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Effect of Pneumococcal Conjugate Vaccine on Nasopharyngeal Colonization among Immunized and Unimmunized Children in a Community-Randomized Trial

  1. Dr. Katherine L. O'Brien1,
  2. Eugene V. Millar1,
  3. Elizabeth R. Zell2,
  4. Melinda Bronsdon2,a,
  5. Robert Weatherholtz1,
  6. Raymond Reid1,
  7. Jocelyn Becenti1,b,
  8. Sheri Kvamme1,a,
  9. Cynthia G. Whitney2 and
  10. Mathuram Santosham1
  1. 1 Center for American Indian Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland
  2. 2 Division of Bacterial Diseases, National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia
  1. Reprints or correspondence: Dr. Katherine O'Brien, 621 N. Washington St., Baltimore, MD 21205 (klobrien{at}jhsph.edu).

  1. Presented in part: 3rd International Symposium on Pneumococci and Pneumococcal Disease, Anchorage, Alaska, 5–8 May 2002 (abstract 7); 41st Interscience Conference on Antimicrobial Agents and Chemotherapy, Chicago, 16–19 December 2001 (abstract 2032); annual meeting of the Society for Pediatric Research, Baltimore, Maryland, 28 April–1 May 2001 (abstract 1463).

  • ↵Present affiliation: Albuquerque Veterans Affairs Medical Center, Albuquerque, New Mexico.

 
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Abstract

Background.Pneumococcal conjugate vaccines (PCVs) prevent vaccine serotype (VT) invasive disease; nonvaccine serotype (NVT) disease increases modestly. The impact of PCV on nasopharyngeal (NP) colonization is essential to understanding disease effects.

Methods.We conducted a community-randomized controlled trial with catch-up vaccination through age 2 years investigating the effect of 7-valent PCV (PnCRM7) on NP colonization among American Indian infants and their unvaccinated contacts. Infants receiving blinded vaccine at 2, 4, 6, and 12–15 months of age had NP cultures obtained at age 7, 12, and 18 months. Serotype-specific colonization was detected by immunoblot.

Results.We enrolled 566 vaccinated and 286 unvaccinated children from 511 households and collected 5157 specimens, of which 3525 (68.4%) had pneumococcus. PnCRM7 vaccinees were less likely to be colonized with VT (odds ratio [OR], 0.40 [95% confidence interval {CI}, 0.23–0.67]) but were more likely to be colonized with NVT pneumococci (OR, 1.67 [95% CI, 1.02–2.78]). PnCRM7 vaccinees were less densely colonized with VT strains than control vaccinees (OR, 0.61 [95% CI, 0.38–0.99]). Day care–attending unvaccinated children in PnCRM7 communities were less likely to have VT colonization than those in control communities (OR, 0.27 [95% CI, 0.07–1.07]).

Conclusions.PnCRM7 reduces the risk of VT acquisition and colonization density but increases the risk of NVT acquisition among vaccinees and their household contacts.

Pneumococcal conjugate vaccines (PCVs) have been shown to be highly efficacious against serotype-specific invasive disease [1–4], chest radiograph–confirmed pneumonia [1, 3, 4], and otitis media (OM) [1, 5–7]. PCVs have also been shown to reduce vaccine serotype (VT) pneumococcal nasopharyngeal (NP) carriage among vaccinated children [8–11]. Some studies have shown a concomitant increase in nonvaccine serotype (NVT) carriage [8, 10, 11], whereas others have not [6, 9, 12]. Increases in NVT pneumococcal disease have been observed in OM efficacy trials [5, 13] and among some age groups in invasive-disease postlicensure studies [14–16]. Because NP colonization is a precondition for developing disease, it is critical to thoroughly understand the effects of PCV on the pneumococcus ecology among vaccinated and unvaccinated persons.

We conducted a phase 3 efficacy trial of a PCV among the Navajo and White Mountain Apache Indians, who are known to be at high risk for invasive pneumococcal disease. Within that trial, we nested an NP colonization study aiming to assess the effect of vaccine on the acquisition risk, density, and duration of pneumococcal carriage among vaccinated and unvaccinated children. Because the assay sensitivity for the detection of multiple-serotype carriage largely determines the ability to interpret the biological basis for observed increases in NVT colonization [17], we detected multiple-serotype carriage by use of a highly sensitive immunoblot method.

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Methods

A group-randomized efficacy trial of a 7-valent PCV (PnCRM7; Wyeth Vaccines; serotypes 4, 6B, 9V, 14, 18C, 19F, and 23F) was conducted on the Navajo and White Mountain Apache reservations between April 1997 and October 2000 [2, 18]. Defined geographic randomization units that had a priori minimal social interactions with other randomization units allowed an evaluation of the indirect effects of PnCRM7 on colonization and disease.

Enrolled children received either PnCRM7 or a control vaccine (Neisseria meningitidis group C protein conjugate vaccine [MnCC]; Wyeth Vaccines); all children <2 years of age were eligible to participate in the trial. Infants in the primary efficacy group were those enrolled between 6 weeks and 7 months of age; they received a 4-dose vaccine regimen, whereas infants enrolling at >7 months of age received a 3- or 2-dose regimen [2]. A total of 8292 children were enrolled in the trial, of whom 5792 (69.8%) were in the primary efficacy group.

Primary efficacy infants receiving their third vaccine dose before 11 months of age (i.e., vaccinees) were recruited for a nested study of NP colonization. Child household members (i.e., <6 years of age) of vaccinees in the nested NP study were also enrolled to assess the indirect effects of vaccination. Children with congenital anomalies of the nasopharynx were excluded from the nested NP study.

The study was approved by the institutional review boards of Johns Hopkins University, the Centers for Disease Control and Prevention (CDC), the Navajo Nation, the Phoenix Area Indian Health Service, and the National Indian Health Service. Tribal approval was given by the Navajo Nation and the White Mountain Apache tribe. Parents or guardians of study children signed a written informed consent document after reading the document or having the consent document read and explained to them in English or in their native language.

NP samples were collected from vaccinees in the nested NP study at 3 scheduled visits: round 1 occurred 1 month after the third vaccine dose (i.e., 7 months of age), round 2 occurred at the booster dose of vaccine (i.e., 12–15 months of age), and round 3 occurred 6–9 months after the booster dose (i.e., 18–24 months of age). NP swabs were collected from the vaccinees and enrolled household children. Within a household, if pneumococcus was isolated from the NP specimen of a vaccinee or household member at a scheduled visit (i.e., round 1, 2, or 3), then follow-up visits were made at 1 and 3 months after the scheduled visit to assess duration of colonization.

Trained field-workers collected the NP specimens by use of pediatric calcium alginate swabs (Fisher Scientific). Swabs were inserted into the posterior nasopharynx, rotated 180 degrees, removed, placed in STGG transport medium (consisting of skim milk, tryptone, glucose, and glycerin) [19], frozen at -70°C, and transported on dry ice to the CDC for pneumococcal isolation and serotyping.

A 10-μL aliquot of each specimen was inoculated onto a gentamicin–tryptic soy agar 5% sheep blood agar plate (Becton Dickinson) and incubated overnight at 37°C in 5% CO2. Phenotypic characteristics (morphology and α-hemolysis) were used for the presumptive pneumococcal identification. Pneumococcal growth was characterized semiquantitatively as 1+ (<25 colonies), 2+ (25 to <100 colonies), 3+ (⩾100 colonies but not confluent), or 4+ (confluent growth). These categories were used in the density-of-colonization analysis.

Pneumococci were identified by an immunoblot method, using the 37-kDa monoclonal antibody to PsaA antigen and serotype-specific monoclonal antibodies as described elsewhere [20]. The immunoblot method was developed to increase the sensitivity for detecting multiple pneumococcal serotypes in NP specimens. For specimens with <25 colonies, 4 colonies were picked from the plate and serotyped by the Quellung reaction.

A second cohort of infants, too young to be immunized, were recruited into a cross-sectional NP carriage study from September 1999 to April 2001. A single NP specimen was collected from 2-month-old infants and was handled as described above, except that a single colony was subcultured and serotyped by the Quellung reaction. If >1 distinct morphological colony type was present, each was serotyped.

Serotypes were grouped into 1 of 2 mutually exclusive categories: (1) vaccine type (VT; i.e., types 4, 6B, 9V, 14, 18C, 19F, and 23F) and (2) nonvaccine type (NVT). A subcategory of the NVT was defined as consisting of vaccine-associated types (VATs) and included isolates of a PnCRM7 serogroup but not serotype (i.e., groups 6, 9, 18, 19, 23 other than 6B, 9V, 18C, 19F, or 23F). Strains belonging to serotypes or serogroups other than 4, 6, 9, 14, 18, 19 and 23 were designated non–vaccine-associated nonvaccine serotypes (NVA/NVTs). Nontypeable isolates were excluded from the multivariable models but were included in other analyses.

Demographic and risk factor information was collected at each visit. Day care was defined as a place with ⩾5 children attended by the child ⩾3 days per week and ⩾4 h per day.

The per-protocol (PP) definitions for NP specimen collection were as follows: round 1, 14–56 days after dose 3; round 2, 0–6 days after the booster dose; round 3, 4 months (120 days) to 1 year (365 days) after the booster dose. The PP definition for the vaccinee was applied to other enrollees in the household for the analysis. For households with >1 vaccinee, the earliest vaccination dates for each dose were used as the reference date.

The risk of pneumococcal carriage was modeled using multivariate logistic regression. We used generalized estimating equations (GEEs) to control for household and community-level clustering between study observations. The following variables were included in the model for carriage among vaccinees: 2 or more children <6 years of age in the household, smoker in the household, OM in the last month, receiving antibiotics, attended day care in the last month, and wood- or coal-burning stove in the household. Two-way interactions were assessed but were not included in the model for vaccinees. In the model for unvaccinated household members, we controlled for day care attendance in the last month. In the univariate analyses, 2 or more children <6 years living in the household, OM in the last month, receiving antibiotics, the presence of a smoker, and the presence of a wood- or coal-burning stove in the household were not significantly associated with carriage and therefore were not included in the final model. To maintain consistent denominators in the odds ratio (OR) calculations for all-serotype pneumococcal colonization and for serotype-specific analyses, the number of children who were not colonized with pneumococcus was used (e.g., OR for all-serotype pneumococcal colonization = [Pnc+/Pnc- among PnCRM7 vaccinees] / [Pnc+/Pnc- among MnCC vaccinees]; OR for VT colonization = [VT+/Pnc- among PnCRM7 vaccinees] / [VT+/Pnc- among MnCC vaccinees]).

The density-of-colonization analysis was conducted using the PP definitions. The univariate analysis compared the proportion of colonized subjects with VT or NVT cultures within each density category. An ordinal logistic regression model including specimens collected at 7, 12, and 18 months of age to assess density by age, receipt of PnCRM7, sex, presence of household smoker, and use of a wood- or coal-burning stove in the household was constructed using GEEs to control for repeated observations in individuals.

Duration of colonization was assessed using the midpoint between the time of initial detection of a serotype and the next swab that was negative for that serotype. We compared the median carriage duration between PnCRM7 and MnCC vaccine recipients using the Wilcoxon-Mann-Whitney U test. Results were considered to be statistically significant if 2-tailed P ⩽ .05.

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Results

We enrolled 566 vaccinees (294 PnCRM7 recipients and 272 MnCC recipients) from 511 households (264 PnCRM7 households and 247 MnCC households) and 286 unvaccinated household members (144 PnCRM7 households and 142 MnCC households) in the nested NP study between February 1998 and April 1999, with follow-up through May 2000. Of the 286 household members, 62 (21.7%) subsequently enrolled in the efficacy trial; NP results obtained after study-vaccine receipt from these children were excluded from analyses. At round 1, 109 subjects (90 vaccinees and 19 household members) did not meet the PP definitions for NP specimen collection and were excluded from the analysis.

Households enrolled from PnCRM7 or MnCC communities were similar (table 1). There were no significant differences in the characteristics of the vaccinees or the household members for any study visits (table 2).

Figure 1.
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Figure 1.

Proportion of vaccine serotype (VT) isolates in each density-of-growth category at the 7-month visit. Children vaccinated with 7-valent pneumococcal conjugate vaccine (n = 110) are represented by solid black bars, and children vaccinated with Neisseria meningitidis group C protein conjugate vaccine (n = 191) are represented by hatched bars (P = .04).

Table 1.
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Table 1.

Comparison of household characteristics among 7-valent pneumococcal conjugate vaccine (PnCRM7)–randomized households and Neisseria meningitidis group C protein conjugate vaccine (MnCC)–randomized households enrolled in the nasopharyngeal carriage study.

Table 2.
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Table 2.

Characteristics of vaccinees and unvaccinated household members at the time of 7-valent pneumococcal conjugate vaccine (PnCRM7) efficacy trial enrollment and at the time of nasopharyngeal study visits, by randomization group.

In total, 5157 NP specimens were collected from the 852 subjects, of which 3525 (68.4%) were positive for pneumococcus. Multiple-serotype carriage was detected in 284 (8.1%) of the pneumococcal specimens; 275 (96.8%) had 2 serotypes, and 9 (3.2%) had 3 serotypes.

Effect of PnCRM7 among vaccinees.There were no statistically significant differences in the risk of overall pneumococcal carriage among PnCRM7- and MnCC-vaccinated children; however, the OR for pneumococcal carriage at 7 months was 0.77, with an upper bound of 1.00. The proportion of households with any child carrying pneumococcus did not vary by vaccine of randomization (table 3).

Table 3.
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Table 3.

Subject characteristics and the prevalence of pneumococcal carriage among vaccinees.

By 1 month after the third dose (round 1), the PnCRM7 vaccinees were at lower risk of carrying VT pneumococci than control vaccinees (OR, 0.40 [95% CI, 0.23–0.67]). There was no statistically significant protection against VATs, nor was there any increase in the risk of NVT colonization at that time.

Immediately before the booster dose (i.e., round 2), the protective effect of PnCRM7 against VT colonization was still observed among the vaccinees (OR, 0.51 [95% CI, 0.34–0.78]); there was an increased risk, although not significant, of NVA/NVT colonization (OR, 1.62 [95% CI, 0.93–2.83]). By 6 months after the booster dose (i.e., round 3), the difference in VT colonization was no longer significant between the 2 groups, but an increased risk of NVT colonization was seen among PnCRM7 vaccinees (OR, 1.67 [95% CI, 1.02–2.78]).

Serotype-specific results are shown in table 4. For each VT, there was less carriage among PnCRM7 vaccinees than among MnCC vaccinees; however, the difference reached statistical significance only for serotype 23F. At the booster dose, reductions in most serotypes were still seen, but none were significant. By 18 months of age, 6 months after the booster dose, nonsignificant reductions were seen only for serotypes 4, 6B, 9V, and 23F. For serotypes 14 and 19F, the point estimates of carriage were higher among PnCRM7 vaccinees than among control vaccinees.

Table 4.
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Table 4.

Serotype-specific efficacy of 7-valent pneumococcal conjugate vaccine (PnCRM7) against nasopharyngeal carriage among vaccinees.

Density of colonization among vaccinees.At each round (i.e., 7, 12 and 18 months of age), PnCRM7 vaccinees had less dense VT colonization than MnCC vaccinees (figure 1). In the regression model, for every increase in colonization density category, PnCRM7 vaccinees were almost 40% less likely to have that colonization density than MnCC vaccinees (OR, 0.61 [95% CI, 0.38–0.99]); there was no effect of PnCRM7 on density of NVT colonization (OR, 1.17 [95% CI, 0.79–1.72]).

Duration of colonization among vaccinees.There was no effect of PnCRM7 on the duration of colonization for any serotype or for any age at sampling (data not shown).

Indirect effect of PnCRM7 on unvaccinated children.In univariate analyses, older siblings living in PnCRM7 communities who were colonized by pneumococcus had a lower risk of VT colonization than colonized siblings living in MnCC communities; however, the reductions did not reach statistical significance (7-month visit OR, 0.82 [95% CI, 0.41–1.64]; 12-month visit OR, 0.74 [95% CI, 0.31–1.79]; 18-month visit OR, 0.64 [0.29–1.41]). The results of the multivariate model are shown in table 5; day care attendance was found to be an effect modifier. Among unvaccinated children attending day care, there was a lower risk of overall pneumococcal colonization, VT colonization (including 6A, a cross-reacting type), and NVA/NVT colonization for those living in a PnCRM7 community, compared with those living in an MnCC community; the effect was seen as early as 1 month after receipt of the third dose by the household vaccinee. There was evidence of an increased risk of overall pneumococcal colonization, VT colonization, and NVT and NVA/NVT colonization among unvaccinated children living in PnCRM7 communities who were not attending day care.

Table 5.
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Table 5.

Subject characteristics and prevalence of pneumococcal carriage among unvaccinated household members.

Children too young to be immunized.We enrolled 598 unimmunized infants 6–12 weeks of age (mean, 51 days old). A single NP sample was collected immediately before their first dose of blinded study vaccine (n = 393) or open-label PnCRM7 (n = 205). Children living in PnCRM7 communities (n = 318) were less likely to be breast-fed at the time of specimen collection than those from MnCC communities (n = 280) (65.4% vs. 55.0%; P = .01). Of the 280 children residing in MnCC communities, 22 (7.8%) lived with a child who had received PnCRM7; these 22 children were excluded from further analyses, leaving 258 infants from MnCC communities with no known PnCRM7 contact.

Infants in PnCRM7 communities were more likely than those in MnCC communities to carry pneumococcus, but the difference did not reach statistical significance (table 6). The proportion of pneumococcal isolates that were VT (plus 6A, a cross-reacting serotype) was significantly lower among those in PnCRM7 communities than MnCC communities (table 6). This reduction was more pronounced among those young infants living in a household with a vaccinee than among those infants without a household vaccinee, although the smaller numbers resulting from this stratification meant that the findings did not reach statistical significance (table 6). Among colonized infants, the proportion of isolates that were NVT or NVA/NVT was greater among those in PnCRM7 communities than MnCC communities.

Table 6.
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Table 6.

Nasopharyngeal colonization among young unimmunized infants living in 7-valent pneumococcal conjugate vaccine (PnCRM7)–randomized communities or Neisseria meningitidis group C protein conjugate vaccine (MnCC)–randomized communities, by PnCRM7 vaccination status of household (HH) children.

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Discussion

PCV has been used for routine infant immunization in the United States since 2000. Reductions in VT invasive pneumococcal disease have been documented among children who are age eligible for the vaccine and among unvaccinated children and adults, the reductions in the latter being the so-called indirect effects [21–24]. Concerns exist about replacement disease caused by NVT strains among vaccinated and unvaccinated people [14–16, 25]. The indirect protective effects against VTs and the indirect and direct replacement effects result in large part from the impact of PCV on NP colonization. It is essential that the effects of PCV on NP colonization be fully understood. The present study offers several unique observations.

This is the first randomized, blinded, controlled trial of the effect of PnCRM7 on NP colonization among infants, the children for whom vaccine is recommended, to be published. Randomized trials of other vaccine products (PnCRM9 [10, 26] and D-4/T-4 [12]), studies of older children [27], and nonrandomized observational studies [22, 28–31] have been published. Furthermore, the present study used a laboratory method that has a very high sensitivity for detecting multiple-serotype pneumococcal carriage [20]. When increases in NVT carriage are observed among PCV vaccinees, 1 of 2 inferences can be drawn: (1) PCV-immunized children are at higher risk of acquiring NVT pneumococci than those who are not immunized (i.e., replacement colonization) or (2) NVT pneumococci are more easily detected in the specimens of PCV-immunized children because VT strains are no longer colonizing (i.e., unmasking). The more sensitive the method for detecting multiple-serotype carriage, the more likely that an observed increase in NVT carriage is attributable to replacement carriage [17]. The present study is also unique in its community-randomized study design, allowing for assessment of the indirect effects of PnCRM7 with a contemporaneous control population. Finally, this is the only published study to assess the effects of PCV on the density of VT colonization.

We have shown that PnCRM7 protects against VT colonization as early as 1 month after the third priming dose of the infant vaccine schedule. We cannot determine whether protection may be conferred even earlier, because samples were not collected. VT protection persisted through the first year of life, although, by 6 months after the booster dose, the effect was no longer statistically significant, likely an effect of the sample size and model complexity. We have shown previously that PnCRM7 vaccinees have a reduced risk of VT colonization 1–4 years after their vaccine series [32]. PnCRM7 vaccinees were also found to have an increased risk of NVT carriage, although this was not conclusively evident until 18 months of age. Because the immunoblot method was used for detection of multiple-serotype carriage, this represents replacement colonization and not unmasking of minor NVT populations otherwise undetectable in the face of significant VT colonization.

The serotype-specific analysis was limited by the number of observations for a given serotype and the model complexity. We demonstrated a reduced risk of colonization for types 6B and 23F 1 month after the primary series, with the latter having statistical significance. Other serotypes (i.e., 9V and 14) appeared to have reductions, but small numbers made the statistical assessment limited. Another randomized trial demonstrated a reduced risk of colonization with serotypes 6B, 6A, 9V, 14, and 23F; however, this study was conducted among toddlers immunized with 1 or 2 doses of PnCRM9 [11].

We also evaluated whether PnCRM7 affects carriage by (1) reducing the density of colonization or (2) reducing the duration of colonization. PnCRM7 vaccinees had less dense VT strain colonization than children not immunized with PnCRM7, with no effect on NVT density. This provides an internal control that the density reductions are likely causally related to PnCRM7 rather than being attributable to uncontrolled confounding.

Consistent with previous findings [11], we found that PnCRM7 did not reduce the duration of VT colonization; however, if modest differences in duration were present, they would have been difficult to detect for either study because of sampling frequency.

Among unvaccinated household members (i.e., older siblings), pneumococcal colonization was somewhat more common in PnCRM7 households than MnCC households. PnCRM7 use in the household and community had no effect on the risk of VT or NVT colonization among these unvaccinated older siblings, except when day care attendance was considered. Among the day care–attending older siblings, PnCRM7 use in the community and household reduced their risk of pneumococcal colonization regardless of serotype, compared with those living in MnCC communities. Among the siblings not in day care, there was an increased risk of pneumococcal colonization (for all serotypes, VTs, and NVTs) among those who lived in PnCRM7 communities, compared with those who lived in MnCC communities. The direction of pneumococcal transmission (i.e., younger to older or vice versa), the choice of day care definition in this cultural setting, or residual confounding all may have contributed to these paradoxical findings.

Among infants too young to be immunized, we found that community PnCRM7 use protected against VT carriage and increased NVT carriage. Among young infants living with a PnCRM7 vaccinee, overall pneumococcal carriage risk also increased. This suggests that NVT replacement carriage among PnCRM7 vaccinees facilitates NVT transmission to younger unvaccinated infants (as seen in the present study) and to adults [33]. The absence of competing VT strains may facilitate NVT colonization among unvaccinated contacts to a degree that results in increased overall pneumococcal colonization.

Protection of these young infants through the indirect effects of PnCRM7 may lessen the need for additional strategies (e.g., maternal immunization and neonatal PCV use) except in the highest infant mortality settings. Finding that the magnitude of the indirect protective effect varies according to the presence of a vaccinee in the household supports the notion that young infants become colonized via children within the household. A 50% reduction in VT invasive disease has been seen among children <3 months of age concomitant with the introduction of PnCRM7 into the US routine vaccine schedule [24].

In summary, this large NP study has demonstrated that PnCRM7 confers protection against VTs through reduced acquisition risk and reduced colonization density. We cannot rule out a reduced duration of colonization, but our study failed to detect this. These mechanisms not only result in reduced VT colonization for vaccinees but also confer protection to their household and community contacts. The reduction in VT colonization, however, is accompanied by a true increased risk of NVT colonization, both among vaccinees and among some subgroups of their unvaccinated pediatric contacts. As PCVs are introduced into diverse epidemiological settings, NP colonization studies will provide an essential bridge to predict the impact of vaccine on vaccinees and their community contacts. The present population, with high pneumococcal carriage rates and disease burden, offers a model for the impact in developing-world settings with similar pneumococcal epidemiological characteristics. NP changes, when combined with the relative invasiveness of pneumococcal strains, offers a pathway to anticipate the long-term impact of PCV. Detailed analyses of the impact of PCV on invasive disease and NP colonization in randomized studies are critical, because they control for secular changes. Postintroduction NP and invasive disease studies provide valuable information, although they are confounded by the natural variability of pneumococcal epidemiology and the effects of antimicrobial resistance. Introduction of PCV into infant vaccination schedules offers an enormous opportunity to reduce the burden of morbidity and mortality from meningitis, pneumonia, and other invasive syndromes, especially in settings with limited access to care. Prospective monitoring of populations for the impact of PCV on VT and NVT disease and colonization is essential.

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Acknowledgments

We gratefully acknowledge the field-workers, nurses, and staff of the Center for American Indian Health for their dedicated work on the American Indian PnCRM7 Efficacy Trial and the commitment of the children and families for their time and effort to participate in the study. We also acknowledge the invaluable support of the institutional review boards that reviewed this study and the data safety monitoring board of the American Indian PnCRM7 Efficacy Trial. We further acknowledge the helpful discussions and technical expertise of Ben Schwartz, Richard Facklam, and George Carlone of the Centers for Disease Control and Prevention.

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Footnotes

  • ↵Retired.

  • Potential conflicts of interest: K.L.O. and M.S. have consulted for or have been a member of an advisory board for Wyeth Vaccines. All other authors report no potential conflicts.

  • Financial support: Wyeth Vaccines; National Institutes of Health; Centers for Disease Control and Prevention; United States Agency for International Development.

  • The opinions expressed in this article are those of the authors and do not necessarily reflect the views of the Indian Health Service or the Centers for Disease Control and Prevention.

  • Received March 27, 2007.
  • Accepted May 22, 2007.
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  1. J Infect Dis. (2007) 196 (8): 1211-1220. doi: 10.1086/521833
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