Systematic Review of the Effect of Pneumococcal Conjugate Vaccine Dosing Schedules on Vaccine-type Nasopharyngeal Carriage

Pneumococcal conjugate vaccines (PCV) reduce nasopharyngeal carriage of vaccine type (VT) pneumococci, an important driver of vaccine programs’ overall benefits. The dosing schedule that best reduces carriage is unclear.  We performed a systematic review of English language publications from 1994 to 2010 (supplemented post hoc with studies from 2011) reporting PCV effects on VT carriage to assess variability in effect by dosing schedule.  We identified 32 relevant studies (36 citations) from 12,980 citations reviewed. Twenty-one (66%) evaluated PCV7; none used PCV10 or PCV13. Five studies evaluated 2 primary doses and 13 three primary doses. After the first year of life, 14 evaluated 3-dose primary series with PCV booster (3+1), seven 3 doses plus 23-valent polysaccharide booster “3+1PPV23,” five “3+0,” four “2+1,” three “2+1PPV23” and two “2+0.” Four studies directly compared schedules. From these, 3 primary doses reduced VT carriage more than 2 doses at 1–7 months following the series (1 study significant; 2 borderline). In a study, the 2+1 schedule reduced VT carriage more than 2+0 at 18, but not at 24 months of age. One study of a 23-valent pneumococcal polysaccharide vaccine booster showed no effect. All 16 clinical trials with unvaccinated controls and 11 observational studies with before-after designs showed reduction in VT carriage.  The available literature demonstrates VT-carriage reduction for 2+0, 2+1, 3+0 and 3+1 PCV schedules, but not for 23-valent pneumococcal polysaccharide vaccine booster. Comparisons between schedules show that 3 primary doses and a 2+1 schedule may reduce carriage more than 2 primary doses and a 2+0 schedule, respectively.

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title: Report from a WHO working group: standard method for detecting upper respiratory carriage of Streptococcus pneumoniae
abstract: Numerousstudies evaluating the efficacy of conjugate pneumococcal vaccines are being conducted or planned throughout the world. Some of these studies are evaluating the effect of vaccine on nasopharyngeal (NP) carriage.  The World Health Organization established a Working Group composed of representatives from these trials and other NP colonization experts to establish core, standardized methods for the study of pneumococcal NP colonization that could be used in these trials. The intent was to reduce or eliminate variability in key methods which themselves could contribute to variability of observed pneumococcal NP colonization. In this way variability of vaccine effects between trials on NP colonization could more easily be analyzed for population or vaccine differences without the confounding effect caused by differences in study methodology.  This paper presents the evidence base supporting the need for standardized NP colonization study methods, the methods themselves (Core Consensus Methods found in the electronic version of this article at www.pidj.com and on the WHO website at http://www.who.int/vaccines-research/rd/docsrd.shtml), including collection techniques, culture media, equipment, serotyping, storage of specimens and transport of isolates agreed on by the Working Group as well as a discussion of research priorities.  The Core Consensus Methods provide a common methodology to conduct pneumococcal NP colonization studies with minimum interstudy method variability. The intention is to allow more meaningful comparisons of study results from conjugate pneumococcal vaccine trials.

title: Streptococcus pneumoniae colonisation: the key to pneumococcal disease.
abstract: Streptococcus pneumoniae is an important pathogen causing invasive diseases such as sepsis, meningitis, and pneumonia. The burden of disease is highest in the youngest and oldest sections of the population in both more and less developed countries. The treatment of pneumococcal infections is complicated by the worldwide emergence in pneumococci of resistance to penicillin and other antibiotics. Pneumococcal disease is preceded by asymptomatic colonisation, which is especially high in children. The current seven-valent conjugate vaccine is highly effective against invasive disease caused by the vaccine-type strains. However, vaccine coverage is limited, and replacement by non-vaccine serotypes resulting in disease is a serious threat for the near future. Therefore, the search for new vaccine candidates that elicit protection against a broader range of pneumococcal strains is important. Several surface-associated protein vaccines are currently under investigation. Another important issue is whether the aim should be to prevent pneumococcal disease by eradication of nasopharyngeal colonisation, or to prevent bacterial invasion leaving colonisation relatively unaffected and hence preventing the occurrence of replacement colonisation and disease. To illustrate the importance of pneumococcal colonisation in relation to pneumococcal disease and prevention of disease, we discuss the mechanism and epidemiology of colonisation, the complexity of relations within and between species, and the consequences of the different preventive strategies for pneumococcal colonisation.

title: Updated recommendations for prevention of invasive pneumococcal disease among adults using the 23-valent pneumococcal polysaccharide vaccine (PPSV23).
abstract: Invasive disease from Streptococcus pneumoniae (pneumococcus) is a major cause of illness and death in the United States, with an estimated 43,500 cases and 5,000 deaths among persons of all ages in 2009. This report provides updated recommendations from the Advisory Committee on Immunization Practices (ACIP) for prevention of invasive pneumococcal disease (IPD) (i.e., bacteremia, meningitis, or infection of other normally sterile sites) through use of the 23-valent pneumococcal polysaccharide vaccine (PPSV23) among all adults aged >or=65 years and those adults aged 19-64 years with underlying medical conditions that put them at greater risk for serious pneumococcal infection. The new recommendations include the following changes from 1997 ACIP recommendations: 1) the indications for which PPSV23 vaccination is recommended now include smoking and asthma, and 2) routine use of PPSV23 is no longer recommended for Alaska Natives or American Indians aged <65 years unless they have medical or other indications for PPSV23. ACIP recommendations for revaccination with PPSV23 among the adult patient groups at greatest risk for IPD (i.e., persons with functional or anatomic asplenia and persons with immunocompromising conditions) remain unchanged. ACIP recommendations for prevention of pneumococcal disease among infants and youths aged <or=18 years using the 13-valent pneumococcal conjugate vaccine (PCV13) and PPSV23 are published separately.

title: Nasopharyngeal colonization: a target for pneumococcal vaccination
abstract: The pneumococcal conjugate vaccine (PCV), licensed in 2000, is highly efficient in preventing serious disease caused by serotypes in the vaccine and also prevents symptomless colonization of the nasopharynx. Prevention of this first step in the infection cycle has important consequences: it reduces chances of spread of the infection and indirectly protects from disease. Through these indirect effects, the protection afforded by the vaccine extends to the whole population, including those not vaccinated (herd immunity). Already now, after 5 years of wide use of PCV for infant immunization in the USA, more cases are prevented through the indirect effects than by vaccine-induced immunity in those vaccinated. The extended protection increases the cost–effectiveness of PCV and should clearly encourage its use in poorly resourced countries. However, the accumulated experience also shows that the herd immunity, due to PCV, is partly offset by replacement of the vaccine serotypes by other, nonvaccine serotypes. Owing to the general reduced virulence of the latter, this has only had a modest effect on disease, but the possibility of more virulent nonvaccine serotypes arising cannot be ignored and should be the focus of continued surveillance.

title: Impact of heptavalent pneumococcal conjugate vaccine on invasive disease, antimicrobial resistance and colonization in Alaska Natives: progress towards elimination of a health disparity.
abstract: We evaluated invasive pneumococcal disease (IPD), antimicrobial resistance and nasopharyngeal colonization before and after introduction of pneumococcal conjugate vaccine (PCV7) in Alaska Natives (AN), a population with high IPD rates. We obtained IPD rates from population-based surveillance. Colonization was determined from annual surveys among rural AN of all ages and from urban children. After vaccine introduction, vaccine-type IPD rates declined by 91% among AN children <2 years, by 80% among non-Natives <2 years, and by 40% for adults of all races (P<0.001 each). IPD decreased for isolates resistant to penicillin, erythromycin and cotrimoxazole (P<0.001 each). Vaccine-type colonization decreased among rural and urban children <5 years and among rural adults (P<0.001 each). PCV7 vaccine has eliminated a longstanding disparity of vaccine-type IPD for AN children. Decreased vaccine-type colonization and IPD in adults demonstrate indirect vaccine effects.

title: Comparing pneumococcal conjugate vaccine schedules based on 3 and 2 primary doses: systematic review and meta-analysis.
abstract: Pneumococcal conjugate vaccines (PCV) were first licensed for use with 3 primary doses in infancy and a booster dose. The evidence for the effects of different schedules was examined in this systematic review and meta-analysis.



We searched 12 databases and trial registers up to March 2010. We selected randomised controlled trials (RCTs), cohort and case-control studies making direct comparisons between PCV schedules with (2p) or (3p) primary doses, with (+1) or without (+0) a booster dose. We extracted data on clinical, nasopharyngeal carriage and immunological outcomes and used meta-analysis to combine results where appropriate.



Seropositivity levels (antibody concentration ≥0.35 μg/ml) following 3p and 2p PCV schedules were high for most serotypes (5 RCTs). Differences between schedules were generally small and tended to favour 3p schedules, particularly for serotypes 6B and 23F; between-study heterogeneity was high. Seropositivity levels following 3p+1 and 2p+1 schedules were similar but small differences favouring 3p+1 schedules were seen for serotypes 6B and 23F. We did not identify any RCTs reporting clinical outcomes for these comparisons. In 2 RCTs there was weak evidence of a reduction in carriage of S. pneumoniae serotypes included in the vaccine when 3p+0 schedules were compared to 2p+0 at 6 months of age.



Most data about the relative effects of different PCV schedules relate to immunological outcomes. Both 3p and 2p schedules result in high levels of seropositivity. The clinical relevance of differences in immunological outcomes between schedules is not known. There is an absence of clinical outcome data from RCTs with direct comparisons of any 2p with any 3p PCV schedule.

title: Methods for a Systematic Review of Pneumococcal Conjugate Vaccine Dosing Schedules
abstract: Streptococcus pneumoniae causes a considerable amount of morbidity and mortality in children <5. However, pneumococcal conjugate vaccines (PCVs) can prevent much of this burden. Until recently, PCVs were mostly available only in developed countries using a variety of dosing schedules. As more lower income countries make decisions to introduce PCV into their national immunization programs, an optimal schedule with which to administer PCV has become a key policy question.  We performed a systematic review of English literature published from 1994 to 2010 on the effects of PCV dosing schedules on immunogenicity, nasopharyngeal carriage, invasive pneumococcal disease and pneumonia. Data were independently double abstracted and cleaned for analysis. Descriptive analyses were performed.  We identified 12,980 citations from the literature search (12,976) and secondary means (44). Double review of titles and abstracts yielded 769 articles that underwent full data abstraction. Of these, 350 were further analyzed and are presented in separate reports in this supplement.  This article presents the methods utilized in our systematic review. Because of the heterogenity of the study methods of the reports identified by this review, we did not conduct formal meta-analyses. However, these methods allow us to present a full landscape of the literature on PCV dosing schedules.

title: Effect of Pneumococcal Conjugate Vaccination on Serotype-Specific Carriage and Invasive Disease in England: A Cross-Sectional Study
abstract: A cross sectional study by Stefan Flasche and coworkers document the serotype replacement of Streptococcus pneumoniae that has occurred in England since the introduction of PCV7 vaccination.

title: The effect of an alternative reduced-dose infant schedule and a second year catch-up schedule with 7-valent pneumococcal conjugate vaccine on pneumococcal carriage: a randomized controlled trial.
abstract: The 7-valent pneumococcal conjugate vaccine (PCV7) was initially licensed for use as 3 infant doses and a booster (3+1). However, 2 infant doses plus a booster schedules only (2+1) are widely used. We compared the effect of these two schedules on pneumococcal carriage in young children. We also assessed the effect of a 2-dose schedule in the second year ("catch-up" schedule; 0+2).



Subjects (n=733) were randomized to the 2+1 (4, 6, 12 m), 3+1 (2, 4, 6, 12 m) or 0+2 (12, 18 m) schedules. Blood samples for serotype-specific IgG (SSIgG) determination were obtained at 2, 7, 13, 19 months, and nasopharyngeal+oropharyngeal pneumococcal cultures were obtained at 2, 4, 6, 7, 12, 13, 18, 19, 24, 30 months.



After primary infant PCV7 series, SSIgG was significantly lower for four out of seven serotypes in children receiving 2 doses compared to 3 doses, particularly for serotypes 6B and 23F. This was associated with a higher acquisition and prevalence rates of vaccine serotype carriage in the 2-dose group, particularly serotypes 6A and 6B. After the booster dose at 12 months of age, most differences were not significant anymore. A single PCV7 dose at age 12 months in previously unvaccinated subjects ("catch up" schedule) resulted in poor SSIgG concentrations for three out of seven serotypes, resulting in higher acquisition and prevalence rates of vaccine serotypes (grouped) compared to infants receiving a booster dose at 12 months (2+1 and 3+1 groups). Similarly, serotypes 6B and 6A also showed significantly higher carriage rates after a single dose at 12 months. After the second catch-up dose at 18 months, the rates were similar to those in the 2+1 or 3+1 schedules, except for serotype 6A.



Three infant doses seem to better protect against PCV7-serotype acquisition and carriage than two. However, after booster, most of these differences disappear. A 2-dose second year catch-up campaign may enhance the reduction of PCV7-serotype spread in the community.

title: TRENDS IN NASOPHARYNGEAL CARRIAGE OF STREPTOCOCCUS PNEUMONIAE AMONG CHILDREN ATTENDING DAYCARE CENTERS IN SOUTHEASTERN FRANCE FROM 1999 TO 2006
abstract: Pneumococcal nasopharyngeal carriage, serotype distribution, and penicillin-susceptibility were monitored among children attending daycare centers in France from 1999 to 2006 to assess the impact of pneumococcal conjugate vaccine and antibiotic-reducing policies. Pneumococcal carriage remained stable. Immunization rates reached 68% in 2006. Serotype distribution shifted significantly from vaccine serotypes to vaccine-related and nonvaccine serotypes. Antibiotic treatments fell by 50%.

title: Changes in pneumococcal serotypes and antibiotypes carried by vaccinated and unvaccinated day-care centre attendees in Portugal, a country with widespread use of the seven-valent pneumococcal conjugate vaccine.
abstract: The seven-valent pneumococcal conjugate vaccine (PCV7) has been available in Portugal since June 2001, but is not included in the National Vaccination Plan. Its impact on colonization is unknown. A point-prevalence study to evaluate PCV7 usage was carried out in 2006 among day-care centre attendees from the Lisbon area. Pneumococcal carriage rates, serotypes, and antibiotypes were determined and compared with results from a similar study conducted in 2001 before vaccine approval. In 2001 and 2006, 717 and 571 children, respectively, were enrolled. In 2006, 45.9% of the participants were appropriately vaccinated and 11.5% were incompletely vaccinated. Carriage of pneumococci remained stable (64.9% in 2001; 68.7% in 2006). Vaccine types (VT) decreased from 53.1% of all pneumococci to 11.2% (p <0.001). Serotype replacement was observed among vaccinated and unvaccinated children. Non-vaccine types (NVT) 1, 6C, 7F, 15A, 16F, 21, 23A, 29, and non-typeable (NT) strains increased significantly; serotype 19A increased, but not significantly. Rates of resistance to penicillin, erythromycin, clindamycin and tetracycline remained stable (p >0.05) due to significant increases in intermediate resistance to penicillin (from 5.5% to 17.8%), erythromycin (from 9.2% to 21.8%), clindamycin (from 6.4% to 19.3%) and tetracycline (from 8.3% to 15.8%) among NVT. Whereas in 2001 resistance among NVT was mostly associated with serotype 19A and NT strains, in 2006 resistance was also found among serotypes 6C, 15A, 24F and 33F. In conclusion, dramatic shifts in serotypes of colonizing pneumococci were observed among vaccinated and unvaccinated children. Rates of antibiotic resistance remained unchanged due to a balance between reduction in VT and an increase in antimicrobial-resistant NVT.

title: Pneumococcal Nasopharyngeal Carriage following Reduced Doses of a 7-Valent Pneumococcal Conjugate Vaccine and a 23-Valent Pneumococcal Polysaccharide Vaccine Booster
abstract: This study was conducted to evaluate the effect of a reduced-dose 7-valent pneumococcal conjugate vaccine (PCV) primary series followed by a 23-valent pneumococcal polysaccharide vaccine (23vPPS) booster on nasopharyngeal (NP) pneumococcal carriage. For this purpose, Fijian infants aged 6 weeks were randomized to receive 0, 1, 2, or 3 PCV doses. Within each group, half received 23vPPS at 12 months. NP swabs were taken at 6, 9, 12, and 17 months and were cultured for Streptococcus pneumoniae. Isolates were serotyped by multiplex PCR and a reverse line blot assay. There were no significant differences in PCV vaccine type (VT) carriage between the 3- and 2-dose groups at 12 months. NP VT carriage was significantly higher (P, <0.01) in the unvaccinated group than in the 3-dose group at the age of 9 months. There appeared to be a PCV dose effect in the cumulative proportion of infants carrying the VT, with less VT carriage occurring with more doses of PCV. Non-PCV serotype (NVT) carriage rates were similar for all PCV groups. When groups were pooled by receipt or nonreceipt of 23vPPS at 12 months, there were no differences in pneumococcal, VT, or NVT carriage rates between the 2 groups at the age of 17 months. In conclusion, there appeared to be a PCV dose effect on VT carriage, with less VT carriage occurring with more doses of PCV. By the age of 17 months, NVT carriage rates were similar for all groups. 23vPPS had no impact on carriage, despite the substantial boosts in antibody levels.

title: The immunogenicity and impact on nasopharyngeal carriage of fewer doses of conjugate pneumococcal vaccine immunization schedule.
abstract: The immunogenicity and impact on carriage of fewer doses of pneumococcal conjugate vaccine (PCV7) followed by booster with pneumococcal polysaccharide vaccine (PPV) were investigated. 684 infants were assigned randomly to one of the three groups that received one (A), two (B) or three (C) doses of PCV7 between 2 and 4 months of age, plus PPV at 10 months. Following primary vaccination protective antibody titers of >0.35 μg/ml against the PCV7 serotypes combined increased significantly with the number of PCV7 doses, 44% vs. 77% vs. 94% (p<0.001), and correlated positively with the opsonophagocytic indices, but negatively with nasopharyngeal carriage of pneumococcus. The differences in antibody responses and pneumococcal carriage between the groups diminished following booster with PPV, implying that administration of one or two doses of PCV7, with a booster dose of PPV might lower the cost of protection against IPD in young children in resource poor countries.

title: Nasopharyngeal Carriage of Streptococcus pneumoniae in Gambian Children who Participated in a 9-valent Pneumococcal Conjugate Vaccine Trial and in Their Younger Siblings
abstract: Nasopharyngeal carriage of Streptococcus pneumoniae is extremely prevalent in The Gambia. We studied the effects of vaccination with pneumococcal conjugate vaccines on the carriage of individual serotypes and on antimicrobial resistance in vaccinated children and their younger siblings.  A longitudinal study of a subsample of children (n = 2342) who participated in a randomized, placebo controlled trial of a 9-valent pneumococcal conjugate vaccines (PCV-9) in The Gambia, and a cross-sectional study of non-PCV-9-vaccinated younger siblings (n = 675).  Recipients of PCV-9 were less likely to carry vaccine serotypes 4, 6B, 9V, 14, 19F, and 23F but more likely to carry vaccine-associated 19A and 9 nonvaccine serotypes at approximately 6 months postvaccination (age, 12 months) than were controls (each P < 0.05). At approximately 16 months postvaccination, carriage of vaccine-associated-serotype 6A was also significantly reduced (P < 0.01) while 3 other nonvaccine serotypes were more prevalent in the PCV-9 recipients (each P < 0.05). At 16 months, but not 6 months, postvaccination PCV-9 recipients had lower rate of carrying isolates resistant to tetracycline and trimethoprim-sulfamethoxazole (TMP-SMZ) than controls (risk ratio: 0.90 and 0.95, respectively; each P < 0.05). There was no difference in patterns of carriage of pneumococci in younger siblings of PCV-9 or placebo recipients.  The effects of 9-valent pneumococcal conjugate vaccines on carriage of pneumococci persisted for at least 16 months postvaccination in Gambian children. Vaccination had no indirect effect on carriage in younger siblings and there was limited impact on antibiotic resistance.

title: Reduction of pneumococcal nasopharyngeal carriage in early infancy after immunization with tetravalent pneumococcal vaccines conjugated to either tetanus toxoid or diphtheria toxoid.
abstract: Pneumococcal nasopharyngeal colonization is important for transmission of the organisms. We assessed the ability of two tetravalent conjugate vaccines administered in early infancy to prevent carriage of vaccine-related pneumococci.



A vaccine containing pneumococcal type 6B, 14, 19F and 23F polysaccharide conjugated to tetanus toxoid (Pnc-T) and a vaccine containing the same four polysaccharides conjugated to diphtheria toxoid (Pnc-D) were compared with placebo, in a double blinded study (25 infants per group). Vaccines (or placebo) were injected at 2, 4 and 6 months of age. At 12 months of age a native (nonconjugate) polysaccharide vaccine was administered as a booster. Serum type-specific anticapsular antibody concentrations were measured and nasopharyngeal cultures were obtained at 2, 4, 6, 7, 12 and 13 months of age.



In general carriage of all pneumococci (vaccine- and non-vaccine-related) was low at age 2 months and increased with age. However, for the vaccine-related serotypes (6A, 6B, 14, 19F and 23F) carriage was not increased with age in Pnc-D or Pnc-T recipients. Of all cultures obtained after the full primary series, 7 of 72 (10%), 3 of 62 (5%) and 19 or 70 (27%) were positive for the vaccine-related pneumococcal serotypes among the Pnc-D, Pnc-T and placebo recipients, respectively (P = 0.001 for Pnc-D vs. placebo; P = 0.014 for Pnc-T vs. placebo). Most of the antibiotic-resistant isolates belonged to the vaccine-related serotypes.



A significant reduction in the carriage of vaccine-related strains after administration of conjugate vaccines was observed. These preliminary results suggest that transmission of specific pneumococcal serotypes most often associated with disease and antibiotic resistance may at least partially be controlled by immunization.

title: Immunogenicity and impact on nasopharyngeal carriage of a nonavalent pneumococcal conjugate vaccine.
abstract: The safety, immunogenicity, and impact on carriage of a nonvalent pneumococcal vaccine given at ages 6, 10, and 14 weeks were examined in a double-blind, randomized, placebo-controlled trial in 500 infants in Soweto, South Africa. No serious local or systemic side effects were recorded. Significant antibody responses to all pneumococcal serotypes were observed 4 weeks after the third dose. Haemophilus influenzae type b polyribosylribitol phosphate (geometric mean titer, 11.62 microg/mL) and diphtheria (1.39 IU/mL) antibodies were significantly higher in children receiving pneumococcal conjugate, compared with placebo recipients (4.58 microgram/mL and 0.98 IU/mL, respectively). Nasopharyngeal carriage of vaccine serotypes decreased in vaccinees at age 9 months (18% vs. 36%), whereas carriage of nonvaccine serotypes increased (36% vs. 25%). Carriage of penicillin-resistant pneumococci (21% vs. 41%) and cotrimoxazole-resistant pneumococci (23% vs. 35%) were significantly reduced 9 months after vaccination, compared with controls.

title: Safety and immunogenicity of a nonavalent pneumococcal vaccine conjugated to CRM197 administered simultaneously but in a separate syringe with diphtheria, tetanus and pertussis vaccines in Gambian infants
abstract: Unrelenting high morbidity and mortality have mandated that immunogenic vaccines be used to combat pneumococcal disease in infants.  To evaluate the safety and immunogenicity of a nonavalent pneumococcal conjugate vaccine and the antigenic interaction when administered simultaneously with diphtheria, tetanus and pertussis vaccines.  Two hundred seven infants were randomized to receive three doses of either nonavalent protein conjugate pneumococcal vaccine (PnCV) or inactivated polio vaccine (IPV) at 2, 3 and 4 months of age with routine Expanded Program of Immunization vaccines as scheduled. Vaccinees were visited on Days 1, 2 and 7 to observe local and systemic adverse reactions. Blood was drawn before the first dose and 1 month after the third dose. Antibody concentrations in sera were measured by standardized enzyme-linked immunosorbent assay. Nasopharyngeal carriage of pneumococci was tested at 5 and 9 months of age.  No serious reactions were observed. Local induration and tenderness were observed more commonly at the site of administration of diphtheria, tetanus and pertussis vaccines than at the site of administration of IPV or PnCV. Between 79 and 91% achieved ≥1 μg/ml antibody against specific pneumococcal serotypes. Antibody responses to diphtheria and pertussis antigens were similar in both groups; however, antibody response to tetanus toxoid was significantly lower in infants who received PnCV (geometric mean concentration, 11.1 vs. 17.4; P < 0.001). Nasopharyngeal carriage in PnCV-vaccinated children was reduced but not significantly different from those vaccinated with IPV.  Simultaneous administration of PnCV with Expanded Program of Immunization vaccines is safe and immunogenic. Immune response to the composite antigens is likely to confer protection.

title: Effect of vaccination with pneumococcal capsular polysaccharides conjugated to Haemophilus influenzae-derived protein D on nasopharyngeal carriage of Streptococcus pneumoniae and H. influenzae in children under 2 years of age.
abstract: Following primary and booster vaccination with an 11-valent pneumococcall protein D conjugate vaccine there was a 42.8% (95% CI: -16.7 to 71.9, ns) reduction in the carriage of Streptococcus pneumoniae vaccine serotypes and a 42.6% (95% CI: 1.3-66.6) reduction in the carriage of Haemophilus influenzae identified by standard microbiological techniques. When PCR and immunoblot assays were used to further improve specificity of non-typeable H. influenzae strain identification, carriage of H. influenzae was still reduced with 38.6% (95% CI: -6.3 to 64.6, ns). Reduction of acute otitis media (AOM) episodes preceded the impact on carriage. These data provide further support of the functional role of the protein D immunity.

title: Heptavalent pneumococcal vaccine conjugated to outer membrane protein of Neisseria meningitidis serogroup b and nasopharyngeal carriage of Streptococcus pneumoniae in infants.
abstract: Streptococcus pneumoniae (Sp) is an important bacterial pathogen in children. Nasopharyngeal (NP) colonization of S. pneumoniae is necessary for person-to-person transmission and often precedes invasive disease.



NP carriage of Sp was studied in 49 infants following administration of a heptavalent pneumococcal conjugate vaccine (PCV) conjugated to the outer membrane protein of serogroup b Neisseria meningitidis (vaccine serotypes: 4, 6B, 9V, 14, 18C, 19F, 23F). The vaccine was administered at 2, 4, 6, and 12 months of age and carriage rates were compared to a concurrent group of 32 infants not given PCV and evaluated over the first 15 months of life.



Overall, Sp was isolated in 86/367 (23%) of NP cultures and 49% of infants. Serotype 23F was significantly less prevalent in the PCV group (1.9%) than the control group (16.1%) (P<0.05). Analysis of the proportion of children with prevalent carriage or acquisition of carriage did not differ between groups when evaluated by age or serotype. We noted, however, decreased acquisition and carriage in the vaccine group 1 month following the 12 month dose of PCV for vaccine serotypes (76 and 52% reduction, respectively), but this did not reach statistical significance (P=0.3). Adjustment for age, daycare and antibiotic use by multivariate modeling revealed no difference in carriage of vaccine containing serotypes or non-vaccine serotypes between groups.



We did not show a significant effect of this heptavalent PCV on NP carriage. Further study of this issue, including a larger population size, is needed.

title: Pneumococcal nasopharyngeal carriage in children following heptavalent pneumococcal conjugate vaccination in infancy
abstract: To ascertain whether the reduction in nasopharyngeal carriage of vaccine serotypes induced by pneumococcal conjugate vaccine (PnCV) administered to infants persists beyond the age of 2 years.  Non-randomised, unblinded controlled study of 2–5 year old children who had received three doses of heptavalent PnCV (7VPnCV) in infancy and 23-valent pneumococcal polysaccharide vaccine at 13 months, and unimmunised controls. Nasopharyngeal swabs were taken in summer (150 vaccinated subjects, 126 controls) and winter (143 vaccinated subjects, 188 controls). The swabs were cultured and serotyped for Streptococcus pneumoniae.  Carriage rates (vaccinated subjects: 24.7% and 43.4%; controls: 27.0% and 41.0%, in summer and winter respectively) and carriage of vaccine serotypes (subjects: 10.0% and 30.0%; controls: 13.5% and 31.5%, in summer and winter respectively) were similar in the two groups.  Effects of vaccination in infancy on rates of nasal carriage of pneumococcus and serotype replacement in children living in a largely unvaccinated population are no longer evident by 2–5 years of age.

title: Nasopharyngeal carriage rate of Streptococcus pneumoniae in children with sickle cell disease before and after the introduction of heptavalent pneumococcal conjugate vaccine.
abstract: Children with sickle cell disease (SCD) are at high risk of severe infection with Streptococcus pneumoniae (SP). From 2002, all children aged <5 years in the UK with SCD were recommended 7-valent pneumococcal conjugate vaccine (PCV-7) in infancy and 23-valent pneumococcal polysaccharide vaccine boosting, in addition to regular penicillin prophylaxis. Our objective was to determine the nasopharyngeal (NP) carriage rate of SP in children aged <5 years with SCD before and after vaccination with PCV-7 (by vaccine, cross-protection and non-vaccine serotypes). NP swabs were obtained from 63 children attending the Royal London Hospital or Newham General Hospital paediatric haematology clinic between April 2001 and April 2002. Later, NP swabs were obtained from 43 children attending the clinic between June and December 2004 after a PCV-7 vaccination programme. All SP isolated by culture were serotyped and susceptibility to penicillin measured. In the first study group, 13 samples grew SP with 1 sample containing 2 different serotypes, giving a carriage rate of 21%. Four (31%) were intermediately susceptible to penicillin. In the second group overall NP carriage rate had decreased to 9% (n=4), and the proportion directly or indirectly covered by the PCV-7 vaccine fell from 13/14 to 2/4 (P=0.11). One (25%) of these isolates was intermediately susceptible to penicillin. The introduction of PCV-7 appears to be associated with a shift in distribution of serotypes carried by children with SCD. This may have implications for vaccine effectiveness.

title: Dynamic of pneumococcal nasopharyngeal carriage in children with acute otitis media following PCV7 introduction in France.
abstract: To determine whether the use of seven valent pneumococcal conjugate vaccine (PCV7) caused a shift in the Streptococcus pneumoniae serotypes distribution and whether it modified the resistance to antibiotics, 3291 nasopharyngeal swabs were obtained between 2001 and 2006, from children aged 6-24 months with acute otitis media. Following the implementation of PCV7, we observed a slight reduction in the overall pneumococcal carriage, a marked decrease of vaccine serotypes, an increase in non-vaccine serotypes carriage and a reduction in the carriage of penicillin non-susceptible strains. Most of the serotype 19A replacement was related to the clonal expansion of ST276 which was found to be the predominant ST among penicillin non-susceptible isolates.

title: Impact of more than a decade of pneumococcal conjugate vaccine use on carriage and invasive potential in Native American communities.
abstract: We assessed the impact of 12 years of pneumococcal conjugate vaccine (PCV7) use on pneumococcal nasopharyngeal carriage and serotype-specific invasive disease potential among Native Americans.



Families were enrolled in a carriage study from 2006 to 2008; nasopharyngeal specimens and risk factor information were collected monthly for 7 visits. Pneumococcal carriage prevalence was compared with that before (1998-2000) and during (2001-2002) PCV7 introduction. We compared invasive disease incidence and carriage prevalence before and after PCV7 introduction to estimate changes in serotype-specific invasive potential.



We enrolled 1077 subjects from 302 households. There was an absolute reduction in carriage prevalence of 8.0% (95% confidence interval [CI], 4.5%-11.4%) in children aged <5 years and 3.1% (95% CI, 1.1%-5.1%) in adults. In children aged <5 years, vaccine-serotype carriage prevalence decreased by 22.8% (95% CI, 20.1%-25.3%), and nonvaccine serotype (NVT) increased by 15.9% (95% CI, 12.4%-19.3%). No significant change was detected in serotype-specific invasive potential after PCV7 introduction.



Pneumococcal carriage prevalence decreased in all ages since PCV7 introduction; vaccine-serotype carriage has been nearly eliminated, whereas the prevalence of NVT carriage has increased. The increase in the NVT invasive disease rate seems to be proportional to the increase in colonization prevalence.

title: Nasopharyngeal Pneumococcal Carriage of Children Attending Day Care Centers in Korea: Comparison between Children Immunized with 7-valent Pneumococcal Conjugate Vaccine and Non-immunized
abstract: To confirm the effect of 7-valent pneumococcal conjugate vaccine (PCV7), pneumococcal nasopharyngeal (NP) carriage was compared between vaccinated (3 + 1 doses PCV7) and non-vaccinated children. Vaccinated subjects were recruited from highly vaccinated regions (≥ 60%), Seoul and Incheon whereas control subjects were recruited from Jeju Island where vaccination rates are low (< 15%). NP swabs were obtained from 400 children aged 18-59 months. Serotype and antibiotic susceptibility was analyzed. Pneumococcal carriage rate was 18.0% (36/200) and 31.5% (63/200) for the vaccinated and control group, respectively. Among those vaccinated, 41.7% (15/36) of the serotypes were vaccine-related type (VRT: 6A, 6C, 19A) with the most common serotype 6C. The next common type was non-typable/non-capsule 30.6% (11/36) followed by non-vaccine type 16.7% (6/36) and vaccine type (VT) serotypes were found in only 11.1% (4/36). In contrast, 52.4% (33/63) of the isolates in the control group were VT. Resistance rates for penicillin and erythromycin were lower in the vaccine group (vaccine vs control; penicillin 45.2% vs 71.4%, erythromycin 74.2% vs 90.5%, P < 0.05). Multi-drug resistance was also lower in vaccinated subjects (vaccine vs control; 45.2% vs 69.8%, P < 0.05). PCV7 reduces carriage in VT which leads to replacement of pneumococci by antibiotic susceptible VRT or non-vaccine type strains.

title: Decline in pneumococcal meningitis after the introduction of the heptavalent-pneumococcal conjugate vaccine in northern France
abstract: The impact of the heptavalent-pneumococcal conjugate vaccine on the incidence of pneumococcal meningitis in Europe has not yet been assessed.  To determine whether heptavalent-pneumococcal conjugate vaccine implementation in northern France has resulted in a decrease in the incidence of pneumococcal meningitis in children.  Multicentre retrospective cohort study from 2000 through 2005.  All paediatric departments of the 18 hospitals in northern France.  Patients <18 years of age, admitted for laboratory-confirmed pneumococcal meningitis during the study period, were included.  Data were collected from medical files and the microbiological laboratories of each hospital and compared with the regional hospital discharge codes, using a capture–recapture method.  The study assessed and compared global and age-related incidence rates of pneumococcal meningitis in 2001 (pre-vaccine era) and 2005.  77 cases were found through the capture–recapture method. The incidence rate of pneumococcal meningitis varied from 1.65/100 000 children <18 years in 2001 to 0.80/100 000 children in 2005 (53% reduction, 95% CI 31 to 74; p = 0.08). This has so far been significant only for children <2 years of age (8.9/100 000 in 2001 to 1.8/100 000 in 2005; 82% reduction, 95% CI 52 to 95; p = 0.03).  A decline in pneumococcal meningitis has been observed in infants since heptavalent-pneumococcal conjugate vaccination began in our area.

title: Impact of 13-valent Pneumococcal Conjugate Vaccine on Pneumococcal Nasopharyngeal Carriage in Children With Acute Otitis Media
abstract: 13-valent pneumococcal conjugate vaccine (PCV13) licensure was based on the immune response (enzyme-linked immunosorbent assay and opsonophagocytic assay) compared with PCV7. National surveillance program of pneumococcal nasopharyngeal (PNP) carriage in children with acute otitis media (AOM) was set up in 2001 when PCV7 was introduced in France and continues to the present. This program was used in 2010–2011 to assess the effect of the implementation of PCV13 on PNP carriage in young children with AOM.  Between October 2010 and March 2011, 58 pediatricians obtained 943 nasopharyngeal swabs from children (6 to 24 months of age) with AOM. The swabs were sent for analysis to the French National Reference Centre for Pneumococci. Demographics, medical history, and physical examination findings were recorded.  Among 943 children enrolled (mean age, 13.4 months), 651 had received at least 1 dose of PCV13 and 285 received PCV7 only. Among PCV13-vaccinated children, overall PNP carriage and carriage of serotypes not in PCV7 were significantly lower as compared with children exclusively vaccinated with PCV7 (53.9% vs. 64.6%, P = 0.002 and 9.5% vs. 20.7%, P < 0.0001, respectively). For serotypes 19A, 7F, and 6C, the carriage rates were also significantly lower in PCV13-vaccinated patients than in patients only vaccinated by PCV7: 7.5% versus 15.4%, P < 0.001, 0.5% versus 2.8%, P = 0.002, and 3.7% versus 8.4%, P = 0.003, respectively.  In young children (<2 years) with AOM, this study suggests that PCV13 has an impact on overall PNP carriage, as well as on serotypes 19A, 7F, and 6C.

title: Temporal and geographic stability of the serogroup-specific invasive disease potential of Streptococcus pneumoniae in children.
abstract: A meta-analysis study design was used to analyze 7 data sets of invasive and carriage pneumococcal isolates recovered from children, to determine whether invasive disease potential differs for each serotype and, if so, whether it has changed over time or differs geographically. Serotype- and serogroup-specific odds ratios (ORs) were calculated for each study and as a pooled estimate, with use of serotype 14 as the reference group. ORs varied widely: the serotypes with the highest ORs (1, 5, and 7) were 60-fold more invasive than those with the lowest ORs (3, 6A, and 15). There was a significant inverse correlation between invasive disease and carriage prevalence for the serotypes that we considered, which implies that the most invasive serotypes and serogroups were the least commonly carried and that the most frequently carried were the least likely to cause invasive disease. There was no evidence of any temporal change or major geographical differences in serotype- or serogroup-specific invasive disease potential.