With the widespread use of effective PCVs in the pediatric population, it is no longer feasible or ethical to perform placebo-controlled clinical efficacy studies for a new vaccine against IPD. Thus, current and future trials will continue to measure only the immune titers induced by a new vaccine. Therefore, evaluation of the potential impact of new PCVs on public health requires a method by which real-world effectiveness data can be reliably predicted from the immunogenicity data. As next-generation PCVs are developed in the coming years, this capability will be increasingly important in order to contextualize differences in immunogenicity between vaccines in terms of expected impact on public health. These modeled estimates provide a bridge between immunogenicity data and VE but should be used with caution and need to be verified with post-licensure evaluations of VE.

The model presented here enables serotype-specific estimates for Cp and for VE values, thus allowing predictions for and comparisons between current and future vaccines. The current standard practice is to use the aggregate Cp value of 0.35 μg/mL, derived for PCV7 serotypes, to predict and compare VE for not only the original seven serotypes, but also additional serotypes whose efficacy has not been shown in trials. Andrews et al. shows that the aggregate value is an imprecise predictor of the probable effectiveness of individual serotypes10. Performance of predicted VE was also evaluated: estimation of serotype-specific Cp results in better alignment between estimated and reported aggregate (incidence rate-weighted) VE (Table 5) compared to using the 0.35 μg/mL aggregate, as also suggested by Andrews et al.10.

Therefore, the serotype-specific estimates for Cp and VE obtained using the method described here provides a more accurate prediction of the probable protection afforded by PCV13 for the serotypes in common with PCV7. This modeling method has the potential to better estimate the effectiveness of next-generation PCVs against the serotypes shared with the current PCV, and, thus, to better inform public health decisions.

Several limitations should be kept in mind about the derivation of Cp and effectiveness as described here. The Cp and effectiveness prediction applies only to the prevention of IPD in children who resemble the trial populations. The lack of generalizability to other populations is because effectiveness is not only dependent on the strength of the immune response the vaccine elicits, but also on other factors13 including age at vaccination and the time interval between vaccination and serum sampling, which were found to explain 17–20% of the variance in antibody response to the serotypes in PCV7 and PCV1314. Geographic differences in the immune response to each serotype are also evident, with higher responses in children from South Africa than children living in the United States9. Such differences could have both genetic and environmental components, and is likely to depend also on dosing schedule and PCV valency15,16. Previous exposure to the serotypes could also be substantially different between countries and even within sub-populations, which may impact vaccine response and partial protection in the unvaccinated populations, resulting in a relative shift in effectiveness which could also change dynamically with fluctuations in relative incidence rates of circulating serotypes.

In addition to these considerations, several underlying assumptions also place limitations on the real-world applicability of our method. The effectiveness prediction does not use a functional assay output, like the pneumococcal opsonophagocytic killing assay, but instead relies on IgG concentration. However, previous work (Siber et al.9) demonstrates the utility of IgG in pediatric populations, thus mitigating any implied risk. Furthermore, opsonophagocytic killing assay titer values were not used in this work due to the relatively large assay variability (both between laboratories and over time) without a standard comparator assay, like the WHO ELISA for IgG concentrations, which is primarily used for licensure decision and to which concordance can be calculated for titer value normalization. The effectiveness is also the result of both uptake (percent of individuals vaccinated) and efficacy (relative risk reduction in a 100% vaccinated group relative to placebo recipients, randomized from an appropriately representative population). It can further depend on resulting secondary effects that include the reduced force of infection such as through “herd immunity,” and on changes over time in vaccine uptake or relative prevalence of serotypes (and concomitant changes in cross-protection). Additionally, this method assumes that equivalent antibody concentrations elicited by different PCVs (e.g., PCV7, PCV10, PCV13) for a specific serotype yield equivalent levels of protection against disease caused by that serotype. Current data across different manufacturers suggest this is a reasonable assumption (i.e., it is consistent with available data) but it needs to be verified with post-licensure VE studies.

In addition to methodological limitations, there were data limitations. One-month post-primary infant placebo titer concentrations were unavailable from the United Kingdom, Australia, and Germany, as no efficacy study was run in these countries. Placebo data were instead used from a PCV7 trial done in the United States, as the population in this study was assumed to have infants, which elicit placebo immune responses that closely mirror placebo immune responses in the United Kingdom, Australia, and Germany. One-month post-primary vaccination for subjects given either PCV7 or PCV13 in a 3 + 0 regimen was also unavailable in the Australian population. Trials from the United States were used here because the primary infant series dosing regimen of 2, 4, and 6 months is the same as the Australian primary infant series dosing regimen represented in the 3 + 0 regimen, and the populations are assumed to have similar immune responses (IgG concentrations) to PCV7 and PCV13. Last, effectiveness needed to be used rather than efficacy, as randomized controlled trials were not run for the vaccines, regions, and time periods of interest.

The method described here can be used to calculate the serotype-specific protective concentrations of antibodies elicited by PCVs, as well their serotype-specific effectiveness. To qualify the method, we applied it to calculate protective concentrations and effectiveness of PCV13 in three different geographic locations (United Kingdom, Australia, and Germany) using each country’s respective PCV7 serotype-specific effectiveness as input, as well as immunogenicity data that reflected the dosing regimen used to estimate the PCV7 effectiveness. No serotype-specific effectiveness has been reported for PCV13 against PCV7 serotypes (4, 6B, 9 V, 14, 18 C, 19 F, and 23 F), but aggregate effectiveness was reported against these seven serotypes for PCV13, and this aggregate was compared to the predictions. The serotype-specific predictions were aggregated (weighting by relative incidence rates) and the aggregated results agreed with the previously reported data, qualifying the method.

Using currently available population-level data, the method can predict serotype-specific effectiveness in next-generation PCVs. As next-generation PCVs are developed in the coming years, it will be important to estimate the shared serotype-specific effectiveness to contextualize differences in immunogenicity between vaccines in terms of expected effectiveness and identify whether next-generation vaccines will maintain (or, possibly, improve) control of serotypes that are currently controlled well. The serotype-specific effectiveness predictions may also be useful in dynamic transmission modeling to assess the potential of breakthrough disease, especially in higher-risk persistent serotypes (e.g., 3 and 19 A in Europe3,17).