. Vaccine serotypes within PCV7 have been replaced by nonvaccine serotypes without significant changes in the overall carriage rate. We hypothesize 1) that serotypes vary in their ability to evade host defenses and establish AOM following colonization and 2) the observed reduction in pneumococcal otitis results from a reduced disease potential by some ‘replacement serotypes’. We compared the capacity of S. pneumoniae serotypes 6C and 19A to produce experimental otitis media (EOM) in a chinchilla model. The proportion of chinchillas that developed culture positive EOM and density of middle ear infection was evaluated. EOM was found in 28/82 (34%) ears challenged with 6C compared to 13/18(72.2%) with 19A [p=0.0003]. When disease due to 6C did occur, it was characterized by lowdensity infection. Our findings demonstrate that challenge with serotype 6C results in EOM less frequently than 19A. These data support the need for greater knowledge regarding differences among serotypes to produce AOM.
doi:10.1016/j.micinf.2012.02.008
PMCID: PMC3382049  PMID: 22414497
Streptococcus pneumoniae; complement; virulence
16.  Differential Occurrence of Streptococcus pneumoniae Serotype 11E Between Asymptomatic Carriage and Invasive Pneumococcal Disease Isolates Reflects a Unique Model of Pathogen Microevolution 
Streptococcus pneumoniae strains expressing serotype 11E commonly occur among disease isolates, rarely occur among carriage isolates, and are clonally unrelated. Thus, 11E strains seem to have emerged after dissemination of serotype 11A progenitors to deeper tissues outside the nasopharynx.
Background. Streptococcus pneumoniae is a commensal colonizer of the human nasopharynx (NP) that causes disease after evasion of host defenses and dissemination. Pneumococcal strains expressing the newly identified serotype 11E arise from antigenically similar 11A progenitors by genetic inactivation of the O-acetyltransferase gene wcjE. Each 11E strain contains a distinct mutation to wcjE, suggesting that 11E strains are not transmitted among hosts despite their recovery from multiple patients with pneumococcal disease. We investigated whether the presumed lack of transmission of serotype 11E is consistent with its inability to survive in the NP.
Methods. More than 400 pneumococcal carriage, middle ear, conjunctiva, and blood isolates, serotyped as 11A by Quellung reaction, were reexamined for reactivity to 11A- and 11E-specific antibodies. We confirmed serotyping of isolates with sequencing of wcjE alleles.
Results. Serotype 11E strains were statistically more likely to occur among blood (4 of 15), conjunctiva (1 of 14), or middle ear (2 of 21) isolates than among carriage isolates (2 of 355). All 11E isolates contained unique mutations that putatively decrease wcjE expression.
Conclusions. The lack of a circulating 11E clone and the increased occurrence of 11E strains among disease isolates supports the idea that serotype 11E independently arises during infection after initial colonization with a serotype 11A progenitor. Factors encountered in the NP likely contribute to relative rarity of 11E among carriage isolates, whereas selective pressures in deeper tissues possibly promote 11E emergence. These findings illustrate a novel model of microevolution that transpires during the span of a single encounter with serotype 11A, highlighting the adaptability of bacterial pathogens within hosts.
doi:10.1093/cid/cir953
PMCID: PMC3284216  PMID: 22267713
17.  Pneumococcal Carriage and Antibiotic Resistance in Young Children before 13-Valent Conjugate Vaccine 
Background
We sought to measure trends in Streptococcus pneumoniae (SP) carriage and antibiotic resistance in young children in Massachusetts communities after widespread adoption of heptavalent pneumococcal conjugate vaccine (PCV7) and before the introduction of the 13-valent pneumococcal conjugate vaccine (PCV13).
Methods
We conducted a cross-sectional study including collection of questionnaire data and nasopharyngeal specimens among children <7 years in primary care practices from 8 Massachusetts communities during the winter season of 2008–9 and compared with to similar studies performed in 2001, 2003–4, and 2006–7. Antimicrobial susceptibility testing and serotyping were performed on pneumococcal isolates, and risk factors for colonization in recent seasons (2006–07 and 2008–09) were evaluated.
Results
We collected nasopharyngeal specimens from 1,011 children, 290 (29%) of whom were colonized with pneumococcus. Non-PCV7 serotypes accounted for 98% of pneumococcal isolates, most commonly 19A (14%), 6C (11%), and 15B/C (11%). In 2008–09, newly-targeted PCV13 serotypes accounted for 20% of carriage isolates and 41% of penicillin non-susceptible S. pneumoniae (PNSP). In multivariate models, younger age, child care, young siblings, and upper respiratory illness remained predictors of pneumococcal carriage, despite near-complete serotype replacement. Only young age and child care were significantly associated with PNSP carriage.
Conclusions
Serotype replacement post-PCV7 is essentially complete and has been sustained in young children, with the relatively virulent 19A being the most common serotype. Predictors of carriage remained similar despite serotype replacement. PCV13 may reduce 19A and decrease antibiotic-resistant strains, but monitoring for new serotype replacement is warranted.
doi:10.1097/INF.0b013e31824214ac
PMCID: PMC3288953  PMID: 22173142
Streptococcus pneumoniae; pneumococcal conjugate vaccine; antibiotic resistance; serotype; colonization
18.  Prevalence and Genetic Diversity of Nontypeable Haemophilus influenzae in the Respiratory Tract of Infants and Primary Caregivers 
BACKGROUND
Nontypeable Haemophilus influenzae (NTHi) causes otitis media, sinusitis, and likely lower respiratory tract infections in children. Colonization, strain diversity, transmission, and antimicrobial susceptibility have implications for both children and their caregivers.
METHODS
For 13 months, we conducted a cross-sectional study of NTHi colonization. 273 infants and children aged 2 to 26 months old and their primary caregivers had upper respiratory tract cultures performed. NTHi isolates were characterized by multilocus sequence typing (MLST) and antibiotic resistance was examined.
RESULTS
Of the 273 infants, 44 (16.1%) were colonized with NTHi. Prevalence of NTHi varied from 14% in infants less than 6 months of age to 32% in infants 19-26 months of age (p=0.003). NTHi colonized infants were more likely to attend daycare (30% vs. 11%), have a recent respiratory infection (68% vs. 38%), recent antibiotic use (27% vs. 9%), and caregiver reported asthma (11% vs. 1%) compared with other infants (p<0.001). Of the 44 infants colonized with NTHi, we identified 33 different MLSTs. Nine (20.5%) of the 44 infant-primary caregiver dyads were colonized with NTHi and 7/9 shared identical NTHi strains. We also found beta-lactamase negative NTHi with minimum inhibitory concentrations >2 μg/mL for amoxicillin and beta-lactamase positive NTHi with minimum inhibitory concentrations >2 μg/mL for amoxicillin clavulanate.
CONCLUSIONS
We found substantial diversity by MLST analysis among NTHi isolates from this community. Infant-primary caregiver dyads usually carried the same strain of NTHi, suggesting that infant-primary caregiver transmission is occurring.
doi:10.1097/INF.0b013e31823aaeb3
PMCID: PMC3261374  PMID: 22051860
Nontypeable Haemophilus influenzae; multilocus sequence typing; prevalence; diversity; transmission
19.  Hepatocyte-specific mutation of both NF-κB RelA and STAT3 abrogates the acute phase response in mice  
The Journal of Clinical Investigation  2012;122(5):1758-1763.
The acute phase response is an evolutionarily conserved reaction in which physiological stress triggers the liver to remodel the blood proteome. Although thought to be involved in immune defense, the net biological effect of the acute phase response remains unknown. As the acute phase response is stimulated by diverse cytokines that activate either NF-κB or STAT3, we hypothesized that it could be eliminated by hepatocyte-specific interruption of both transcription factors. Here, we report that the elimination in mice of both NF-κB p65 (RelA) and STAT3, but neither alone, abrogated all acute phase responses measured. The failure to respond was consistent across multiple different infectious, inflammatory, and noxious stimuli, including pneumococcal pneumonia. When the effects of infection were analyzed in detail, pneumococcal pneumonia was found to alter the expression of over a thousand transcripts in the liver. This outcome was inhibited by the combined loss of RelA and STAT3. Moreover, this interruption of the acute phase response increased mortality and exacerbated bacterial dissemination during pneumonia, possibly as a result of acute humoral enhancement of macrophage opsonophagocytosis, which was impaired in the mutant mice. Thus, we conclude that RelA and STAT3 are essential for stress-induced transcriptional remodeling in the liver and the subsequent activation of the acute phase response, whose functional role includes compartmentalization of local infection.
doi:10.1172/JCI59408
PMCID: PMC3336975  PMID: 22466650
20.  Carried Pneumococci in Massachusetts Children; The Contribution of Clonal Expansion and Serotype Switching 
doi:10.1097/INF.0b013e318201a154
PMCID: PMC3175614  PMID: 21085049
MLST; conjugate vaccination; Streptococcus pneumoniae; nasopharyngeal carriage
21.  RE-EMERGENCE OF THE TYPE 1 PILUS AMONG STREPTOCOCCUS PNEUMONIAE ISOLATES IN MASSACHUSETTS, USA 
Vaccine  2010;28(30):4842-4846.
Pneumococcal type 1 pilus proteins have been proposed as potential vaccine candidates. Following conjugate pneumococcal vaccination, the prevalence of the pneumococcal type 1 pilus declined dramatically, a decline associated with the elimination of vaccine-type (VT) strains. Here we show that between 2004 and 2007, there has been a significant increase in pilus prevalence, now exceeding rates from the pre-conjugate vaccine era. This increase is primarily due to non-VT strains. These emerging piliated non-VT strains are mostly novel clones, with some exceptions. The rise in pilus type 1 frequency across multiple distinct genetic backgrounds suggests that the pilus may confer an intrinsic advantage.
doi:10.1016/j.vaccine.2010.04.042
PMCID: PMC2897942  PMID: 20434550
S. pneumoniae pilus; PCV7; vaccine- and non-vaccine-types
22.  Evidence that pneumococcal serotype replacement in Massachusetts following conjugate vaccination is now complete 
Epidemics  2010;2(2):80-84.
Invasive pneumococcal disease (IPD) has been reduced in the US following conjugate vaccination (PCV7) targeting seven pneumococcal serotypes in 2000. However, increases in IPD due to other serotypes have been observed, in particular 19A. How much this “serotype replacement” will erode the benefits of vaccination and over what timescale is unknown. We used a population genetic approach to test first whether the selective impact of vaccination could be detected in a longitudinal carriage sample, and secondly how long it persisted for following introduction of vaccine in 2000. To detect the selective impact of the vaccine we compared the serotype diversity of samples from pneumococcal carriage in Massachusetts children collected in 2001, 2004 and 2007 with others collected in the pre-vaccine era in Massachusetts, the UK and Finland. The 2004 sample was significantly (p >0.0001) more diverse than pre-vaccine samples, indicating the selective pressure of vaccination. The 2007 sample showed no significant difference in diversity from the pre-vaccine period, and exhibited similar population structure, but with different serotypes. In 2007 the carriage frequency of 19A was similar to that of the most common serotype in pre-vaccine samples. We suggest that serotype replacement involving 19A may be complete in Massachusetts due to similarities in population structure to pre-vaccine samples. These results suggest that the replacement phenomenon occurs rapidly with high vaccine coverage, and may allay concerns about future increases in disease due to 19A. For other serotypes, the future course of replacement disease remains to be determined.
doi:10.1016/j.epidem.2010.03.005
PMCID: PMC2963072  PMID: 21031138
Streptococcus pneumoniae; Infectious disease epidemiology; Nasopharyngeal carriage; Population genetics
24.  Streptococcus pneumoniae Clonal Complex 199: Genetic Diversity and Tissue-Specific Virulence 
PLoS ONE  2011;6(4):e18649.
Streptococcus pneumoniae is an important cause of otitis media and invasive disease. Since introduction of the heptavalent pneumococcal conjugate vaccine, there has been an increase in replacement disease due to serotype 19A clonal complex (CC)199 isolates. The goals of this study were to 1) describe genetic diversity among nineteen CC199 isolates from carriage, middle ear, blood, and cerebrospinal fluid, 2) compare CC199 19A (n = 3) and 15B/C (n = 2) isolates in the chinchilla model for pneumococcal disease, and 3) identify accessory genes associated with tissue-specific disease among a larger collection of S. pneumoniae isolates. CC199 isolates were analyzed by comparative genome hybridization. One hundred and twenty-seven genes were variably present. The CC199 phylogeny split into two main clades, one comprised predominantly of carriage isolates and another of disease isolates. Ability to colonize and cause disease did not differ by serotype in the chinchilla model. However, isolates from the disease clade were associated with faster time to bacteremia compared to carriage clade isolates. One 19A isolate exhibited hypervirulence. Twelve tissue-specific genes/regions were identified by correspondence analysis. After screening a diverse collection of 326 isolates, spr0282 was associated with carriage. Four genes/regions, SP0163, SP0463, SPN05002 and RD8a were associated with middle ear isolates. SPN05002 also associated with blood and CSF, while RD8a associated with blood isolates. The hypervirulent isolate's genome was sequenced using the Solexa paired-end sequencing platform and compared to that of a reference serotype 19A isolate, revealing the presence of a novel 20 kb region with sequence similarity to bacteriophage genes. Genetic factors other than serotype may modulate virulence potential in CC199. These studies have implications for the long-term effectiveness of conjugate vaccines. Ideally, future vaccines would target common proteins to effectively reduce carriage and disease in the vaccinated population.
doi:10.1371/journal.pone.0018649
PMCID: PMC3077395  PMID: 21533186
25.  Capacity of serotype 19A and 15B/C Streptococcus pneumoniae isolates for experimental otitis media: implications for the conjugate vaccine 
Vaccine  2010;28(12):2450-2457.
Non-vaccine Streptococcus pneumoniae serotypes are increasingly associated with disease. We evaluated isolates of the same sequence type (ST199) but different serotype (15B/C, 19A) for growth in vitro, and pathogenic potential in a chinchilla otitis media model. We also developed a qPCR assay to quantitatively assess each isolate, circumventing the need for selectable markers. In vitro studies showed faster growth of serotype 19A over 15B/C. Both were equally capable of colonization and middle ear infection in this model. Serotype 19A is included in new conjugate vaccine formulations while serotype 15B/C is not. Non-capsular vaccine targets will be important in disease prevention efforts.
doi:10.1016/j.vaccine.2009.12.078
PMCID: PMC2851619  PMID: 20067753
Streptococcus pneumoniae; conjugate vaccine; qPCR assay

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