Alaska Native (AN) people comprise approximately 16% of Alaska’s population. AN people are the majority population in the northern and western regions of Alaska and most live in small rural communities of 50–1000 persons dispersed through nonmetropolitan areas.1 These communities are not connected by roads and many do not have in-home piped water systems.
High rates of invasive pneumococcal disease (IPD) have been recognized in rural AN people for several decades.2,3 IPD rates among children in the Yukon Kuskokwim Delta (YKD) region of western Alaska were among the highest in the world. During 1996 to 2000, before 7-valent pneumococcal conjugate vaccine (PCV7; Wyeth, Philadelphia, PA) introduction, IPD rates were 10-fold higher for AN children aged <5 years from YKD compared with non-AN Alaskan children (547 versus 56 per 100,000 children/yr).4
After PCV7 introduction, the Active Bacterial Core surveillance network, an active laboratory-based and population-based surveillance system for invasive bacterial pathogens of public health importance, reported a 77% decline in IPD rates among US children by 2005, with a 98% decline in IPD caused by vaccine serotypes.5 In the early postvaccine period, there was a similar initial decline in IPD in AN children.4,6 Among YKD children aged <5 years, overall IPD decreased by 73%, from 547 per 100,000 children during 1996 to 2000 to 148 per 100,000 children during 2001 to 2004, with a 98% decline in PCV7-serotype disease. However, IPD then increased in YKD children to 426 per 100,000 children during 2005 to 2007 due to an increased incidence of disease caused by non-PCV7 serotypes,4 predominantly serotypes 7F and 19A, which caused 31% and 24% of IPD, respectively, in YKD children aged <5 years (unpublished data: Arctic Investigations Program-Centers for Disease Control and Prevention). By 2008, 28% of serotype 19A IPD isolates were resistant to 1 or more antibiotics. During this period, Wyeth (Pfizer Inc, Philadelphia, PA) was developing a 13-valent PCV (PCV13; Pfizer Inc) containing the 7 serotypes in PCV7 plus 6 additional serotypes: 1, 3, 5, 6A, 7F and 19A. Phase 17,8 and phase 29 studies of immunogenicity and safety showed no safety concerns, good immune responses and no impact on concomitant vaccine responses, and phase 3 studies were ongoing globally.10–14 Interest in PCV13 was high in the YKD as the region had the highest rate of IPD caused by PCV13 serotypes in the United States.3,4 Accordingly, the Yukon Kuskokwim Health Corporation participated with Wyeth (Pfizer Inc) in a clinical trial of PCV13 administered to children aged <5 years in the YKD region in 2009.
MATERIALS AND METHODS
Alaska’s YKD region is home to approximately 25,000 primarily Yup’ik Eskimo people (85% of the region’s population) who live in 48 villages or the regional town of Bethel. There are approximately 625 live births annually, and approximately 3250 children aged <5 years. The region has no road system, and villages are reached by airplane, boat or snow machine. Most homes are small, and approximately 40% are without running water or flush toilets.4,15 The YKD Regional Hospital (YKDRH) is the only hospital in the region, and children requiring intensive care must be transferred to hospitals in Anchorage, AK.
This was a phase 3, open-label trial conducted at YKDRH and 23 satellite sites in the YKD. Healthy YKD children aged 6 weeks to <5 years living in participating villages were eligible for inclusion in the study. Children were enrolled and received age-appropriate PCV13 doses with routine pediatric vaccines. All subjects were followed for 6 months after their last study vaccination for safety evaluation. Blood samples were collected for immunogenicity evaluation in a subset of subjects living near the main site whose parents consented to blood draws at times specified in the protocol. PCV13 was licensed16–18 and became commercially available in YKD on March 25, 2010, as part of the routine childhood immunization program. Following this, PCV13 administration under the study protocol was discontinued and parents/legal guardians were offered PCV13 routinely for all YKD children.
The study was approved by the Alaska Area and National Indian Health Service Institutional Review Boards, the Yukon Kuskokwim Health Corporation and Alaska Native Tribal Health Consortium Boards of Directors and Wyeth (Pfizer Inc). This study was conducted in accordance with the International Conference on Harmonization Guideline for Good Clinical Practice and the ethical principles that have their origins in the Declaration of Helsinki. Written informed consent was obtained from parents/legal guardians of every subject before enrollment in the study and before performance of any study-related procedure.
The primary objectives of the study were to evaluate the impact of PCV13 on the incidence of IPD in YKD due to the 13 vaccine serotypes and to any Streptococcus pneumoniae serotypes. Pneumococcal immune responses induced by PCV13 measured 1 month postinfant series and posttoddler dose were assessed in a subset of subjects, and the safety profile of PCV13 was evaluated.
Enrollment was offered to all healthy YKD children aged 6 weeks to <5 years at participating sites. Children were excluded from the study if they had a previous anaphylactic reaction to any vaccine component, bleeding diathesis, major congenital anomalies, neurologic disorders or other significant disorders or any contraindication to vaccination with pneumococcal vaccine. Eligible children were included if their parents/legal guardians were able and willing to comply with all study procedures and could be reached by telephone.
Study subjects received PCV13 vaccinations as appropriate for their age and prior vaccination history in accordance with the following groups (Table 1):
* Group 1: Subjects aged 6 weeks to <10 months with no prior doses of PCV7.
* Group 2: Subjects aged <12 months with 1 prior dose of PCV7.
* Group 3: Subjects aged <12 months with 2 prior doses of PCV7 (Note: recruitment of subjects aged <12 months with 3 prior doses of PCV7 was delayed until age 12 months).
* Group 4: Subjects aged ≥12 months to <2 years.
* Group 5: Subjects aged ≥2 years to <5 years.
PCV13 contains polysaccharides from pneumococcal serotypes 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F and 23F, individually conjugated to cross-reacting molecule 197, which is a nontoxic variant of diphtheria toxin. PCV13 contains 2.2 µg of each polysaccharide (except for 4.4 µg of 6B), 5mM succinate buffer, 0.02% polysorbate 80 and 0.125mg of aluminum as aluminum phosphate per 0.5-mL dose. PCV13 was administered by intramuscular injection into the left anterolateral thigh muscle for subjects aged <12 months, or into the left limb according to local practice for subjects aged ≥12 months.
Subjects who lived near YKDRH were invited to participate in the immunogenicity subset. In this subset, blood was drawn 1 month after the infant series and 1 month after the toddler dose for groups 1, 2 and 3; whereas for groups 4 and 5, blood was drawn prior to vaccination and 1 month after relevant catch-up doses. Serotype-specific IgG concentration was measured using standard pneumococcal anticapsular polysaccharide enzyme-linked immunosorbent assay.19 Functional antibacterial opsonophagocytic activity (OPA) was measured by OPA assay.20
Before vaccination (visit 1), subjects’ medical history was reviewed and a physical examination was performed. All serious adverse events (SAEs), adverse events (AEs) leading to withdrawals and clinically important related events as assessed by the investigator were collected. A local safety monitoring board was established to review safety data on a quarterly basis.
For subjects in groups 4 and 5, additional safety data were collected. For 7 days after each vaccination, local reactions (redness, swelling and tenderness) at the site of the PCV13 injection, systemic events (decreased appetite, irritability, increased sleep, decreased sleep, urticaria and fever) and antipyretic medication use were assessed. Parents/legal guardians recorded local reactions, systemic events and use of antipyretic medication in a paper diary. Tenderness was categorized as none, present or interfered with limb movement. Redness and swelling were measured with a caliper. Redness and swelling were categorized as none, mild (0.5–2.0cm), moderate (2.5–7.0cm) or severe (>7.0cm). Temperature was measured daily at bedtime, or whenever a fever was suspected, using an age-appropriate method. Fever was categorized as none (<38.0°C), mild (≥38.0°C to ≤39.0°C), moderate (>39.0°C to ≤40.0°C) or severe (>40.0°C). Study personnel contacted parents/legal guardians on approximately days 3 and 7 to collect reactogenicity data.
The Centers for Disease Control and Prevention’s Arctic Investigations Program has conducted statewide IPD surveillance since 1986.2,3 Cases of IPD (defined as isolation of S. pneumoniae from a normally sterile site) are reported from clinical laboratories throughout Alaska. Isolates are sent to the Arctic Investigations Program, where identification, serotyping and antimicrobial susceptibility testing are performed using standard techniques. Annually, participating laboratories compare their records with a list of isolates received by the Arctic Investigations Program and report any missing cases.
Data on cases of IPD in YKD children aged <5 years, identified from January 1, 2005, through August 31, 2011, were used to assess the impact of PCV13 compared with a period of PCV7 use:
* Late PCV7 period (2005 to 2008) during which IPD rates in YKD children increased above the early PCV7 period due to increases in non-PCV7 IPD.
* PCV13 period (January 30, 2009, through August 31, 2011) during the PCV13 clinical trial and subsequent routine vaccination after availability of licensed PCV13.
The number and proportion of YKD children aged <5 years who received 1 or more doses of PCV13 were determined from electronic immunization records at the YKDRH, during the study period and following routine use of licensed PCV13.
Immunogenicity endpoints included the proportion of subjects who achieved serotype-specific IgG concentrations ≥0.35 µg/mL,21 and the proportion of subjects achieving pneumococcal OPA titers greater than or equal to the lower limit of quantitation, along with the corresponding exact, unconditional, 2-sided 95% confidence intervals. The number of subjects in the evaluable immunogenicity population was too low for meaningful evaluation of IgG geometric mean concentrations or OPA geometric mean titers. Disease rates by period were compared using “mid-P” exact significance.22 For comparisons of incidence among vaccinated and unvaccinated children, Mantel–Haenszel weighting was used to adjust for age. Rates are presented with exact binomial confidence intervals.
Of 1365 children who were screened or whose parents were approached, 376 consented, 373 were enrolled and 372 were vaccinated with ≥1 dose of PCV13 during the clinical trial, including 151 in group 1, 51 in group 2, 25 in group 3, 66 in group 4 and 79 in group 5. A total of 354 subjects completed the study, and 19 discontinued: 3 for AEs (all nonfebrile convulsions), 2 at investigator request (1 with hives 4 days after vaccine, and 1 child aged 641 days on new daily medication for asthma was temporarily withdrawn), 2 deaths (1 sudden infant death syndrome in a child aged 144 days, 85 days after receiving study vaccine; 1 pneumonia with cardiopulmonary failure in a child aged 109 days, 20 days after receiving study vaccine), 1 failed to return, 9 parent requests and 2 due to other reasons. The 2 deaths are discussed in the Safety section. A total of 182 (49%) subjects completed the full vaccination series per protocol for their group before PCV13 became available and replaced PCV7 for routine vaccination. A total of 37 subjects had blood drawn within the protocol-specified time period after the infant series, of whom 11 in group 1, 6 in group 2 and 3 in group 3 were eligible to be included in the evaluable infant immunogenicity population.
Of the 376 subjects who were consented, 193 (51.3%) were female, 337 (89.6%) were AN, 12 (3.2%) were White, 2 (0.5%) were Asian and 25 (6.6%) were of other race. In the group 1 evaluable immunogenicity population, 6 of 11 subjects (54.5%) were female, 9 (81.8%) were AN, 1 (9.1%) was White and 1 (9.1%) was of other race.
During the prelicensure study period, monthly enrollment ranged from 1 to 47 children. Approximately 10% of YKD children aged <5 years (n = 372) were enrolled and received ≥1 dose of PCV13 during the study between January 30, 2009, and March 25, 2010. Administration of PCV13 under the study protocol was discontinued when licensed PCV13 became available on March 25, 2010, after which uptake was rapid (90–551 first PCV13 vaccinations per month). Review of YKDRH electronic immunization records showed that by August 31, 2011, a total of 3714 children (91% of children aged <5 years) had received ≥1 PCV13 dose, including 3342 children after licensure, and 71% were considered protected5,23 (≥2 PCV13 doses in all children aged <5 years or ≥1 PCV13 dose received after age 2 years; Fig. 1).
Immunogenicity results are presented in Table 2 for evaluable group 1 subjects only, as enrollment for the blood draws in the other groups was very low (≤6 subjects per group). Blood samples were collected 1 month (28–56 days) after completion of the infant series at a median age of 228 days (range 215–256 days). The proportion of responders after the infant series with serotype-specific antibody concentration ≥0.35 µg/mL ranged from 90.9% to 100.0%. The proportion of subjects with OPA titer ≥ lower limit of quantitation was ≥60% for all serotypes with the exception of serotype 9V (30.0%). After the toddler dose, the evaluable group 1 subjects achieved both serotype-specific IgG concentrations ≥0.35 µg/mL and OPA titer ≥ lower limit of quantitation, although it should be noted that the sample size was small (n = 2 in group 1) at this time point.
In groups 4 and 5, for whom additional safety data were collected using a paper diary, injection site reactions were noted for 37.5%–50.6% of subjects following dose 1 or 2 (Table 3). Severe swelling or redness were uncommon (0%–2.6% of subjects; Table 3). Similarly, while mild fever (≥38°C but ≤39°C) was common (23.1%–42.9% of subjects), fever >40°C was uncommon (0%–7.1% of subjects; Table 4). In groups 1–3, for whom no safety diary data were collected, 18 vaccine-related AEs were reported, including 15 cases of fever, 2 local site reactions (1 swelling and 1 redness) and 1 crying. In group 4, 1 vaccine-related AE, a case of maculopapular rash, was reported. In group 5, no vaccine-related AEs were reported.
A total of 94 SAEs were reported in 49 subjects during the study period. Of these, 91 were associated with 63 hospitalizations in 47 subjects within 6 months of receipt of the study vaccine, according to electronic health records at YKDRH or the Alaska Native Medical Center, Anchorage, AK. SAEs that led to hospitalizations included: 23 pneumonia, 12 bronchiolitis, 7 influenza, 5 abscess/cellulitis; 3 or 4 episodes each of asthma, tracheobronchitis/croup, respiratory distress, laryngomalacia; and 1 or 2 episodes each of apnea, urinary tract infection, respiratory failure, anemia, eczema, dehydration, esophageal foreign body, septic arthritis, upper respiratory infection, hyponatremia, breath-holding spell, bacteremia, viral meningitis, Haemophilus influenzae meningitis, lymphadenitis, gastroenteritis, herpangina and gastroesophageal reflux. Five seizures in 4 subjects occurred during hospitalizations with concurrent illness; all occurred well after receipt of study vaccine (median 70 days, range 46–256 days). Two deaths occurred in study subjects: 1 diagnosed as sudden infant death syndrome in a child aged 144 days, 85 days after receiving study vaccine; and the other as cardiopulmonary failure secondary to pneumonia in a child aged 109 days, 20 days after receiving study vaccine (no organism was identified from samples obtained premortem and postmortem). With the exception of the 2 deaths, all other SAEs resolved and were generally consistent with illnesses common in this YKD child population. None were determined to be causally related to the study vaccine.
Overall IPD Rates in YKD Children
No cases of IPD caused by PCV13 serotypes occurred among children who received PCV13 (3680 person follow-up years), whereas 7 occurred among children who had not received PCV13 (5007 person follow-up years, P = 0.021; Mantel–Haenszel adjusting for age P = 0.190; Table 5). A total of 52 IPD cases occurred in YKD children aged <5 years in the late PCV7 period before the study (2005 to 2008; 399.0 per 100,000 children), and 9 cases occurred after study commencement (PCV13 period; January 30, 2009, to August 31, 2011; 106.7 per 100,000 children; P < 0.001; Table 6). Thirty-one cases of IPD caused by PCV13 serotypes and 17 caused by serotypes not in PCV13 occurred in the late PCV7 period (237.9 per 100,000 children and 130.5 per 100,000 children, respectively) compared with 7 cases caused by PCV13 serotypes and 1 caused by a non-PCV13 serotype after study commencement (83.0 per 100,000 children and 11.9 per 100,000 children, respectively; P = 0.007 and P = 0.002, respectively, comparing late PCV7 period versus after study commencement). Three of the 17 non-PCV13 serotype cases during the late PCV7 period (6C, 9N and 23B) were the same serogroup as serotypes in PCV13, and thus would have been potentially subject to cross protection. After the licensed vaccine was available, 2 cases of IPD (1 case of serotype 19A in May 2010 and 1 case of serotype 7F in April 2011) occurred in unvaccinated YKD children aged <5 years (Fig. 2).
This study evaluated the impact of PCV13 in children in the YKD, and immunogenicity and safety of PCV13 in a subset of children in this population. Before 2000, YKD children aged <5 years experienced extremely high rates of IPD.4 PCV7 introduction was followed by a sharp decline in IPD during 2001 to 2004.4,6 However, despite elimination of IPD caused by the serotypes in PCV7, high rates of IPD were re-established in YKD during 2005 to 2008 due to an increase in non-vaccine type IPD. Introduction of PCV13 with catch-up vaccination to age 5 years was temporally associated with a 73% decrease in overall IPD, a 65% decrease in PCV13-type IPD and a 91% decrease in non-PCV13 IPD in YKD children aged <5 years. No breakthrough cases of PCV13-type IPD occurred in children who had received ≥1 dose of PCV13. Although rates of disease caused by non-PCV13 serotypes also fell during the clinical trial and after PCV13 licensure, the fact that there were no cases of IPD caused by PCV13 serotypes in children who received PCV13 suggests a protective effect. These data provide early evidence suggesting that PCV13 is effective in preventing vaccine-type IPD in children; however, follow-up surveillance of these preliminary trends is crucial in order to establish stable estimates of PCV13 impact.
Both PCV13- and non-vaccine serotype disease decreased dramatically in YKD children, with increases in the proportion of children vaccinated with PCV13. The decrease in non-vaccine serotype disease is unlikely to be due to cross protection against serotypes related to those in PCV13 because only 3 of the 17 IPD cases (18%) caused by non-PCV13 serotypes during the pre-PCV13 period had potentially cross-reacting capsular types (serotypes 6C, 9N and 23B). Recent in vitro data suggest that such cross protection exists at least for serotype 6C.23,24 The disappearance of both vaccine-type and non-vaccine-type disease is not easily explained; however, it should be noted that a similar phenomenon occurred after introduction of PCV7 in YKD children in 2001.4 During that year, when coverage with at least 1 dose of PCV7 rose from 0% to nearly 90%, both vaccine-type and non-vaccine type disease decreased substantially immediately following introduction (Fig. 2).4,6 It is clear that rapid uptake of any PCV disrupts the normal ecology of the colonized nasopharynx, and this impacts both vaccine and non-vaccine serotype organisms.25 Dynamic changes in the pneumococcal component of the nasopharyngeal milieu could have contributed to a decline in IPD due to any pneumococci. With PCV13 introduction, changes in antibiotic resistance patterns driven by the decrease in serotype 19A could have impacted serotype trends.26 Factors other than PCV13 introduction could have also played a role in the changes in non-vaccine serotype IPD, including acquired population immunity to these serotypes, their ability to cause invasive disease, resistance to commonly prescribed antibiotics and age-based susceptibility to different serotypes.27,28
The primary future concern is whether replacement IPD with non-PCV13 serotypes could encroach on what is apparently early PCV13 success, as occurred in the YKD after PCV7 introduction.4,6 Factors favoring respiratory transmission (household crowding, lack of running water, indoor wood smoke, etc.) in YKD children not only contributed to the high baseline IPD rates in this population but also likely supported replacement with non-PCV7 serotypes.4,29 If replacement disease occurs after PCV13, it is likely to show up first in populations such as those in YKD, with high-level transmission of respiratory pathogens.30 Continued surveillance is crucial to confirm this impact.
Immunogenicity results were available for a very small number of subjects. However, the proportion of IgG responders is similar to that reported in the prelicensure PCV13 immunogenicity studies,9–13 and shows that PCV13 is immunogenic in this high-risk population. The proportion of OPA responders, particularly for serotype 9V, was lower than has been reported in other PCV13 clinical trials;10–13 but there is no explanation for this discrepancy, which may be an artifact of the small sample size in this study.
AEs were similar to those reported in other PCV13 clinical trials.9–13 Most SAEs were for hospitalization of study subjects for common childhood infections unrelated to the study vaccine. The study period overlapped with the pandemic 2009 H1N1 outbreak and an unusually severe respiratory syncytial virus season (incidence rate: 108 hospitalizations per 1000 YKD infants/yr). A total of 62% of these reported hospitalizations were associated with lower respiratory tract infections. Most hospitalized lower respiratory tract infections occurred during the 2009 to 2010 winter season, and 20 of 63 reported hospitalizations had an associated influenza or respiratory syncytial virus diagnosis. Although YKD infants have historically experienced extremely high lower respiratory tract infection hospitalization rates (284.9 per 1000 infants/yr) compared with that for the general population of US infants (37.1 per 1000 infants/yr), 31 the overall hospitalization rate, which was assessed in all YKD children, was slightly lower among study subjects than among nonstudy children. Although we cannot exclude the possibility that study subjects were at lower risk for hospitalization than nonstudy children, our data support the safety of PCV13 in this high-risk population.
There were limitations to this study. The likely utility of PCV13 for prevention of IPD in YKD led to considerable interest in early use of the vaccine in this region and the development of the vaccine trial. However, clinical trial enrollment was lower than anticipated. Major reasons for nonenrollment cited by parents were the time required for study procedures, such as informed consent, and “not wanting to participate in research.” Additionally, many village healthcare providers were intimidated by the complexity and time requirements of the study procedures, and ambivalent about enrolling neighbors and relatives into a clinical research trial. After licensure, when PCV13 was incorporated into the routine vaccine schedule, uptake was rapid, and nearly 90% of YKD children aged <5 years received at least 1 dose of PCV13 within 12 months of licensure. The decrease in IPD rates in YKD children is encouraging, but interpretation of these results is complicated by the small population size and the simultaneous unexplained decrease in disease caused by serotypes not included in PCV13. Although it is interesting that the same pattern (decrease in vaccine and non-vaccine disease) was observed after introduction of PCV7 in this population, it is still possible that the patterns observed were coincidental temporal trends. Generalizability of the results should also be guided by awareness of the unique characteristics of this high-risk population, and it is not clear how patterns observed in this population—with very high baseline rates of pneumococcal carriage and respiratory disease—apply to populations in other areas. However, many of the characteristics of this population are shared by populations outside of North America and Europe, and vaccine effectiveness in YKD will carry a strong message of effectiveness worldwide. Finally, our low enrollment numbers resulted in small numbers of vaccinated children before licensure and very small numbers in the immunogenicity subset, limiting the conclusions on the immunologic response of this population.
In conclusion, PCV13 was well tolerated and immunogenic in YKD children. Use of PCV13 in YKD children was associated with a dramatic decrease in PCV13-serotype IPD. Non-PCV13 serotype IPD also declined during the clinical trial and after PCV13 licensure. No PCV13-serotype disease occurred among children who had received 1 or more doses of PCV13, suggesting that PCV13 is effective in preventing IPD caused by PCV13 serotypes. Continued surveillance of the YKD population and evaluation of IPD in other populations are important to confirm these findings.
The authors acknowledge the Yukon Kuskokwim Health Corporation, the study personnel (Chris Desnoyers, Christine Wiscombe, Allison Samuelson, Bessie Francis, Adrienne Schoenberg, Kerry Cobbledick, Peggy Byrd, Martina Lauterbach, Robin Gosney and Sarah Welch), study personnel supervisor (William Schreiner), immunization coordinator (Kathleen Stanton), coinvestigators (Ellen Hodges, Jane McClure, Jane Russell and Carolyn Lorenz), members of the local safety monitoring board (Joseph Klejka, Cynthia Mondesir, Janet Johnston, Deborah Michael, Maxine Brink, Dana Bruden and Jay Wenger) and numerous other staff from Yukon Kuskokwim Health Corporation, Arctic Investigations Program and Alaska Native Tribal Health Consortium who assisted with study implementation, data analysis and served on the local safety monitoring board.
2. Rudolph KM, Parkinson AJ, Reasonover AL, et al. Serotype distribution and antimicrobial resistance patterns of invasive isolates of Streptococcus pneumoniae: Alaska, 1991-1998. J Infect Dis. 2000;182:490–496
3. Davidson M, Parkinson AJ, Bulkow LR, et al. The epidemiology of invasive pneumococcal disease in Alaska, 1986-1990–ethnic differences and opportunities for prevention. J Infect Dis. 1994;170:368–376
4. Wenger JD, Zulz T, Bruden D, et al. Invasive pneumococcal disease in Alaskan children: impact of the seven-valent pneumococcal conjugate vaccine and the role of water supply. Pediatr Infect Dis J. 2010;29:251–256
5. Centers for Disease Control and Prevention (CDC). . Invasive pneumococcal disease in children 5 years after conjugate vaccine introduction–eight states, 1998–2005. MMWR Morb Mortal Wkly Rep. 2008;57:144–148
6. 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;297:1784–1792
7. Scott DA, Komjathy SF, Hu BT, et al. Phase 1 trial of a 13-valent pneumococcal conjugate vaccine in healthy adults. Vaccine. 2007;25:6164–6166
8. Scott D, Ruckle J, Dar M, et al. Phase 1 trial of 13-valent pneumococcal conjugate vaccine in Japanese adults. Pediatr Int. 2008;50:295–299
9. Bryant KA, Block SL, Baker SA, et al.PCV13 Infant Study Group. Safety and immunogenicity of a 13-valent pneumococcal conjugate vaccine. Pediatrics. 2010;125:866–875
10. Yeh SH, Gurtman A, Hurley DC, et al.004 Study Group. Immunogenicity and safety of 13-valent pneumococcal conjugate vaccine in infants and toddlers. Pediatrics. 2010;126:e493–e505
11. Kieninger DM, Kueper K, Steul K, et al.006 study group. Safety, tolerability, and immunologic noninferiority of a 13-valent pneumococcal conjugate vaccine compared to a 7-valent pneumococcal conjugate vaccine given with routine pediatric vaccinations in Germany. Vaccine. 2010;28:4192–4203
12. Snape MD, Klinger CL, Daniels ED, et al. Immunogenicity and reactogenicity of a 13-valent-pneumococcal conjugate vaccine administered at 2, 4, and 12 months of age: a double-blind randomized active-controlled trial. Pediatr Infect Dis J. 2010;29:e80–e90
13. Esposito S, Tansey S, Thompson A, et al. Safety and immunogenicity of a 13-valent pneumococcal conjugate vaccine compared to those of a 7-valent pneumococcal conjugate vaccine given as a three-dose series with routine vaccines in healthy infants and toddlers. Clin Vaccine Immunol. 2010;17:1017–1026
14. Vanderkooi OG, Scheifele DW, Girgenti D, et al.Canadian PCV13 Study Group. Safety and immunogenicity of a 13-valent pneumococcal conjugate vaccine in healthy infants and toddlers given with routine pediatric vaccinations in Canada. Pediatr Infect Dis J. 2012;31:72–77
15. Hennessy TW, Ritter T, Holman RC, et al. The relationship between in-home water service and the risk of respiratory tract, skin, and gastrointestinal tract infections among rural Alaska natives. Am J Public Health. 2008;98:2072–2078
16. Nuorti JP, Whitney CGCenters for Disease Control and Prevention (CDC). . Prevention of pneumococcal disease among infants and children—use of 13-valent pneumococcal conjugate vaccine and 23-valent pneumococcal polysaccharide vaccine - recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep. 2010;59(RR-11):1–18
17. Centers for Disease Control and Prevention (CDC). . Licensure of a 13-valent pneumococcal conjugate vaccine (PCV13) and recommendations for use among children – Advisory Committee on Immunization Practices (ACIP), 2010. MMWR Morb Mortal Wkly Rep. 2010;59:258–261
18. Rubin JL, McGarry LJ, Strutton DR, et al. Public health and economic impact of the 13-valent pneumococcal conjugate vaccine (PCV13) in the United States. Vaccine. 2010;28:7634–7643
19. Quataert S, Martin D, Anderson P, et al. A multi-laboratory evaluation of an enzyme-linked immunoassay quantitating human antibodies to Streptococcus pneumoniae polysaccharides. Immunol Invest. 2001;30:191–207
20. Hu BT, Yu X, Jones TR, et al. Approach to validating an opsonophagocytic assay for Streptococcus pneumoniae. Clin Diagn Lab Immunol. 2005;12:287–295
21. World Health Organization. Recommendations for the Production and Control of Pneumococcal Conjugate Vaccines. Annex 2. 2005 Geneva, Switzerland World Health Organization
22. Rothman KJ Modern Epidemiology. 1986 Boston, MA Little, Brown and Company
23. De Serres G, Pilishvili T, Link-Gelles R, et al. Use of surveillance data to estimate the effectiveness of the 7-valent conjugate pneumococcal vaccine in children less than 5 years of age over a 9 year period. Vaccine. 2012;30:4067–4072
24. Cooper D, Yu X, Sidhu M, et al. The 13-valent pneumococcal conjugate vaccine (PCV13) elicits cross-functional opsonophagocytic killing responses in humans to Streptococcus pneumoniae serotypes 6C and 7A. Vaccine. 2011;29:7207–7211
25. Hanage WP, Finkelstein JA, Huang SS, et al. Evidence that pneumococcal serotype replacement in Massachusetts following conjugate vaccination is now complete. Epidemics. 2010;2:80–84
26. Moore MR, Gertz RE Jr, Woodbury RL, et al. Population snapshot of emergent Streptococcus pneumoniae serotype 19A in the United States, 2005. J Infect Dis. 2008;197:1016–1027
27. Feikin DR, Klugman KP. Historical changes in pneumococcal serogroup distribution: implications for the era of pneumococcal conjugate vaccines. Clin Infect Dis. 2002;35:547–555
28. Brueggemann AB, Griffiths DT, Meats E, et al. Clonal relationships between invasive and carriage Streptococcus pneumoniae and serotype- and clone-specific differences in invasive disease potential. J Infect Dis. 2003;187:1424–1432
29. Pilishvili T, Zell ER, Farley MM, et al. Risk factors for invasive pneumococcal disease in children in the era of conjugate vaccine use. Pediatrics. 2010;126:e9–e17
30. Weinberger DM, Malley R, Lipsitch M. Serotype replacement in disease after pneumococcal vaccination. Lancet. 2011;378:1962–1973
invasive pneumococcal disease; children; Alaska Native; pneumococcal conjugate vaccine© 2013 Lippincott Williams & Wilkins, Inc.