Pediatric Invasive Pneumococcal Disease Caused by
Vaccine Serotypes following the Introduction of
Conjugate Vaccination in Denmark
Catherine C. Bjerre2, David Goldblatt3, Lindsey Ashton3, Mitch Haston3, Helle B. Konradsen1,
Lotte Lambertsen1, on behalf of the Danish Pneumococcal Surveillance Collaborating Group"
1Neisseria and Streptococcus Reference Center, Department of Microbiology and Infection Control, Statens Serum Institut (SSI), Copenhagen, Denmark, 2Department of
Infectious Disease Epidemiology, Statens Serum Institut (SSI), Copenhagen, Denmark, 3Immunobiology Unit, University College London Institute of Child Health, London,
A seven-valent pneumococcal conjugate vaccine (PCV7) was introduced in the Danish childhood immunization program
(2+1 schedule) in October 2007, followed by PCV13 starting from April 2010. The nationwide incidence of IPD among
children younger than 5 years nearly halved after the introduction of PCV7 in the program, mainly due to a decline in IPD
caused by PCV7-serotypes. We report the results from a nationwide population-based cohort study of laboratory confirmed
IPD cases in children younger than 5 years during October 1, 2007 to December 31, 2010 and describe the characteristics of
children suspected to present with a vaccine failure. The period between April 19 and December 31, 2010 was considered a
PCV7/PCV13 transitional period, where both vaccines were offered. We identified 45 episodes of IPD caused by a PCV7
serotype (23% of the total number) and 105 (55%) caused by one of the 6 additional serotypes in PCV13. Ten children had
received at least one PCV7 dose before the onset of IPD caused by a PCV7 serotype. Seven children were considered to be
incompletely vaccinated before IPD, but only three cases fulfilled the criteria of vaccine failure (caused by serotypes 14, 19F
and 23F). One case of vaccine failure was observed in a severely immunosuppressed child following three PCV7 doses, and
two cases were observed in immunocompetent children following two infant doses before they were eligible for their
booster. None of the IPD cases caused by the additional PCV13 serotypes had been vaccinated by PCV13 and there were
therefore no PCV13-vaccine failures in the first 8-months after PCV13 introduction in Denmark.
Citation: Harboe ZB, Valentiner-Branth P, Ingels H, Rasmussen JN, Andersen PHS, et al. (2013) Pediatric Invasive Pneumococcal Disease Caused by Vaccine
Serotypes following the Introduction of Conjugate Vaccination in Denmark. PLoS ONE 8(1): e51460. doi:10.1371/journal.pone.0051460
Editor: Ray Borrow, Health Protection Agency, United Kingdom of America
Received October 24, 2011; Accepted November 6, 2012; Published January 24, 2013
Copyright: ? 2013 Harboe et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits
unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Funding: This research was supported by Statens Serum Institut, since data were collected routinely for national surveillance purposes through funding allocated
to national surveillance. The funding entity did not have any influence in the study design; collection, analysis, and interpretation of data; writing of the paper;
and decision to submit it for publication.
Competing Interests: The authors have declared that no competing interests exist.
* E-mail: firstname.lastname@example.org
. These authors contributed equally to this work.
" Membership of the Danish Pneumococcal Surveillance Collaborating Group is provided in the Acknowledgments.
A seven-valent pneumococcal conjugate vaccine (PCV7) was
introduced in the Danish childhood immunization program in
October 2007. Shortly after its introduction, the incidence of
invasive pneumococcal disease (IPD) declined markedly, in
particular among children younger than 2 years, where the
incidence halved compared to the pre-vaccination period [1,2].
The decline was mainly related to a decrease in the incidence of
IPD caused by vaccine serotypes (VT-IPD) . These results are
consistent with those observed in other industrialized countries
and support the high effectiveness of PCV7 against VT-IPD [3–6].
Changes in the serotype distribution of invasive pneumococci
were described to occur at an early stage in the post-vaccination
period in Denmark and non-vaccine serotypes 7F and 1 were
found predominantly as a cause of non-VT-IPD in children .
However, and similarly to what has been observed in other
countries, cases of VT-IPD are still observed in the population
during the post-PCV7 period among children for whom vaccina-
tion was offered [8,9].
Cases of VT-IPD raise concerns related to the vaccine’s
effectiveness and to the possibility of immunological disorders in
the affected child. It is well recognized that not all serotypes in the
pneumococcal conjugate vaccines (PCV) are equally immunogenic
and that the immune response also varies according to the number
of doses administered [10–12]. Furthermore, incomplete vaccina-
tion and co-morbid conditions (such as immunodeficiencies,
malignancies, prematurity, and several chronic diseases, among
others) have been identified as factors contributing to VT-IPD in
vaccinated children [8,9]. Also, cases of vaccine failure in
apparently immunocompetent children have been described
In October 2007, an enhanced nationwide, population-based
surveillance of laboratory confirmed IPD cases in children younger
PLOS ONE | www.plosone.org1 January 2013 | Volume 8 | Issue 1 | e51460
than 5 years was implemented in Denmark in order to identify
patients where a vaccine failure could be suspected. This
information is considered valuable in order to understand the
underlying mechanisms behind a case of vaccine failure and may
contribute to identify a subpopulation of children that might need
additional immunological investigation.
We hereby report the results from a nationwide population-
based cohort study of laboratory confirmed IPD cases in children
younger than 5 years of age and describe the characteristics of
children with vaccine-type IPD during a 31-month surveillance
Materials and Methods
Study Setting and Design
We conducted a nationwide cohort study based on population-
based surveillance data on laboratory confirmed IPD in children
younger than 5 years of age after the introduction of PCV in the
Danish childhood immunization program. Laboratory surveil-
lance data on IPD from October 1, 2007 to December 31, 2010
were linked to the Danish Childhood Vaccination Registry as
previously described . Information regarding the patients’
clinical course and blood samples for immunological testing were
routinely collected by a physician in cases where a vaccine failure
was suspected. Since data and samples from patients were
collected routinely for national surveillance purposes, no ethical
approval or informed consent from patients were required. The
study was approved by the Danish Data Protection Agency
Pneumococcal Conjugate Vaccination in Denmark
A PCV has been offered free of charge as a part of the routine
childhood immunization program since October 1, 2007 in a
reduced 2+1 schedule at the ages of 3, 5, and 12 months. PCV7
started to be offered from October 1, 2007. For an introduction
period, children aged 12–17 months at the first vaccination (born
after April 30, 2006) were offered a catch-up program of two doses
of PCV7 with a minimum interval of two months . The
thirteen-valent pneumococcal conjugate vaccine (PCV13) started
to be offered on April 19, 2010 . General practitioners were
recommended to use their stocks of PCV7 before start using
PCV13, and therefore the period following the introduction of
PCV13 can only be considered as a transition period, where both
PCV7 and PCV13 were administered.
During 2007–2010, approximately 64.000 children were born
annually in Denmark (http://www.statistikbanken.dk). The vac-
cination uptake of PCV7 and the concomitantly administered
single shot vaccine against diphtheria, tetanus, acellular pertussis,
poliomyelitis and Haemophilus influenzae type b (DTaP-IPV/Hib
Statens Serum Institut, Copenhagen, Denmark) has been reported
elsewhere [1,18]. In brief, PCV7’s uptake was reported to be
approximately two percentage points lower than the uptake of
DTaP-IPV/Hib vaccine. The uptake of the primary vaccination
program with PCV7 for the birth cohorts 2007–2009 was 81–91%
for the first, second and booster doses. The uptake of the catch-up
program was lower, 51–76% depending on the age of the child
and the number of doses given . No shortages in stockpiles or
interruption of the distribution of the vaccines have been reported.
National Surveillance of Pediatric IPD and PCV-Failures
Figure 1 shows the components and setup of the national
surveillance system of pediatric IPD and PCV-failures. In brief, all
departments of clinical microbiology in Denmark send invasive
Streptococcus pneumoniae isolates for determination of serotype to the
National Neisseria and Streptococcus Reference Center (NSR),
Statens Serum Institut (SSI). The characteristics and completeness
of the national surveillance system for IPD have previously been
described . Approximately 90% of the isolates are obtained
from hospitalized patients . Notification of IPD in children
younger than 5 years of age and submission of pneumococcal
isolates causing IPD in all age groups became mandatory by law
after October 1, 2007 in order to monitor the effectiveness of PCV
Children who present with IPD due to one of PCV7-serotypes
or one of the six additional serotypes included in PCV13 (after
PCV13 became available in Denmark) are considered suspects of
having a vaccine failure. PCV7 contains the capsular polysaccha-
ride antigens of 7 serotypes (4, 6B, 9V, 14, 18C, 19F, and 23F).
Serotypes 1, 3, 5, 6A, 7F, 19A are the six additional serotypes
included in PCV13. Clinical information and vaccination status of
patients are collected by telephone interview with clinicians in
charge of the patient and by verification of discharge diagnoses
and medical files (Figure 1). During the transition period when
both PCV7 and PCV13 were administered, the vaccine’s batch
number was used to verify the valence of the vaccine administered
to the child, if relevant. If a case fulfills the case definition of
vaccine failure, supplementary blood samples from patients are
requested for additional immunological investigation, in consulta-
tion with the patient’s physician (Figure 1). Cases of VT-IPD in
vaccinated children, regardless of the number of vaccines they had
received, are reported to the Danish Medicines Agency (Læge-
middelstyrelsen) by the Department of Infectious Disease Epide-
Invasive Pneumococcal Disease (IPD).
defined as the occurrence of IPD confirmed by a positive culture
for S. pneumoniae from a patient’s cerebrospinal fluid (CSF), blood
or other sterile site. When both CSF and blood isolates are
received from a patient, the case is categorized as meningitis.
Patients are considered having a recurrence if a new IPD isolate is
obtained within 30 days after the initial incidence, or if a new
pneumococcal serotype is isolated within 30 days.
group targeted for primary PCV7/PCV13 vaccination or catch-up
program with PCV7.
targeted for primary PCV7/PCV13 vaccination or catch-up
program who presented an IPD episode before vaccination.
Children who presented an IPD episode
after PCV7 immunization, regardless of the number of doses
received, the time of onset of illness after vaccination and the age
Defined as IPD caused by any of the serotypes
included in all the vaccine- doses the child has received, and where
one of the following criteria are met: 1) the child is under 13
months of age at IPD onset and has received two doses of PCV7 or
PCV13 but not yet the booster dose, and becomes ill more than
two weeks after the last dose was given; 2) the child is at least 12
months old at IPD onset, completed the primary vaccination
before 12 months of age, and becomes ill more than one week after
administration of the booster dose 3) the child is at least 6 months
old at IPD onset, received two doses of PCV7 as a part of the
catch-up program and becomes ill more than two weeks after the
administration of the last dose. Children included in the first two
categories were targeted during their primary vaccination and
children in the third category were targeted by the catch-up
A case of IPD is
Children outside the age
Children within the age group
Vaccine Serotypes-IPD after PCV7 in Denmark
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failure was confirmed is retrieved through the surveillance system.
Death is considered to be related with IPD when the date of death
is registered within 30 days after the clinical sample was obtained
from the patient.
Vital status of children where PCV-
routinely serotyped by using pneumotest latex and/or Quellung
All IPD isolates received are
reaction using type-specific pneumococcal rabbit-antisera from
SSI (SSI-Diagnostica, Copenhagen, Denmark) [2,22,23].
In cases that fulfilled criteria for PCV-
failure, blood samples are requested in order to characterize the
patient’s antibody response after vaccination and infection. Serum
samples are assayed for individual antibodies included in PCV7 or
PCV13 according to the immunization schedule. Samples are
analyzed by ELISA after absorption with polysaccharide 22F and
cell wall polysaccharide and results expressed as concentrations of
antibody against each PCV serotype. A serotype specific antibody
Figure 1. Danish surveillance system of pediatric invasive pneumococcal disease (IPD) and pneumococcal conjugate vaccine (PCV)-
failures. Cases of IPD caused by a serotype included in PCV7 or one of the additional serotypes included in PCV13 are identified among all IPD cases
in children ,5 years in order to explore possible cases of vaccine failure. PCV7 was administered in the national childhood immunization program
free of charge from October 1, 2007 to April 19, 2010 and then PCV13 was offered. CSF: Cerebrospinal fluid; NSR: National Neisseria and Streptococcus
Reference Center, Statens Serum Institut: SSI, MBL: Mannose-Binding Lectin, RTI: Respiratory Tract Infections, WBC: White Blood Cells.
Vaccine Serotypes-IPD after PCV7 in Denmark
PLOS ONE | www.plosone.org3 January 2013 | Volume 8 | Issue 1 | e51460
value of 0.35 mg/mL is considered protective. ELISA assays are
carried out at the Pneumococcal Serology Laboratory (SSI) and in
this study, at the WHO reference laboratory for Pneumococcal
Serology at the UCL Institute of Child Health, London, as
previously described [24–26]. Functional activity of specific
pneumococcal antibodies (PCV7 antibodies+6A) was measured
by a opsonophagocytic assay (OPA) at the laboratories in London
. Additional immunological testing is carried out according to
the child’s clinical presentation (Figure 1).
From October 1, 2007 to December 31, 2010, 191 laboratory-
confirmed IPD cases in 188 children younger than 5 years were
reported, corresponding to an approximate estimated incidence of
14.6 (95% confidence interval (CI) 12.6–16.7) per 100,000
population (Table 1, Figure 2). The median age of children was
20 months (age range 0–59 months), 80% (n=154) of isolates were
obtained from blood, 20% (n=36) CSF and only one isolate from
other sterile sites (,1%). Pneumococcal serotype and vaccination
status was available for all patients except in one, presenting with
an IPD due to serotype 35F.
We identified 45 IPD episodes (23% of the total number) caused
by a PCV7 serotype and 105 (55%) caused by one of the 6
additional serotypes in PCV13 (Table 1). None of the patients
presenting IPD due to PCV7 or one of the 6 additional serotypes
in PCV13 were vaccinated with PCV13. The most frequent
situation was a case of IPD caused by one of the additional
serotypes included in PCV13 in a child who had received at least
one dose of PCV7 since the beginning of the immunization
program. Among these patients, the most frequently isolated
serotype was serotype 7F, 19A and 1. Among cases of non-PCV7/
PCV13 serotypes after PCV13 started to be used, we identified
two cases of 12F-IPD, two cases of 24F-IPD and one case caused
by 33F serotype, All these patients received at least 2 doses of
PCV7 before IPD.
Three patients (1.6%) presented a recurrent IPD episode: one
child presented a 16F and a serotype 14 infection, one presented
6A and 6C infection, and one presented two episodes of 19A
bacteremia caused by serotype 19A of MLST type ST994 in both
episodes. The child received 2 doses of PCV7 before the first IPD,
and had a history of recurrent acute otitis media with no other
additional comorbidity. The isolates were sensitive to penicillin
(MIC #0.1 mg/mL). No further immunological tests were carried
out in this child.
IPD Caused by PCV7-Serotypes in Vaccinated Children
Ten children had received at least one PCV7 dose before the
onset of IPD caused by a PCV7 serotype (Table 1, Table 2),
corresponding to an estimated incidence of 0.8 cases (95% CI 0.3–
1.3) per 100.000 population. No fatal cases directly related with
the IPD episode were observed in these children.
Seven children were considered to be incompletely vaccinated
before IPD onset and did not fulfill the criteria of vaccine-failure.
Table 1. Invasive Pneumococcal Disease in Children Younger than 5 years after the introduction of the Heptavalent Pneumococcal
Conjugate Vaccine in Denmark.
all 19 (42%)16 (36%)10 (22%) 45 (100%)
Additional serotypes in PCV13
11 12 12 25
7F2 1529 46
all10 (10%)32 (30%)63 (60%)105 (100%)
16 (42%)022 (58%)38 (100%)
PCR2 (67%)1 (33%)03(100%)
Total4749 95 191
1Eligible: child within the age group targeted for primary PCV7/PCV13 vaccination or catch-up program who presented an IPD episode before vaccination.
2Not-eligible: child outside the age group targeted for primary PCV7/PCV13 vaccination or catch-up program with PCV7.
3PCV7-vaccinated: children who presented an IPD episode after PCV7 immunization, regardless of the number of doses received, the time of onset of illness after
vaccination and the age of immunization.
4Other serotypes: 6C, 8, 10B, 12F, 15B/C, 16F, 18F, 22F, 23F, 24F, 33F, 35B, 35F. No clear predominance of any serotype was observed. None of the patients presenting
IPD due to PCV7 or PCV13 serotypes were vaccinated with PCV13.
Vaccine Serotypes-IPD after PCV7 in Denmark
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Among them, three children presented important comorbid
conditions (Table 2). Three other cases fulfilled the criteria of
vaccine failure, two following the second dose and one following
the booster dose:
The first case identified as vaccine failure was observed in a 30
month old girl, who presented with pneumococcal bacteremia
caused by serotype 14 after she had received a complete
immunization with PCV7 at the age of 3, 5 and 12 months.
The isolate was susceptible to penicillin. The child was severely
immunocompromised at IPD onset; she was admitted to the
hospital with febrile leukopenia after chemotherapy due to an
acute myeloid leukemia (neutrophil count ,200/mm3). The child
recovered well after IPD and at 12-months follow-up the child did
not present signs of relapse. Due to the critical clinical condition of
the child and the severe immunosuppression at IPD onset, no
assays for pneumococcal antibodies or additional immunological
investigation were conducted.
The second case of vaccine failure was observed in a 12-month
old girl, who received primary immunization with PCV7 at 4 and
6 months of age. The child was admitted to the hospital due to
febrile illness, blood cultures demonstrated S. pneumoniae serotype
19F, susceptible to penicillin. The child was discharged from the
hospital shortly after admission with the clinical diagnosis of acute
otitis media and received phenoxymethylpenicillin for oral
Table 2. Invasive pneumococcal disease due to PCV7 serotypes in PCV7 vaccinated children, Denmark 2007–2010 (n=10).
No. of PCV7 doses
received before IPD
No. of days between last
PCV7 dose and IPD
at admission Comorbid ConditionsVital status
M17 SepsisNone knownalive No
F2516Bacteremia Complement (C2) deficiency
(homozygote), MBL deficiency
F3 536 Bacteremia, febrile
Acute myeloid leukaemiaaliveYes
F1 20Meningitis, sepsis None knownaliveNo
M1 145 SepsisAcute myeloblastic leukaemiaaliveNo
F2 207Acute otitis media,
None known aliveYes
F110 ArthritisNone knownalive No
None knownalive No
M2 71 MeningitisNone known aliveYes
M1263 Bacteremic pneumonia Multi-handicapped childalive No
A case of vaccine failure is defined as a child with IPD caused by any of the serotypes included in all the vaccine doses the child has received, and where one of the three
following criteria are met: 1) the child is under 13 months of age at IPD onset and has received 2 doses of PCV7/PCV13 but not yet the booster dose and becomes ill
more than 2 weeks after the last dose was given; 2) the child is at least 12 months old at IPD onset, completed primary vaccination before 12 months of age and
becomes ill more than 1 week after administration of the booster dose 3) the child is at least 6 months old at IPD onset, received 2 doses of PCV7 as a part of the catch-
up program and becomes ill more than 2 weeks after the administration of the last dose. Vital status was recorded at 30 days after IPD. None of the patients presenting
IPD due to PCV7 or one of the 6 additional serotypes in PCV13 were vaccinated with PCV13.
Figure 2. Serotype distribution of cases of Invasive pneumococcal disease in children , ,5 years, Denmark 2007–2010 (n=191).
Information on pneumococcal serotypes was available for all cases, but not for three cases diagnosed by PCR (not shown in the figure). Vaccination
status was available for all patients but one (IPD due to serotype 35F).
Vaccine Serotypes-IPD after PCV7 in Denmark
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treatment. The child was previously healthy, and had no clinical
history of recurrent infections. The child did not have specific
testing for pneumococcal antibodies or immunologic deficiencies
conducted after the clinicians’ consideration.
The third case of vaccine failure was observed in an 8-month
old boy, who presented with pneumococcal meningitis caused by
serotype 23F after 2 doses of PCV7 given at 3 and 5 months of
age. The isolate was sensitive to penicillin. The child was
considered as immune competent by the clinicians in charge of
the patient. The full blood count including white blood cells
differential, the levels of immunoglobulins (IgG, IgA, and IgM),
the Mannose-Binding lectin level, and the antibody titers to
tetanus, H. influenzae type b, and diphtheria toxin were within
normal ranges. The antibody response to PCV7 and OPA profiles
are shown in Table 3. The GMC for all PCV7 serotypes but 23F
were over the protective threshold, for 23F the concentration was
below the threshold (0.06 mg/mL). The OPA analysis confirmed
that there was incomplete (poor) killing activity for 23F. On the
follow-up after 6 months the child was clinically well with no signs
or symptoms of underlying medical conditions, no other episodes
of invasive bacterial disease and no evidence of recurrent
respiratory tract infections. The child recovered from the episode
without neurological sequelae.
Results from our population-based cohort study support that
PCV7 has been effective in preventing IPD caused by vaccine
serotypes in the context of a 2+1 PCV program in Denmark.
PCV7-type IPD in ,5 year-olds occurred mainly in unvaccinated
children, with only seven cases in those who received at least one
dose of PCV7 (less than 1 case per 100.000 person-years) and only
three cases of true vaccine failures due to serotypes 14, 19F and
23F. Among these cases, one case of vaccine failure was observed
in a severely immunosuppressed child following three PCV7 doses,
and two cases were observed in immunocompetent children
following two infant doses before they were eligible for their
booster. In addition, none of the IPD cases caused by the
additional PCV13 serotypes had been observed in children
vaccinated with PCV13. Thus no PCV13-vaccine failures have
been observed in the first 8-months after PCV13 was started to be
used in Denmark.
Concomitantly with the decrease of PCV7 serotypes observed
shortly after PCV7’s introduction , the six additional serotypes
included in PCV13 were found to be the predominant cause of
pediatric IPD in our cohort of patients, similarly to what has been
reported from other countries . However, following the
introduction of PCV13 in the program, it is not clear from our
data whether further benefit in preventing IPD in children under 5
years could potentially be achieved by including additional
serotypes in a pediatric vaccine, since no additional serotypes
have been shown to be clearly dominating the pneumococcal
population causing replacement disease. This observation could be
both related to differences in the invasive potential of pneumococci
and characteristics of the population [29,30]. Nevertheless, the
surveillance period after PCV7/PCV13 introduction is relatively
short (8 months), and serotype replacement has to be closely
followed in the future in order to evaluate replacement disease in
During the surveillance period immediately following the
introduction of PCV7, we found that nearly one-fourth of IPD
cases (n=45/191) were caused by a serotype included in PCV7,
but only 10 children were partially or completely vaccinated with
PCV7 before IPD, and only 3 cases fulfilled criteria of vaccine
failure (Table 1, Table 2). Comorbid conditions were identified in
one-third of vaccinated children with IPD due to PCV7 serotypes,
regardless of the number of doses administered (Table 2). Similar
results have been reported from the US, where children belonging
to moderate and high-risk groups are recommended to receive
PCV-vaccination . We have previously reported an approx-
imated 8% prevalence of comorbid conditions in a nationwide
cohort of patients with pediatric IPD in Denmark . However,
the methods used for collecting data on comorbidity and
estimating the prevalence of such conditions differ greatly between
the two studies (by calculation of the Charlson index vs. telephonic
interviews with physicians), which make direct comparison of the
findings difficult. In any case, our findings underline the
importance of continued vigilance for pneumococcal disease in
febrile children with comorbidity or other risk factors that make
them more susceptible to the disease even after immunization with
The first case identified as a vaccine failure was due to a
serotype 14 infection, a serotype which has been otherwise
considered to be quite immunogenic [11,14,31]. A case of serotype
14-vaccine failure has previously been described in a patient
enrolled in the efficacy trial carried out among Navajo and White
Mountain Apache children in the US . In contrast to this case,
our patient was severely immunosuppressed before IPD onset. In
the case from the US, the child was not known to have underlying
medical conditions and had a high concentration of antibodies
against serotype 14, which were also found to be functional in the
OPA assay. The authors suggest that serotype-specific correlates of
protection based on the ELISA cut-off values from population-
based vaccine efficacy studies are not necessarily adequate to
predict the level of protection at the individual level. Due to the
critical clinical condition of the patient in our cohort, it was
considered inappropriate to collect samples for immunological
testing in this patient and they would probably be of limited value.
Serotype 19F has been found to be the most frequent serotype
causing pneumococcal meningitis in PCV7-vaccinated children in
France . In spite of its good immunogenicity, serotype 19F has
been described to induce antibodies of lower avidity that decline
faster compared to other antibodies induced by the vaccine . A
case of vaccine failure due to serotype 19F has previously been
described in the literature, in a child who presented with
pneumococcal meningitis in spite of three PCV7 doses and who
Table 3. IgG antibody concentrations and opsonophagocytic
activity with type-specific polysaccharide in a child with PCV7-
activity (GMT)% inhibition*
The child presented with meningitis caused by serotype 23F after receiving 2
doses of PCV7. A serotype specific antibody value of 0.35 mg/mL was
*Percent inhibition of opsonophagocytic activity after addition of type-specific
polysaccharide. NR: no result given incomplete (poor) killing of the sample.
Vaccine Serotypes-IPD after PCV7 in Denmark
PLOS ONE | www.plosone.org6January 2013 | Volume 8 | Issue 1 | e51460
was considered immunocompetent . In our case, the clinical
course was not severe; the child was discharged shortly after
admission to the hospital with oral antibiotics. The clinicians
decided not to investigate the antibody profile after IPD and had
no clinical suspicion of immunosuppression in this patient.
Although the infant we described with 23F vaccine failure had
received only 2 doses of PCV7, the antibody response to all the
vaccine serotypes except serotype 23F was satisfactory, both
measured by ELISA and OPA assay (Table 2). The child was
considered to be immunocompetent. A lower vaccine response to
this serotype has previously been reported, with the protective
threshold for antibodies to this serotype (alike serotype 6B) being
reached only after the booster dose .
Recommendations regarding clinical management and revac-
cination of children presenting vaccine failures must be tailored to
the individual child in different clinical settings. Probably, an
additional vaccine-dose followed by antibody responses and OPA
measurements are suitable recommendations, since it is well
documented that in some cases of vaccine failures the patient
remains refractory to responses to the invading serotype despite
further doses after the infection [5,29,31].
Concerning IPD caused by PCV7 serotypes in non-vaccinated
patients, we found that nearly 40% of children were eligible for
vaccination but presented with IPD before the first dose, mainly
children who were targeted by the catch-up program. It has also
been described that the coverage of PCV7 is slightly lower than
the coverage of DTaP-IPV/Hib, and particularly for the catch-up
program. The reasons for this difference are currently unknown
. Still, PCV7’s uptake achieved in Denmark is one of the highest
in Europe, where large differences in PCV7 vaccination schemes
and use of PCV7 between regions have been reported .
Among the strengths of our study, we can mention that we were
able to report high-quality data collected through an enhanced
surveillance system based on collaboration between NSR, the
Department of Epidemiology, the departments of clinical micro-
biology and clinicians across the country (Figure 1). The register of
pediatric IPD due to PCV7 serotypes or to one of the six serotypes
included in PCV13 includes complete clinical, epidemiological
and laboratory information on patients, which will allow us to
closely monitor and improve our understanding on cases of
vaccine failure. Among the needs and opportunities for our
surveillance system in the future we envisage the collection of
information on vaccination history from IPD-cases due to other
serotypes than those included in the vaccines. This would allow us
to investigate whether certain groups of children are at higher risk
of getting IPD and directly assess the effectiveness of the vaccines
using the indirect cohort method [5,34].
The results of our study may be limited by several factors. We
present the results from a relatively short surveillance period (39
months) which followed the introduction of PCV7 in the
immunization program. This may be of importance in terms of
evaluation of replacement disease among vaccinated children,
considering that pneumococcal populations are highly dynamic
over time and susceptible to external factors such as conjugate
vaccination pressure . Also, children in the study population
have recently been vaccinated with PCV and a large part of the
population is still incompletely vaccinated, limiting the extrapo-
lation of these results in the long term.
A selection bias may also be present in our study, since we used
a highly specific case definition including only culture confirmed
IPD cases in a setting were blood- and CSF-cultures are almost
exclusively obtained in hospital settings. Furthermore, we were not
able to investigate the immunological status after IPD in all
children with vaccine failure, which could have contributed to the
understanding the underlying mechanisms.
In summary, IPD in children younger than 5 years of age was a
rare event and occurred mainly in unvaccinated children in our
cohort of patients. Only three cases of PCV7-failure were
confirmed during a 31-month surveillance period. Seven addi-
tional IPD cases due to PCV7- serotypes were observed in
incompletely vaccinated children. So far, no PCV13-vaccine
failure cases have been observed, however the surveillance period
was short. Children with confirmed or suspected immunosuppres-
sion should be closely monitored and assessed on an individual
We would like to thank the departments of clinical microbiology in
Denmark for routinely sending pneumococcal isolates for surveillance. We
acknowledge the dedicated work of the staff performing the serotyping of
the isolates and entering the data at the NSR Center and the staff
performing serological testing of the samples at the Pneumococcal Serology
Center, SSI. We thank Bente Gahrn-Hansen (Department of clinical
microbiology, Odense) for the submission of isolates to NSR and critical
reading of the manuscript. The contents of the article are solely the
responsibility of the authors and do not necessarily represent the official
views of Statens Serum Institut.
Members of the Danish Pneumococcal Surveillance Collaborating group 2007–2010
follow: Participants from SSI: Department of Infectious Disease Epidemiology:
Peter H. Andersen, Steffen Glismann, Michael Howitz, Jeppe Rasmussen,
Palle Valentiner-Branth. Department of Microbiological Surveillance and Research:
Jens Jørgen Christensen, Zitta B. Harboe, Steen Hoffmann, Helene Ingels,
Helle B. Konradsen, Lotte Lambertsen. Department of Microbiological
Diagnostics: Charlotte S. Jørgensen. Participants from Departments of Clinical
Microbiology in Denmark: Ram B. Dessau (Slagelse, Nykøbing F, Næstved),
Poul Kjældgaard (Sønderborg), Jenny Dahl Knudsen (Hvidovre), Brian
Kristensen (Skejby), Lene Leerbeck (Hillerød), Steen Lomborg (Herning),
Jørgen Prag (Viborg), Per Schouenborg (Vejle), Henrik C. Schønheyder
(Aalborg), Robert Skov (SSI), Michael Tvede (Rigshospitalet), Christian
Østergaard (Herlev). Participants from Clinical Departments: Jon Helgestad
(Pediatric Department Aalborg), Thomas Benfield (Infectious Diseases
Department, Hvidovre), Mette Rokkjær (Pediatric Department, Syddan-
mark), Birgitte Lausen (Pediatric Department, Rigshospitalet).
Culture, identification and submission of isolates and clinical samples from
the departments of clinical microbiology across the country to the Neisseria
and Streptococci Reference Center, Statens Serum Institut: Danish
Pneumococcal Surveillance Collaborating Group. Conceived and designed
the experiments: ZBH PVB PHA DG HBK LL. Performed the
experiments: ZBH PVB HI PHA JNR DG LA MH LL HBK. Analyzed
the data: ZBH PVB HI JNR PHA CCB DG LA MH HBK LL.
Contributed reagents/materials/analysis tools: Danish Pneumococcal
Surveillance Collaborating Group. Wrote the paper: ZBH PVB.
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