Systematic review of pneumococcal conjugate vaccine schedules: Executive summary of findings about reduced dose schedules

Systematic review of pneumococcal conjugate vaccine schedules: Executive summary of findings about reduced dose schedules Pippa Scott, 1 Matthias Egger, 1 Anne W.S. Rutjes, 1,2 Lilian Bermetz, 1 Nadège Robert, 1 Susana Scott, 3 Tania Lourenço, 4 Nicola Low. 1 1 Institute of Social and Preventive Medicine (ISPM), University of Bern, Switzerland 2 Clinical Center for Aging Sciences (Ce.S.I.), University G. d'annunzio Foundation, Chieti, Italy 3 London School of Hygiene and Tropical Medicine (LSHTM), United Kingdom 4 Health Services Research Unit, University of Aberdeen, United Kingdom Corresponding author: Nicola Low, Institute of Social and Preventive Medicine (ISPM), University of Bern, Finkenhubelweg 11, CH-3012 Bern, Switzerland. Tel: +41 31 631 30 92; Fax: +41 31 631 35 20; low@ispm.unibe.ch 1

Aims and objectives To perform a systematic review of evidence on pneumococcal conjugate vaccine (PCV) schedules from all available sources to summarize the data available to date and identify gaps in evidence. To identify key methodological issues in conducting systematic reviews on vaccine schedule-related questions. Key policy questions for review What is the evidence for the effectiveness of fewer doses of PCV compared with alternative schedules? What is the evidence for the effectiveness of simplified schedules compared with alternative schedules? Are there differences in outcomes according to age at first dose, interval between doses and number of doses? Are there differences in the effectiveness of various schedules among populations and in populations with different rates of carriage? Process Groups with expertise in both the subject area and review methodology were involved in the conduct of the review. A protocol was developed in consultation with experts in the field. The protocol has been reviewed and approved by QUIVER members. The overall approach was supported. The expert group commented on draft reports at each stage of the review. 1 A face to face meeting was held to discuss the major findings with an ad hoc group. In addition to PCV experts, this group included observers from industry and a representative of other groups reviewing surveillance about the impact of various PCV schedules. Key policy findings Levels of seropositivity were higher in two primary (2p) or three primary (3p) dose schedules than 1 primary dose (1p) schedules (PCV7). There was strong statistical evidence of a difference for most serotypes. There were only small differences between 3p and 2p schedules of PCV7, PCV9 and PCV10, but there was marked variation between studies. Levels of seropositivity following both schedules were high for most serotypes. We did not find any evidence about clinical outcomes for these comparisons from studies which we considered to have a low risk of bias. Lessons learned This systematic review has collated a valuable resource for the study of the effects of PCV7, PCV9, PCV10 and PCV13 from RCTs, cohort studies and case-control studies. Review questions need to be clearly and precisely formulated in the review protocol. We were able to give an overview that synthesises the data collected from studies of clinical, carriage and immunological outcomes. The systematic review process allowed us to identify important areas where there is an absence of evidence about the effectiveness of PCV, and areas for additional research. The inclusion of data from observational studies did not alter the conclusions about PCV schedule-schedule comparisons that would have been obtained by examining RCTs only. We have yet to synthesise data that addressed the herd effects of PCV administration. We have established communication with other groups conducting PCV systematic reviews. Some of these efforts will complement the current work, in particular by adding the review of emerging data from surveillance systems on the impact of PCV on circulating serotypes. 1 Interpretations contained in this document are those of the systematic review team. Interpretation of experts will be incorporated in the final report. 2

Overall limitations We did not find data with a low risk of bias comparing clinical outcomes for different PCV schedules. Data about pneumococcal carriage were scarce. The clinical relevance of differences in immunogenicity between PCV schedules is not known because of limitations in understanding the correlation between antibody concentrations and pneumococcal disease. High levels of variability between studies in outcomes measured and in results obtained limited the conclusions that could be drawn. 3

Summary of key findings for selected schedule comparisons Evidence for effectiveness of 1 primary dose in infancy (1p) vs. no PCV 1 dose of PCV7 before 7 months might give some protection against IPD due to vaccine serotypes (1 case-control study in the USA). Carriage of vaccine serotypes was slightly lower in children receiving 1 dose of PCV7 (1 RCT in Fiji). We found no evidence from RCTs about the clinical efficacy of 1p schedules compared with no PCV. Evidence for effectiveness of 2 or 3 primary doses (2p or 3p) vs. 1 primary dose (1p) 2p or 3p schedules of PCV7 were more immunogenic than 1p schedules at 6 months (2 RCTs, Fiji and The Gambia). The clinical relevance of differences in immunogenicity are not known. Carriage of VT was only slightly lower with 2p or 3p vs. 1p schedules. Seropositivity to serotypes 6B and 23F was low. We found no data from RCTs about IPD or pneumonia for this comparison and no conclusions could be drawn from mortality data (1 RCT, The Gambia). Evidence for effectiveness of 3 primary doses (3p) vs. 2 primary doses (2p) Seropositivity levels following 3p and 2p schedules of PCV7, PCV9 and PCV10 both were high for most serotypes; the slight differences between schedules tend to favour 3p schedules but between study heterogeneity was high (5 RCTs). For serotypes 6B and 23F there were larger differences in seropositivity levels, which favoured 3p schedules but between study heterogeneity was high (5 RCTs). The immunogenicity profile of PCV10 was similar to that for PCV7 and PCV9 for most serotypes. The clinical relevance of differences in immunogenicity is not known. There was no evidence of differences in carriage of VT at 6 months (2 RCTs) or 12 months (1 RCT) between 2p and 3p schedules. We found no data from RCTs about IPD or pneumonia for this comparison and no conclusions could be drawn from observational data about IPD (case-control study USA) or mortality data (1 RCT, The Gambia). 3 primary doses (3p) vs. 2 primary doses + booster (2p+1) At 13 months, 1 month after the booster dose, antibody concentrations were substantially higher in the 2p+1 group but these differences were attenuated by 19 months. After the primary series, there were modest differences in seropositivity favouring the 3p schedule. Antibody concentrations appeared to decline markedly after the primary series. We identified 1 RCT assessing immunogenicity for 3p vs. 2p+1 schedules (PCV7 Israel). We found no evidence from RCTs about the clinical efficacy of 3p vs. 2p+1 schedules and no conclusions could be drawn from observational studies (1 case-control study, USA). 4

Overview of systematic review We considered the following population, interventions, comparisons and outcomes: Population Children in any country Interventions PCV7, PCV9, PCV13, conjugated to diphtheria toxoid protein CRM197 PCV10, conjugated to either protein D, tetanus toxoid or diphtheria toxoid Comparisons PCV experts noted that besides the number of doses given there are other factors that influence the effectiveness including: Age at first dose Intervals between doses Time of sample collection after each dose and after completion of the vaccination series. Methods We searched 12 electronic databases of published articles, trial registers and industry information from the earliest date until August 2009 (updated March 2010). Searches and screening for eligible studies were conducted simultaneously for all study questions and outcomes. A sequential approach based on vaccine valency and outcome was used for data extraction and analysis. We selected studies that reported on randomized controlled trials (RCT), quasi-rct, cohort or case-control studies in children up to 18 years. We used structured piloted forms to extract available data about: numbers of events, ratio measures of effect, and vaccine efficacy (VE); study characteristics, and potential sources of bias and heterogeneity. We used random effects meta-analysis to combine results statistically, where appropriate. We described between-trial heterogeneity using the I 2 statistic and did not pool results if there was a high level of heterogeneity (I 2 >50%). We analysed data on: o o o clinical outcomes: invasive pneumococcal disease (IPD); pneumonia; otitis media (OM); mortality; nasopharyngeal carriage of pneumococci for: all serotypes; serotypes included in the vaccine (VT); non-vaccine serotypes (NVT); and, where reported on vaccineassociated serotypes (VAT); and NVT, excluding VAT (NVT-VAT); and immunological outcomes: seropositivity (at ELISA antibody concentration cutpoints of 0.35µg/ml, 0.20µg/ml and 0.50µg/ml); opsonophagocytosis assay (OPA) at cut-point titre 8), geometric mean concentrations or titres (both ELISA and OPA data). The ELISA cut-point 0.35µg/ml for all serotypes is recommended by WHO for vaccine licensure studies [1]. For PCV10 a cut-point of 0.20µg/ml in the ELISA used was accepted as being equivalent to 0.35µg/ml in other assays. 5

Results Summary for SAGE meeting, November 2010: preliminary data Total 3121 hits (and ~200 additional citations); 38 randomised controlled trials, 15 observational studies. For comparisons between schedules we found no RCTs that had planned to collect data on clinical outcomes. One case-control study (USA) studied IPD cases and age- and postcode-matched controls without IPD [2]. Limited clinical data were collected from studies that reported safety outcomes. Pneumococcal carriage was reported in 3 studies making schedule-schedule comparisons. Table 1: Summary of clinical, carriage and immunogenicity data Schedule Clinical, planned* no. studies Clinical, safety no. studies Carriage no. studies Serology no. studies Schedule vs. no PCV 11 2 12 15 Schedule vs. schedule 1 5 3 23 Legend: Some studies report more than one endpoint, so total is greater than the sum of the number of RCT and observational studies; * Includes studies that were designed to investigate vaccine efficacy with specified clinical endpoints; Includes studies that included vaccine safety as an outcome and for which episodes of IPD, pneumonia or OM were reported as serious adverse events or other adverse events. Evidence for effectiveness of 1 primary dose in infancy (1p) vs. no PCV One RCT (Fiji) [3] and 1 case-control study (USA) [2] reported on this outcome for PCV7. Clinical outcomes One case-control study (USA) studied IPD cases and age- and postcode-matched controls without IPD. Vaccine efficacy against vaccine-type IPD was estimated to be 73% (95%CI 43-87%) for infants receiving 1 PCV7 dose at <7 months compared with unvaccinated children. It is unclear whether this analysis was adjusted for confounding factors. We did not identify any RCT with data about IPD, pneumonia, or OM for this comparison. Pneumococcal carriage One RCT compared carriage of VT in infants receiving 1 dose of PCV to no doses (Fiji 7v). At 6 months of age there was a slight reduction, with wide confidence intervals including the null value) in carriage of VT in those receiving vaccine compared to those who did not (risk ratio, RR 0.91 95%CI 0.46-1.79). At 18 months of age this slight reduction was maintained but still with wide confidence intervals (risk ratio 0.83 95%CI 0.28-2.45). Immunogenicity Immunogenicity data have not yet been analysed for this comparison. 6

Evidence for effectiveness of 2 or 3 primary doses (2p or 3p) vs. 1 primary dose (1p) Two RCTs examining PCV7 reported on this comparison (Fiji [3], The Gambia [4]). Clinical outcomes We found 1 RCT that compared mortality rates in children in The Gambia who received PCV7 in 2p or 3p vs. 1p schedules (PPV given at 10 months in all groups). There were 2 deaths among 214 (0.9%) children in the 1-dose group, 8/211 (3.8%) in the 2-dose group 5/207 (2.4%) in the 3-dose group. Relative risks of death were higher in children receiving 2 or 3 doses but confidence intervals were very wide and included the null value (2p vs. 1p, RR 4.06 95%CI 0.87-18.88; 3p vs. 1p, RR 2.58 95%CI 0.51-13.17). No causes of death were reported. We found no data from RCTs or observational studies about IPD or pneumonia for this comparison. Pneumococcal carriage Two RCTs (in Fiji and The Gambia) compared carriage of VT for 2p and 3p vs. 1p schedules. At 6 months of age carriage rates were slightly lower for 1p schedules but confidence intervals were wide and included the null effect (2p vs. 1p, pooled RR 0.93, 95%CI 0.66, 1.30; 3p vs. 1p, RR 0.73 95%CI 0.51, 1.06). By 18 months of age, point estimates favoured schedules with more doses but confidence intervals were still too wide to exclude no effect. Carriage of NVT (1 RCT in Fiji) was similar for 2p or 3p vs. 1p schedules. Immunogenicity For these analyses we report seropositivity from studies that documented the percentage of specimens with an ELISA antibody concentration 0.35µg/ml. Seropositivity levels following 1p PCV7 schedules were lower than those following 2p or 3p schedules at 6 months for all serotypes assessed for both seropositivity and GMC (RCTs in Fiji and The Gambia). There were only 2 serotypes (4 and 14 in the Fiji trial) for which confidence intervals for the difference in seropositivity did not include the null value. Figure 1 shows the forest plot displaying the differences in seropositivity for each VT and each trial comparing 2p vs. 1p schedules. After 2 PCV7 doses seropositivity levels were >80% for all serotypes except 6B and 23F for which seropositivity was 48-82%. After 1 PCV7 dose seropositivity to serotypes 6B and 23F was only 12-30%. Differences between schedules in seropositivity and GMC at 12 months (Fiji only) were less marked. There was severe heterogeneity between the results from Fiji and The Gambia; data could only be pooled for serotype 19F. The pattern of differences was similar for the comparison of 3p vs. 1p schedules (forest plot not shown). In The Gambia, differences in seropositivity between groups receiving 2 or 3 doses compared with 1 dose could be due, in part, to the longer delay between the date of the last dose and the date of immunological assessment for 1p than 2p or 3p schedules. The clinical relevance of these differences is not known. 7

Figure 1: 2p vs. 1p schedules, seropositivity at ~6 months, ELISA cut-point 0.35µg/mL, by serotype and study Legend: n/n, number seropositive/total in group; Risk diff, difference in seropositivity between groups shown as a proportion; Horizontal axis represents the difference, expressed as a proportion between groups receiving schedules of 2 primary vs. 1 primary doses; vertical line through risk difference of 0 shows no difference in levels of seropositivity between groups. Solid black diamonds represent point estimate of odds ratio; horizontal black line represents 95% confidence interval; Open diamond represents the pooled estimate, combined using random effects meta-analysis; vertical points of diamond represent point estimate and horizontal points represent 95% confidence interval; I 2 value is the level of statistical heterogeneity between trials (<25% low heterogeneity); where I 2 >50% no pooled estimate is shown. 8

Evidence for effectiveness of 3 primary doses (3p) vs. 2 primary doses (2p) Five RCTs, including 3 with PCV7 (Fiji [3], The Gambia [4], Israel [5]) 1 with PCV9 (Iceland [6]) and 1 with PCV10 (Denmark, Norway, Slovakia, Sweden) [7] and one case-control study (USA) [2] reported on this comparison. Clinical outcomes In The Gambia, mortality rates were 2.4% (5/207) in the 3p group and 3.8% (8/211) in the 2p group (RR 0.64 95%CI 0.21, 1.97). No causes of death were reported. We found no RCTs reporting on IPD or pneumonia comparing 3p and 2p schedules. One case-control study (USA) studied IPD cases and age- and postcode-matched controls without IPD. The matched, adjusted odds ratio for IPD caused by vaccine serotypes in children receiving 3 PCV7 doses before 7 months compared with 2 doses before 7 months was 1.5 (95%CI 0.54, 4.35) after adjustment for underlying disorders. Pneumococcal carriage The RCTs of PCV7 in Fiji and The Gambia reported carriage for this comparison. At 6 months, carriage of VT was high in all children; there was no evidence of a difference in VT carriage for 3p vs. 2p schedules (RR 0.97, 95%CI 0.90, 1.05). At 18 months (Fiji) VT carriage levels were low in both groups with no statistical evidence of a difference for the 3p vs. 2p schedule (RR 0.36, 95%CI 0.04, 3.54). Immunogenicity We analyzed data from the 5 RCTs (Figure 2) with seropositivity at an ELISA antibody concentration 0.35µg/ml for all vaccines. Seropositivity levels following both 3p and 2p schedules with all vaccines were >90% for most serotypes other than 6B and 23F. For serotypes other than 6B and 23F the differences in seropositivity levels between 3p and 2p schedules were slight and confidence intervals for most comparisons were wide and included the null value. There was severe between study heterogeneity for all serotypes except 5 and 19F. The differences seen at 6 months appeared to persist at 12 months (results not shown). The clinical relevance of differences in seropositivity is not known OPA results were assessed in 2 RCTs comparing 3p and 2p schedules (PCV7 in The Gambia, PCV10 in Denmark, Norway, Slovakia and Sweden). In general, the pattern of differences in OPA titres (cut-point 1:8) was similar to that for seropositivity (ELISA cut-point 35µg/ml. There were some differences between absolute levels of the measures for some serotypes. For serotypes 6B and 23F, in the PCV10 trial where the percentages of children with antibody concentrations >0.20ug/ml were low, the percentages of children with OPA titres >1:8 tended to be higher. 9

Figure 2: 3p vs. 2p schedules, seropositivity at ~6 months, ELISA cut-point 0.35µg/mL, by serotype and study Legend: n/n, number seropositive/total in group; Risk diff, difference in seropositivity between groups shown as a proportion; Schedules reported as intended age in months for each dose. Horizontal axis represents the difference, expressed as a proportion between groups receiving schedules of 3 primary vs. 2 primary doses; vertical line through risk difference of 0 shows no difference in levels of seropositivity between groups. Solid black diamonds represent point estimate of odds ratio; horizontal black line represents 95% confidence interval; Open diamond represents the pooled estimate, combined using random effects meta-analysis; vertical points of diamond represent point estimate and horizontal points represent 95% confidence interval; I 2 value is the level of statistical heterogeneity between trials (<25% low heterogeneity); where I 2 >50% no pooled estimate is shown. 10

3 primary doses (3p) vs. 2 primary doses + booster (2p+1) One RCT (Israel) [5] and 1 case-control study [2] reported on this comparison for PCV7. Clinical outcomes We found no clinical data about IPD or pneumonia from RCTs for this comparison. One case-control study (USA) reported on this comparison. There were few IPD cases in both groups, limiting statistical power. This study compared 3 doses at <7 months with 2 doses at <7 months and a booster at 12-16 months. The matched, adjusted odds ratio for VT IPD for the 3p vs. 2p+1 schedule was 1.5 (95%CI 0.15, 14.6) after adjustment for underlying disorders. Pneumococcal carriage We found not data about pneumococcal carriage for this comparison. Immunogenicity We only identified 1 RCT that had compared 3p vs. 2p+1 schedules (PCV7 Israel). At 7 months, 1 month after the last primary dose in each group, there were modest differences in seropositivity (5 to 22%) between the groups for serotypes 6B, 14, 18C, 19F, 23F, favouring the 3p schedule. Antibody concentrations appeared to decline markedly after the primary series; at 13 months, 7 months after the last dose in the 3p schedule, antibody concentrations for all serotypes had fallen back towards pre-vaccination levels. In contrast, in the 2p+1 group, assessed 1 month after the booster dose, antibody concentrations were high (Table 2). These differences had attenuated by 19 months. There were no samples taken at 12 months in this study so immunological responses 6 months after the primary series could not be compared between groups. Table 1: 3p vs. 2p + 1 schedules. Geometric mean antibody concentrations and seropositivity at 13 months, Israel PCV7 trial, by serotype 11

Interpretation and discussion This systematic review is one component of a larger project to examine the evidence for all WHO Expanded Programme on Immunisation childhood diseases and to assess the merits of various immunisation schedules in different epidemiological scenarios. Interpretation of the clinical, carriage and immunogenicity data from this review with experts in the field of pneumococcal vaccines is ongoing. Further analyses that might aid interpretation are being undertaken. Final reports will be available in early 2011. Schedules of two primary (2p) or three primary (3p) doses of PCV7 resulted in markedly higher levels of seropositivity than 1 primary dose (1p) with strong statistical evidence of a difference for most serotypes. Levels of seropositivity following both 3p and 2p schedules of PCV7, PCV9 and PCV10 were high for most serotypes; differences between schedules were slight with marked variation between studies. We did not find any high quality unbiased data about clinical outcomes on which to base decisions about different PCV schedules for the vaccines studied. Data about pneumococcal carriage were scarce. There were some differences between schedules in immunogenicity but their clinical relevance is not known because of limitations in understanding the correlation between antibody concentrations and pneumococcal disease. There were high levels of between study heterogeneity that limited the interpretation of data from multiple studies examining the same outcome. The systematic review identified key methodological issues that are relevant to the conduct of future vaccine schedule-related reviews. The development of a protocol with clear study questions defined in collaboration with vaccine experts is essential. Additional components to be incorporated at the protocol stage in future reviews include: prioritisation of key scheduleschedule comparisons, outcomes and vaccine types (e.g. if there is more than 1 formulation of vaccine). The inclusion of observational study designs needs to be considered; in this case these data did not alter the conclusions obtained from RCTs. We found that, owing to the large number of studies eligible for inclusion in this review, a stepwise approach to data extraction and analysis was most efficient. The hierarchy of questions should be guided by experts for the specific vaccine, and those who will be using data produced by the review such as modellers and policy makers. Further streamlining processes such as online data entry and consensus systems are also in development. Methodological aspects relating to data-analysis were also highlighted by this review. Key considerations include, but are not limited to: the effect measure to be used (e.g. odds ratios vs. risk ratios vs. risk differences) [8]; the most relevant and interpretable immunological outcomes, cut-points and timing of specimens; the grouping of schedules (e.g. can all studies comparing 3p and 2p be combined if the age at the first dose varies by a month between studies), and identifying and investigating heterogeneity between study results. The decisions on which methods are most appropriate are heavily based on the specific purposes for which the analyses are to be used, alongside statistical appropriateness. This further highlights the need for input from those who will use data from this review at an early stage of review planning. Further statistical techniques such as network meta-analysis [9] are being explored for making indirect comparisons of outcomes where direct comparison data are scarce. 12

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