The 13-valent pneumococcal conjugate vaccine (PCV13) was marketed in Spain in 2010. Up to that time, the 7-valent (PCV7, since 2001) and 10-valent (PCV10, since 2009) conjugate vaccines had been available. In the autonomous community of Catalonia, the regional reference laboratory reported that in 2009, 72% of serotypes causing invasive disease were included in PCV13,1 data that concurred with the 80% detected in 2007 by the Spanish national reference laboratory.2 Although the Vaccination Advisory Committee of the Spanish Association of Pediatrics has recommended the routine administration of PCV13,3 nowadays it is not financed by the Spanish Health System and it is available only in the private market.
Previous data from Catalonia indicate a 67% decrease in the rate of invasive pneumococcal disease (IPD) in 2 of the participating hospitals (Hospital Sant Joan de Déu and Hospital Vall d’Hebron) since the introduction of PCV13.4 Mean annual number of cases of IPD in the 2007–2009 period in those 2 hospitals were 106 and mean annual number of cases from 2012 to 2013 were 35. These data concur with the results from the autonomous community of Madrid.5 However, despite this notable decrease, some children still develop IPD, particularly in the form of pneumonia, which may be associated with pleural effusion or empyema. In this sense, Antachopoulos et al6 reported a high incidence of complicated pneumonia caused by serotype 3, and one-third of the affected patients had received a complete vaccination series with PCV13.
The aim of this study is to analyze vaccine failures observed following PCV13 vaccination in the catchment population of 3 hospitals in the city of Barcelona (Catalonia, Spain).
During 2012 and 2013, we prospectively recorded all IPD cases in children from 3 to 59 months admitted in 3 pediatric hospitals in the Barcelona area: Hospital Sant Joan de Déu, Hospital Vall d’Hebron and Hospital de Nens de Barcelona. These 3 hospitals concentrate 32.2% of pediatric hospitalizations in Catalonia, a region of 7,500,000 of inhabitants. Microbiological or epidemiologic mandatory surveillance of cases of IPD is not implemented in our region.
IPD was defined based on Streptococcus pneumoniae isolation by culture or pneumococcal DNA detection by real-time PCR in any normally sterile body fluid. Serotype identification was made using PCR and Quellung reaction when it was possible.
The PCV13 vaccination schedule in our country follows the 3 + 1 scheme, that is, 3 doses in the first 6 months of life (at 2, 4 and 6 months old) followed by a booster dose at 12 to 15 months old.3
Information related to vaccination status was retrieved from the personal vaccination card. If it was not available, registers of the primary health care center where the child was usually attended were consulted.
PCV13 vaccine failure was defined according by The Council for the International Organizations of Medical Sciences and the World Health Organization Working Group as the occurrence of the illness (IPD produced by a PCV13 serotype) in a person who is appropriately and fully vaccinated.7 IPD should have occurred 2 weeks or longer after the last dose of PCV13.
Patients were classified according to the following clinical forms: complicated pneumonia (with pleural effusion, empyema or necrotizing pneumonia), uncomplicated pneumonia, meningitis, occult bacteremia, osteoarticular infection, septic shock and bacterial mastoiditis.
Pneumococcal vaccination coverage in general population was estimated from vaccination status of children visited in our outpatient clinic by causes other than infectious diseases, matched with IPD cases for age, date of visit and medical risk conditions for IPD.8 If one patient had received any dose of PCV7 or PCV10 and any dose of PCV13, he/she was considered to be vaccinated with PCV13.
A total of 86 patients were included. Two of them were excluded because the serotype could not be studied. Among the remaining 84 patients, 3 were aged 3 to 6 months, 32 were aged 7 to 23 months and 49 were aged 24 to 59 months. Fifty-one patients (60.7%) presented complicated pneumonia, 13 (15.5%) uncomplicated pneumonia, 8 (9.5%) occult bacteremia, 7 (8.3%) meningitis, 2 (2.4%) osteoarticular infection, 2 (2.4%) bacteriemic mastoiditis and 1 (1.2%) septic shock.
The most common causative serotypes were serotype 3 (21 cases), serotype 1 (13 cases), serotype 19A (10 cases), serotype 14 (5 cases) and serotype 11A (3 cases). The remaining serotypes were responsible for 2 cases or fewer. Sixty serotypes were included in PCV13.
PCV13, PCV10 and PCV7 vaccination coverage in matched controls of patients was 55.1%, 1.4% and 12.5%, respectively. Of the 84 IPD cases recorded, 32 patients (38.1%) had received at least one dose of PCV13. Seventeen of them had IPD produced by a PCV13 serotype.
Nine patients had PCV13 vaccine failure. The other 8 patients who had IPD produced by a PCV13 serotype were not considered to be appropriately or fully vaccinated with PCV13. Three out of the 9 of them presented PCV13 vaccine failure after the primary schedule. The characteristics and the vaccine schedules of those patients are described in Table 1. No other pneumococcal vaccines were used in those patients except for one patient (patient number 5) who received 3 doses of PCV7 at 3, 5 and 7 months before receiving a single dose of PCV13 at age of 25 months. Serotype 3 was isolated in 6 patients, serotype 19A in 2 patients and serotype 6B in the remaining patient.
Four years after the availability of PCV13, the information on the problem of PCV13-related vaccine failure remains scarce. In the present study, conducted in a geographic area with 55% vaccination coverage, 9 patients properly vaccinated with PCV13 had a vaccine failure, with serotype 3 being the serotype most often implicated. Formerly, serotype 3 was thought to produce IPD mainly in adults, as it was rarely detected in the pediatric population in studies based on S. pneumoniae isolation by culture techniques.9 However, with the use of detection by real-time PCR, serotype 3 is now known to account for most IPD cases occurring in children younger than 5 years. This technique improves the diagnostic yield for IPD caused by serotype 3, particularly in pleural fluid of patients with empyema or pleural effusion.10
Immunogenicity studies for PCV13 in children with the 3 + 1 schedule (2, 4, 6 and 12–15 months) have shown that the level of opsonophagocytic antibodies against serotype 3 is lower than that of the remaining serotypes present in the vaccine.10–12 In a recent study performed in 2012 in Greece, one-third of serotype 3 pleural pneumococcal pneumonia cases occurred in patients who had been properly vaccinated.6 However, in that study, PCV13 was complemented with PCV7 in 2 of the patients, and the remaining ones had only received 1 or 2 PCV13 doses because they were older than 1 or 2 years old. Vanderkooi et al.13 in a study, carried out in Canada, found that serotype 3 had the lowest immunogenicity after the infant series and also after the toddler dose, suggesting lower protection against that serotype. In another study, serotype 6B has been found the least immunogenic after the infant series.12 However, a recently published cohort study has found that the real vaccine effectiveness for PCV7 and PCV13 is lower than predicted by the aggregate correlate of protection of 0.35 mcg/mL used during licensing and that serotype-specific correlates of protection vary widely, so further studies should be done to understand better the relation between immunogenicity and effectiveness.14 In that study, adjusted PCV13 vaccine effectiveness for a 2 + 1 schedule was 79% (95% CI: 25–94) for PCV13 serotypes not included in PCV7 and 90% (95% CI: 34–98) for PCV7 serotypes in children who had received at least 2 doses before age 12 months or one dose from age 12 months onwards. Predicted vaccine effectiveness was higher than observed effectiveness for individual serotypes 1, 3, 7F, 19A and 19F.
In our series, there is an elevated number of serotype 3 failures resulting in pneumonia. One possible explanation for this could be that the low level of antibodies against serotype 3 generated by the vaccine would not impede nasopharyngeal colonization, leading to pneumonia by airborne transmission rather than by hematogenous route. Once in the lung, serotype 3 could invade the pleura due to its intrinsic pathogenic potential. Another explanation might be vaccination by the same lot in all patients, but this possibility was ruled out in our study.
We have also detected serotype 19A in 2 vaccinated patients older than 12 months. In one multicenter study underwent in 8 USA hospitals, some vaccine failures were detected. Most of them were caused by serotype 19A (the more prevalent circulating serotype) and most of these infections occurred in the first 6 months of life. None of the patients had received 4 PCV13 doses and only one had received 3 doses.15
Circulation of both serotype 3 and serotype 19A are still very high, probably due the absence of herd protection. This is consistent with the fact that both serotypes are the main producers of vaccine failures in our series. A higher vaccination rate would probably increase the herd immunity and consequently IPD caused by the most prevalent circulating serotypes would likely decrease.
One limitation of this study is that we were unable to carry out an exhaustive analysis of immune status in all patients to rule out the presence of immunodeficiencies that might be responsible for the insufficient vaccination response. Nor were we able to determine the presence or not of anti-S. pneumoniae antibodies. During a follow-up of all the patients, that was both retrospective (clinical history) and prospective (over 1 year following onset of the disease), there was apparently no clinical suspicion of a possible immunodeficiency.
In conclusion, serotype 3 followed by serotype 19A were the most frequent serotypes involved in PCV13 failures in a geographic area with 55% vaccination coverage, in which a significant decrease in IPD has been documented after PCV13 vaccine was available. Future studies should focus on whether this lower incidence is generalized over all the serotypes included in the vaccine. It is likely that greater PCV13 vaccination coverage in the population would have probably decreased the possibility of infection by serotype 3 due to a herd protection.
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