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Original Contribution |

Effect of Reduced-Dose Schedules With 7-Valent Pneumococcal Conjugate Vaccine on Nasopharyngeal Pneumococcal Carriage in Children:  A Randomized Controlled Trial FREE

Elske J. M. van Gils, MD; Reinier H. Veenhoven, MD, PhD; Eelko Hak, PhD; Gerwin D. Rodenburg, MD; Debby Bogaert, MD, PhD; Ed P. F. IJzerman, MD, PhD; Jacob P. Bruin; Loek van Alphen, PhD; Elisabeth A. M. Sanders, MD, PhD
[+] Author Affiliations

Author Affiliations: Department of Pediatric Immunology and Infectious Diseases, Wilhelmina Children's Hospital (Drs van Gils, Hak, Rodenburg, Bogaert, and Sanders), and Julius Center for Health Sciences and Primary Care (Dr Hak), University Medical Center Utrecht, Utrecht; Department of Pediatrics, Spaarne Hospital, Hoofddorp (Drs van Gils, Veenhoven, and Rodenburg); Department of Epidemiology, University Medical Center Groningen, Groningen (Dr Hak); Regional Laboratory of Public Health, Haarlem (Dr IJzerman and Mr Bruin); and Netherlands Vaccine Institute, Bilthoven (Dr van Alphen), the Netherlands.


JAMA. 2009;302(2):159-167. doi:10.1001/jama.2009.975.
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Context The effects of reduced-dose schedules of 7-valent pneumococcal conjugate vaccine (PCV-7) on pneumococcal carriage in children are largely unknown, although highly relevant in the context of subsequent herd effects.

Objective To examine the effects of a 2-dose and 2 + 1-dose PCV-7 schedule on nasopharyngeal pneumococcal carriage in young children compared with controls.

Design, Setting, and Patients A randomized controlled trial of nasopharyngeal carriage of Streptococcus pneumoniae enrolling 1003 healthy newborns and 1 of their parents in a general community in the Netherlands, with follow-up to age 24 months and conducted between July 7, 2005, and February 14, 2008.

Intervention Infants were randomly assigned to receive 2 doses of PCV-7 at 2 and 4 months; 2 + 1 doses of PCV-7 at 2, 4, and 11 months; or no dosage (control group).

Main Outcome Measure Vaccine serotype pneumococcal carriage rates in infants in the second year of life.

Results At 12 months, vaccine serotype pneumococcal carriage was significantly decreased after both PCV-7 schedules, with vaccine serotype pneumococcal carriage rates of 25% (95% confidence interval [CI], 20%-30%) and 20% (95% CI, 16%-25%) in the 2-dose and 2 + 1-dose schedule groups, respectively, vs 38% (95% CI, 33%-44%) in the control group (both P < .001). At 18 months, in the 2 + 1-dose schedule group, vaccine serotype pneumococcal carriage had further decreased to 16% (95% CI, 12%-20%) and, at 24 months, to 14% (95% CI, 11%-18%; both P < .001); whereas in the 2-dose schedule group, vaccine serotype pneumococcal carriage had remained stable at 18 months (24%; 95% CI, 20%-29%), but at 24 months had further decreased to 15% (95% CI, 11%-19%; both P < .001). In the control group, vaccine serotype pneumococcal carriage remained around 36% to 38% until 24 months.

Conclusion Compared with no pneumococcal vaccination, a 2 + 1-dose and 2-dose schedule of PCV-7 resulted in significant reductions of vaccine serotype pneumococcal carriage in the second year of life.

Trial Registration clinicaltrials.gov Identifier: NCT00189020

Figures in this Article

The success of the introduction in 2000 in the United States of routine infant vaccination with the licensed 7-valent pneumococcal conjugate vaccine (PCV-7) is based on direct protection against vaccine serotype pneumococcal disease among vaccinees but also on the observed and unexpectedly large and widespread reduction in invasive and respiratory (eg, pneumonia and otitis media) vaccine serotype pneumococcal disease in nonimmunized individuals (indirect effect or herd protection).16 This herd effect has been attributed to reduced carriage of vaccine serotype pneumococci in vaccinated infants and subsequent transmission to (household) adult contacts and spread in the community. The resulting decreased circulation of the 7 serotypes and herd effects have contributed substantially to the public health benefit and cost-effectiveness of PCV-7 programs.7,8

Increasingly crowded infant vaccine schedules and less favorable cost-effectiveness calculations have prompted exploration of reduced-dose vaccine schedules other than the currently recommended 3 + 1-dose schedule of PCV-7, comprising 3 primary doses before age 6 months followed by a booster vaccination in the second year of life. Clinically, protection against invasive pneumococcal disease (IPD) after less than 4 doses was observed in the Northern California Kaiser Permanente study.1 In this study, clinical efficacy against IPD in the intention-to-treat analysis was high (93.9%), even though only 58% of the children had received the full PCV-7 schedule. Furthermore, the association between use of reduced-dose schedules and prevention of vaccine serotype IPD in vaccinees was demonstrated in a large case-control study from the United States showing high reductions associated with a 2 + 1-dose schedule (98%; 95% confidence interval [CI], 75%-100%) and even a 2-dose schedule (96%; 95% CI, 88%-99%) during a period of vaccine shortage.9 A recent immunogenicity study from the United Kingdom also supported introduction of a reduced-dose schedule.10 Consequently, several European countries such as the United Kingdom and Norway have recently implemented a 2 + 1-dose schedule. Norway has reported high direct protection against vaccine serotype IPD in the first 2 years following national implementation of PCV-7 vaccination at 3, 5, and 12 months.11

Difficulty in implementing the 3 + 1-dose schedule in developing countries is another reason for exploring reduced schedules. Although Streptococcus pneumoniae is still the leading cause of meningitis, bacteremia, and pneumonia worldwide with an estimated annual death rate of 1 million children younger than 5 years, the overwhelming majority of deaths are due to pneumonia and occur in developing countries.12 Despite the World Health Organization's recommendations of global implementation of pneumococcal vaccine in national immunization programs for infants, only a few countries have actually introduced PCV-7.12 Poor resources and programmatic differences (eg, the current expanded program on immunization for developing countries lacks a health visit for a booster in the second year of life) are among reasons for the low implementation rates.

Receiving fewer primary doses or missing a booster dose may, however, affect the size and duration of reduction in vaccine serotype carriage and subsequent herd effects.13 Evaluation of herd effects after widespread introduction of conjugate vaccines needs long-term and high-quality disease surveillance. Investigating vaccine effects on nasopharyngeal pneumococcal carriage provides an important surrogate in exploring alternative vaccine schedules for potential herd effects on pneumococcal disease.14,15

We assessed the effects of a 2-dose and a 2 + 1-dose schedule of PCV-7 on vaccine serotype pneumococcal carriage in children and unvaccinated household adult contacts in a large randomized controlled trial in the Netherlands before nationwide implementation of PCV-7 for all infants.

Study Population

The study area covered 5 participating well-baby clinic organizations (birth cohort of approximately 16 000 per year) in the western region of the Netherlands. All parents living in this region were informed about the study by written information in their newborn's first weeks of life and asked to participate. Infants younger than 12 weeks, not yet having received any infant vaccination and living in the study region, were eligible for inclusion. Exclusion criteria were known immunodeficiency, craniofacial or chromosomal abnormalities, language barrier, or expected relocation within the follow-up period. Enrollment started on July 7, 2005, and was completed on February 9, 2006, before the introduction of PCV-7 in the Dutch National Immunization Program for infants born after March 31, 2006. Follow-up ended February 14, 2008. Participants did not receive any financial compensation.

Study Design

We conducted a randomized controlled trial to assess the effect of reduced-dose schedules with PCV-7 on vaccine serotype nasopharyngeal carriage of S pneumoniae. After written informed consent had been obtained from both parents or guardians, infants were randomly allocated by simple randomization via a computer randomization interface during the first home-visit to receive (1) PCV-7 at 2 and 4 months (2-dose schedule group); (2) PCV-7 at 2, 4, and 11 months (2 + 1-dose schedule group); or (3) no dosage (control group). Children in the control group were offered a PCV-7 vaccination free of charge after completing the study. Parents were aware of the child's vaccine schedule. Laboratory personnel assessing pneumococcal carriage were unaware of treatment allocation and the randomization key was not disclosed until after the study was completed.

The intervention vaccine was the 7-valent pneumococcal polysaccharide-CRM197 protein conjugate vaccine (CRM197-PCV-7; Wyeth Pharmaceuticals). Each 0.5-mL dose contained 2 μg each of serotypes 4, 9V, 14, 19F, and 23F polysaccharides, 2 μg of serotype 18C oligosaccharide, and 4 μg of serotype 6B polysaccharide, conjugated individually to the CRM197 protein, and 0.5 mg of aluminum phosphate as an adjuvant. Vaccinations were administered intramuscularly in the leg or upper arm during regular well-baby clinic visits, together with routine immunizations according to the Dutch National Immunization Program (DTaP-IPV-Hib [diphtheria and tetanus toxoids and acellular pertussis; inactivated polio vaccine; Haemophilus influenzae type b]; DTaP-IPV-Hib-Hep-B or DTaP-IPV-Hib and Hep-B for children at high risk for hepatitis B [n = 54]). During the first home-visit at age 6 weeks old and 4 follow-up visits at ages 6, 12, 18, and 24 months, a nasopharyngeal sample was obtained from the children and, at ages 12 and 24 months, also from 1 of the parents. With each nasopharyngeal swab, a questionnaire on risk factors for pneumococcal carriage in children and parents was obtained from the parents. Because pneumococcal yield in adults is known to be higher when taking a transnasal and transoral nasopharyngeal swab, both swabs were collected from parents.16

An acknowledged national ethics committee from the Netherlands (Stichting Therapeutische Evaluatie Geneesmiddelen, http://www.stegmetc.org) approved the study protocol. The trial was undertaken in accordance with the European Statements for Good Clinical Practice, which includes the provisions of the Declaration of Helsinki of 1989. An external committee was appointed to review progress and advise on data eligibility for analysis.

Nasopharyngeal Swabs

Deep nasopharyngeal samples were taken transnasally with a flexible, sterile, dry cotton-wool swab (Transwab Pernasal Plain, Medical Wire and Equipment Co, Corsham, Wiltshire, England) by trained study nurses according to World Health Organization standard procedures.17 Transoral nasopharyngeal swabs were taken under direct observation of the posterior pharynx with a rigid, sterile, dry cotton-wool swab (Transwab Plain). After sampling, swabs were immediately inoculated in Transwab (modified Amies) transport medium, stored at room temperature, and plated within 24 hours onto two 5% sheep-blood agar plates, with and without 5-mg/L gentamicin and incubated aerobically at 35°C for 48 hours (the gentamicin plate with increased carbon dioxide levels). Identification of S pneumoniae was based on colony morphology and conventional methods of determination (optochin susceptibility and bile solubility assays). One S pneumoniae colony per plate was then subcultured, harvested, and kept frozen at −70°C for further testing. Pneumococcal serotyping was performed by capsular swelling method (Quellung reaction) using type-specific antisera from the Statens Seruminstitut (Copenhagen, Denmark). Pneumococcal isolates were defined nontypeable when optochin susceptible and bile soluble but negative with the Quellung reaction. Validation of the typing procedures was performed in collaboration with the National Reference Laboratory for Bacterial Meningitis (Amsterdam, the Netherlands).

Statistical Analyses

Pneumococcal vaccine serotypes are the serotypes included in PCV-7 (serotypes 4, 6B, 9V, 14, 18C, 19F, and 23F) and nonvaccine serotypes are all remaining serotypes (including nontypeables). The primary outcome measure was the proportion of children positive for vaccine serotype pneumococcal carriage in the second year of life. The sample size was calculated with the assumption of a vaccine serotype carriage rate of 35% in children in the second year of life based on previous experience.18,19 The smallest clinically significant difference to detect was an estimated 33% relative reduction in vaccine serotype carriage (25% vaccine serotype carriage rate) after a 2-dose schedule of PCV-7 compared with the control group, with 80% power at a 5% significance level. This resulted in a sample size of 330 infants per group, including a 10% dropout rate. All other outcomes are designated secondary outcomes for statistical analysis, including nonvaccine serotype carriage in children and vaccine serotype and nonvaccine serotype carriage in parents. The study was not adequately powered to evaluate nonvaccine serotype carriage, individual serotypes, or indirect effects on vaccine serotype and nonvaccine serotype carriage in adults.

Statistical analyses followed the intention-to-treat principle, meaning that all available data from all randomized participants were analyzed according to the assigned intervention. Because the dropout rate (<2%) and the amount of missing data for the primary analysis (<2%) were low, available data were analyzed without using imputation methods.20 Per-protocol analyses yielded similar results due to the low number of protocol violations (n = 20). Proportional differences in pneumococcal carriage between treatment groups and controls were analyzed by using χ2 test or 2-sided Fisher exact test, where appropriate. In a post-hoc analysis, we also compared vaccine serotype pneumococcal carriage between the 2-dose and 2 + 1-dose vaccine schedules. We verified the primary analyses using a repeated measurements model taking more than 1 measurement per child into account using generalized linear models in SAS version 9.1 (SAS Institute Inc, Cary, North Carolina) with an autoregressive correlation structure, with correlations becoming smaller over time.21,22 The generalized linear models results are reported for the primary and post-hoc analyses. Results were virtually the same indicating that potential within-person dependency was not substantially affecting the precision of our estimates. P < .05 was considered significant and all reported P values are 2-sided. We did not correct for multiple testing in the analysis of the secondary outcomes (eg, by using the Bonferroni method). Adjustments for multiple testing are mostly concerned with the general null hypothesis that all null hypotheses are true simultaneously, which was not true for the secondary outcome comparisons in our trial.23

Parents of 9782 newborns were asked to participate. A total of 1003 children (including 15 twin pairs), representing 10.3% of the total birth cohort, were enrolled and assigned to the 3 study groups (Figure); 2 of the original 1005 were excluded because a parent did not provide consent. There were no major differences in demographics or distribution of risk factors (eg, number of siblings, day care attendance) between the 3 study groups (Table 1). A total of 4939 (98.5% of planned) nasopharyngeal swabs were collected from all children, of which 50% were positive for S pneumoniae. We were unable to determine the serotypes of 34 isolates (<1%) due to lack of growth on culture.

Place holder to copy figure label and caption
Figure. Enrollment Flow Diagram
Graphic Jump Location

PCV-7 indicates 7-valent pneumococcal conjugate vaccine. aParents of children interested in participating in the study were redundant because they were still in the information process of the study after enrollment target had already been achieved and informed consent process was cancelled.

Table Graphic Jump LocationTable 1. Characteristics of the Children and Parents at Time of Enrollment and During Follow-up
Pneumococcal Carriage in PCV-7 Unvaccinated Control Children

At 6 weeks and before the first vaccination, the overall pneumococcal carriage rate in children was 17% (95% CI, 15%-20%) in all groups. In unvaccinated control children, pneumococcal carriage increased to 49% (95% CI, 43%-54%) at 6 months and stabilized around 67% (95% CI, 62%-72%) between 12 and 24 months. The vaccine serotype carriage rate gradually increased from 5% (95% CI, 3%-8%) to 23% (95% CI, 19%-28%) at 6 weeks and 6 months, respectively, and reached its plateau at 12 months at 38% (95% CI, 33%-44%) (Table 2).

Table Graphic Jump LocationTable 2. Frequencies of Pneumococcal Nasopharyngeal Carriage in Vaccinated Children After a 2-Dose and 2 + 1-Dose PCV-7 Schedule and Unvaccinated Control Children at 12, 18, and 24 Monthsa
Effects of PCV-7 Vaccinations on Pneumococcal Carriage in Children

No significant differences in vaccine serotype, nonvaccine serotype, and overall pneumococcal carriage were observed at 6 months in both vaccine groups compared with the control group. At 12 months, vaccine serotype carriage rates were significantly lower in both vaccine groups compared with the control group, with 25% (95% CI, 20%-30%) in the 2-dose schedule group, 20% (95% CI, 16%-25%) in the 2 + 1-dose schedule group, and 38% (95% CI, 33%-44%) in the control group (Table 2). A further decrease of vaccine serotype carriage was found at 18 months after the 2 + 1-dose schedule and at 24 months after 2 primary doses compared with the control group (Table 2). In the post-hoc analysis comparing the 2-dose and 2 + 1-dose schedules, we observed a significant difference in vaccine serotype carriage at 18 months with 24% (95% CI, 20%-29%) vaccine serotype carriage in the 2-dose schedule group compared with 16% (95% CI, 12%-20%) in the 2 + 1-dose schedule group (P = .01). At 24 months, the point estimates for vaccine serotype carriage in both vaccine groups were at the same level with 15% (95% CI, 11%-19%) in the 2-dose schedule group and 14% (95% CI, 11%-18%) in the 2 + 1-dose schedule group, compared with 36% (95% CI, 30%-41%) in the control group.

Although this study was not powered for detecting differences in individual serotypes, both vaccine schedules showed lower point estimates for frequently carried serotype 23F at 12 and 18 months. Also, the point estimates for serotype 19F at 12 months and serotypes 6B and 19F at 18 months were lower in children having received a booster dose than in children in the 2-dose schedule group (Table 3). At 24 months, both vaccine schedules showed point estimates at the same level for all vaccine serotypes.

Table Graphic Jump LocationTable 3. Frequencies of Nasopharyngeal Carriage of Individual Pneumococcal Vaccine and Nonvaccine Serotypes in Vaccinated Children After a 2-Dose and 2 + 1-Dose PCV-7 Schedule and Unvaccinated Control Children at 12, 18, and 24 Monthsa

Coinciding with the reduction in vaccine serotype carriage in vaccinees, we observed a significant increase in nonvaccine serotype carriage during the second year of life, with 38% (95% CI, 33%-43%), 38% (95% CI, 33%-43%), and 29% (95% CI, 24%-34%) at 12 months and 40% (95% CI, 35%-45%), 43% (95% CI, 38%-49%), and 30% (95% CI, 25%-35%) at 24 months for the 2-dose schedule, 2 + 1-dose schedule, and control groups, respectively (Table 2). No cross-protection against vaccine-related serotype 6A for either vaccine schedule was observed (Table 3). Vaccine-related serotype 19A carriage was found increased at 12 months in the 2-dose schedule and 2 + 1-dose schedule groups and at 24 months in the 2 + 1-dose schedule group, becoming the second most prevalent nonvaccine serotype after serotype 6A (Table 3).

The decrease in vaccine serotype carriage together with the smaller increase in nonvaccine serotype carriage resulted in a significant decrease in overall pneumococcal carriage for the 2 + 1-dose schedule group from 12 months onward and for the 2-dose schedule group at 24 months (Table 3).

Effect of PCV-7 Vaccinations on Pneumococcal Carriage in Parents

A total of 3823 (96.7% of planned) nasopharyngeal swabs were collected from parents, of which 13.7% were positive for S pneumoniae. Results from parents of twins were excluded (n = 15), because the effect of different randomized vaccine schedules could compromise the analyses. Nine parents (9%) with both a positive transoral and transnasal swab had different serotypes isolated from the transoral and transnasal swabs. All collected serotypes were included in the analysis. No statistically significant differences in vaccine serotype and overall pneumococcal carriage were observed between parents of vaccinees and parents of controls at the index child's age of 12 and 24 months. However, at the index child's age of 24 months, nonvaccine serotype carriage in parents of vaccinees in the 2-dose and 2 + 1-dose schedule groups had increased by 80% and 102%, respectively (Table 4). Numbers were too small to evaluate serotype-specific results. The most frequent serotypes identified in parents of controls (n ≥ 5) at the child's age of 24 months were serotypes 19F, 6B, 14, and 3, and in parents of vaccinees (n ≥ 10) were 19A, 19F, 11A, and 6A.

Table Graphic Jump LocationTable 4. Frequencies of Nasopharyngeal Pneumococcal Carriage in Parents of Children Vaccinated With a 2-Dose or 2 + 1-Dose PCV-7 Schedule and Parents of Unvaccinated Controls at the Child's Age of 12 and 24 Monthsa

This is to our knowledge the first large, randomized controlled trial investigating the effects of reduced-dose PCV-7 schedules on nasopharyngeal pneumococcal carriage in a PCV-7 unvaccinated population. We have shown that a PCV-7 schedule with only 2 primary doses results in significantly decreased vaccine serotype carriage in immunized children from 12 months onward compared with unvaccinated controls. The booster dose resulted in an earlier further reduction of vaccine serotype carriage at 18 months compared with no booster dose. At 24 months, both vaccine schedules produced a similar reduction in vaccine serotype carriage. The observed reduction in vaccine serotype carriage after the 2 + 1-dose schedule is furthermore comparable with the reductions after 3 primary doses with or without a later booster dose as reported by others, despite variation in vaccination intervals, study population, and study vaccines.24,25 Only in 1 previous nonrandomized, case-control study26 of 2 doses of 5-valent pneumococcal conjugate vaccine administered to infants younger than 6 months with a 1-month interval between doses was vaccine serotype carriage reduction at 24 months reported less than what we observed (26% reduction in vaccine serotype carriage vs 58% in our study). This may be due to the shorter 1-month interval between vaccinations.26

The administration of a booster dose has been suggested as important for the magnitude and duration of vaccine serotype carriage reduction.14,27 The difference in vaccine serotype carriage reduction between both schedules at 18 months was primarily due to an earlier significant reduction of serotype 6B and 19F after administration of the booster dose compared with no booster dose. In our study, the temporary advantage of the booster on vaccine serotype carriage reduction observed at 18 months was not observed at 24 months when both schemes showed a reduction of approximately 60% vaccine serotype carriage. This suggests that the booster dose may contribute to an earlier reduction of vaccine serotype carriage in particular for lower immunogenic serotypes like serotype 6B or for serotypes requiring high antibody levels such as serotype 19F,10,28 but may not be necessary for long-term carriage reduction. However, the effect of natural boosting of the immune system by circulating vaccine serotype strains in the population in this trial setting may differ after widespread PCV-7 implementation with disappearance of circulating vaccine serotype pneumococci and making a booster dose necessary.

The reduction in serotype 6B carriage was not observed until 18 months in our study, which is late compared with other studies.24,25 Lower point estimates for serotype 6B carriage in children at 9 and 12 months following 3 priming doses with a 1- and 2-month interval but without a booster dose have been observed.24,25 Three priming doses may be more efficient in eliciting adequate antibody levels at an early age10,28 and may be required for early serotype 6B carriage reduction. For early protection against invasive disease caused by serotype 6B, however, 2 primary doses may still be sufficient.9 Although threshold protective antibody levels are not well understood yet and seem to differ by serotype, the levels needed to prevent carriage29 are likely higher than what is needed for invasive disease1,30 and possibly also for pneumonia and otitis media.31 Effect of reduced schedules on disease, in particular respiratory disease like pneumonia and otitis, thus needs to be evaluated.

One of the drawbacks of current pneumococcal conjugate vaccination with limited serotype coverage is serotype replacement, with nonvaccine serotype pneumococci filling the ecological vacant nasopharyngeal niche and counterbalancing the reduction in vaccine serotype carriage, thereby potentially causing increased nonvaccine serotype disease.24,25,32 This replacement phenomenon seems to be more common in otitis media with a direct connection to the nasopharynx via the Eustachian tube but much less in IPD.33 For IPD, a discrete increase of nonvaccine serotype–associated episodes has been reported but particularly among high-risk populations and elderly persons.2,3436 In our study, we also observed nasopharyngeal serotype replacement in vaccinated children, but the reduction in vaccine serotype carriage still resulted in a net decrease in overall pneumococcal carriage in children. The observed net decrease in our study may however disappear with time after widespread PCV-7 implementation when nonvaccine serotypes may become more frequent colonizers of the nasopharynx in the community.

The sample size in our study was not adequately powered for detecting significant changes in vaccine serotype carriage in parents. However, we observed an increase of nonvaccine serotype carriage in adult contacts of vaccinees over time. This suggests that serotype replacement in vaccinated children leads to a prolonged period of increased colonization in parents because of increased exposure of these adults to a higher diversity of pneumococcal serotypes. Our observation is in line with studies from Alaska, where an increase in nonvaccine serotype carriage and IPD was observed in Alaskan Native adults, who are highly susceptible to IPD, upon PCV-7 vaccination of children.34,37 Furthermore, parents of 12-month-old children in the control group showed high pneumococcal carriage rates (28%) compared with adults from the general population in a previous study in the Netherlands,19 but these higher carriage rates decreased over time in parents of children in the control group.

Considering the increase of nonvaccine serotype carriage in vaccinated children and adult contacts and the potential loss of natural boosting after widespread implementation of reduced-dose PCV-7 schedules, monitoring of pneumococcal carriage and disease remains mandatory in all age groups. A booster dose may be necessary for long-term protection.38,39 Surveillance will provide us with timely information on vaccine efficacy and potential shifts in serotype distribution that may require adjusting vaccine strategies such as extending vaccine-valency. Considering the observed increase in serotype 19A and the reported disease potential, serotype 19A seems an important future vaccine candidate.40

To appreciate our results, some potential limitations should be addressed. First, we used a single colony–method for serotyping and other simultaneously carried serotypes may have been missed. Considering the reported low rate (1%-8%) of multiple serotype carriage by others, the use of multiple colony serotyping would not have substantially affected our results.24,41 Second, our study was not powered to detect changes in children at 6 months, when pneumococcal carriage rates are still relatively low in the Netherlands, similar to most western countries. The study by O’Brien et al24 observed a significant reduction in vaccine serotype carriage in vaccinated children at 7 months, but this study was performed in a high-risk population already at its peak vaccine serotype carriage rate, in contrast with our study where the peak was later at 12 months. Third, when extrapolating our results to other countries, especially non-western countries, geographical differences need to be taken into account (eg, carriage dynamics, serotype distribution). Finally, we chose not to correct for multiple testing in the statistical analysis of our secondary outcomes, because such multiple testing in our trial with different hypotheses and dependency between data are too conservative. However, the results of the significant secondary outcomes need to be cautiously interpreted and we need to be aware that significant results may have occurred by chance. Therefore, to confirm these results, the corresponding hypotheses have to be tested in confirmatory studies.

Strengths of our study include the randomized controlled study design with an adequate sample size, virtual absence of loss to follow-up, high sampling rates (99%), and relatively high carriage rates compared with other western countries. The level of antibiotic resistance that may result in selection of multiresistant serotypes (eg, serotype 19A) in the United States is very low in the Netherlands.42 Finally, the study ended well before potential herd effects of the introduction of PCV-7 in the Dutch National Immunization Program could have affected our results.

In conclusion, both 2-dose and 2 + 1-dose schedules of PCV-7 significantly reduce vaccine serotype pneumococcal carriage in children. This study supports future implementation of reduced-dose PCV-7 schedules.

Corresponding Author: Elisabeth A. M. Sanders, MD, PhD, Department of Pediatric Immunology and Infectious Diseases, Wilhelmina Children's Hospital, University Medical Center Utrecht, PO Box 85090, 3508 AB Utrecht, the Netherlands (l.sanders@umcutrecht.nl).

Author Contributions: Drs van Gils and Sanders had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Hak, van Alphen, Sanders.

Acquisition of data: van Gils, Veenhoven, Rodenburg, IJzerman, Bruin.

Analysis and interpretation of data: van Gils, Veenhoven, Hak, Bogaert, van Alphen, Sanders.

Drafting of the manuscript: van Gils, Veenhoven, Hak, Bogaert, van Alphen, Sanders.

Critical revision of the manuscript for important intellectual content: van Gils, Veenhoven, Hak, Rodenburg, Bogaert, IJzerman, Bruin, van Alphen, Sanders.

Statistical analysis: van Gils, Hak, Bogaert.

Obtained funding: Sanders.

Administrative, technical, or material support: van Gils, Veenhoven, Rodenburg, IJzerman, Bruin.

Study supervision: Veenhoven, Sanders.

Financial Disclosures: Dr Veenhoven reported receiving grant support from GlaxoSmithKline and Wyeth for vaccine studies and consulting fees from GlaxoSmithKline. Dr Sanders reported receiving unrestricted grants from Wyeth and Baxter for research, consulting fees from Wyeth and GlaxoSmithKline, lecturing fees from Wyeth, and grant support from Wyeth and GlaxoSmithKline for vaccine studies. No other authors reported any financial disclosures.

Funding/Support: This work was supported by the Dutch Ministry of Health.

Role of the Sponsor: The Dutch Ministry of Health played no role in the study design and conduct of the study, in the data collection, management, analysis, and interpretation of the data, or in the preparation, review, or approval of the manuscript.

Additional Contributions: We thank the participating children and their families for their time and effort, the members of the research team for their invaluable dedicated work and support, and all cooperating organizations for their support.

Black S, Shinefield H, Fireman B,  et al; Northern California Kaiser Permanente Vaccine Study Center Group.  Efficacy, safety and immunogenicity of heptavalent pneumococcal conjugate vaccine in children.  Pediatr Infect Dis J. 2000;19(3):187-195
PubMed   |  Link to Article
Eskola J, Kilpi T, Palmu A,  et al; Finnish Otitis Media Study Group.  Efficacy of a pneumococcal conjugate vaccine against acute otitis media.  N Engl J Med. 2001;344(6):403-409
PubMed   |  Link to Article
Lexau CA, Lynfield R, Danila R,  et al; Active Bacterial Core Surveillance Team.  Changing epidemiology of invasive pneumococcal disease among older adults in the era of pediatric pneumococcal conjugate vaccine.  JAMA. 2005;294(16):2043-2051
PubMed   |  Link to Article
Whitney CG, Farley MM, Hadler J,  et al; Active Bacterial Core Surveillance of the Emerging Infections Program Network.  Decline in invasive pneumococcal disease after the introduction of protein-polysaccharide conjugate vaccine.  N Engl J Med. 2003;348(18):1737-1746
PubMed   |  Link to Article
Grijalva CG, Nuorti JP, Arbogast PG, Martin SW, Edwards KM, Griffin MR. Decline in pneumonia admissions after routine childhood immunisation with pneumococcal conjugate vaccine in the USA: a time-series analysis.  Lancet. 2007;369(9568):1179-1186
PubMed   |  Link to Article
Poehling KA, Talbot TR, Griffin MR,  et al.  Invasive pneumococcal disease among infants before and after introduction of pneumococcal conjugate vaccine.  JAMA. 2006;295(14):1668-1674
PubMed   |  Link to Article
Whitney CG. Impact of conjugate pneumococcal vaccines.  Pediatr Infect Dis J. 2005;24(8):729-730
PubMed   |  Link to Article
Ray GT, Whitney CG, Fireman BH, Ciuryla V, Black SB. Cost-effectiveness of pneumococcal conjugate vaccine: evidence from the first 5 years of use in the United States incorporating herd effects.  Pediatr Infect Dis J. 2006;25(6):494-501
PubMed   |  Link to Article
Whitney CG, Pilishvili T, Farley MM,  et al.  Effectiveness of seven-valent pneumococcal conjugate vaccine against invasive pneumococcal disease: a matched case-control study.  Lancet. 2006;368(9546):1495-1502
PubMed   |  Link to Article
Goldblatt D, Southern J, Ashton L,  et al.  Immunogenicity and boosting after a reduced number of doses of a pneumococcal conjugate vaccine in infants and toddlers.  Pediatr Infect Dis J. 2006;25(4):312-319
PubMed   |  Link to Article
Vestrheim DF, Lovoll O, Aaberge IS,  et al.  Effectiveness of a 2+1 dose schedule pneumococcal conjugate vaccination programme on invasive pneumococcal disease among children in Norway.  Vaccine. 2008;26(26):3277-3281
PubMed   |  Link to Article
Centers for Disease Control and Prevention (CDC).  Progress in introduction of pneumococcal conjugate vaccine—worldwide, 2000-2008.  MMWR Morb Mortal Wkly Rep. 2008;57(42):1148-1151
PubMed
Jones VF, Harrison C, Stout GG, Hopkins J. Nasopharyngeal colonization with heptavalent pneumococcal conjugate vaccine serotypes of Streptococcus pneumoniae with prolonged vaccine dosing intervals.  Pediatr Infect Dis J. 2005;24(11):969-973
PubMed   |  Link to Article
Trotter CL, McVernon J, Ramsay ME,  et al; SAGE subgroup.  Optimising the use of conjugate vaccines to prevent disease caused by Haemophilus influenzae type b, Neisseria meningitidis and Streptococcus pneumoniae.  Vaccine. 2008;26(35):4434-4445
PubMed   |  Link to Article
Käyhty H, Auranen K, Nohynek H, Dagan R, Mäkelä H. Nasopharyngeal colonization: a target for pneumococcal vaccination.  Expert Rev Vaccines. 2006;5(5):651-667
PubMed   |  Link to Article
Watt JP, O'Brien KL, Katz S,  et al.  Nasopharyngeal versus oropharyngeal sampling for detection of pneumococcal carriage in adults.  J Clin Microbiol. 2004;42(11):4974-4976
PubMed   |  Link to Article
O'Brien KL, Nohynek H.World Health Organization Pneumococcal Vaccine Trials Carriage Working Group.  Report from a WHO Working Group: standard method for detecting upper respiratory carriage of Streptococcus pneumoniae.  Pediatr Infect Dis J. 2003;22(2):e1-e11
PubMed
Veenhoven RH, Bogaert D, Schilder AG,  et al.  Nasopharyngeal pneumococcal carriage after combined pneumococcal conjugate and polysaccharide vaccination in children with a history of recurrent acute otitis media.  Clin Infect Dis. 2004;39(7):911-919
PubMed   |  Link to Article
Bogaert D, van Belkum A, Sluijter M,  et al.  Colonisation by Streptococcus pneumoniae and Staphylococcus aureus in healthy children.  Lancet. 2004;363(9424):1871-1872
PubMed   |  Link to Article
Harrell FE Jr. Regression Modeling Strategies With Applications to Linear Models, Logistic Regression, and Survival Analysis. New York, NY: Springer; 2001
Zeger SL, Liang KY. Longitudinal data analysis for discrete and continuous outcomes.  Biometrics. 1986;42(1):121-130
PubMed   |  Link to Article
Zeger SL, Liang KY, Albert PS. Models for longitudinal data: a generalized estimating equation approach.  Biometrics. 1988;44(4):1049-1060
PubMed   |  Link to Article
Perneger TV. What's wrong with Bonferroni adjustments.  BMJ. 1998;316(7139):1236-1238
PubMed   |  Link to Article
O'Brien KL, Millar EV, Zell ER,  et al.  Effect of pneumococcal conjugate vaccine on nasopharyngeal colonization among immunized and unimmunized children in a community-randomized trial.  J Infect Dis. 2007;196(8):1211-1220
PubMed   |  Link to Article
Mbelle N, Huebner RE, Wasas AD, Kimura A, Chang I, Klugman KP. Immunogenicity and impact on nasopharyngeal carriage of a nonavalent pneumococcal conjugate vaccine.  J Infect Dis. 1999;180(4):1171-1176
PubMed   |  Link to Article
Obaro SK, Adegbola RA, Banya WA, Greenwood BM. Carriage of pneumococci after pneumococcal vaccination.  Lancet. 1996;348(9022):271-272
PubMed   |  Link to Article
Ghaffar F, Barton T, Lozano J,  et al.  Effect of the 7-valent pneumococcal conjugate vaccine on nasopharyngeal colonization by Streptococcus pneumoniae in the first 2 years of life.  Clin Infect Dis. 2004;39(7):930-938
PubMed   |  Link to Article
Käyhty H, Ahman H, Eriksson K, Sorberg M, Nilsson L. Immunogenicity and tolerability of a heptavalent pneumococcal conjugate vaccine administered at 3, 5 and 12 months of age.  Pediatr Infect Dis J. 2005;24(2):108-114
PubMed   |  Link to Article
Goldblatt D, Hussain M, Andrews N,  et al.  Antibody responses to nasopharyngeal carriage of Streptococcus pneumoniae in adults: a longitudinal household study.  J Infect Dis. 2005;192(3):387-393
PubMed   |  Link to Article
Siber GR, Chang I, Baker S,  et al.  Estimating the protective concentration of anti-pneumococcal capsular polysaccharide antibodies.  Vaccine. 2007;25(19):3816-3826
PubMed   |  Link to Article
Jokinen JT, Ahman H, Kilpi TM, Makela PH, Kayhty MH. Concentration of antipneumococcal antibodies as a serological correlate of protection: an application to acute otitis media.  J Infect Dis. 2004;190(3):545-550
PubMed   |  Link to Article
Obaro SK, Adegbola RA, Chang I,  et al.  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.  Pediatr Infect Dis J. 2000;19(5):463-469
PubMed   |  Link to Article
Bogaert D, De Groot R, Hermans PW. Streptococcus pneumoniae colonisation: the key to pneumococcal disease.  Lancet Infect Dis. 2004;4(3):144-154
PubMed   |  Link to Article
Singleton RJ, Hennessy TW, Bulkow LR,  et al.  Invasive pneumococcal disease caused by nonvaccine serotypes among Alaska native children with high levels of 7-valent pneumococcal conjugate vaccine coverage.  JAMA. 2007;297(16):1784-1792
PubMed   |  Link to Article
Flannery B, Heffernan RT, Harrison LH,  et al.  Changes in invasive pneumococcal disease among HIV-infected adults living in the era of childhood pneumococcal immunization.  Ann Intern Med. 2006;144(1):1-9
PubMed   |  Link to Article
Hicks LA, Harrison LH, Flannery B,  et al.  Incidence of pneumococcal disease due to non-pneumococcal conjugate vaccine (PCV7) serotypes in the United States during the era of widespread PCV7 vaccination, 1998-2004.  J Infect Dis. 2007;196(9):1346-1354
PubMed   |  Link to Article
Hammitt LL, Bruden DL, Butler JC,  et al.  Indirect effect of conjugate vaccine on adult carriage of Streptococcus pneumoniae: an explanation of trends in invasive pneumococcal disease.  J Infect Dis. 2006;193(11):1487-1494
PubMed   |  Link to Article
Heath PT, McVernon J. The UK Hib vaccine experience.  Arch Dis Child. 2002;86(6):396-399
PubMed   |  Link to Article
Kelly DF, Moxon ER, Pollard AJ. Haemophilus influenzae type b conjugate vaccines.  Immunology. 2004;113(2):163-174
PubMed   |  Link to Article
Centers for Disease Control and Prevention (CDC).  Emergence of antimicrobial-resistant serotype 19A Streptococcus pneumoniae—Massachusetts, 2001-2006.  MMWR Morb Mortal Wkly Rep. 2007;56(41):1077-1080
PubMed
Huebner RE, Dagan R, Porath N, Wasas AD, Klugman KP. Lack of utility of serotyping multiple colonies for detection of simultaneous nasopharyngeal carriage of different pneumococcal serotypes.  Pediatr Infect Dis J. 2000;19(10):1017-1020
PubMed   |  Link to Article
Bogaert D, Engelen MN, Timmers-Reker AJ,  et al.  Pneumococcal carriage in children in the Netherlands: a molecular epidemiological study.  J Clin Microbiol. 2001;39(9):3316-3320
PubMed   |  Link to Article

Figures

Place holder to copy figure label and caption
Figure. Enrollment Flow Diagram
Graphic Jump Location

PCV-7 indicates 7-valent pneumococcal conjugate vaccine. aParents of children interested in participating in the study were redundant because they were still in the information process of the study after enrollment target had already been achieved and informed consent process was cancelled.

Tables

Table Graphic Jump LocationTable 3. Frequencies of Nasopharyngeal Carriage of Individual Pneumococcal Vaccine and Nonvaccine Serotypes in Vaccinated Children After a 2-Dose and 2 + 1-Dose PCV-7 Schedule and Unvaccinated Control Children at 12, 18, and 24 Monthsa
Table Graphic Jump LocationTable 4. Frequencies of Nasopharyngeal Pneumococcal Carriage in Parents of Children Vaccinated With a 2-Dose or 2 + 1-Dose PCV-7 Schedule and Parents of Unvaccinated Controls at the Child's Age of 12 and 24 Monthsa
Table Graphic Jump LocationTable 2. Frequencies of Pneumococcal Nasopharyngeal Carriage in Vaccinated Children After a 2-Dose and 2 + 1-Dose PCV-7 Schedule and Unvaccinated Control Children at 12, 18, and 24 Monthsa
Table Graphic Jump LocationTable 1. Characteristics of the Children and Parents at Time of Enrollment and During Follow-up

References

Black S, Shinefield H, Fireman B,  et al; Northern California Kaiser Permanente Vaccine Study Center Group.  Efficacy, safety and immunogenicity of heptavalent pneumococcal conjugate vaccine in children.  Pediatr Infect Dis J. 2000;19(3):187-195
PubMed   |  Link to Article
Eskola J, Kilpi T, Palmu A,  et al; Finnish Otitis Media Study Group.  Efficacy of a pneumococcal conjugate vaccine against acute otitis media.  N Engl J Med. 2001;344(6):403-409
PubMed   |  Link to Article
Lexau CA, Lynfield R, Danila R,  et al; Active Bacterial Core Surveillance Team.  Changing epidemiology of invasive pneumococcal disease among older adults in the era of pediatric pneumococcal conjugate vaccine.  JAMA. 2005;294(16):2043-2051
PubMed   |  Link to Article
Whitney CG, Farley MM, Hadler J,  et al; Active Bacterial Core Surveillance of the Emerging Infections Program Network.  Decline in invasive pneumococcal disease after the introduction of protein-polysaccharide conjugate vaccine.  N Engl J Med. 2003;348(18):1737-1746
PubMed   |  Link to Article
Grijalva CG, Nuorti JP, Arbogast PG, Martin SW, Edwards KM, Griffin MR. Decline in pneumonia admissions after routine childhood immunisation with pneumococcal conjugate vaccine in the USA: a time-series analysis.  Lancet. 2007;369(9568):1179-1186
PubMed   |  Link to Article
Poehling KA, Talbot TR, Griffin MR,  et al.  Invasive pneumococcal disease among infants before and after introduction of pneumococcal conjugate vaccine.  JAMA. 2006;295(14):1668-1674
PubMed   |  Link to Article
Whitney CG. Impact of conjugate pneumococcal vaccines.  Pediatr Infect Dis J. 2005;24(8):729-730
PubMed   |  Link to Article
Ray GT, Whitney CG, Fireman BH, Ciuryla V, Black SB. Cost-effectiveness of pneumococcal conjugate vaccine: evidence from the first 5 years of use in the United States incorporating herd effects.  Pediatr Infect Dis J. 2006;25(6):494-501
PubMed   |  Link to Article
Whitney CG, Pilishvili T, Farley MM,  et al.  Effectiveness of seven-valent pneumococcal conjugate vaccine against invasive pneumococcal disease: a matched case-control study.  Lancet. 2006;368(9546):1495-1502
PubMed   |  Link to Article
Goldblatt D, Southern J, Ashton L,  et al.  Immunogenicity and boosting after a reduced number of doses of a pneumococcal conjugate vaccine in infants and toddlers.  Pediatr Infect Dis J. 2006;25(4):312-319
PubMed   |  Link to Article
Vestrheim DF, Lovoll O, Aaberge IS,  et al.  Effectiveness of a 2+1 dose schedule pneumococcal conjugate vaccination programme on invasive pneumococcal disease among children in Norway.  Vaccine. 2008;26(26):3277-3281
PubMed   |  Link to Article
Centers for Disease Control and Prevention (CDC).  Progress in introduction of pneumococcal conjugate vaccine—worldwide, 2000-2008.  MMWR Morb Mortal Wkly Rep. 2008;57(42):1148-1151
PubMed
Jones VF, Harrison C, Stout GG, Hopkins J. Nasopharyngeal colonization with heptavalent pneumococcal conjugate vaccine serotypes of Streptococcus pneumoniae with prolonged vaccine dosing intervals.  Pediatr Infect Dis J. 2005;24(11):969-973
PubMed   |  Link to Article
Trotter CL, McVernon J, Ramsay ME,  et al; SAGE subgroup.  Optimising the use of conjugate vaccines to prevent disease caused by Haemophilus influenzae type b, Neisseria meningitidis and Streptococcus pneumoniae.  Vaccine. 2008;26(35):4434-4445
PubMed   |  Link to Article
Käyhty H, Auranen K, Nohynek H, Dagan R, Mäkelä H. Nasopharyngeal colonization: a target for pneumococcal vaccination.  Expert Rev Vaccines. 2006;5(5):651-667
PubMed   |  Link to Article
Watt JP, O'Brien KL, Katz S,  et al.  Nasopharyngeal versus oropharyngeal sampling for detection of pneumococcal carriage in adults.  J Clin Microbiol. 2004;42(11):4974-4976
PubMed   |  Link to Article
O'Brien KL, Nohynek H.World Health Organization Pneumococcal Vaccine Trials Carriage Working Group.  Report from a WHO Working Group: standard method for detecting upper respiratory carriage of Streptococcus pneumoniae.  Pediatr Infect Dis J. 2003;22(2):e1-e11
PubMed
Veenhoven RH, Bogaert D, Schilder AG,  et al.  Nasopharyngeal pneumococcal carriage after combined pneumococcal conjugate and polysaccharide vaccination in children with a history of recurrent acute otitis media.  Clin Infect Dis. 2004;39(7):911-919
PubMed   |  Link to Article
Bogaert D, van Belkum A, Sluijter M,  et al.  Colonisation by Streptococcus pneumoniae and Staphylococcus aureus in healthy children.  Lancet. 2004;363(9424):1871-1872
PubMed   |  Link to Article
Harrell FE Jr. Regression Modeling Strategies With Applications to Linear Models, Logistic Regression, and Survival Analysis. New York, NY: Springer; 2001
Zeger SL, Liang KY. Longitudinal data analysis for discrete and continuous outcomes.  Biometrics. 1986;42(1):121-130
PubMed   |  Link to Article
Zeger SL, Liang KY, Albert PS. Models for longitudinal data: a generalized estimating equation approach.  Biometrics. 1988;44(4):1049-1060
PubMed   |  Link to Article
Perneger TV. What's wrong with Bonferroni adjustments.  BMJ. 1998;316(7139):1236-1238
PubMed   |  Link to Article
O'Brien KL, Millar EV, Zell ER,  et al.  Effect of pneumococcal conjugate vaccine on nasopharyngeal colonization among immunized and unimmunized children in a community-randomized trial.  J Infect Dis. 2007;196(8):1211-1220
PubMed   |  Link to Article
Mbelle N, Huebner RE, Wasas AD, Kimura A, Chang I, Klugman KP. Immunogenicity and impact on nasopharyngeal carriage of a nonavalent pneumococcal conjugate vaccine.  J Infect Dis. 1999;180(4):1171-1176
PubMed   |  Link to Article
Obaro SK, Adegbola RA, Banya WA, Greenwood BM. Carriage of pneumococci after pneumococcal vaccination.  Lancet. 1996;348(9022):271-272
PubMed   |  Link to Article
Ghaffar F, Barton T, Lozano J,  et al.  Effect of the 7-valent pneumococcal conjugate vaccine on nasopharyngeal colonization by Streptococcus pneumoniae in the first 2 years of life.  Clin Infect Dis. 2004;39(7):930-938
PubMed   |  Link to Article
Käyhty H, Ahman H, Eriksson K, Sorberg M, Nilsson L. Immunogenicity and tolerability of a heptavalent pneumococcal conjugate vaccine administered at 3, 5 and 12 months of age.  Pediatr Infect Dis J. 2005;24(2):108-114
PubMed   |  Link to Article
Goldblatt D, Hussain M, Andrews N,  et al.  Antibody responses to nasopharyngeal carriage of Streptococcus pneumoniae in adults: a longitudinal household study.  J Infect Dis. 2005;192(3):387-393
PubMed   |  Link to Article
Siber GR, Chang I, Baker S,  et al.  Estimating the protective concentration of anti-pneumococcal capsular polysaccharide antibodies.  Vaccine. 2007;25(19):3816-3826
PubMed   |  Link to Article
Jokinen JT, Ahman H, Kilpi TM, Makela PH, Kayhty MH. Concentration of antipneumococcal antibodies as a serological correlate of protection: an application to acute otitis media.  J Infect Dis. 2004;190(3):545-550
PubMed   |  Link to Article
Obaro SK, Adegbola RA, Chang I,  et al.  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.  Pediatr Infect Dis J. 2000;19(5):463-469
PubMed   |  Link to Article
Bogaert D, De Groot R, Hermans PW. Streptococcus pneumoniae colonisation: the key to pneumococcal disease.  Lancet Infect Dis. 2004;4(3):144-154
PubMed   |  Link to Article
Singleton RJ, Hennessy TW, Bulkow LR,  et al.  Invasive pneumococcal disease caused by nonvaccine serotypes among Alaska native children with high levels of 7-valent pneumococcal conjugate vaccine coverage.  JAMA. 2007;297(16):1784-1792
PubMed   |  Link to Article
Flannery B, Heffernan RT, Harrison LH,  et al.  Changes in invasive pneumococcal disease among HIV-infected adults living in the era of childhood pneumococcal immunization.  Ann Intern Med. 2006;144(1):1-9
PubMed   |  Link to Article
Hicks LA, Harrison LH, Flannery B,  et al.  Incidence of pneumococcal disease due to non-pneumococcal conjugate vaccine (PCV7) serotypes in the United States during the era of widespread PCV7 vaccination, 1998-2004.  J Infect Dis. 2007;196(9):1346-1354
PubMed   |  Link to Article
Hammitt LL, Bruden DL, Butler JC,  et al.  Indirect effect of conjugate vaccine on adult carriage of Streptococcus pneumoniae: an explanation of trends in invasive pneumococcal disease.  J Infect Dis. 2006;193(11):1487-1494
PubMed   |  Link to Article
Heath PT, McVernon J. The UK Hib vaccine experience.  Arch Dis Child. 2002;86(6):396-399
PubMed   |  Link to Article
Kelly DF, Moxon ER, Pollard AJ. Haemophilus influenzae type b conjugate vaccines.  Immunology. 2004;113(2):163-174
PubMed   |  Link to Article
Centers for Disease Control and Prevention (CDC).  Emergence of antimicrobial-resistant serotype 19A Streptococcus pneumoniae—Massachusetts, 2001-2006.  MMWR Morb Mortal Wkly Rep. 2007;56(41):1077-1080
PubMed
Huebner RE, Dagan R, Porath N, Wasas AD, Klugman KP. Lack of utility of serotyping multiple colonies for detection of simultaneous nasopharyngeal carriage of different pneumococcal serotypes.  Pediatr Infect Dis J. 2000;19(10):1017-1020
PubMed   |  Link to Article
Bogaert D, Engelen MN, Timmers-Reker AJ,  et al.  Pneumococcal carriage in children in the Netherlands: a molecular epidemiological study.  J Clin Microbiol. 2001;39(9):3316-3320
PubMed   |  Link to Article
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