Discussion
EVENTS, DISEASE, SECONDARY
Immunisation of children with PCV13 in the 14-week 1 + 1 compared with the 2 + 1 group was associated with a transient reduction in PCV13 colonisation following the booster dose, and particularly a 2·9-fold reduction in 19F colonisation. Serotype 19F is the dominant PCV13 colonising serotype in the era of PCV immunisation in South Africa, as also shown in our study, and elsewhere in Africa;The putative correlates of protection, defined by Voysey and colleagues and applied in our study, were determined by a sero-epidemiological analysis of PCV10 immunogenicity studies.If we used less stringent criteria to define non-inferiority (ie, by less than 10%), then the PCV13 1 + 1 groups would be non-inferior to the 2 + 1 group. Furthermore, it cannot be ruled out that serum serotype-specific IgG itself might be a proxy for some other mediator of protection against colonisation. Some studies have shown that carriage is not affected by the serotype-specific serum IgG responses,The study indicates that there might be serotype differences in the effect a 1 + 1 schedule might have on colonisation, as a proxy for disease, and not necessarily that a 1+1 schedule will be inferior to the current 2 + 1 schedule. This is important in the context of higher valency formulations, such as Pfizer's PCV20 (Prevenar-20), which is currently being evaluated in children. If the UK transitions from PCV13 to PCV20, a further consideration arises of whether it is appropriate to remain on the 1 + 1 schedule or return to the 2 + 1 schedule. Serotype-level differences in PCV formulation and schedule demonstrated here indicate that it is not possible to predict the effect of different dosing schedules. In our study, PCV13 administered in a 14-week 1 + 1 schedule seems to be more immunogenic and associated with a lower risk of 19F colonisation compared with the 2 + 1 schedule. Consequently, further head-to-head dosing schedule studies are relevant, including the effect on colonisation by the additional serotypes in PCV20 (8, 10A, 11A, 12F, 15B, 22F, and 33F). In addition to the 2·9-fold reduction in the colonisation prevalence by 19F at 15 months of age, this study showed signals that a reduced PCV13 14-week 1 + 1 dosing schedule might be associated with a reduction in serogroup 11A/D (47% decrease) colonisation and increases in serotype 10A (2-fold increase) and serogroup 15B/C (69% increase) colonisation 6 months after the booster, although changes in these low-prevalence serotypes were not significant.Our study was limited in that it was not adequately powered to evaluate differences in serotype-specific pneumococcal colonisation between the study groups. For this reason, we did not adjust for multiplicity as the findings address a secondary objective of the study and were hypothesis generating. Larger studies that are adequately powered to assess serotype-level differences are still needed to corroborate our findings. Another limitation of the study was that colonisation was assessed at three timepoints (9 months, 15 months, and 18 months of age), only allowing for analysis of serotype acquisition at 15 months and 18 months of age, and it is plausible that acquisition events outside the sampling period were missed. Last, the Standard BioTools method is unable to differentiate between vaccine serotypes 7F, 9V, and 18C from non-vaccine serotypes 7A, 9A, and 18B, respectively, and colonisation prevalence for these vaccine serotypes might have been overestimated. Also, the method does not directly detect non-typeable pneumococcus, and it is thus possible that a small proportion of pneumococcal positive samples were either non-typeable pneumococcus or a non-detected pneumococcal serotype. Nevertheless, the serotypes not covered by the assay (ie, 7D) are uncommon in carriage.The findings from this study, together with the experience in the UK, which transitioned to a 1 + 1 schedule, is being considered by the National Advisory Group on Immunization in South Africa to determine whether there should be policy changes to a 1 + 1 schedule in South Africa. Ongoing monitoring of colonisation will, however, be important as a possible early indicator of whether transitioning to a 1 + 1 schedule might inadvertently lead to an increase in vaccine-serotype disease.