Noninferiority Assessment of PCV-10 as an Alternative 12-month Booster (PP Population)
Table 3 shows the results of the primary endpoint analysis. IgG responses to serotypes 5 and 9V in the PCV-10 group were inferior to the PCV-13 group at 13 months when proportions of participants with serotype-specific IgG concentrations ≥0.35 µg/mL were compared between groups.
Short-term Antibody Response to a Booster Dose of PCV-10 Compared With PCV-13 (ITT Population)
One month following the booster vaccine, at least 97% of participants in each group had IgG concentrations ≥0.35 µg/mL for the serotypes they were vaccinated against with the exception of serotypes 5 and 9V in the PCV-10 group. For these 2 serotypes, which are common to both PCV-10 and PCV-13, the proportions of participants with serotype-specific IgG above the threshold were significantly higher in PCV-13 compared with PCV-10 recipients (Figure S1 and Table S2, Supplemental Digital Content 1, http://links.lww.com/INF/C454). In addition, these proportions were also higher in the PCV-13 group for 2 out of the 3 serotypes only included in PCV-13, namely serotypes 3 and 6A but not serotype 19A (Figure S1 and Table S2, Supplemental Digital Content 1, http://links.lww.com/INF/C454).
Post booster IgG GMC were significantly higher in the PCV-13 compared with the PCV-10 group for the majority of serotypes common to both vaccines (1, 5, 6B, 7F, 9V, 14 and 23F) as well as for the serotypes only included in PCV-13 (3, 6A and 19A) whereas GMCs were significantly higher in PCV-10 compared with PCV-13 recipients only for serotypes 4, 18C and 19F (Fig. 2; Table S4, Supplemental Digital Content 1, http://links.lww.com/INF/C454).
An analysis of covariance model that adjusted for baseline values, age, sex and ethnicity was used to investigate changes from baseline in IgG concentrations between groups. Significant increases in IgG concentrations were observed in both groups for all serotypes between 12 and 13 months of age and group differences from adjusted and unadjusted analyses were similar to differences observed in analysis of 13-month values alone (Table S6, Supplemental Digital Content 1, http://links.lww.com/INF/C454).
Serotype-specific functional antibodies were assessed by OPA for all PCV-13 serotypes. One month following the booster, at least 98% of participants had titers ≥8 and there were no observable group differences for all PCV-10 serotypes except for serotypes 1, 5 and 9V; for these serotypes the proportion of participants with OPA titers ≥8 was higher in the PCV-13 than the PCV-10 group. These proportions were also higher for all 3 serotypes (3, 6A and 19A) only contained in PCV-13 (Table S7 and Figure S2, Supplemental Digital Content 1, http://links.lww.com/INF/C454).
Significantly higher post booster GMT were seen in the PCV-13 than the PCV-10 group for most serotypes common to both vaccines as well as for all 3 serotypes only included in PCV-13. For serotypes 4 and 18C, there were no significant differences between the groups and for serotype 19F, the OPA response was significantly higher in the PCV-10 than the PCV-13 group (Fig. 3; Table S9, Supplemental Digital Content 1, http://links.lww.com/INF/C454).
For both study groups, significant increases in OPA titers for all serotypes with the exception of serotype 3 in the PCV-10 group were seen between 12 and 13 months of age (Table S11, Supplemental Digital Content 1, http://links.lww.com/INF/C454). Analyses of change from baseline to 13 months in OPA titers with adjustment for baseline values, age, sex and ethnicity gave similar results to unadjusted analyses of 13 month values although group differences in immunogenicity for serotypes 1 and 19F were no longer observed (Table S11, Supplemental Digital Content 1, http://links.lww.com/INF/C454).
One-year Antibody Persistence Following a Booster Dose of PCV-10 Compared With PCV-13 (ITT Population)
Group differences in proportions above the IgG or OPA thresholds were observed for a number of serotypes at 24 months of age, that is, 12 months following the booster. These proportions were similarly greater for both measurements for PCV-13 compared with PCV-10 recipients for serotypes 6B, 7F and 6A and lower for serotype 19F (Figures S1 and S2, Supplemental Digital Content 1, http://links.lww.com/INF/C454.).
When persistence of IgG concentrations and OPA titers were assessed at 24 months of age, significant differences remained between the groups. IgG GMCs and OPA GMTs were greater in PCV-13 compared with PCV-10 recipients for serotypes 6B, 7F, 9V and 6A, whereas both measurements were significantly higher in the PCV-10 compared with the PCV-13 group for serotype 19F (Figs. 2 and 3; Tables S5 and S10, Supplemental Digital Content 1, http://links.lww.com/INF/C454.).
When analyses of change from baseline to 24 months were adjusted for baseline antibody, age, sex and ethnicity, group differences were similar to unadjusted analyses (Tables S12 and S13, Supplemental Digital Content 1, http://links.lww.com/INF/C454.) with a significant decline in serotype-specific IgG antibodies and OPA titers from 13 to 24 months for all serotypes except for OPA titers against serotype 3 in the PCV-10 group (not shown).
The reactogenicity profile of the booster vaccination was similar regardless of whether participants had received PCV-10 or PCV-13 (Table S14, Supplemental Digital Content 1, http://links.lww.com/INF/C454). Local reactions such as redness, hardness and swelling were either absent or mild in most cases. Moderate or severe localized pain was reported by almost 13% of parents of study participants across both groups; irritability, drowsiness and decreased appetite were recorded in 53%, 29% and 29% of participants of both groups combined, respectively (Table S15, Supplemental Digital Content 1, http://links.lww.com/INF/C454). Low-grade fever (38–39°C) was noted in 4% of participants and 4 children (2%) had a temperature of >39°C in the first 4 days following booster vaccination (Table S15, Supplemental Digital Content 1, http://links.lww.com/INF/C454). The majority of these reported adverse effects of vaccination were short-lived lasting 1–3 days (Table S16, Supplemental Digital Content 1, http://links.lww.com/INF/C454).
This is the first study to investigate the interchangeability of PCV-10 and PCV-13 as a 12-month booster in children primed with PCV-13; the immune response to a PCV-13 booster given to children primed with PCV-10 was not assessed in the study. A robust antibody response was induced by both vaccines at 1 year of age when administered to PCV-13 primed children. For the primary objective, PCV-10 was noninferior to PCV-13 for 8 of the PCV-10 serotypes. However, there were 22% and 10% less study participants with IgG concentrations ≥0.35 µg/mL against serotypes 5 and 9V, respectively, in the PCV-10 than the PCV-13 group (Table 3). Children with IgG concentrations ≥0.35 µg/mL following 3 infant doses have previously been described as having clinical protection against IPD.14 However, the significance of this threshold in a situation where post booster immune responses are assessed is unknown and may underestimate the true differences between the 2 studied vaccines, as antibody responses are generally higher following booster doses and with older age.15,16 In addition, a quantitatively and qualitatively better vaccine response is thought to have greater potential to prevent carriage of vaccine serotypes and therefore providing herd protection. This is most relevant for some serotypes17 and young children who are responsible for pneumococcal transmission.18 Therefore, the vaccine with the best post booster immune response may help providing better indirect protection for unvaccinated individuals.
When post booster serotype-specific IgG GMC and OPA GMT were considered, PCV-13 was more immunogenic for the majority of serotypes common to both vaccines. There are no published large head-to-head clinical trials comparing PCV-10 and PCV-13. In a recent small study in which children were vaccinated with either PCV-10 or PCV-13 at 2, 3, 4 and 11 months of age, serotype-specific antibodies, plasma and memory B cells against PCV-10 serotypes were investigated and compared between the groups before as well as 7–9 days and 1 month following the booster dose.19,20 This study showed statistically superior post booster IgG responses in the PCV-13 group to the majority of serotypes common to both vaccines, including serotype 19F, but not serotypes 4 and 18C. In the same study, 1 week post booster OPA GMTs were higher for 2 (9V and 23F) of the 10 common serotypes in PCV-13 compared with PCV-10 recipients. For no serotype were post booster antibody responses in the PCV-13 group significantly lower than in the PCV-10 group.20 These findings are partly in contrast to our study in which responses to serotype 19F were lower in PCV-13 recipients for both IgG levels and OPA titers at 1 and 12 months following the booster.
In our study, only responses against serotypes 4, 18C and 19F were consistently similar or statistically superior (19F) at 13 months in the PCV-10 compared with the PCV-13 group. Interestingly, these 3 serotypes are contained in PCV-10 in a higher concentration than the other serotypes (3 vs. 1 µg) and also compared with the same serotypes in PCV-13 (3 vs. 2.2 µg). In addition, PCV-10 serotypes 18C and 19F are conjugated to a non-protein D carrier protein—tetanus and diphtheria toxoid, respectively—and both these antigens are included in previously administered routine childhood vaccines. This may also partly explain the better antibody response to these 2 serotypes compared with other serotypes in PCV-10 recipients as carrier priming would have already happened through these other vaccines. The enhanced immunogenicity of serotype 19F compared with other serotypes in the PCV-10 group may also be explained by the overall very similar structure of the 2 carrier proteins to which serotype 19F is conjugated in PCV-10 (diphtheria toxoid) and PCV-13 (CRM197).21 Although there are no immunogenicity studies directly comparing PCV-10 with PCV-13, antibody responses to PCV-10 have previously been compared with those elicited by PCV-7.22 Vesikari et al22 showed that post booster antibody responses in participants who had exclusively received either vaccine were superior in the PCV-7 group for the majority of PCV-7 serotypes with the exception of serotypes 18C (similar) and 19F (inferior) indicating that PCV-7 is generally more immunogenic than PCV-10. In the same study, antibody responses were largely similar between the group of children who had exclusively received PCV-7 and those who had been primed with PCV-7 followed by a booster dose of PCV-10. These findings suggest that similar antibody responses can be achieved when switching from one PCV to another containing similar capsular serotypes despite a difference in carrier proteins. However, Vesikari et al22 also demonstrated that there were markedly lower antibody responses to serotypes 1, 5 and 7F (not included in PCV-7) in children in the PCV-7/PCV-10 compared with the PCV-10/PCV-10 group indicating that serotype-specific priming even when performed with a different vaccine and carrier protein is essential for obtaining booster responses. In a case–control study performed in Canada, the effectiveness against all IPD caused by PCV-13 serotypes of a mixed PCV schedule consisting of 2 doses of PCV-10 followed by 1 dose of PCV-13 was similar to alternative schedules in which children were only vaccinated with PCV-10 or PCV-13.4 Although this study suffered from a small sample size, and therefore the lack of significant differences between the vaccine schedules may not represent equivalence, these findings suggest that interchanging PCVs does not per se result in inferior protection compared with schedules using a single type of PCV. The combination of priming with PCV-13 and boosting with PCV-10 was also not assessed in the study.
In a previous study examining the effect of a booster dose of the 23-valent plain pneumococcal conjugate vaccine (PPV-23) given to 12-month-old children, researchers found that a good immune response could be elicited by PPV-23 in children primed with PCV-7. However, these children subsequently showed hyporesponsiveness when challenged with a 20% PPV-23 dose,23 suggesting that measuring antibody alone may not be sufficient when comparing the immunogenicity of different polysaccharide-containing vaccines. Further assessments of the immune response such as antibody persistence and memory B cells may be needed to better capture the immune response to a vaccine booster.
For the 3 serotypes that are exclusive to PCV-13 (3, 6A and 19A), not only PCV-13 but also PCV-10 recipients showed an increased antibody response following booster vaccination, which may represent generation of cross-reactive antibodies through vaccination with the related serotypes 6B and 19F. Not surprisingly, the antibody responses against these 3 serotypes were greatly lower in the PCV-10 compared with the PCV-13 group (Figs. 2 and 3).
In this study, antibody persistence up to 1 year following the booster was assessed using both serotype-specific IgG antibody concentrations and OPA titers against PCV-13 serotypes. Over the 12-month period following the booster, there was a rapid decline in antibody in both groups. IgG levels and OPA titers at 24 months were largely determined by the amount of antibody detected 1 month post booster at 13 months of age, which has been previously demonstrated where the same PCV was used for both priming and boosting.24 These findings suggest that boosting with a different vaccine containing the same capsular serotypes, albeit conjugated to different carrier proteins, induces an immune response that is not only driven by short-lived extrafollicular B cells but also the generation of long-lived plasma cells, a hallmark of immune memory.
Our study showed that a booster dose of PCV-10 at 12-months of age is generally less immunogenic than a PCV-13 booster in PCV-13 primed children. Post booster antibody responses that were similar or superior in the PCV-10 group were seen for serotypes 4, 18C and 19F, which are contained in PCV-10 with higher antigen content and/or conjugation to a diphtheria or tetanus toxoid carrier protein. The clinical significance of the observed differences in immunogenicity remains unknown although our findings suggest that it may be more appropriate to give a PCV-13 booster to PCV-13 primed children. Further studies in children primed with PCV-10 and then boosted with PCV-13 are needed to expand our understanding and the clinical implications of interchangeable PCV schedules.
The authors are grateful to all the study participants, without whom this study would have not been possible. A.J.P. and M.D.S. are Jenner Institute Investigators. We thank Dominic F. Kelly for his critical review of the manuscript.
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interchangeability; pneumococcal conjugate vaccine; immunogenicity; children
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