Community-acquired pneumonia in children is at times complicated by the development of parapneumonic pleural effusion (PPE); the latter often necessitates drainage and is associated with prolonged hospitalization. Streptococcus pneumoniae is the most common cause of community acquired pneumonia in children and adults.1 The 13-valent conjugated pneumococcal vaccine (PCV13) was introduced in Greece in 2010 for prevention of invasive pneumococcal disease, pneumonia and otitis media caused by vaccine serotypes, such as 4, 6B, 9V, 14, 18C, 19F, 23F (included in PCV7) plus 1, 3, 5, 6A, 7F and 19A.2 Based on data provided by the National Meningitis Reference Laboratory (NMRL), the 3 most common serotypes causing pneumonia complicated by PPE in Greece over the 6-year period between 2006 and 2011 were 3 (26/61, 42% of cases), 19A (21/61, 34%) and 1 (10/61, 16%), all of them included in PCV13.3
During the last year, physicians participating in the study noticed the occurrence of pneumococcal pneumonia complicated by PPE caused by serotype 3 among children previously vaccinated with PCV13. After communication with the NMRL, where pathogen and serotype identification was performed and with each other, such cases that occurred in the participating centers were collected and analyzed. We herein present these cases of vaccine failure, together with data provided by NMRL on the distribution of S. pneumoniae serotypes associated with PPE in Greece 2–3 years after the introduction of PCV13 vaccine.
MATERIALS AND METHODS
All pleural fluid specimens from patients ≤14 years of age with PPE that were sent to the NMRL during January 1 to December 31, 2012 were studied by molecular methods for species identification and serotyping of S. pneumoniae. The NMRL accepts biological specimens from hospitalized patients all over Greece for molecular identification of common bacterial pathogens. These specimens are sent to NMRL at the discretion of the patients’ treating physicians. In all patients included in this study, pleural fluid specimens were collected after chest tube placement, which was considered necessary by the treating physicians for drainage of PPE.
Identification of S. pneumoniae in pleural fluid specimens was performed by the use of species-specific multiplex polymerase chain reaction.4 Further identification of 9 pneumococcal serotypes (1, 3, 4, 6B, 14, 18C, 19A, 19F and 23F) was carried out by the use of 2 multiplex polymerase chain reaction assays with a specific primer pair for each serotype as described previously (overall specificity 100%).5
Immunization history pertaining to pneumococcal vaccines was recorded for all patients from whom pleural fluids were studied. In addition, for those patients previously vaccinated with PCV13 that were found to have PPE caused by a PCV13-serotype, clinical characteristics, such as the need for chest tube placement, fibrinolysis, surgery, admission to intensive care unit (ICU) and length of hospitalization, were recorded. The recommended schedule for PCV13 immunization in Greece is 3+1 doses (at 2, 4, 6 and 11–15 months) for infants, 2 doses with an interval of ≥2 months for nonimmunized children 12–23 months of age and 1 dose for those 2–5 years of age.
The study was approved by the Ethics Committees of Hippokration General Hospital of Thessaloniki, “P. and A. Kyriakou” Children’s Hospital, Athens and University Hospital of Patras, Greece.
In total, pleural fluid specimens from 30 pediatric patients with PPE were studied with molecular methods at the NMRL during 2012. In 20 (66%) out of these specimens, S. pneumoniae was identified. Among the serotypes investigated, serotype 3 was identified in 15/20 (75%) specimens, followed by serotypes 19A (3/20, 15%) and 14 (1/20, 5%), whereas 1 specimen was negative by the current serotypes available in the polymerase chain reaction assay used.
Among 15 children with infection due to serotype 3, 5 (33%) had been previously immunized with PCV13 according to the recommended schedule and are described in this report. The immunization history of the remaining 10 children was unknown, because it was not reported to the NMRL by the referring hospitals. Some of the demographic and clinical characteristics of these 5 children, as well as their previous pneumococcal immunization history, are presented in Table 1. The time interval between PCV13 vaccination and the onset of pneumonia complicated by PPE ranged from 5 to 18 months. In all cases, blood and pleural fluid cultures were negative; 1 of the patients (female, age 3½ years) had received oral amoxicillin/clavulanate for 3 days before admission. All 5 children recovered completely.
Two to 3 years after the introduction of the PCV13 vaccine, PPEs among Greek children were predominantly caused by S. pneumoniae serotype 3; serotype 19A was identified in a small number of patients and none of those studied had PPE caused by serotype 1. Compared with the 2006–2011 period,3 there appears to be a trend for decrease in frequency of serotypes 19A and 1 (P = 0.15 and P = 0.06, respectively, by Fisher’s exact test); this decrease coincides with the inclusion of PCV13 vaccine in the national immunization program and could potentially reflect the effect of the vaccine.
A notable finding was that 5/15 children with PPE caused by serotype 3 had been completely immunized with PCV13 according to the recommended schedule. This finding raises concerns regarding the effectiveness of PCV13 in preventing pneumonia complicated by PPE caused by serotype 3. In a study by Yeh et al6 on immunogenicity of PCV13 in children receiving a 3+1 schedule (at 2, 4, 6 and 12–15 months), pneumococcal antipolysaccharide IgG antibodies elicited against serotype 3 were lower than those elicited against other serotypes included in the vaccine both after the infant vaccination series and also before and after the toddler dose. In the same study, the proportion of subjects with antipolysaccharide IgG concentrations of ≥0.35 μg/mL after the infant vaccination series was lower for serotype 3 compared with other PCV13 serotypes.6 Similarly, in 3 more studies of immunogenicity of PCV13 administered at a 3+1 schedule (2, 3, 4 and 12 months)7 or 2+1 schedules (2, 4 and 12 months8 or 3, 5 and 11 months9), pneumococcal antipolysaccharide IgG responses for serotype 3 before and after toddler dose were lower than those elicited for other PCV13 serotypes. Despite these differences in antipolysaccharide IgG responses, opsonophagocytic assay titers elicited against serotype 3 were comparable with those elicited for other PCV13 serotypes in all of the above studies.6–9
It should be noted, however, that all 5 children previously vaccinated with PCV13 that developed PPE caused by serotype 3 had received PCV13 immunization after the age of 12 months (with 1 or 2 doses, according to their age). Another study by Frenck et al10 on immunogenicity of PCV13 in children previously vaccinated with PCV7 who received 2 doses of PCV13 if they were 15 months to 2 years of age or 1 dose of PCV13 if they were 2–5 years of age, the percentage of children with postvaccination pneumococcal anticapsular IgG titers of ≥ 0.35 μg/mL was lower for serotype 3 (92–94.5%) compared with other serotypes (98.2–100%). In the same study, anticapsular IgG titers elicited against serotype 3 were lower than those elicited against other serotypes.10
As none of the 5 children presented herein had received the infant series (3+1 schedule), it is likely that our observation of reduced protection of PCV13 against complicated pneumonia caused by serotype 3 does not apply for children who received the infant series. There are currently no reports of PCV13 failure in preventing complicated pneumonia caused by serotype 3 among children vaccinated with the full 3+1 schedule.
A potential limitation of the study is that these findings may not accurately reflect the epidemiology of PPE and vaccine failures throughout the country because certain hospitals may have not sent specimens and/or detailed information on the patients’ vaccination status to the NMRL; however, these data still come from 3 different major centers in Greece and, we believe, reliably describe the overall disease trend.
In conclusion, serotype 3 is currently the most frequent S. pneumoniae serotype causing PPE in Greece. A significant proportion of children with PPE caused by serotype 3 had been previously vaccinated with PCV13 after the age of 12 months, according to the recommended schedule. To our knowledge, this is the first report of failure of PCV13 vaccine to prevent complicated pneumonia cases caused by serotype 3. Taking into account the results of previous PCV13 immunogenicity studies, our finding warrants close monitoring and further investigation to evaluate the protection afforded by PCV13 against serotype 3.
1. Resti M, Moriondo M, Cortimiglia M, et al.Italian Group for the Study of Invasive Pneumococcal Disease. Community-acquired bacteremic pneumococcal pneumonia in children: diagnosis and serotyping by real-time polymerase chain reaction using blood samples. Clin Infect Dis. 2010;51:1042–1049
2. Gruber WC, Scott DA, Emini EA. Development and clinical evaluation of Prevnar 13, a 13-valent pneumocococcal CRM197 conjugate vaccine. Ann N Y Acad Sci. 2012;1263:15–26
3. Kremastinou J, Tzanakaki G. Apologismos EKAM 2011 Available at Accessed June 8, 2013
4. Tzanakaki G, Tsopanomichalou M, Kesanopoulos K, et al. Simultaneous single-tube PCR assay for the detection of Neisseria meningitidis, Haemophilus influenzae type b and Streptococcus pneumoniae
. Clin Microbiol Infect. 2005;11:386–390
5. Xirogianni A, Tsolia M, Voyiatzi A, et al. Diagnosis of upper and lower respiratory tract bacterial infections with the use of multiplex PCR assays. Diagnostics. 2013;3:222–231
6. 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
7. 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
8. 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
9. 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
10. Frenck R Jr, Thompson A, Yeh SH, et al.3011 Study Group. Immunogenicity and safety of 13-valent pneumococcal conjugate vaccine in children previously immunized with 7-valent pneumococcal conjugate vaccine. Pediatr Infect Dis J. 2011;30:1086–1091