A novel pneumococcal serotype 6C was discovered in 2007.1 It was earlier identified as serotype 6A in addition to the true 6A serotypes.
The first 7-valent pneumococcal conjugate vaccine (PCV7, Prevenar/Prevnar, Pfizer, Philadelphia, PA), including the serotype 6B polysaccharide antigen but not 6A, showed cross-protective immune reaction to 6A.2 This activity was later shown to be clinically protective also against 6A invasive pneumococcal disease.3
In the Finnish Otitis Media (FinOM) vaccine trial conducted in 1995–1999,4 we reported cross-protective serotype-specific vaccine efficacy (VE) of the PCV7 for 6A acute otitis media (AOM) as 57% [95% confidence interval (CI): 24–76]. We retyped all 6A isolates to evaluate the VE against 6C AOM.
The FinOM vaccine trial was a phase III randomized, double-blind controlled trial conducted in 1995–1999 in Finland.4 Children received PCV7 or hepatitis B vaccine as control at 2, 4, 6 and 12 months of age. Follow-up for AOM was conducted in specific study clinics from 2 to 24 months of age. Myringotomy with middle ear fluid aspiration was performed in each case of AOM. Middle ear fluid samples were cultured, Streptococcus pneumoniae were identified and serotyped using serological methods.5
Per protocol follow-up started 14 days after the third vaccination and ended at 24 months of age or at the time of protocol violation. Intention-to-treat follow-up started at the first vaccine dose and ended at 24 months of age. Generalized Cox regression6 was used to estimate VE against 6A/6C AOM episodes.4
Nasopharyngeal swab samples were taken at 12 and 18 months and also at the age of 4–5 years in long-term follow-up study.7 The carriage prevalences at different time-points were compared between the vaccine groups using χ2 test.
Eight hundred and thirty-one children were enrolled both in the PCV7 and control arms. In the control group intention-to-treat follow-up, serotype 6C was found in 12.5% (6 of 48) of the episodes originally serotyped as 6A, in 1.3% (6 of 467) of all culture-confirmed pneumococcal AOM and in 0.4% (6 of 1532) of all episodes of AOM confirmed with myringotomy.
During the per protocol follow-up period, there were 5 AOM episodes because of serotype 6C both in PCV7 and control groups with an incidence of 0.42 per 100 person-years (VE: −1; 95% CI: −248 to 71).
The updated incidence for serotype 6A AOM, now excluding 6C episodes, was 3.4 per 100 person-years in the control group (40 episodes in the control group and 14 in the PCV7 group); the cross-protective PCV7 VE estimate was 65% (95% CI: 31–82).
The VE analyses were also performed using intention-to-treat follow-up producing similar results.
For carriage, serotype 6C was detected in control vaccine recipients in 20% of the carriage isolates originally serotyped as 6A at 12 and 18 months of age. There was no 6C carriage in the control group at 4–5 years of age. The 6A and 6C carriage prevalences are shown in Figure 1. There were no statistically significant differences in any of the comparisons between carriage prevalences.
PCV7 offered no cross-protection against 6C AOM but had excellent efficacy against 6A AOM, even higher than reported previously,4 and the updated VE against 6A AOM exceeded the VE point estimate against the vaccine serotypes (57%), yet was lower than VE against 6B AOM (VE: 84%; 95% CI: 62–93). No statistically significant impact on 6A carriage at 12 and 18 months was observed. Thus, in concordance with our previous results,8 it seems that the PCV7 impact against 6A AOM is not mediated through carriage only.
To date, FinOM vaccine trial remains the only trial that has evaluated PCV7 efficacy against serotype-specific AOM. The second trial with serotype-specific AOM conducted to estimate the efficacy of the PHiD-CV11, precursor of the PHiD-CV10, showed 63% VE (95% CI: −14 to 88) against 6A AOM, including potential 6C cases.9
All PCVs that have been introduced (PCV7, PCV10, PCV13) include the 6B antigen, and the PCV13 includes also the 6A antigen. However, both PCV7 and PCV10 have shown evidence of clinical cross-protection against 6A.10,11 PCV7 has also been shown to induce indirect protection, mediated through carriage, against 6A invasive pneumococcal disease, yet in a longer time frame compared with the true vaccine types.10 Therefore, although we did not observe any statistically significant impact against 6A carriage, the PCV7 appears to have some impact on 6A carriage. There are recent data that PCV13, which includes the 6A antigen, offers cross-protection against 6C carriage12,13 and thus probably also against 6C AOM.
The randomized double-blind design with detection of AOM confirmed by myringotomy in high incidence underlines the validity of the serotype-specific results. The reserotyping was performed in a blinded fashion, although study was unblinded already in 1999.
However, because of the low occurrence of 6C AOM, our study lacked power, and the confidence intervals for the VE estimate against 6C AOM were wide.
This retrospective reanalysis of the pivotal trial data confirms the high cross-protection of PCV7 against serotype 6A but does not support cross-protection against serotype 6C AOM. These data help to interpret the PCV7 data earlier published regarding the serotype 6A.
The authors acknowledge Mika Lahdenkari for statistical analysis support.
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