Immunogenicity and seroefficacy of pneumococcal conjugate vaccines: a systematic review and network meta-analysis

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Chapter 1 Background

Chapter 2 Methods

Our systematic review is reported in line with the recommendations from the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement plus the extension statements for network and individual patient data systematic reviews. 11–13

Chapter 3 Results

Search results

Database registry and hand searches identified 4697 publication records (see Appendix 2, Figure 19), of which 47 studies (78 publication reports) satisfied our eligibility criteria. 8,9,17–93 Nineteen studies (24 publication reports) were excluded from the analysis: 6 studies did not provide individual patient or aggregate data,70–73 and 13 studies (18 publication reports) were studies directly comparing the vaccines of interest, but it was not possible to form a loop within the NMA to provide indirect evidence (Figure 1). 17,74–88 Of these 13 studies, 8 reported results from different, mainly unlicensed PCVs, including a new Cuban PCV7, PCV10-SII, PCV11, PCV12, a Chinese PCV13, PCV14, PCV15, PCV20, PCV24 and PCV SP0202-VI.

FIGURE 1.

Network of studies included for (a) all eligible cohorts, (b) immunogenicity analysis cohorts and (c) seroefficacy analysis cohorts. Studies with no closed loop to enable use of indirect evidence (n = 13), or where data were unavailable (n = 6), are included in panel a but not in panel b or c. PCV7 Cuba, a Cuban PCV7; PCV13 CNY, a Chinese PCV13.

The remaining 28 studies (54 publication records) from 2009 to 2023 were included in the NMAs. 8,9,18–69,89 Twenty-two studies provided individual participant data with a further six studies reporting aggregate data (see Appendix 3, Tables 3 and 4).

The 28 included studies comprised 31 cohorts of children as 1 study conducted in 2 countries reported results separately,21,22 and 1 study included comparisons of 3 vaccination schedules19,48 (see Appendix 3, Table 3). Studies with multiple National Clinical Trial (NCT) numbers or publications, but the same population, were counted as one cohort. These 31 cohorts were representative of 38 countries in 6 continents: Europe (n = 11 cohorts), Asia (n = 9 cohorts), North America (n = 3 cohorts), Africa (n = 3 cohorts), Oceania (n = 4 cohorts) and South America (n = 1 cohort). Four cohorts were from studies conducted in multiple countries in Europe, and analyses were combined across sites. 24,53–55,64,66

There were 7 studies comparing PCV10 versus PCV7, 14 studies comparing PCV13 versus PCV7 and 8 studies comparing PCV13 versus PCV10. Two cohorts used a single prime, single boost (1 + 1) schedule with the first dose administered at either 6 or 14 weeks of age to South African infants and compared PCV13 with PCV10. 48 Five cohorts used a 2 + 1 prime-boost schedule: one study in Vietnam comparing PCV13 versus PCV10,57 one in South Africa comparing PCV13 versus PCV10 with additional comparisons with 1 + 1 schedules48 and two from studies conducted in Europe comparing PCV13 versus PCV7. 31,56 Three cohorts used a 3 + 0 schedule: one in the Gambia comparing PCV13 versus PCV10,50 one in the USA comparing PCV13 versus PCV767 and one in Germany comparing PCV10 versus PCV7. 39 The remaining 20 cohorts tested a 3 + 1 schedule, with most cohorts receiving a primary series at 2–4–6 months (n = 9) and a booster at around 12 months (n = 18).

Infants’ age at receipt of the first dose ranged from 1 to 3.5 months, and the age of the booster dose ranged from 9 to 18 months, resulting in an interval between primary and booster dose (used for the calculation of seroefficacy) of between 6 and 12 months. Most cohorts reported or cited types of co-administered vaccines (n = 24), and PCVs were commonly co-administered with routine childhood vaccine including diphtheria, tetanus and acellular/whole-cell pertussis vaccines (n = 23), Haemophilus influenzae type b tetanus toxoid (TT) conjugate vaccine (n = 23), hepatitis B vaccine (n = 20), inactivated/oral polio vaccine (n = 22) and group C meningococcal vaccine (n = 3) (see Appendix 3, Table 3). Serotype-specific IgG antibody responses were defined as primary outcomes in all studies. Studies comparing PCV10 versus PCV7 (n = 7) assessed serotypes included in PCV10, while all other studies assessed all serotypes included in PCV13. Geometric mean concentrations (GMCs) were reported at 28 days post-primary series (n = 29 cohorts), prior to a booster (n = 17 cohorts) and 28 days post booster (n = 25 cohorts). Fourteen cohorts (46.7%) reported GMC at all three time points. Individual participant data were available from 25 of 30 (83.3%) cohorts.

Immunogenicity

Figure 2 shows the number of study cohorts included in each analysis and the estimated GMR for each serotype and time point from the NMAs/meta-analyses, and Appendix 5, Tables 5 and 6 summarise the heterogeneity statistics and inconsistency of the networks. Substantial heterogeneity and network inconsistency were present for most serotypes at all three time points.

FIGURE 2.

Geometric mean ratios from meta-analyses at (a) 28 days post-primary vaccination series, (b) pre booster and (c) 28 days post booster. Each line in the figure shows the output from NMAs (PCV7 serotypes) or direct meta-analyses (PCV13 but non-PCV7 serotypes). Blue boxes and blue lines show the point estimates and CIs for GMRs comparing PCV13 versus PCV10. Points to the right of the vertical line are those with higher antibody responses in the PCV13 arm of the study, and points to the left are those with higher antibody responses in the PCV10 arm. The direct evidence column shows the percentage of evidence from studies directly comparing PCV13 versus PCV10 that contributes to the estimates presented in the figure in blue (PCV13 vs. PCV10). GMR of PCV13 versus PCV10 for PCV10 and PCV13 serotypes are from a meta-analysis of only studies which directly compared PCV13 with PCV10.

Geometric mean ratios for comparisons between PCV13 and PCV10 for any primary series schedule were higher for PCV13 for serotypes 4, 7F, 9V and 23F at 1 month after primary vaccination series, with 1.14- to 1.54-fold higher IgG responses with PCV13. Additional serotypes contained only in the PCV13 vaccine (3, 6A and 19A) also favoured PCV13 as expected. GMRs were similar for the remaining serotypes (1, 5, 6B, 14, 18C, 19F; Figure 2A). GMRs favoured PCV7 over either PCV13 or PCV10 for serotypes 4, 6B, 9V, 14 and 23F. There was no difference in GMRs for serotypes 18C and 19F across three vaccines (see Figure 2A).

Direct evidence was available from studies comparing PCV10 and PCV13, and indirect evidence for the difference between PCV13 and PCV10 was provided from studies comparing either PCV10 or PCV13 with PCV7 (see Figure 3). GMRs from direct and indirect comparisons were very similar across time points for most serotypes. However, there were statistical inconsistencies between direct and indirect evidence identified (p-value for inconsistency < 0.05) for serotype 6B, 14, 18C and 19F (see Appendix 5, Table 5).

FIGURE 3.

Direct and indirect evidence on GMRs comparing PCV13 vs. PCV10 at (a) 28 days post-primary vaccination series, (b) pre booster and (c) 28 days post booster. Each line in the figure shows the output from NMAs. Dark grey diamonds and lines show the point estimates and CIs for GMRs from studies directly comparing PCV13 versus PCV10. Light grey diamonds and lines show the point estimates and CIs for GMRs from studies comparing PCV13 versus PCV10 through PCV7. Black boxes and lines show the point estimates and CIs incorporating both direct and indirect evidence.

At the pre-booster time point, data were available from 18 cohorts. IgG responses were lower with PCV13 compared with PCV10 for all PCV7 serotypes except for serotype 14, with the point estimates of GMRs comparing PCV13 versus PCV10 ranging from 0.44 to 0.78. IgG responses were higher for PCV13 for serotypes 1, 5 and 7F. GMRs comparing PCV13 versus PCV7 showed higher IgG with PCV7 for serotypes 4, 6B, 9V, 14 and 23F, and higher IgG with PCV13 for serotype 19F (see Figure 2B).

At 28 days post booster, data were available from 26 cohorts. GMRs favoured PCV13 over PCV10 for serotype 6B, 9V, 14 and 23F and favoured PCV10 over PCV13 for serotype 18C (see Figure 2C). For serotype 1, 5 and 7F, antibody responses were higher in PCV13 compared with PCV10. PCV7 recipients had higher GMCs compared with PCV13 for all PCV7 serotypes except 6B, for which there was no difference, and 19F, which favoured PCV13. For PCV13-only serotypes (3, 6A and 19A), GMRs favour PCV13 at all three time points. Inconsistencies were found for serotype 4 and 6B between direct and indirect evidence (see Appendix 5, Table 5 and Figure 3).

To explore potential reasons for the observed heterogeneity, we summarised cohort-level GMRs and RRs for each vaccine comparison and present these with concomitant vaccines and vaccine schedules at all three time points in Appendix 5, Figures 21–59 (GMRs) and Figures 60–69 (RRs). These descriptive analyses revealed a lack of consistency in the direction of study-level estimates within each vaccine comparison, resulting in the significant heterogenicity. There was also no observable pattern in any trial-level variable (region, co-administered vaccines, vaccine schedule), from which one might propose a mechanism that would adequately explain this variation in GMRs, although studies which compared vaccines with the same carrier protein seemed to have more consistent estimates. In sensitivity analysis, we restricted to 11 cohorts providing IgG results for all the three time points and observed similar results (see Appendix 6, Figure 70). Additional sensitivity analyses stratified by region and vaccine schedule demonstrated reduced heterogeneity for some serotypes and similar patterns compared with main analysis (see Appendix 6, Figures 71–73). Sensitivity analyses excluding the two studies having overall ‘high risk of bias’ did not provide different results. Excluding the one study comparing PCV13 and PCV10 with a 1 + 1 schedule did not affect the results.

Seroefficacy

There were 12 studies (15 cohorts) with available individual participant antibody data at both post-primary and prior to the booster dose, allowing serotype-specific estimation of seroefficacy from a total of 5152 participants. Of these 15 cohorts, 6 compared PCV10 versus PCV7, 3 compared PCV13 versus PCV7 and 6 compared PCV13 versus PCV10 (see Figure 1).

The RR of seroinfection from the NMA for each serotype is summarised in Figure 4, and a summary of direct and indirect evidence is given in Figure 5. The I² and p-value indicate some heterogeneity for all PCV7 serotypes except for serotype 4 and 19F (see Appendix 5, Table 6).

FIGURE 4.

Meta-analyses of the RR of seroinfection. Each line in the figure shows the output from NMAs (PCV7 serotypes) or direct meta-analyses (PCV10 serotypes). Blue boxes and blue lines show the point estimates and CIs of RR of seroinfection comparing PCV13 versus PCV10. The direct evidence column shows the percentage of evidence from studies directly comparing PCV13 versus PCV10. Results for PCV10 serotypes are from a meta-analysis of only studies comparing PCV13 with PCV10; therefore, estimates of PCV7 versus PCV10 and PCV13 versus PCV7 were not available.

FIGURE 5.

Direct and indirect estimates of the RR of seroinfection. Each line in the figure shows the output from NMAs. Dark grey diamonds and lines show the point estimates and CIs RRs from studies directly comparing PCV13 versus PCV10. Light grey diamonds and lines show the point estimates and CIs for RRs from studies comparing PCV13 versus PCV10 through PCV7. Black boxes and lines show the point estimates and CIs incorporating both direct and indirect evidence.

Among PCV7 serotypes, the risk of seroinfection was lower with PCV13 than PCV10 for serotypes 4, 6B, 9V, 18C and 23F, while no difference was seen for serotype 14 and 19F (see Figure 4). The RRs of seroinfection (PCV13 vs. PCV10) for PCV7 serotypes ranged from 0.32 (95% CI 0.19 to 0.52) for serotype 4 to 1.28 (95% CI 0.95 to 1.74) for serotype 14. The direct evidence contributed to around 80–95% of total evidence, and we found no inconsistency between direct and indirect evidence for all but serotype 19F (p > 0.05; see Appendix 5, Table 6 and Figures 60–69).

For serotypes 1, 5 and 7F, evidence was summarised from six studies directly comparing PCV13 with PCV10. Heterogeneity was observed for serotype 5, and all CIs overlapped 1.0. Comparisons between PCV13 and PCV7 favoured neither vaccine over the other, whereas comparisons between PCV7 and PCV10 favoured PCV7 for serotypes 5, 6B, 9V, 18C and 23F.

Sensitivity analyses of studies conducted in Europe and, using 3 + 1 schedule, showed similar RRs as estimated from the main analysis (see Appendix 6, Figures 74 and 75). The seroefficacy analysis results remained consistent after removing one ‘high risk of bias’ study from the analysis.

Association between ratios of immunogenicity and seroefficacy

Figure 6 shows the serotype-specific relationships between trial-level immunogenicity (GMRs) and seroefficacy (RRs). Log-GMRs and log-RRs were highly or moderately correlated for all PCV7 serotypes [with weighted Pearson’s correlation coefficients (r) ranging from –0.76 to –0.60, all p < 0.05] except for serotype 14 (r = –0.30, p = 0.26).

FIGURE 6.

Association between study-level GMRs and RRs of seroinfection. Each point shows results of a serotype-specific comparison between two vaccines from one study. Solid line shows the relationship between RR predicted from the crude model and GMR. Dashed line shows the CIs of predicted RR. Reference lines show GMR equivalent to one (vertical) and RR equivalent to one (horizontal) which represent values associated with no difference between vaccines. Points sizes represent sample size of the trial. Each panel shows one PCV7 serotype (4, 6B, 9V, 14, 18C, 19F and 23F).

In the combined analysis across all serotypes, vaccines that produced the same amount of antibody (GMR = 1) had very similar protection (adjusted RR 0.80, 95% CI 0.41 to 1.58; see Figure 7). The model estimate indicates that for each twofold increase in antibody response, the risk of seroinfection was halved (GMR of 2.0; RR 0.46, 95% CI 0.23 to 0.96; see Figure 7A and B). The estimates were stable when estimates of PCV13 versus PCV7 were analysed in reverse as PCV7 versus PCV13 (GMR of 2.0; RR 0.51, 95% CI 0.23 to 1.15; see Figure 7C).

FIGURE 7.

Overall association between trial-level GMRs and RRs across all serotypes included in PCV10. Each point shows results of a serotype-specific comparison between two vaccines from one study. Solid line shows the relationship between RR predicted from the model and GMR. Dashed line shows the CIs of predicted RR. Reference lines show GMR equivalent to one (vertical) and RR equivalent to one (horizontal) which represent values associated with no difference between vaccines. Points sizes represent sample size of the trial. Panel (a) shows the relationship by 13 serotypes covered by PCV13; (b) shows the same data as panel a classified by vaccine comparison groups; (c) shows the same data as panel B; however, studies comparing PCV13 versus PCV7 are analysed and displayed as PCV7 versus PCV13 as a sensitivity analysis; and (d) shows a further sensitivity analysis that excludes studies of PCV13 versus PCV7 and only shows studies that compared vaccines from two different manufacturers.

When analyses were restricted to comparison between products from different manufacturers, the relationship between immunogenicity and seroprotection remained similar to the main analysis with a CI that incorporates 1.0 (GMR 1.0; RR 0.73, 95% CI 0.36 to 1.47; see Figure 7D).

Chapter 4 Mathematical modelling of differential impact of PCV10 and PCV13 on invasive pneumococcal diseases

To illustrate the use of serotype-specific estimates of seroefficacy in modelling vaccine impact and cost-effectiveness, we developed a mathematical model of pneumococcal transmission dynamics to compare the differential impact of PCV10 and PCV13 introduction on invasive pneumococcal disease cases with vaccine serotypes in England and Wales. The model estimated the impact over a 25-year time period from 2005–6 to 2029–30.

Model structure and inputs

The mathematical model is a compartmental, deterministic, serotype-specific and realistic age structure model to describe the pneumococcal transmission dynamics with two PCV programmes. The model is a susceptible–infectious–susceptible model which assumes no natural immunity. When susceptibles acquire carriage infection, they become infectious for the duration of carriage. The duration of carriage for all serotypes is assumed to be age dependent, and the values were obtained from Melegaro et al. 94 After the duration of carriage, infectious people become susceptible again. For simplicity, invasive pneumococcal disease was assumed to occur at the time of carriage infection.

Serotypes

The systematic review described in Chapters 1–3 provided estimates of the RR of seroinfection by the time of the booster dose which is interpreted as the relative reduction in vaccine efficacy of PCV10 against carriage acquisition compared with PCV13. The systematic review found no significant difference in RRs for serotypes 1, 5, 7F, 15 and 19F among 10 serotypes common in PCV10 and PCV13. Hence, we have only included five serotypes (18C, 23F, 4, 6B and 9V) for this modelling study. For each serotype, 100 random draws were taken from the CI around the estimates of the RR of seroinfection from Chapter 3, assuming a normal distribution around the log-RR (see Figure 4).

Carriage

Data for the pre-PCV equilibrium were obtained from carriage prevalence estimates from the 10-month longitudinal nasopharyngeal swab study with 3869 swabs conducted in 2001–2 in England. 95 Due to the detailed stratification for age groups and serotypes needed, there were some categories in the swabbing study with no positive samples. For simplicity, we substituted 0.5 positive sample in these groups. The carriage prevalence for the five serotypes is presented in Figure 8.

FIGURE 8.

Carriage prevalence of five serotypes (18C, 23F, 4, 6B and 9V) in seven age groups (data from Hussain et al. 95).

Invasive disease cases

Data on the invasive pneumococcal disease cases for the five serotypes and 16 age groups were obtained for England and Wales in 2005–6 (see Figure 9). Similar to the carriage data, there were some groups with no positive samples, and for these groups, one positive sample was substituted to enable calculation of incidence.

FIGURE 9.

Invasive pneumococcal disease cases for five serotypes (18C, 23F, 4, 6B and 9V) and 16 age groups in 2005–6 in England and Wales. M, months; Y, years.

Contact patterns

The contact patterns for the seven age groups for the forces of infection were obtained by combining the GB POLYMOD close contact matrix,96 and additional data on under-1-year-olds. 97

Parameter estimations

Using a static model, we fitted the force of infection by age groups for each target serotype (see Figure 10) using the carriage prevalence in Figure 8. Upon these forces of infection values, we calculate the transmission probabilities per contact in seven age groups (see Figure 11) using the 2005 England and Wales population and the contact pattern matrix.

FIGURE 10.

Force of pneumococcal infection for seven age groups and five serotypes in 2005–6 obtained using the pre-PCV carriage prevalence and individual patient data cases in 2005–6 in England and Wales. 98

FIGURE 11.

Pneumococcal transmission probabilities per contact for seven age groups and five serotypes in 2005–6 obtained using the pre-PCV carriage prevalence and individual patient data cases in 2005–6 in England and Wales. 98

We calculated case : carrier ratios (CCRs) (see Figure 12) by age groups for each serotype by dividing the number of invasive disease cases for the corresponding age group and serotype with the number of new infections during the baseline year. 98 As a sensitivity analysis, we tested an alternative assumption and used the number of infectious people instead of new infections to calculate the CCRs. Both assumptions produced almost identical results.

FIGURE 12.

Case : carrier ratios by 16 age groups for five pneumococcal serotypes using the pre-PCV carriage prevalence and individual patient data cases in 2005–6 in England and Wales. M, months; Y, years. 98

Population

We used the England and Wales population data from 2006/7 until 2030/1 for the long-term impact of two PCV programmes for 25 years from 2006 to 2007 (see Figure 13).

FIGURE 13.

Annual population sizes by age groups between 2005 and 2030 in England and Wales (projections obtained from the Office of National Statistics). Y, years.

Baseline projections for invasive pneumococcal disease cases without PCV programmes would be increased due to these increasing population size in Figure 13.

Vaccination programme

The PCV programme schedule was assumed to be introduced in the beginning of 2006–7 (first week of June 2006) with 2 + 1 at 2, 4 and 12 months of age in the model. The coverage for the first dose was fixed at 90%, 95% for the second dose among the first-dosed infants and 95% of the second-dosed infants for third-dose coverage. There was no catch-up programme assumed in the model. The vaccine efficacy against carriage for PCV13 was assumed to be 55% for the fully vaccinated compartments, and half this value for those partially protected. The duration of partial and full protection is assumed to be 5 years. 98 Those losing partial or full protection move to waned and partially protected compartments of the model, respectively. The average duration of full vaccine protection is assumed to be 10 years. Those in the waned and partially protected compartments move to fully protected after receiving their booster dose. The flow diagram in Figure 14 describes the movement between compartments due to vaccine doses and waning vaccine protection.

FIGURE 14.

Flow diagram showing how vaccination status of individuals is tracked in the model, based on the number of doses received and waning of vaccine protection.

Results

The model showed that in the absence of any vaccine programme, an increase in invasive pneumococcal disease cases caused by all five serotypes would be seen over the 25-year time frame (Figure 15). With the introduction of either PCV13 or PCV10 vaccine programmes in 2006, case counts decreased, achieving near eradication of all serotypes within the time frame modelled. The decrease in cases was most rapid for serotype 6B and least rapid for serotype 4. The decrease in cases was less rapid for PCV10 than for PCV13.

FIGURE 15.

Modelled long-term yearly number of invasive pneumococcal disease cases in England and Wales after introduction of PCV10, or PCV13 in 2006, compared with no PCV programme.

The PCV programme is assumed to be introduced in the beginning of June 2006 in the 2006–7 epidemiological year. a–e present results for five serotypes (4, 6B, 9V, 18C and 23F). Box plots show the modelled long-term impact of PCV10 on invasive pneumococcal disease cases. The dotted blue line shows the trajectory of invasive pneumococcal disease cases in the absence of any PCV programme (general increase reflects increasing population over years and age-dependent CCR by serotypes). The dark blue line shows the long-term impact of PCV13.

Chapter 5 Retrospective economic evaluation of vaccinating infants with PCV13 compared to vaccination with PCV10 to prevent pneumococcal disease in England and Wales

Results

The introduction of an infant PCV13 programme was predicted to avoid an additional 2808 (95% CI 2690 to 2925) cases of invasive pneumococcal disease compared with PCV10 introduction between 2006 and 2030. This includes an estimated 326 cases of meningitis, 578 cases of sepsis, 1770 cases of invasive pneumonia and 30,680 cases of non-invasive pneumonia. Under base-case assumptions, this resulted in discounted healthcare savings of £13 million (95% CI £12 to £14 million). Including non-invasive pneumonia increased the savings to £27 million (95% CI £25 to £29 million). A breakdown of healthcare cost savings by disease presentation is shown in Figure 16.

FIGURE 16.

Discounted healthcare costs averted (£2006) by an infant PCV13 introduction compared with a PCV10 programme between 2006 and 2030, stratified by disease presentation.

In the base case, averting additional cases of invasive pneumococcal disease resulted in a gain of an additional 4545 (95% CI 4465 to 4724) discounted QALYs, which increased to a gain of 6625 (95% CI 6352 to 6899) QALYs when using a discount rate of 1.5%. Again, inclusion of non-invasive disease had only a small impact (see Figure 17).

FIGURE 17.

Discounted QALYs gained by an infant PCV13 programme introduction compared to PCV10 introduction between 2006 and 2030 stratified by disease presentation under different scenario assumptions.

Figure 18 shows the maximum additional price that should be paid for a PCV13 dose under different scenarios. In the base-case analysis, introduction of PCV13 instead of PCV10 in 2006 would have been cost-effective in England and Wales provided the price of PCV13 was no more than an additional £3.57 (95% CI £3.42 to £3.71) per dose higher than PCV10, at a CET of £20,000 per QALY. Using a higher CET of £30,000 per QALY, additional threshold price increased to £5.13 (95% CI £4.92 to £5.33).

FIGURE 18.

Additional threshold price per dose in £2006 at which PCV13 becomes cost-effective compared to PCV10 under different scenario assumptions.

Chapter 6 Discussion

In our study, we used a novel methodology to define seroinfection from immunogenicity data to compare the relative efficacy of PCVs in preventing infection. Our results using individual-level data from a global meta-analysis provide the first estimates of the comparative protection afforded by different pneumococcal vaccines and show that for many serotypes, carriage events are less common after PCV13 than PCV10, likely due to a higher antibody response. In addition, we quantify the relationship between the immune response to vaccination and protection against infection, measured serologically, and show that higher antibody responses in infants are associated with greater protection from infection.

The observed heterogenicity in immune responses was unexpected. We assumed that if one vaccine is able to induce more antibody than another, then it would do so with some degree of consistency across all trials. However, this was not what was observed. Comparisons of the same vaccines in different studies gave widely varying estimates, and although we have reported the summary GMR estimates in our immunogenicity meta-analyses, the large degree of between-study heterogeneity in these models means these overall estimates are difficult to interpret. In some settings, PCV13 performed better; yet, in others, PCV10 was the more immunogenic vaccine. Although there was no single study-level factor that could be identified that might explain the variation in estimates, only three candidate factors could be considered (location, schedule and co-administered vaccines) and data reporting on co-administered vaccines were not always comprehensive. The assays used have been WHO standardised and unlikely to cause this variation, and additionally, only studies directly comparing the two vaccines were included.

Of note, comparisons between vaccines from the same manufacturer (PCV13 vs. PCV7) were more consistent than comparisons between vaccines from different manufacturers. Immune interference (‘bystander effects’) has been noted when vaccines with similar components are co-administered,108 and this may affect the responses to one vaccine over another. It is interesting that 18C and 19F were serotypes that showed a very large degree of between-study heterogeneity. These two serotypes in PCV10 have different carrier proteins (18C is conjugated to TT and 19F is conjugated to diphtheria toxoid) and may be more susceptible than other serotypes to the co-administration of vaccines containing tetanus or diphtheria components. An additional potential confounder that is unmeasured in these studies is the degree of exposure to circulating serotypes of pneumococcus in each setting, which also has the potential to influence the immune response to vaccines.

These diverse immunogenicity findings from studies of the same vaccines raise the question of whether such differences in immunogenicity lead to meaningful differences in protection. If so, it may be important to know which vaccine performs better in which setting and further investigation into the predictors of the immune response to vaccines may be warranted. We addressed this question by modelling the relationship between seroefficacy estimates and immunogenicity comparisons (GMRs), analysed at the trial level across all serotypes and studies. This method capitalises on the observed between-study heterogenicity rather than being hindered by it. In our model, vaccines with higher antibody levels were also those with greater protection against subclinical infections in general. A vaccine with twice the antibody production was predicted to halve the rate at which carriage occurred.

Licensure of new vaccines is based on non-inferiority comparisons with current vaccines and the proportion of antibody responses above the agreed threshold as a minimum requirement. Once a vaccine meets this ‘at-least-as-good-as’ immunogenicity criteria, it has previously not been clear whether exceeding it is of benefit, and the WHO position paper states ‘It is unknown whether a lower serotype-specific GMC of antibody indicates less efficacy’. 3 Our results show that lower protection against subclinical infection does indeed follow from lower antibody production and that two vaccines that produce a similar level of antibody will provide similar levels of protection, even if they are from different manufacturers.

The implications of these findings are of greatest importance when a new vaccine roll-out is being considered. Lower antibody production or lower seroefficacy for one vaccine product does not necessarily imply limited effectiveness against invasive pneumococcal diseases when considering vaccines such as PCV10 and PCV13 which are highly effective vaccines in many settings. Instead, lower antibody responses lead to less rapidly observed indirect protection after implementation into a national programme as a smaller proportion of transmission events are blocked by the vaccine. This is evident in the mathematical modelling in Chapter 4 which showed less rapid decreases in the number of cases of invasive disease when introducing PCV10 compared with PCV13.

For serotypes where protective impact has not been observed (serotype 3), new vaccines with substantially higher antibody responses may be needed. A Phase II clinical trial of PCV15 compared with PCV13 reported almost twice the antibody level for serotype 3 at 28 days post-primary series for PCV15 (GMR 1.93, 95% CI 1.71 to 2.18). 82 Based on our modelled association between GMR and RR, the RR of seroinfection with PCV15 versus PCV13 would be 0.48 (95% CI 0.21 to 0.87). Previously reported vaccine effectiveness estimates against nasopharyngeal carriage of serotype 3 include –27% (95% CI –180 to 44) and 1% (95% CI –106 to 52),30,109 and these translate to point estimates of 39% (95% CI –16% to 66%) and 52% (95% CI 9% to 79%) vaccine effectiveness against carriage of this serotype with PCV15 based on the relationship: (VE_(pcv15) = (1 − RR_{(pcv15 vs pcv13)} × (1 − VE_(pcv13)/100%)) × 100%).

Additional information

References

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113. Ferreira DM, Neill DR, Bangert M, Gritzfeld JF, Green N, Wright AKA, et al. Controlled human infection and rechallenge with Streptococcus pneumoniae reveals the protective efficacy of carriage in healthy adults. Am J Respir Crit Care Med 2013;187:855-64.

Appendix 1 Search strategy

MEDLINE (Ovid MEDLINE Epub Ahead of Print, In-Process and Other Non-Indexed Citations, Ovid MEDLINE Daily and Ovid MEDLINE) 1946–present.

EMBASE 1974–present

Global Health <1973 to 2022 Week 29>

ClinicalTrials.gov – 1 June 2019

WHO ICTRP

Cochrane (CDSR – limited to publication date: 1 June 2019–27 July 2022, CENTRAL – limited to added to database date: 1 June 2019–27 July 2022)

Appendix 2 PRISMA flow diagram

FIGURE 19.

PRISMA flow diagram. CDSR, Cochrane Database of Systematic Reviews; CENTRAL, Cochrane Central Register of Controlled Trials; ICTRP, International Clinical Trials Registry Platform.

Appendix 3 Study characteristics

Appendix 4 Risk of bias

FIGURE 20.

Assessment of RoB for included studies.

Appendix 5 Heterogeneity and inconsistency assessments

FIGURE 21.

Trial-level GMRs for serotype 4 post-primary vaccination series. Each solid line in the figure shows the GMR from each trial. Blue boxes and lines show the point estimates and CIs for GMRs comparing vac1 vs. vac2. Concomitant vaccines are vaccines co-administered with PCV primary vaccine series. Information on co-administered vaccine is not always available (e.g. study ID 11 and 23). Concomitant vaccines in the bracket are those administered in some but not all of the study sites. enr 3–6 m, 4–8 w int, enrolment at 3–6 months of age and at 4–8 weeks interval of three doses primary vaccines in total; N/A, not applicable.

FIGURE 22.

Trial-level GMRs for serotype 6B post-primary vaccination series. Each solid line in the figure shows the GMR from each trial. Blue boxes and lines show the point estimates and CIs for GMRs comparing vac1 vs. vac2. Concomitant vaccines are vaccines co-administered with PCV primary vaccine series. Information on co-administered vaccine is not always available (e.g. study ID 11 and 23). Concomitant vaccines in the bracket are those administered in some but not all of the study sites. enr 3–6 m, 4–8 w int, enrolment at 3–6 months of age and at 4–8 weeks interval of three doses primary vaccines in total; N/A, not applicable.

FIGURE 23.

Trial-level GMRs for serotype 9V post-primary vaccination series. Each solid line in the figure shows the GMR from each trial. Blue boxes and lines show the point estimates and CIs for GMRs comparing vac1 vs. vac2. Concomitant vaccines are vaccines co-administered with PCV primary vaccine series. Information on co-administered vaccine is not always available (e.g. study ID 11 and 23). Concomitant vaccines in the bracket are those administered in some but not all of the study sites. enr 3–6 m, 4–8 w int, enrolment at 3–6 months of age and at 4–8 weeks interval of three doses primary vaccines in total; N/A, not applicable.

FIGURE 24.

Trial-level GMRs for serotype 14 post-primary vaccination series. Each solid line in the figure shows the GMR from each trial. Blue boxes and lines show the point estimates and CIs for GMRs comparing vac1 vs. vac2. Concomitant vaccines are vaccines co-administered with PCV primary vaccine series. Information on co-administered vaccine is not always available (e.g. study ID 11 and 23). Concomitant vaccines in the bracket are those administered in some but not all of the study sites. enr 3–6 m, 4–8 w int, enrolment at 3–6 months of age, and at 4–8 weeks interval of three doses primary vaccines in total; N/A, not applicable.

FIGURE 25.

Trial-level GMRs for serotype 18C post-primary vaccination series. Each solid line in the figure shows the GMR from each trial. Blue boxes and lines show the point estimates and CIs for GMRs comparing vac1 vs. vac2. Concomitant vaccines are vaccines co-administered with PCV primary vaccine series. Information on co-administered vaccine is not always available (e.g. study ID 11 and 23). Concomitant vaccines in the bracket are those administered in some but not all of the study sites. enr 3–6 m, 4–8 w int, enrolment at 3–6 months of age and at 4–8 weeks interval of three doses primary vaccines in total; N/A, not applicable.

FIGURE 26.

Trial-level GMRs for serotype 19F post-primary vaccination series. Each solid line in the figure shows the GMR from each trial. Blue boxes and lines show the point estimates and CIs for GMRs comparing vac1 vs. vac2. Concomitant vaccines are vaccines co-administered with PCV primary vaccine series. Information on co-administered vaccine is not always available (e.g. study ID 11 and 23). Concomitant vaccines in the bracket are those administered in some but not all of the study sites. enr 3–6 m, 4–8 w int, enrolment at 3–6 months of age and at 4–8 weeks interval of three doses primary vaccines in total; N/A, not applicable.

FIGURE 27.

Trial-level GMRs for serotype 23F post-primary vaccination series. Each solid line in the figure shows the GMR from each trial. Blue boxes and lines show the point estimates and CIs for GMRs comparing vac1 vs. vac2. Concomitant vaccines are vaccines co-administered with PCV primary vaccine series. Information on co-administered vaccine is not always available (e.g. study ID 11 and 23). Concomitant vaccines in the bracket are those administered in some but not all of the study sites. enr 3–6 m, 4–8 w int, enrolment at 3–6 months of age and at 4–8 weeks interval of three doses primary vaccines in total; N/A, not applicable.

FIGURE 28.

Trial-level GMRs for serotype 1 post-primary vaccination series. Each solid line in the figure shows the GMR from each trial. Blue boxes and lines show the point estimates and CIs for GMRs comparing vac1 vs. vac2. Concomitant vaccines are vaccines co-administered with PCV primary vaccine series. Information on co-administered vaccine is not always available. Concomitant vaccines in the bracket are those administered in some but not all of the study sites. enr 3–6 m, 4–8 w int, enrolment at 3–6 months of age and at 4–8 weeks interval of three doses primary vaccines in total; N/A, not applicable.

FIGURE 29.

Trial-level GMRs for serotype 5 post-primary vaccination series. Each solid line in the figure shows the GMR from each trial. Blue boxes and lines show the point estimates and CIs for GMRs comparing vac1 vs. vac2. Concomitant vaccines are vaccines co-administered with PCV primary vaccine series. Information on co-administered vaccine is not always available. Concomitant vaccines in the bracket are those administered in some but not all of the study sites. enr 3–6 m, 4–8 w int, enrolment at 3–6 months of age and at 4–8 weeks interval of three doses primary vaccines in total; N/A, not applicable.

FIGURE 30.

Trial-level GMRs for serotype 7F post-primary vaccination series. Each solid line in the figure shows the GMR from each trial. Blue boxes and lines show the point estimates and CIs for GMRs comparing vac1 vs. vac2. Concomitantvaccines are vaccines co-administered with PCV primary vaccine series. Information on co-administered vaccine is notalways available. Concomitant vaccines in the bracket are those administered in some but not all of the study sites. enr 3–6 m, 4–8 w int, enrolment at 3–6 months of age and at 4–8 weeks interval of three doses primary vaccines in total; N/A, not applicable.

FIGURE 31.

Trial-level GMRs for serotype 3 post-primary vaccination series. Each solid line in the figure shows the GMR from each trial. Blue boxes and lines show the point estimates and CIs for GMRs comparing vac1 vs. vac2. Concomitant vaccines are vaccines co-administered with PCV primary vaccine series. Information on co-administered vaccine is not always available. Concomitant vaccines in the bracket are those administered in some but not all of the study sites. enr 3–6 m, 4–8 w int, enrolment at 3–6 months of age and at 4–8 weeks interval of three doses primary vaccines in total; N/A, not applicable.

FIGURE 32.

Trial-level GMRs for serotype 6A post-primary vaccination series. Each solid line in the figure shows the GMR from each trial. Blue boxes and lines show the point estimates and CIs for GMRs comparing vac1 vs. vac2. Concomitant vaccines are vaccines co-administered with PCV primary vaccine series. Information on co-administered vaccine is not always available. Concomitant vaccines in the bracket are those administered in some but not all of the study sites. enr 3–6 m, 4–8 w int, enrolment at 3–6 months of age and at 4–8 weeks interval of three doses primary vaccines in total; N/A, not applicable.

FIGURE 33.

Trial-level GMRs for serotype 19A post-primary vaccination series. Each solid line in the figure shows the GMR from each trial. Blue boxes and lines show the point estimates and CIs for GMRs comparing vac1 vs. vac2. Concomitant vaccines are vaccines co-administered with PCV primary vaccine series. Information on co-administered vaccine is not always available. Concomitant vaccines in the bracket are those administered in some but not all of the study sites. enr 3–6 m, 4–8 w int, enrolment at 3–6 months of age and at 4–8 weeks interval of three doses primary vaccines in total; N/A, not applicable.

FIGURE 34.

Trial-level GMRs for serotype 4 pre booster. Each solid line in the figure shows the GMR from each trial. Blue boxes and lines show the point estimates and CIs for GMRs comparing vac1 vs. vac2. Concomitant vaccines are vaccines co-administered with PCV primary vaccine series. Information on co-administered vaccine is not always available. Concomitant vaccines in the bracket are those administered in some but not all of the study sites. enr 3–6 m, 4–8 w int, enrolment at 3–6 months of age and at 4–8 weeks interval of three doses primary vaccines in total; N/A, not applicable.

FIGURE 35.

Trial-level GMRs for serotype 6B pre booster. Each solid line in the figure shows the GMR from each trial. Blue boxes and lines show the point estimates and CIs for GMRs comparing vac1 vs. vac2. Concomitant vaccines are vaccines co-administered with PCV primary vaccine series. Information on co-administered vaccine is not always available. Concomitant vaccines in the bracket are those administered in some but not all of the study sites. bOPV, bivalent oral poliovirus vaccine; enr 3–6 m, 4–8 w int, enrolment at 3–6 months of age and at 4–8 weeks interval of three doses primary vaccines in total; MR, measles and rubella combined vaccine; N/A, not applicable; YF, yellow fever vaccine.

FIGURE 36.

Trial-level GMRs for serotype 9V pre booster. Each solid line in the figure shows the GMR from each trial. Blue boxes and lines show the point estimates and CIs for GMRs comparing vac1 vs. vac2. Concomitant vaccines are vaccines co-administered with PCV primary vaccine series. Information on co-administered vaccine is not always available. Concomitant vaccines in the bracket are those administered in some but not all of the study sites. bOPV, bivalent oral poliovirus vaccine; enr 3–6 m, 4–8 w int, enrolment at 3–6 months of age and at 4–8 weeks interval of three doses primary vaccines in total; MR, measles and rubella combined vaccine; N/A, not applicable; YF, yellow fever vaccine.

FIGURE 37.

Trial-level GMRs for serotype 14 pre booster. Each solid line in the figure shows the GMR from each trial. Blue boxes and lines show the point estimates and CIs for GMRs comparing vac1 vs. vac2. Concomitant vaccines are vaccines co-administered with PCV primary vaccine series. Information on co-administered vaccine is not always available. Concomitant vaccines in the bracket are those administered in some but not all of the study sites. bOPV, bivalent oral poliovirus vaccine; enr 3–6 m, 4–8 w int, enrolment at 3–6 months of age and at 4–8 weeks interval of three doses primary vaccines in total; MR, measles and rubella combined vaccine; N/A, not applicable; YF, yellow fever vaccine.

FIGURE 38.

Trial-level GMRs for serotype 18C pre booster. Each solid line in the figure shows the GMR from each trial. Blue boxes and lines show the point estimates and CIs for GMRs comparing vac1 vs. vac2. Concomitant vaccines are vaccines co-administered with PCV primary vaccine series. Information on co-administered vaccine is not always available. Concomitant vaccines in the bracket are those administered in some but not all of the study sites. enr 3–6 m, 4–8 w int, enrolment at 3–6 months of age and at 4–8 weeks interval of three doses primary vaccines in total; N/A, not applicable.

FIGURE 39.

Trial-level GMRs for serotype 19F pre booster. Each solid line in the figure shows the GMR from each trial. Blue boxes and lines show the point estimates and CIs for GMRs comparing vac1 vs. vac2. Concomitant vaccines are vaccines co-administered with PCV primary vaccine series. Information on co-administered vaccine is not always available. Concomitant vaccines in the bracket are those administered in some but not all of the study sites. bOPV, bivalent oral poliovirus vaccine; enr 3–6 m, 4–8 w int, enrolment at 3–6 months of age and at 4–8 weeks interval of three doses primary vaccines in total; MR, measles and rubella combined vaccine; N/A, not applicable; YF, yellow fever vaccine.

FIGURE 40.

Trial-level GMRs for serotype 23F pre booster. Each solid line in the figure shows the GMR from each trial. Blue boxes and lines show the point estimates and CIs for GMRs comparing vac1 vs. vac2. Concomitant vaccines are vaccines co-administered with PCV primary vaccine series. Information on co-administered vaccine is not always available. Concomitant vaccines in the bracket are those administered in some but not all of the study sites. bOPV, bivalent oral poliovirus vaccine; enr 3–6 m, 4–8 w int, enrolment at 3–6 months of age and at 4–8 weeks interval of three doses primary vaccines in total; MR, measles and rubella combined vaccine; N/A, not applicable; YF, yellow fever vaccine.

FIGURE 41.

Trial-level GMRs for serotype 1 pre booster. Each solid line in the figure shows the GMR from each trial. Blue boxes and lines show the point estimates and CIs for GMRs comparing vac1 vs. vac2. Concomitant vaccines are vaccines co-administered with PCV primary vaccine series. Information on co-administered vaccine is not always available. Concomitant vaccines in the bracket are those administered in some but not all of the study sites. bOPV, bivalent oral poliovirus vaccine; enr 3–6 m, 4–8 w int, enrolment at 3–6 months of age and at 4–8 weeks interval of three doses primary vaccines in total; MR, measles and rubella combined vaccine; N/A, not applicable; YF, yellow fever vaccine.

FIGURE 42.

Trial-level GMRs for serotype 5 pre booster. Each solid line in the figure shows the GMR from each trial. Blue boxes and lines show the point estimates and CIs for GMRs comparing vac1 vs. vac2. Concomitant vaccines are vaccines co-administered with PCV primary vaccine series. Information on co-administered vaccine is not always available. Concomitant vaccines in the bracket are those administered in some but not all of the study sites. bOPV, bivalent oral poliovirus vaccine; enr 3–6 m, 4–8 w int, enrolment at 3–6 months of age and at 4–8 weeks interval of three doses primary vaccines in total; MR, measles and rubella combined vaccine; N/A, not applicable; YF, yellow fever vaccine.

FIGURE 43.

Trial-level GMRs for serotype 7F pre booster. Each solid line in the figure shows the GMR from each trial. Blue boxes and lines show the point estimates and CIs for GMRs comparing vac1 vs. vac2. Concomitant vaccines are vaccines co-administered with PCV primary vaccine series. Information on co-administered vaccine is not always available. Concomitant vaccines in the bracket are those administered in some but not all of the study sites. bOPV, bivalent oral poliovirus vaccine; enr 3–6 m, 4–8 w int, enrolment at 3–6 months of age and at 4–8 weeks interval of three doses primary vaccines in total; MR, measles and rubella combined vaccine; N/A, not applicable; YF, yellow fever vaccine.

FIGURE 44.

Trial-level GMRs for serotype 3 pre booster. Each solid line in the figure shows the GMR from each trial. Blue boxes and lines show the point estimates and CIs for GMRs comparing vac1 vs. vac2. Concomitant vaccines are vaccines co-administered with PCV primary vaccine series. Information on co-administered vaccine is not always available. Concomitant vaccines in the bracket are those administered in some but not all of the study sites. enr 3–6 m, 4–8 w int, enrolment at 3–6 months of age and at 4–8 weeks interval of three doses primary vaccines in total; N/A, not applicable.

FIGURE 45.

Trial-level GMRs for serotype 6A pre booster. Each solid line in the figure shows the GMR from each trial. Blue boxes and lines show the point estimates and CIs for GMRs comparing vac1 vs. vac2. Concomitant vaccines are vaccines co-administered with PCV primary vaccine series. Information on co-administered vaccine is not always available. Concomitant vaccines in the bracket are those administered in some but not all of the study sites. bOPV, bivalent oral poliovirus vaccine; enr 3–6 m, 4–8 w int, enrolment at 3–6 months of age and at 4–8 weeks interval of three doses primary vaccines in total; MR, measles and rubella combined vaccine; N/A, not applicable; YF, yellow fever vaccine.

FIGURE 46.

Trial-level GMRs for serotype 19A pre booster. Each solid line in the figure shows the GMR from each trial. Blue boxes and lines show the point estimates and CIs for GMRs comparing vac1 vs. vac2. Concomitant vaccines are vaccines co-administered with PCV primary vaccine series. Information on co-administered vaccine is not always available. Concomitant vaccines in the bracket are those administered in some but not all of the study sites. bOPV, bivalent oral poliovirus vaccine; enr 3–6 m, 4–8 w int, enrolment at 3–6 months of age and at 4–8 weeks interval of three doses primary vaccines in total; MR, measles and rubella combined vaccine; N/A, not applicable; YF, yellow fever vaccine.

FIGURE 47.

Trial-level GMRs for serotype 4 post booster. Each solid line in the figure shows the GMR from each trial. Blue boxes and lines show the point estimates and CIs for GMRs comparing vac1 vs. vac2. Concomitant vaccines are vaccines co-administered with PCV primary vaccine series. Information on co-administered vaccine is not always available. Concomitant vaccines in the bracket are those administered in some but not all of the study sites. enr 3–6 m, 4–8 w int, enrolment at 3–6 months of age and at 4–8 weeks interval of three doses primary vaccines in total; N/A, not applicable.

FIGURE 48.

Trial-level GMRs for serotype 6B post booster. Each solid line in the figure shows the GMR from each trial. Blue boxes and lines show the point estimates and CIs for GMRs comparing vac1 vs. vac2. Concomitant vaccines are vaccines co-administered with PCV primary vaccine series. Information on co-administered vaccine is not always available. Concomitant vaccines in the bracket are those administered in some but not all of the study sites. bOPV, bivalent oral poliovirus vaccine; enr 3–6 m, 4–8 w int, enrolment at 3–6 months of age and at 4–8 weeks interval of three doses primary vaccines in total; MR, measles and rubella combined vaccine; N/A, not applicable; YF, yellow fever vaccine.

FIGURE 49.

Trial-level GMRs for serotype 9V post booster. Each solid line in the figure shows the GMR from each trial. Blue boxes and lines show the point estimates and CIs for GMRs comparing vac1 vs. vac2. Concomitant vaccines are vaccines co-administered with PCV primary vaccine series. Information on co-administered vaccine is not always available. Concomitant vaccines in the bracket are those administered in some but not all of the study sites. bOPV, bivalent oral poliovirus vaccine; enr 3–6 m, 4–8 w int, enrolment at 3–6 months of age and at 4–8 weeks interval of three doses primary vaccines in total; MR, measles and rubella combined vaccine; N/A, not applicable; YF, yellow fever vaccine.

FIGURE 50.

Trial-level GMRs for serotype 14 post booster. Each solid line in the figure shows the GMR from each trial. Blue boxes and lines show the point estimates and CIs for GMRs comparing vac1 vs. vac2. Concomitant vaccines are vaccines co-administered with PCV primary vaccine series. Information on co-administered vaccine is not always available. Concomitant vaccines in the bracket are those administered in some but not all of the study sites. bOPV, bivalent oral poliovirus vaccine; enr 3–6 m, 4–8 w int, enrolment at 3–6 months of age and at 4–8 weeks interval of three doses primary vaccines in total; MR, measles and rubella combined vaccine; N/A, not applicable; YF, yellow fever vaccine.

FIGURE 51.

Trial-level GMRs for serotype 18C post booster. Each solid line in the figure shows the GMR from each trial. Blue boxes and lines show the point estimates and CIs for GMRs comparing vac1 vs. vac2. Concomitant vaccines are vaccines co-administered with PCV primary vaccine series. Information on co-administered vaccine is not always available. Concomitant vaccines in the bracket are those administered in some but not all of the study sites. enr 3–6 m, 4–8 w int, enrolment at 3–6 months of age and at 4–8 weeks interval of three doses primary vaccines in total; N/A, not applicable.

FIGURE 52.

Trial-level GMRs for serotype 19F post booster. Each solid line in the figure shows the GMR from each trial. Blue boxes and lines show the point estimates and CIs for GMRs comparing vac1 vs. vac2. Concomitant vaccines are vaccines co-administered with PCV primary vaccine series. Information on co-administered vaccine is not always available. Concomitant vaccines in the bracket are those administered in some but not all of the study sites. bOPV, bivalent oral poliovirus vaccine; enr 3–6 m, 4–8 w int, enrolment at 3–6 months of age and at 4–8 weeks interval of three doses primary vaccines in total; MR, measles and rubella combined vaccine; N/A, not applicable; YF, yellow fever vaccine.

FIGURE 53.

Trial-level GMRs for serotype 23F post booster. Each solid line in the figure shows the GMR from each trial. Blue boxes and lines show the point estimates and CIs for GMRs comparing vac1 vs. vac2. Concomitant vaccines are vaccines co-administered with PCV primary vaccine series. Information on co-administered vaccine is not always available. Concomitant vaccines in the bracket are those administered in some but not all of the study sites. bOPV, bivalent oral poliovirus vaccine; enr 3–6 m, 4–8 w int, enrolment at 3–6 months of age and at 4–8 weeks interval of three doses primary vaccines in total; MR, measles and rubella combined vaccine; N/A, not applicable; YF, yellow fever vaccine.

FIGURE 54.

Trial-level GMRs for serotype 1 post booster. Each solid line in the figure shows the GMR from each trial. Blue boxes and lines show the point estimates and CIs for GMRs comparing vac1 vs. vac2. Concomitant vaccines are vaccines co-administered with PCV primary vaccine series. Information on co-administered vaccine is not always available. Concomitant vaccines in the bracket are those administered in some but not all of the study sites. bOPV, bivalent oral poliovirus vaccine; enr 3–6 m, 4–8 w int, enrolment at 3–6 months of age and at 4–8 weeks interval of three doses primary vaccines in total; MR, measles and rubella combined vaccine; N/A, not applicable; YF, yellow fever vaccine.

FIGURE 55.

Trial-level GMRs for serotype 5 post booster. Each solid line in the figure shows the GMR from each trial. Blue boxes and lines show the point estimates and CIs for GMRs comparing vac1 vs. vac2. Concomitant vaccines are vaccines co-administered with PCV primary vaccine series. Information on co-administered vaccine is not always available. Concomitant vaccines in the bracket are those administered in some but not all of the study sites. bOPV, bivalent oral poliovirus vaccine; enr 3–6 m, 4–8 w int, enrolment at 3–6 months of age and at 4–8 weeks interval of three doses primary vaccines in total; MR, measles and rubella combined vaccine; N/A, not applicable; YF, yellow fever vaccine.

FIGURE 56.

Trial-level GMRs for serotype 7F post booster. Each solid line in the figure shows the GMR from each trial. Blue boxes and lines show the point estimates and CIs for GMRs comparing vac1 vs. vac2. Concomitant vaccines are vaccines co-administered with PCV primary vaccine series. Information on co-administered vaccine is not always available. Concomitant vaccines in the bracket are those administered in some but not all of the study sites. bOPV, bivalent oral poliovirus vaccine; enr 3–6 m, 4–8 w int, enrolment at 3–6 months of age and at 4–8 weeks interval of three doses primary vaccines in total; MR, measles and rubella combined vaccine; N/A, not applicable; YF, yellow fever vaccine.

FIGURE 57.

Trial-level GMRs for serotype 3 post booster. Each solid line in the figure shows the GMR from each trial. Blue boxes and lines show the point estimates and CIs for GMRs comparing vac1 vs. vac2. Concomitant vaccines are vaccines co-administered with PCV primary vaccine series. Information on co-administered vaccine is not always available. Concomitant vaccines in the bracket are those administered in some but not all of the study sites. enr 3–6 m, 4–8 w int, enrolment at 3–6 months of age and at 4–8 weeks interval of three doses primary vaccines in total; N/A, not applicable.

FIGURE 58.

Trial-level GMRs for serotype 6A post booster. Each solid line in the figure shows the GMR from each trial. Blue boxes and lines show the point estimates and CIs for GMRs comparing vac1 vs. vac2. Concomitant vaccines are vaccines co-administered with PCV primary vaccine series. Information on co-administered vaccine is not always available. Concomitant vaccines in the bracket are those administered in some but not all of the study sites. bOPV, bivalent oral poliovirus vaccine; enr 3–6 m, 4–8 w int, enrolment at 3–6 months of age and at 4–8 weeks interval of three doses primary vaccines in total; MR, measles and rubella combined vaccine; N/A, not applicable; YF, yellow fever vaccine.

FIGURE 59.

Trial-level GMRs for serotype 19A post booster. Each solid line in the figure shows the GMR from each trial. Blue boxes and lines show the point estimates and CIs for GMRs comparing vac1 vs. vac2. Concomitant vaccines are vaccines co-administered with PCV primary vaccine series. Information on co-administered vaccine is not always available. Concomitant vaccines in the bracket are those administered in some but not all of the study sites. bOPV, bivalent oral poliovirus vaccine; enr 3–6 m, 4–8 w int, enrolment at 3–6 months of age and at 4–8 weeks interval of three doses primary vaccines in total; MR, measles and rubella combined vaccine; N/A, not applicable; YF, yellow fever vaccine.

FIGURE 60.

Trial-level RR for serotype 4. Each solid line in the figure shows the RR from each trial. Blue boxes and lines show the point estimates and CIs for RRs comparing vac1 vs. vac2. Co-adm vaccines are vaccines co-administered with PCV primary vaccine series. Information on co-administered vaccine is not always available. Concomitant vaccines in the bracket are those administered in some but not all of the study sites.

FIGURE 61.

Trial-level RR for serotype 6B. TT, tetanus toxoid conjugate; NA, not applicable. Each solid line in the figure shows the RR from each trial. Blue boxes and lines show the point estimates and CIs for RRs comparing vac1 vs. vac2. Co-adm vaccines are vaccines co-administered with PCV primary vaccine series. Information on co-administered vaccine is not always available. Concomitant vaccines in the bracket are those administered in some but not all of the study sites.

FIGURE 62.

Trial-level RR for serotype 9V. Each solid line in the figure shows the RR from each trial. Blue boxes and lines show the point estimates and CIs for RRs comparing vac1 vs. vac2. Co-adm vaccines are vaccines co-administered with PCV primary vaccine series. Information on co-administered vaccine is not always available. Concomitant vaccines in the bracket are those administered in some but not all of the study sites.

FIGURE 63.

Trial-level RR for serotype 14. Each solid line in the figure shows the RR from each trial. Blue boxes and lines show the point estimates and CIs for RRs comparing vac1 vs. vac2. Co-adm vaccines are vaccines co-administered with PCV primary vaccine series. Information on co-administered vaccine is not always available. Concomitant vaccines in the bracket are those administered in some but not all of the study sites.

FIGURE 64.

Trial-level RR for serotype 18C. Each solid line in the figure shows the RR from each trial. Blue boxes and lines show the point estimates and CIs for RRs comparing vac1 vs. vac2. Co-adm vaccines are vaccines co-administered with PCV primary vaccine series. Information on co-administered vaccine is not always available. Concomitant vaccines in the bracket are those administered in some but not all of the study sites.

FIGURE 65.

Trial-level RR for serotype 4. Each solid line in the figure shows the RR from each trial. Blue boxes and lines show the point estimates and CIs for RRs comparing vac1 vs. vac2. Co-adm vaccines are vaccines co-administered with PCV primary vaccine series. Information on co-administered vaccine is not always available. Concomitant vaccines in the bracket are those administered in some but not all of the study sites.

FIGURE 66.

Trial-level RR for serotype 23F. Each solid line in the figure shows the RR from each trial. Blue boxes and lines show the point estimates and CIs for RRs comparing vac1 vs. vac2. Co-adm vaccines are vaccines co-administered with PCV primary vaccine series. Information on co-administered vaccine is not always available. Concomitant vaccines in the bracket are those administered in some but not all of the study sites.

FIGURE 67.

Trial-level RR for serotype 1. Each solid line in the figure shows the RR from each trial. Blue boxes and lines show the point estimates and CIs for RRs comparing vac1 vs. vac2. Co-adm vaccines are vaccines co-administered with PCV primary vaccine series. Information on co-administered vaccine is not always available. Concomitant vaccines in the bracket are those administered in some but not all of the study sites.

FIGURE 68.

Trial-level RR for serotype 5. Each solid line in the figure shows the RR from each trial. Blue boxes and lines show the point estimates and CIs for RRs comparing vac1 vs. vac2. Co-adm vaccines are vaccines co-administered with PCV primary vaccine series. Information on co-administered vaccine is not always available. Concomitant vaccines in the bracket are those administered in some but not all of the study sites.

FIGURE 69.

Trial-level RR for serotype 7F. Each solid line in the figure shows the RR from each trial. Blue boxes and lines show the point estimates and CIs for RRs comparing vac1 vs. vac2. Co-adm vaccines are vaccines co-administered with PCV primary vaccine series. Information on co-administered vaccine is not always available. Concomitant vaccines in the bracket are those administered in some but not all of the study sites.

Appendix 6 Sensitivity analyses

FIGURE 70.

Geometric mean ratios from sensitivity analysis restricted to studies providing data for all three time points: (a) post-primary vaccination series, (b) pre boost and (c) post boost. Each line in the figure shows the output from NMAs (PCV7 serotypes) or direct meta-analyses (PCV13 but non-PCV7 serotypes). Blue boxes and blue lines show the point estimates and CIs for GMRs comparing PCV13 vs. PCV10. Points to the right of the vertical line are those with higher antibody responses in the PCV13 arm of the study, and points to the left are those with higher antibody responses in the PCV10 arm. The direct evidence column shows the percentage of evidence from studies directly comparing PCV13 vs. PCV10 that contributes to the estimates presented in the figure in blue (PCV13 vs. PCV10). GMR of PCV13 vs. PCV10 for PCV10 and PCV13 serotypes are from a meta-analysis of only studies comparing PCV13 with PCV10. SA, sensitivity analysis.

FIGURE 71.

Geometric mean ratios from sensitivity analyses restricted to studies conducted in Europe at (a) post-primary vaccination series, (b) pre boost and (c) post boost. Each line in the figure shows the output from NMSs (PCV7 serotypes) or direct meta-analyses (PCV13 but non-PCV7 serotypes). Blue boxes and blue lines show the point estimates and CIs for GMRs comparing PCV13 vs. PCV10. Points to the right of the vertical line are those with higher antibody responses in the PCV13 arm of the study, and points to the left are those with higher antibody responses in the PCV10 arm. The direct evidence column shows the percentage of evidence from studies directly comparing PCV13 vs. PCV10 that contributes to the estimates presented in the figure in blue (PCV13 vs. PCV10). GMR of PCV13 vs. PCV10 for PCV10 and PCV13 serotypes are from a meta-analysis of only studies comparing PCV13 with PCV10.

FIGURE 72.

Geometric mean ratios from sensitivity analyses of studies conducted in Asia at (a) post-primary vaccination series and (b) post boost. Each line in the figure shows the output from NMAs (PCV7 serotypes) or direct meta-analyses (PCV13 but non-PCV7 serotypes). Blue boxes and blue lines show the point estimates and CIs for GMRs comparing PCV13 vs. PCV10. Points to the right of the vertical line are those with higher antibody responses in the PCV13 arm of the study, and points to the left are those with higher antibody responses in the PCV10 arm. The direct evidence column shows the percentage of evidence from studies directly comparing PCV13 vs. PCV10 that contributes to the estimates presented in the figure in blue (PCV13 vs. PCV10). GMR of PCV13 vs. PCV10 for PCV10 and PCV13 serotypes are from a meta-analysis of only studies comparing PCV13 with PCV10.

FIGURE 73.

Geometric mean ratios from sensitivity analyses of studies that used a 3 + 1 schedule at (a) post-primary vaccination series, (b) pre boost and (c) post boost. Each line in the figure shows the output from NMAs (PCV7 serotypes) or direct meta-analyses (PCV13 but non-PCV7 serotypes). Blue boxes and blue lines show the point estimates and CIs for GMRs comparing PCV13 vs. PCV10. Points to the right of the vertical line are those with higher antibody responses in the PCV13 arm of the study, and points to the left are those with higher antibody responses in the PCV10 arm. The direct evidence column shows the percentage of evidence from studies directly comparing PCV13 vs. PCV10 that contributes to the estimates presented in the figure in blue (PCV13 vs. PCV10). GMR of PCV13 vs. PCV10 for PCV10 and PCV13 serotypes are from a meta-analysis of only studies comparing PCV13 with PCV10.

FIGURE 74.

Sensitivity analysis of RR of seroinfection for studies conducted in Europe. Each line in the figure shows the output from NMAs (PCV7 serotypes) or direct meta-analyses (PCV10 serotypes). Blue boxes and blue lines show the point estimates and CIs of RR of seroinfection comparing PCV13 vs. PCV10. The direct evidence column shows the percentage of evidence from studies directly comparing PCV13 vs. PCV10. Results for PCV10 serotypes are from a meta-analysis of only studies comparing PCV13 with PCV10; therefore, estimates of PCV7 vs. PCV10 and PCV13 vs. PCV7 were not available.

FIGURE 75.

Sensitivity analysis of RR of seroinfection for studies using a 3 + 1 schedule. Each line in the figure shows the output from NMAs (PCV7 serotypes) or direct meta-analyses (PCV10 serotypes). Blue boxes and blue lines show the point estimates and CIs of RR of seroinfection comparing PCV13 vs. PCV10. The direct evidence column shows the percentage of evidence from studies directly comparing PCV13 vs. PCV10. Results for PCV10 serotypes are from a meta-analysis of only studies comparing PCV13 with PCV10; therefore, estimates of PCV7 vs. PCV10 and PCV13 vs. PCV7 were not available.

Appendix 7 R syntax

1. # network meta-analysis

2. library(netmeta)

3. net.pcv <- netmeta(TE = lgGMR, seTE = lgGMR.se, treat1 = vac2, treat2 = vac1, studlab = cohort.ID, data = data, sm = ‘MD’, reference.group = ‘pcv10’)

4. #Split direct and indirect evidence to evaluate inconsistency

5. net.pcv.split <- netsplit(net.pcv)

6. #format output

7. ind <- net.pcv.split$random

8. ind <- ind[which(ind$comparison %in% c(‘pcv10:pcv13’, ‘pcv13:pcv10’)),]

9. output.nma$random.nma <- round(ind$TE, 3)

10. output.nma$random.lower <- round(ind$lower, 3)

11. output.nma$random.upper <- round(ind$upper, 3)

12. output.nma$random.se <- round(ind$seTE, 3)

13. output.nma$random.CI <- paste(sprintf(‘%0.3f’, ind$TE), ‘ (‘, sprintf(‘%0.3f’, ind$lower), ‘, ‘, sprintf(‘%0.3f’, ind$upper), ‘)’, sep = ‘‘)

14. # Association between immunogenicity and seroefficacy

15. library(lme4)

16. #fit linear mixed effects model

17. random <- lmer(logRR ~ lgGMR * sero.type + (1 | cohort.ID), data = data, weights = study.weights)

List of abbreviations

AIC

Akaike information criterion

CCR

case : carrier ratio

CDSR

Cochrane Database of Systematic Reviews

CET

cost-effectiveness threshold

CENTRAL

Cochrane Central Register of Controlled Trials

CRM

cross-reacting material

DTaP

diphtheria, tetanus, acellular pertussis

DTwP

diphtheria, tetanus, whole-cell pertussis

ELISA

enzyme-linked immunosorbent assay

GMC

geometric mean concentration

GMR

geometric mean ratio

HBV

hepatitis B vaccine

Hib-TT

Haemophilus influenzae type b tetanus toxoid conjugate vaccine

ICTRP

International Clinical Trials Registry Platform

IgG

immunoglobulin G

iNMB

incremental net monetary benefit

IPV

inactivated polio vaccine

mcg/ml

micrograms per millilitre

MenC

group C meningococcal vaccine

NCT

National Clinical Trial

NMA

network meta-analysis

OPV

oral polio vaccine

PCV

pneumococcal conjugate vaccine

PCV10-SII

Pneumosil

QALY

quality-adjusted life-year

RCT

randomised controlled trial

RoB

risk of bias

RR

relative risk

SE

standard error

TT

tetanus toxoid

WHO

World Health Organization