Effect of the 7‐Valent Pneumococcal Conjugate Vaccine on Nasopharyngeal Colonization by Streptococcus pneumoniae in the First 2 Years of Life

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Effect of the 7‐Valent Pneumococcal Conjugate Vaccine on Nasopharyngeal Colonization by Streptococcus pneumoniae in the First 2 Years of Life

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  930  •  CID 2004:39 (1 October)  •  Ghaffar et al. M A J O R A R T I C L E Effect of the 7-Valent Pneumococcal ConjugateVaccine on Nasopharyngeal Colonization by  Streptococcus pneumoniae   in the First 2 Years of Life Faryal Ghaffar, 1 Theresa Barton, 1 Juanita Lozano, 1 Luz Stella Muniz, 1 Patricia Hicks, 2 Vanthaya Gan, 2 Naveed Ahmad, 2 and George H. McCracken, Jr. 1 1 University of Texas Southwestern Medical Center and  2 Continuity Care Clinics of Children’s Medical Center, Dallas Background.  Studies suggest that the 7-valent pneumococcal conjugate vaccine (PCV7) reduces carriage of vaccine-type (VT)  Streptococcus pneumoniae   (SP). We studied the effect of PCV7 on carriage of VT- and non-VT(NVT) SP, by studying the effect of PCV7 on nasopharyngeal (NP) colonization by VT and NVT SP during early childhood. Methods.  At 2 months of age, 278 infants were enrolled in this study. To determine carriage of SP, NP sampleswere obtained before each PCV7 dose, at 9 months of age, and 2–3 months after the booster dose of vaccine. Results.  The carriage of SP increased slightly, from 12% (95% confidence interval [CI], 8%–16%) of subjectsat 2 months of age to 18% (95% CI, 13%–23%) at 4 months of age ( ). Carriage of SP remained in 24%– P  ! .0530% of subjects during subsequent months. Between the 12- and 18-month visits, the carriage rate of VT SPdecreased significantly, from 18% (95% CI, 13%–23%) to 9% (95% CI, 5%–13%) of subjects ( ). The P  p .001trend of a decrease in carriage of penicillin-nonsusceptible SP, from 16% of subjects (95% CI, 11%–21%) at the12–15-month visit to 9% (95% CI, 5%–13%) at the 15–18-month visit, was found after the booster dose of vaccine. Conclusion.  The reduction of VT-SP colonization and replacement by NVT SP after the booster dose of vaccine suggests the possibility that widespread vaccination will result in replacement of pneumococci mainly by antibiotic-susceptible NVT SP. Streptococcus pneumoniae   (SP) is an important cause of morbidity and mortality worldwide, with the highestincidence of disease among children  ! 2 years of age.Invasive pneumococcal disease is preceded by naso-pharyngeal (NP) colonization. Inchildren,colonizationoccurs early in life, and organisms can persist in thenasopharynx for relatively long periods and can be af-fected by repeated exposure to antibiotic therapy. Themean age at first acquisition of SP is 6 months, and Received 8 January 2004; accepted 20 April 2004; electronically published 13September 2004.Presented in part: 41st Interscience Conference on Antimicrobial Agents andChemotherapy, Chicago, December 2001 (abstract 80); 42nd InterscienceConference on Antimicrobial Agents and Chemotherapy, San Diego, September2002 (abstract G-140); and 43rd Interscience Conference on Antimicrobial Agentsand Chemotherapy, Chicago, September 2003 (abstract G-894).Reprints or correspondence: Dr. Faryal Ghaffar, Dept. of Pediatrics, Div. ofInfectious Disease, University of Texas Southwestern Medical Center, 5323 HarryHines Blvd., Dallas, TX 75235 (faryal.ghaffar@utsouthwestern.edu). Clinical Infectious Diseases 2004;39:930–8   2004 by the Infectious Diseases Society of America. All rights reserved.1058-4838/2004/3907-0005$15.00 carriage rates peak among children of preschool age [1,2]. Carriers usually remainasymptomaticbutcantrans-mit the organism to others. Haemophilus influenzae   conjugate vaccineshavebeensuccessful in reducing NP carriage of this organism ininfants and children, which has contributed greatly tothe success of immunization programs, by providing asubstantial herd effect [3, 4]. We, as well as other re-searchers [5–7], have postulated that vaccination withthe 7-valent pneumococcal conjugate vaccine (PCV7)would have an effect on pneumococcal carriage similarto that seen with the  H. influenzae   conjugate vaccine.However, factors affecting carriage and serotype re-placement are complex, and the effect of vaccinationon the carriage of different organisms will vary. Thepneumococcal polysaccharide-protein conjugate vac-cines have been shown to be highly immunogenic forinfants [8, 9], and studies have suggested that thesevaccines reduce NP carriage of vaccine-type(VT)pneu-mococci in toddlers, possibly by preventing acquisitionrather than by eradicating established SP colonization   b  y g u e  s  t   on O c  t   o b  e r  6  ,2  0 1  6 h  t   t   p :  /   /   c i   d  . oxf   or  d  j   o ur n a l   s  . or  g /  D o wnl   o a  d  e  d f  r  om   Pneumococcal Colonization  •  CID 2004:39 (1 October)  •  931 [3, 10], but that they increase carriage of non-VT (NVT) pneu-mococci [11–14]. These studies, however, were performed inareas of the world that possibly have a different pneumococcalepidemiology than that seen in the United States.Results of studies of the effect of PCV7 on NP colonizationamong US infants receiving the primary vaccine series duringinfancy and the booster dose at 12–15 months of age have notbeen published. Thus, the primary objective of this study wasto determine the effect of vaccination with primary andboosterdoses of PCV7 on NP colonization by VT strains of SP. Ad-ditional objectives were to investigate whether a reduction inthe rate of carriage of VT pneumococci is associated with aparallel increase in the rate of carriage of NVT pneumococciand to assess whether the administration of this vaccine resultsin reduction of carriage of antimicrobial-resistant SP. METHODS Study population.  At 2 months of age, 150 infants who wereto receive primary immunizations were enrolled from a privatepractice in Plano, TX. Similarly, at 2 months of age, a secondgroup of 128 infants were enrolled from the Continuity CareClinics of Children’s Medical Center in Dallas. The enrollmentperiod was September 2000 through August 2001.Inclusion criteria were male or female children of any raceor ethnicity who were 2 months of age, were candidates toreceive primary immunizations, and were available for follow-up visits. Exclusion criteria were hypersensitivity to any com-ponent of the vaccine, including diphtheria toxoid. Swabs (cal-cium alginate, cotton tipped [Fisher]) were used to obtain NPsamples at 2, 4, 6, and 12–15 months of age, before each doseof PCV7; at 9 months of age; and at 15–18 months of age, 2–3 months after the booster dose of vaccine. These subjects werefollowed up until 15–18 months of age for collection of dataregarding acquisition, persistence, and clearance of NP colo-nization by SP.NP samples from all subjects were obtained by introducingthe swab into the nostril and advancing until resistance wasfound. At the time of enrollment, the following informationwas recorded from office chart records for each child: age, sex,number of siblings, age of siblings,hoursofdaycareattendance,type of day care attendance, presence of any underlying illness,and history of acute otitis media and of antibiotic therapy within 1 month prior to enrollment. Information regardingday care attendance, history of acute otitis media, prior use of an-tibiotic therapy, and presence of siblings in the household wasalso obtained at the 12–15-month and 15–18-month visits.Parents gave informed, written permission for enrollment of their child. The study protocol was approved by the Institu-tional Review Board of the University of Texas SouthwesternMedical Center at Dallas, and clinical research was conductedin accordance with the guidelines for human experimentationof the US Department of Health and Human Services. Microbiologicalanalysis.  Swabs used to collectNPsampleswere kept moist in nutrient broth and were stored at 4  C fora maximum of 12 h before samples were plated. NP sampleswere plated onto trypticase soy agar with 5% sheep blood. Inan effort to distinguish between coresiding penicillin-suscep-tible and penicillin-nonsusceptible (PNS) strains, 2 sets of blood-agar plates—one with 0.1 m g/mL penicillinandonewith-out penicillin—were used. All blood-agar plates contained 1 m g/mL gentamicin.  a -hemolytic colonies growing on blood-agar plates containing 0.1  m g/mL penicillin were inoculatedonto plates containing 1 and 2  m g/mL penicillin, to separatepneumococcal strains with different penicillin susceptibilities.Two  a -hemolytic colonies from each type of blood-agar plate(with and without penicillin) were tested for each patient (thecolonies were selected randomly, except when morphologically distinct colonies were present). Pneumococci were distin-guished from other  a -hemolytic streptococci on the basis of colony morphology, optochin inhibition (ethylhydrocupreine;Difco) [15], and bile solubility (10% sodium desoxycholate[Bactidrop; Difco]).Susceptibility of SP to penicillin, cefotaxime, and azithro-mycin was determined by use of the epsilometric test (Etest;AB Biodisk) [16]. SP isolates were classified as penicillin sus-ceptible (MIC,  0.06  m g/mL), intermediate penicillin resistant(MIC,  1 0.06–1.0  m g/mL), or penicillin resistant (MIC,  1 1.0  m g/mL) and as cefotaxime or azithromycin susceptible (MIC,  0.5 m g/mL) or resistant (MIC,  1 0.5  m g/mL). These definitions havebeen modified from NCCLS guidelines [17] to include resultsfrom Etest strips that fall between those defined for microdi-lution methods. The category PNS includes both intermediatepenicillin-resistant and penicillin-resistant strains.Serogroups and serotypes of SP isolates were determined by the Neufeld-Quellung reaction, using pooled Danish (80 se-rotypes) and individual (serotypes 6A, 6B, 9A, 9L, 9N, 9V, 19F,19A, 19B, 19C, 23F, 23A, and 23B) pneumococcal serotype–specific antiserum samples [18]. Isolates that tested negative by all pooled and individual pneumococcal serotype–specific an-tiserum samples were classified as nontypeable. Isolates thattested positive for serotypes 4, 6B, 9V, 14, 18C, 19F, and 23Fwere classified as VT pneumococci. Serotypes in the same se-rogroup as the VT serotypes were classified as vaccine-relatedserotypes (6A, 19 non-F, 23 non-F, and 9 non-V). Serotypesother than VT were classified as NVT. DNA analysis.  DNA-fingerprint patterns were determinedfor pneumococcal isolates with similar MICs for penicillin, ce-fotaxime, and azithromycin, to determine their genetic relat-edness and the possibility of serotype switching. Strain-specificgenomic DNA–fingerprint patterns for SP were determined by using the enterobacterial repetitiveintergenicconsensus(ERIC)   b  y g u e  s  t   on O c  t   o b  e r  6  ,2  0 1  6 h  t   t   p :  /   /   c i   d  . oxf   or  d  j   o ur n a l   s  . or  g /  D o wnl   o a  d  e  d f  r  om   Table 1. Demographic and clinical characteristics of the study group. Characteristic PP group CCC group Total  P  a No. of subjects at enrollment 150 128 278No. of siblings, median (range) 1 (0–7) 0 (0–6) 0 (0–7)Age, years (range)  5 1 (0–4) 1 (0–2) 1 (0–4) 1 5 1 (0–3) 1 (0–4) 1 (0–4)No. of household members, median (range) 4 (2–8) 2 (2–10) 4 (2–10)Male sexNo. (%) of subjects 82 (55) 37 (29) 119 (43)  ! .00195% CI, % 47–63 21–37 37–49Minority ethnicityOverallNo. (%) of subjects 16 (11) 68 (53) 84 (30)  ! .00195% CI, % 6–16 44–62 25–35No. of black subjects 7 33 40No. of hispanic subjects 4 35 39No. of Asian subjects 5 0 5Day care attendanceAt enrollmentNo. (%) of subjects 6 (4) 5 (4) 11 (4) .95995% CI, % 1–7 1–7 2–6At 12–15-month visitNo. (%) of subjects 17 (15) 15 (18) 32 (16) .50195% CI, % 9–21 10–26 11–21At 15–18-month visitNo. (%) of subjects 15 (14) 14 (19) 29 (16) .41595% CI, % 7–21 10–28 11–21History of acute otitis mediaAt enrollmentNo. (%) of subjects 12 (8) 14 (11) 26 (9) .41295% CI, % 4–12 6–16 6–12At 12–15-month visitNo. (%) of subjects 27 (23) 15 (18) 42 (21) .39295% CI, % 15–31 10–36 15–27At 15–18-month visitNo. (%) of subjects 15 (14) 8 (11) 23 (13) .48895% CI, % 7–21 4–18 8–18Prior use of antibioticsAt enrollmentNo. (%) of subjects 18 (12) 25 (20) 43 (16) .08395% CI, % 7–17 13–27 12–20At 12–15-month visitNo. (%) of subjects 51 (44) 30 (36) 81 (41) .29195% CI, % 35–53 26–46 34–48At 15–18-month visitNo. (%) of subjects 32 (30) 20 (27) 52 (29) .60695% CI, % 21–39 17–37 22–36 Streptococcus pneumoniae   colonizationAt enrollmentNo. (%) of subjects 14 (9) 19 (15) 33 (12) .16395% CI, % 4–14 9–21 8–16 (continued)    b  y g u e  s  t   on O c  t   o b  e r  6  ,2  0 1  6 h  t   t   p :  /   /   c i   d  . oxf   or  d  j   o ur n a l   s  . or  g /  D o wnl   o a  d  e  d f  r  om   Pneumococcal Colonization  •  CID 2004:39 (1 October)  •  933 Table 1.  (Continued.)  Characteristic PP group CCC group Total  P  a At 12–15-month visitNo. (%) of subjects 30 (26) 28 (34) 58 (29) .21495% CI, % 18–34 24–44 23–35At 15–18-month visitNo. (%) of subjects 26 (25) 22 (29) 48 (27) .47195% CI, % 17–33 19–39 21–33PNS  S. pneumoniae   colonizationAt enrollmentNo. (%) of subjects 3 (2) 3 (2) 6 (2) .99995% CI, % 0–4 0–4 0–4At 12–15-month visitNo. (%) of subjects 21 (18) 10 (12) 31 (16) .25695% CI, % 11–25 5–19 11–21At 15–18-month visitNo. (%) of subjects 12 (11) 5 (7) 17 (9) .29095% CI, % 5–16 1–13 5–13 NOTE.  CCC, Continuity Care Clinics of Children’s Medical Center, Dallas; PNS, penicillin nonsuscep-tible; PP, private practice (Plano, TX). a Calculated by means of  x 2 analysis or Fisher’s exact test, as appropriate. 1R/ERIC 2 PCR primer sets [19]. In addition, the genotypicprofile of penicillin-binding protein (PBP) in pneumococcalNP isolates was determined by using PCR and restriction frag-ment–length polymorphism analyses for the 1a, 2b, and 2x binding sites [20, 21]. Strains of SP were considered to beidentical if no change was found in the repetitive-PCR finger-print pattern or the PBP fingerprint pattern, other than a 1-band difference at the 1a gene.Patterns of pneumococcal colonization also weredeterminedon the basis of susceptibility testing, serotyping, and, in selectedcases, by analysis of repetitive-PCR fingerprint patterns. New acquisition of SP by a subject was defined as colonization witha strain not isolated at a previous visit, persistent colonizationwas determined when the same isolate was present at a sub-sequent visit, and clearance was determined when the pneu-mococcal strain was not isolated at a subsequent visit. Statistical analysis.  Statistical analyses were performed by use of SPSS software, version 11.0 (SPSS). Group comparisonswere made between subjects recruited from the private practiceand those from Continuity Care Clinics, between subjects withand those without SP colonization, and between subjects withand those without penicillin resistance. Sex, ethnicity, numberof siblings, day care attendance, history of acute otitis media,antibiotic usage and resistance, and rate of SP colonizationwerecompared by using x 2 analysis or Fisher’sexacttest.Proportionsof children with colonization by SP, VT or NVT SP, and pen-icillin-susceptible or PNS pneumococci were calculated at 2, 4,6, 9, 12–15, and 15–18 months of age. Overall, the trend of pneumococcal carriage across the 6 data points was analyzedby using Cochran’s  Q   test for related proportions. This analysisonly included those subjects who were present at all data-collection time points, and no imputation of missing valueswas performed. The McNemar test was performedtodeterminethe significance at each consecutive time point (e.g., 2 vs. 4months of age). Similar analyses were performed to analyze thepatterns of pneumococcal colonization (new acquisition, per-sistent colonization, or clearance) for each relevant time pointand for changes during the study period. All data are reportedas median values (ranges) or as percentages (95% CIs). Posthoc comparisons were corrected by means of the Bonferronimethod for multiple comparisons. RESULTS The study cohort consisted of a total of 278 subjects (150 fromprivate practice and 128 from Continuity Care Clinics). Thebaseline characteristics of the group of children enrolled fromboth sites are given in table 1. Approximately one-half (53%[95% CI, 44%–62%]) of the subjects recruited from Continuity Care Clinics were of a minority ethnicity, compared with only 11% (95% CI, 6%–16%) from the private practice. Forty-threepercent (95% CI, 37%–49%) of the study cohort was male; themedian number of siblings was 0 (range, 0–7), and the mediannumber of household members was 4 (range, 2–10), for thestudy population. Only 4% of subjects (95% CI, 2%–6%) wereattending day care centers at 2 months of age, compared with16% (95% CI, 11%–21%) and 16% (95% CI, 11%–21%) at12–15 and 15–18 months of age, respectively. A history of acuteotitis media was reported for 9% of subjects (95% CI, 6%–12%) at enrollment, for 21% (95% CI, 15%–27%) at the 12–   b  y g u e  s  t   on O c  t   o b  e r  6  ,2  0 1  6 h  t   t   p :  /   /   c i   d  . oxf   or  d  j   o ur n a l   s  . or  g /  D o wnl   o a  d  e  d f  r  om   934  •  CID 2004:39 (1 October)  •  Ghaffar et al. Table 2. Association between  Streptococcus pneumoniae   (SP) colonization and subjectcharacteristics. CharacteristicSPcolonizationNo SPcolonization  P  a PNS-SPcolonizationNo PNS-SPcolonization  P  a Having sibling(s)At enrollmentNo. (%) of subjects 24 (73) 96 (39)  ! .001 5 (83) 115 (42) .08895% CI, % 58–88 33–45 53–113 36–48At 12–15-month visitNo. (%) of subjects 34 (59) 68 (48) .168 18 (58) 84 (50) .39295% CI, % 44–72 40–56 41–75 42–58At 15–18-month visitNo. (%) of subjects 27 (56) 66 (50) .431 10 (59) 83 (51) .51995% CI, % 42–70 42–58 36–82 43–59Day care attendanceAt enrollmentNo. (%) of subjects 1 (3) 10 (4)  1 .999 0 (0) 11 (4)  1 .99995% CI, %   3 to 9 2–6 0 2–6At 12–15-month visitNo. (%) of subjects 10 (17) 22 (16) .760 6 (19) 26 (15) .57995% CI, % 7–27 10–22 5–33 10–20At 15–18-month visitNo. (%) of subjects 9 (19) 20 (15) .548 5 (29) 24 (15) .11495% CI, % 8–30 9–21 7–51 10–20History of acute otitis mediaAt enrollmentNo. (%) of subjects 3 (9) 23 (9)  1 .999 1 (17) 25 (9) .45095% CI, %   1 to 19 5–13   13 to 47 6–12At 12–15-month visitNo. (%) of subjects 12 (21) 30 (21) .945 6 (19) 36 (21) .80795% CI, % 11–31 14–28 5–33 15–27At 15–18-month visitNo. (%) of subjects 7 (15) 16 (12) .649 1 (6) 22 (13) .70195% CI, % 5–25 6–18   5 to 17 8–18Prior use of antibioticsAt enrollmentNo. (%) of subjects 7 (21) 36 (15) .336 2 (33) 41 (15) .23595% CI, % 7–35 11–19   5 to 71 11–19At 12–15-month visitNo. (%) of subjects 18 (31) 63 (44) .081 8 (26) 73 (43) .07095% CI, % 19–33 36–52 11–41 36–50At 15–18-month visitNo. (%) of subjects 19 (40) 33 (25) .053 5 (29) 47 (29) .94895% CI, % 26–54 18–32 7–51 22–36 NOTE.  PNS, penicillin nonsusceptible. a Calculated by means of  x 2 or Fisher’s exact test, as appropriate. 15-month visit, and for 13% (95% CI, 8%–18%) at the 15–18-month visit. The use of an antibiotic within 1 month priorto study enrollment was reported for 16% of subjects (95% CI,12%–20%), compared with 41% (95% CI, 34%–48%) at the12–15-month visit and 29% (95% CI, 22%–36%) at the 15–18-month visit. No significant difference was found betweensubjects from the private practice and those from Continuity Care Clinics for day care attendance, history of acute otitismedia, antibiotic use within 1 month prior to a study visit,pneumococcal colonization, and colonization with PNS strains(table 1).The association of variables of interest with pneumococcalcolonization and colonization with PNS strains is given in table2. Penicillin-resistant strains were found in 18% (95% CI, 5%–31%) of the subjects with pneumococcal colonization at en-rollment; this proportion increased to 53% (95% CI, 40%–66%) at the 12–15-month visit and then dropped to 35% (95%CI, 22%–48%) at the 15–18-month visit. Day care attendance,   b  y g u e  s  t   on O c  t   o b  e r  6  ,2  0 1  6 h  t   t   p :  /   /   c i   d  . oxf   or  d  j   o ur n a l   s  . or  g /  D o wnl   o a  d  e  d f  r  om 
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