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VACCINE REPORTS

Impact of 13-valent Pneumococcal Conjugate Vaccine on


Pneumococcal Nasopharyngeal Carriage in Children With Acute
Otitis Media
Robert Cohen, MD,* Corinne Levy, MD,* Edouard Bingen, PhD, Marc Koskas, MD,*
Isabelle Nave, MD, and Emmanuelle Varon, MD

Agency and the US Food and Drug Administration have granted a


Background: 13-valent pneumococcal conjugate vaccine (PCV13) licen-
market authorization to new PCVs purely on the immune response
sure was based on the immune response (enzyme-linked immunosorbent
(enzyme-linked immunosorbent assay [ELISA] and opsonophago-
assay and opsonophagocytic assay) compared with PCV7. National sur-
cytic assay [OPA]) compared with PCV7 (serotypes 4, 6B, 9V, 14,
veillance program of pneumococcal nasopharyngeal (PNP) carriage in
18C, 19F, and 23F). Because there are limitations to the ability of
children with acute otitis media (AOM) was set up in 2001 when PCV7
immunogenicity data to predict protective efficacy conferred by
was introduced in France and continues to the present. This program was
these new PCVs, postmarketing surveillance and/or effectiveness
used in 2010 2011 to assess the effect of the implementation of PCV13 on
studies are critical, particularly for the added serotypes.2 The
PNP carriage in young children with AOM.
nasopharynx acts as the primary reservoir from which pneumo-
Methods: Between October 2010 and March 2011, 58 pediatricians ob-
coccus is spread within the community and represents the site
tained 943 nasopharyngeal swabs from children (6 to 24 months of age)
where the selective pressure exhibited by antibiotics or vaccines
with AOM. The swabs were sent for analysis to the French National
occurs.3 In addition to surveillance of invasive pneumococcal
Reference Centre for Pneumococci. Demographics, medical history, and
disease (IPD), monitoring the changes in pneumococcal nasopha-
physical examination findings were recorded.
ryngeal (PNP) colonization is important because it may provide
Results: Among 943 children enrolled (mean age, 13.4 months), 651 had
early information relevant to vaccine effectiveness. It is reasonable
received at least 1 dose of PCV13 and 285 received PCV7 only. Among
to believe that prevention of new acquisition of a given serotype
PCV13-vaccinated children, overall PNP carriage and carriage of serotypes
will be associated with clinical protection against noninvasive and,
not in PCV7 were significantly lower as compared with children exclusively
consequently, invasive disease.4 Furthermore, it is important to
vaccinated with PCV7 (53.9% vs. 64.6%, P 0.002 and 9.5% vs. 20.7%, P
document any effects on carriage because they are the basis of
0.0001, respectively). For serotypes 19A, 7F, and 6C, the carriage rates
indirect (herd) protection. To determine whether the use of PCV7
were also significantly lower in PCV13-vaccinated patients than in patients
caused any shift in the Streptococcus pneumoniae serotype distri-
only vaccinated by PCV7: 7.5% versus 15.4%, P 0.001, 0.5% versus 2.8%,
bution from nasopharyngeal samples of children with acute otitis
P 0.002, and 3.7% versus 8.4%, P 0.003, respectively.
media (AOM), a national epidemiologic study was initiated in
Conclusion: In young children (2 years) with AOM, this study suggests
France in 2001 (when PCV7 was introduced) and continues
that PCV13 has an impact on overall PNP carriage, as well as on serotypes
currently.5 This study was requested by the European Medicines
19A, 7F, and 6C.
Agency as a postlicensing commitment originally for PCV7 that
Key Words: pneumococcal nasopharyngeal carriage, children, 13-valent was extended for PCV13 (PCV7 serotypes 1, 3, 5, 6A, 7F, 19A).
pneumococcal conjugate vaccine Each year, during the fall and the winter, more than 700 infants
and toddlers 6 to 24 months of age who have AOM are enrolled in
(Pediatr Infect Dis J 2012;31: 297301) a prospective PNP carriage surveillance study. In 2010, French
authorities recommended routine infant immunization with PCV13
at 2, 4, and 12 months to replace PCV7. During the transition
period, switching from PCV7 to PCV13 was recommended at any
P lacebo-controlled trials to evaluate the protection conferred by
new pneumococcal conjugate vaccines (PCVs) with extended
serotype coverage face ethical challenges. Therefore, WHO has
point in the schedule to complete the immunization series. In
addition, a catch-up dose of PCV13 was recommended for all
children 1 to 2 years of age who had been completely vaccinated
recommended the use of immunologic correlates of protection as
previously with PCV7.6 In France, PCV13 was progressively
the basis of evaluation of new PCVs.1 The European Medicines
introduced during a period of 3 months, between early June and
early September 2010. Therefore, many of the children 6 months to 2
Accepted for publication December 22, 2011. years of age with AOM enrolled in the 2010 2011 nasopharyngeal
From the *ACTIV (Association Clinique et Therapeutique Infantile du Val de carriage study year had been immunized with PCV13. This situation
Marne), Paris, France; Departement de Microbiologie, Centre Hospitalier
Intercommunal de Creteil, Creteil, France; Service de Microbiologie, provides a unique opportunity to evaluate the impact of PCV13 on
Hopital Robert-Debre (AP-HP), Universite Denis-Diderot Paris 7, Paris, PNP carriage by comparing the pneumococcal carriage in children
France; AFPA (Association Francaise de Pediatrie Ambulatoire), Selestat, vaccinated by PCV13 with those vaccinated with PCV7 only.
France; and HEGP (Hopital Europeen Georges Pompidou), (AP-HP)
Centre National de Reference des Pneumocoques, Universite Paris 5, Paris,
France.
Supported by Pfizer Pharmaceuticals France. The authors have no other funding PATIENTS AND METHODS
or conflicts of interest to disclose.
Address for correspondence: Robert Cohen, MD, ACTIV, 27 rue Inkermann, Study Design
F94100 Saint Maur des Fosses, France. E-mail: robert.cohen@wanadoo.fr, Between October 2010 and May 2011, 58 pediatricians
activ@wanadoo.fr.
Copyright 2012 by Lippincott Williams & Wilkins
distributed throughout France took part in this prospective study.
ISSN: 0891-3668/12/3103-0297 Children of either sex, 6 months to 24 months of age, with AOM
DOI: 10.1097/INF.0b013e318247ef84 were enrolled. Diagnostic criteria for AOM included the Paradise

The Pediatric Infectious Disease Journal Volume 31, Number 3, March 2012 www.pidj.com | 297
Cohen et al The Pediatric Infectious Disease Journal Volume 31, Number 3, March 2012

algorithm for acute suppurative otitis media (effusion plus marked ratios and 95% confidence intervals). Analyses of pneumococcal
redness or marked bulging or moderate redness and bulging) carriage (ie, overall carriage or carriage by serotype) are based on
associated with fever and/or otalgia and/or irritability and/or con- the denominator of all children evaluated, rather than only on those
junctivitis.7 Exclusion criteria were as follows: antibiotic treatment carrying S. pneumoniae because pneumococcal vaccination might
within 7 days before enrollment, severe underlying disease, or influence the carriage rate and the serotype distribution in the
previous inclusion in the study during the last 12 months. Once population. To assess the effect of PCV13 vaccine, we defined 2
written informed consent was obtained, we queried the parents or groups of patients. The first one, children as adequately PCV13
guardians regarding the childs demographic information, risk vaccinated for the age if they had received 2 doses before 12
factors for carriage of resistant bacteria (including use of antibi- months or at least 1 dose after this age and the second one, children
otics and day care attendance modalities), and immunization his- as partially PCV13 vaccinated if they had received 1 dose of
tory. All data about vaccination schedule were taken from the PCV13 according to the French guidelines. The cohort of children
immunization chart (health records book) of each child and vaccinated only with PCV7 served as the reference group. The
checked in the investigators medical dossier for each patient. The analyses were conducted in 3 populations: the first one compared
study was approved by the Saint Germain en Laye Hospital Ethics the reference group versus the group of children PCV13 vacci-
Committee. nated; the second one compared the reference group versus chil-
In the prevaccine era, our research group conducted several dren received a partial immunization series with PCV13; and the
studies on the nasopharyngeal flora of young children (6 to 30 last one compared the reference group versus children adequately
months) with AOM.8 These studies showed that the carriage of S. immunized with PCV13 for the age. The 2 test and logistic
pneumoniae in this population exceeded 50%, and that serogroups regression were used in univariate analysis to identify potential
covered by PCV7 accounted for more than 80% of the strains. factors (P 0.25) for overall carriage and carriage of serotypes
Despite year-to-year fluctuations, none of the nonvaccine sero- 19A, 6C, and 7F. Variables identified by univariate analysis were
types, except 19A and 6A, were carried by more than 5% of age, PCV7 and/or PCV13 vaccination status, existence of siblings,
children or accounted for more than 10% of pneumococcal iso- daycare attendance modalities, recent antibiotic treatment (within
lates. Therefore, any nonvaccine serotype (excluding 6A and 19A) 3 months before enrollment), fever, and conjunctivitis. They were
isolated in more than 5% of children was defined as emergent. For introduced into multivariate logistic regression models.
a period of 5 years, a sample size of 1825 patients carrying S.
pneumoniae was required to confer an acceptable precision of the RESULTS
estimate of the carriage rate for a given serotype defined as
Between October 2010 and May 2011, 943 infants and
emergent, that is, approximately 5% 1%. Because this study
toddlers (mean age SD, 13.4 5.0 months) were enrolled; 7
lasted several years, it was therefore necessary to enroll an average
children (0.7%) had not received PCV and 936 (99.3%) were
of 365 carrier patients per year. Assuming that the rate of pneu-
immunized with PCV7 and/or PCV13. Among the vaccinated
mococcal carriage among children with AOM was 50%, it was
children, 285 (30.4%) were vaccinated with PCV7 only, and 651
necessary to enroll a total of 730 patients per year.
(69.6%) had received at least 1 dose of PCV13. In this last cohort
Microbiologic Investigations of PCV13 vaccinated children, 486 (74.7%) were adequately
immunized with PCV13 for the age, and 165 (25.3%) had received
On inclusion, deep nasopharyngeal samples were taken
a partial PCV13 immunization series. PCV vaccination status
transnasally with a flexible, sterile, soft rayon swab tip. After
according to age and classification used for PCV13 vaccination
sampling, swabs were immediately inoculated in transport medium
status (partially or adequately) is summarized in Figure 1. The
(Copan Venturi Transystem, Brescia, Italy), stored at room tem-
demographic characteristics, histories, signs, and symptoms of
perature, and sent within 48 hours to the National Reference
patients enrolled are described in Table 1. Except for age, patients
Center for Pneumococci at G. Pompidou European Hospital and to
demographic characteristics (sex, day care attendance modalities,
Robert Debre Hospital, in Paris. Each swab was swirled in 200 L
siblings, use of antibiotics 3 months before enrollment, and history
of brain-heart infusion, and 20 L were smeared onto Columbia
of AOM) were similar across the groups. The percentage of
blood agar supplemented with colistin and nalidixic acid. Bacterial
patients with conjunctivitis differed between groups. Table 2
isolates were identified based on colony morphology and Gram
compares pneumococcal carriage, serotypes distribution as well as
staining. S. pneumoniae serotyping and antibiotic susceptibility
penicillin susceptibility by vaccination status. Overall pneumococ-
testing were performed at the National Reference Center for
cal carriage, that of the additional serotypes in PCV13 (in partic-
Pneumococci. Serotyping was performed using latex particles
ular serotypes 19A and 7F) and that of serotype 6C, was signifi-
coated with a complete panel of antisera and factor sera (Statens
cantly reduced among PCV13-vaccinated patients as compared
Serum Institut, Copenhagen, Denmark), which enable us to iden-
with children exclusively vaccinated with PCV7. The proportion
tify the 91 known serotypes.5,9,10 Pneumococcal strains of known
of patients carrying non-PCV13 vaccine serotypes (excluding 6C)
serotypes from the Statens Serum Institute and from the French
did not change significantly according to vaccination status. Con-
National Reference Center for Pneumococci were used as internal
sistent with the univariate analysis, the results of the multivariate
controls. Susceptibility of S. pneumoniae isolates to penicillin G
logistic regression analysis also show that the odds ratio of carry-
was determined from minimal inhibitory concentrations (MICs) by
ing a serotype in PCV13 but not in PCV7 ( the serotype 6C) was
the agar dilution method. Isolates were classified as penicillin
significantly reduced in those who received one or more doses of
susceptible (MIC 0.06 g/mL), intermediate-resistant (0.12
PCV13 and was unaffected by age, siblings, day care attendance,
MIC 1.0 g/mL), penicillin nonsusceptible (PNSP) (MIC 0.12
recent antibiotics, the presence of fever, or conjunctivitis (results
g/mL), or resistant (MIC 2 g/mL), according to the Clinical
not shown).
and Laboratory Standards Institute.11

Statistical Analyses DISCUSSION


Data were double entered using 4D software (version 6.4) As a result of the transition from PCV7 to PCV13 in the
and analyzed using Stata SE 9.1 (Stata Corp., College Station, TX) French national vaccination program, the 2010 2011 year of the
for univariate analysis and multivariate logistic regression (odds study allowed us to investigate pneumococcal carriage in patients

298 | www.pidj.com 2012 Lippincott Williams & Wilkins


The Pediatric Infectious Disease Journal Volume 31, Number 3, March 2012 Impact of PCV13

FIGURE 1. PCV vaccination status according to age and classification used for PCV13 vaccination status (partially or
adequately).

who had been vaccinated with PCV13 during the same time this study, 15.4% (PCV7 vaccinated) versus 7.5% (PCV13 vacci-
period. Although this study is not a randomized controlled trial, nated), could be associated with a decline in disease due to this
patients assigned to the different analysis groups were comparable serotype and further reduction in the prevalence of pneumococcal
demographically, bacteriologic analysis was conducted in labora- strains that are PNSP.
tories that were blinded, and the end point is robust. Moreover, the Like serotype 19A, serotype 7F also plays a major role in
observed results are consistent enough to substantiate impact of IPD after PCV7 implementation.14 With the reduction of carriage
PCV13 on pneumococcal carriage. In fact, among children who observed in our results, we could also expect a reduction of
received 1 dose or more of PCV13, the impact is clear. The rates systemic infections caused by this serotype.
of carriage overall, that of the 6 additional serotypes taken to- We found no significant effect on serotype 3 carriage.
gether, that of serotypes 19A, 7F, and 6C, as well as that of isolates Although the carriage rate of this serotype seems slightly lower in
with reduced susceptibility to penicillin were significantly reduced. PCV13 vaccinated children, the number of children carrying se-
After introduction of PCV7 vaccination in France, we ob- rotype 3 in the PCV7-vaccinated group of patients was too small
served a slight reduction in the overall pneumococcal carriage to assess the effect of PCV13 on this serotype. The low carriage
(20%), a marked decrease in vaccine serotypes (45%), and a rate of serotype 6A across all study groups of this population
reduction in the carriage of PNSP strains (20%) in children with attests to the effect of PCV7. Of note, our findings indicate that
AOM.5,12 In this first year after the introduction of PCV13, PCV13 will likely provide some protection against disease caused
vaccination with at least 1 dose of PCV13 likewise reduced the by serotype 6C. The observed reduction in carriage rate (8.4% vs.
overall pneumococcal carriage by 16.5% (64.6% vs. 53.9%), 6 3.7%) concurs with the serologic data from immunized infants
additional serotype carriage by 49.2% (20.7% vs. 10.5%), and supporting that the 6A conjugate in PCV13 induces a strong
PNSP carriage by 26.5% (29.8% vs. 21.9%). opsonophagocytic response to serotype 6C.19
In France as in many other countries where a national We did not observe in this study a significant increase of
immunization program with PCV7 was implemented, serotype nonvaccine PCV13 serotypes, only serotypes 15A and 11A
19A subsequently became the serotype most often identified in reached 5% of patients enrolled.
invasive isolates from young children, in specimen from middle PCV-induced immune response protects against pneumo-
ear fluid and from nasopharyngeal swabs.1317 In addition, an coccal disease through opsonophagocytic activity (ie, serotype-
important degree of antibiotic resistance is associated with sero- specific antibody to the capsular polysaccharide, in association
type 19A.18 The dramatic decrease of the 19A carriage observed in with complement). During the PCV13 clinical development, im-

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Cohen et al The Pediatric Infectious Disease Journal Volume 31, Number 3, March 2012

TABLE 1. Nasopharyngeal Carriage, Serotypes Distribution, and Penicillin Resistance According to Vaccination
Status

PCV13 Recipients
PCV7 Vaccinated Only
(Non PCV13 Vaccinated) Adequately PCV13 Partially PCV13 PCV13 Vaccinated
n (%) [95% CI] Vaccinated Vaccinated (1 Dose)
P* P P
n 285 n (%) [95% CI] n (%) [95% CI] n (%) [95% CI]
n 486 n 165 n 651

Streptococcus pneumoniae 184 (64.6) [59.0 70.1] 266 (54.9) [50.559.4] 0.008 84 (50.9) [43.258.6] 0.004 351 (53.9) [50.157.8] 0.002
PCV7 serotypes 4 (1.4) [0.32.8] 12 (2.5) [1.13.9] 0.3 3 (1.8) [0 3.9] 0.7 15 (2.3) [1.13.5] 0.4
6 additional serotypes 59 (20.7) [16.0 25.4] 48 (9.9) [7.4 12.8] 0.001 14 (8.5) [4.212.8] 0.001 62 (9.5) [7.311.8] 0.001
in PCV13
19A 44 (15.4) [11.219.7] 39 (8.2) [5.8 10.7] 0.001 10 (6.1) [2.4 9.7] 0.003 49 (7.5) [5.59.6] 0.001
7F 8 (2.8) [0.9 4.7] 2 (0.4) [0 1.0] 0.005 1 (0.6) [0 1.8] 0.1 3 (0.5) [0 1.0] 0.002
6A 0 2 (0.4) [0 1.0] 0.3 1 (0.6) [0 1.8] 0.2 3 (0.5) [0 1.0] 0.3
3 7 (2.5) [0.6 4.3] 5 (1.0) [0.11.9] 0.1 2 (1.2) [0 2.9] 0.4 7 (1.1) [0.31.9] 0.1
1 0 0 0 0
5 0 0 0 0
6C 24 (8.4) [5.211.7] 17 (3.5) [1.9 5.1] 0.003 7 (4.2) [1.17.4] 0.009 24 (3.7) [2.25.1] 0.003
Non-PCV13 serotypes 97 (34.0) [28.8 39.7] 189 (38.9) [34.7 43.3] 0.1 60 (36.4) [29.4 43.9] 0.4 250 (38.4) [34.7 42.2] 0.1
(excluding 6C)
Predominant non-PCV13
serotypes
35B 12 (4.2) [1.9 6.6] 24 (4.9) [3.0 6.9] 0.6 3 (1.8) [0 3.9] 0.2 27 (4.2) [2.6 5.7] 0.08
15A 12 (4.2) [1.9 6.6] 30 (6.2) [4.0 8.3] 0.2 5 (3.0) [0.4 5.7] 0.5 35 (5.5) [3.8 7.3] 0.4
15B/C 13 (4.6) [2.17.0] 24 (4.9) [3.0 6.9] 0.8 6 (3.6) [0.8 6.5] 0.6 30 (4.6) [3.0 6.2] 0.9
11A 11 (3.9) [1.6 6.1] 22 (4.5) [2.7 6.4] 0.7 4 (2.4) [0.5 4.8] 0.4 26 (4.0) [2.55.5] 0.9
Penicillin nonsusceptible
Intermediate 79 (27.7) [22.532.9] 103 (21.2) [17.524.8] 0.04 28 (17.0) [11.222.8] 0.01 131 (20.1) [17.0 23.2] 0.01
Resistant 6 (2.1) [0.4 3.8] 8 (1.7) [0.52.8] 0.6 4 (2.4) [0.5 4.8] 0.8 12 (1.8) [0.8 2.9] 0.8
*P compares PCV7 vaccinated only versus adequately PCV13 vaccinated.

P compares PCV7 vaccinated only versus partially PCV13 vaccinated.

P compares PCV7 vaccinated only versus PCV13 vaccinated.

Carried by more than 3% of infants.

TABLE 2. Demographic Characteristics According to Vaccination Status

PCV13 Recipients
PCV7 Vaccinated Only
(Non-PCV13 Vaccinated) Adequately PCV13 Partially PCV13 PCV13 Vaccinated
Vaccinated Vaccinated (1 Dose)

No. infants enrolled 285 486 165 651


Mean age SD (mo) 14.4 5.0* 13.8 5.3 10.5 3.0 13.0 5.0*
12 mo 55.4 (49.6 61.2) 63.6 (59.3 67.9) 26.1 (19.332.8) 54.2, (50.4 58.1)
Male 52.6 (46.8 58.5) 53.5 (49.0 57.9) 44.2 (36.6 51.9) 51.2 (47.355.0)
Type of care
Day care centre 47.7 (41.9 53.6) 46.5 (42.151.0) 45.5 (37.8 53.1) 46.4 (42.550.2)
Childminder 28.8 (23.534.1) 32.5 (28.336.7) 29.7 (22.736.7) 31.8 (28.235.4)
Home 23.5 (18.6 28.5) 21.0 (17.4 24.6) 24.8 (18.231.5) 21.8 (18.6 25.0)
Siblings 56.1 (50.3 61.9) 54.7 (50.359.2) 58.8 (51.2 66.4) 55.6 (51.8 59.4)
Use of antibiotics 3 mo 44.0 (38.2 49.8) 45.1 (40.6 49.5) 45.5 (37.8 53.1) 45.2 (41.3 49.0)
before enrolment
Conjunctivitis 23.9 (18.9 28.8) 30.5 (26.334.6) 32.1 (24.9 39.3) 30.9 (27.334.4)
Otalgia 75.8 (70.8 80.8) 74.5 (70.6 78.4) 73.9 (67.2 80.7) 74.3 (71.0 77.7)
Fever 38.5C 58.3 (52.5 64.1) 54.2 (49.8 58.7) 61.0 (53.4 68.5) 55.9 (52.0 59.7)
History of AOM 57.5 (51.8 63.3) 60.5 (56.1 64.9) 49.1 (41.4 56.8) 57.8 (54.0 61.6)
Otitis-prone children 16.5 (12.220.8) 20.0 (16.4 23.5) 14.6 (9.120.0) 18.7 (15.721.7)
Values are given as % (95% CI) unless otherwise indicated.
*P 0.0001, P compares PCV7 vaccinated only versus PCV13 vaccinated.

P 0.0001, P compares PCV7 vaccinated only versus partially PCV13 vaccinated.

P 0.02, P compares PCV7 vaccinated only versus adequately PCV13 vaccinated.

P 0.03, P compares PCV7 vaccinated only versus PCV13 vaccinated.

mune responses were evaluated in opsonophagocytic activity as- ryngeal flora and the first one describing the biologic effect of
says, considered as appropriate in vitro assays to measure the PCV13 on serotype 6C. The induced antibodies against 6B and 6A
potential vaccine-induced protective capacity. are biologically active in vivo, as manifested by the reduction of
Recently, Miller et al showed an impact of PCV13 on IPD, nasopharyngeal carriage of 6C. This observation is reassuring
particularly for serotypes 19A and 7F.20 The data of our study are because such an effect on nasopharyngeal carriage is likely to
the first observation indicating the impact of PCV13 on nasopha- mean protection against pneumococcal disease in vaccinated chil-

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The Pediatric Infectious Disease Journal Volume 31, Number 3, March 2012 Impact of PCV13

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