Systematic review of the effect of pneumococcal conjugate vaccine dosing schedules on immunogenicity.

BACKGROUND: Despite the breadth of studies demonstrating benefits of pneumococcal conjugate vaccine (PCV), uncertainty remains regarding the optimal PCV dosing schedule in infants. METHODS: We conducted a systematic literature review of PCV immunogenicity published from 1994 to 2010 (supplemented post hoc with studies from 2011). Studies included for analysis evaluated ≥2 doses of 7-valent or higher product (excluding Aventis-Pasteur PCV11) administered to nonhigh-risk infants ≤6 months of age. Impact of PCV schedule on geometric mean antibody concentration (GMC) and proportion of subjects over 0.35 mcg/mL were assessed at various time points; the GMC 1 month postdose 3 (for various dosing regimens) for serotypes 1, 5, 6B, 14, 19F and 23F was assessed in detail using random effects linear regression, adjusted for product, acellular diphtheria-tetanus-pertussis/whole-cell diphtheria- tetanus-pertussis coadministration, laboratory method, age at first dose and geographic region. RESULTS: From 61 studies, we evaluated 13 two-dose (2+0) and 65 three-dose primary schedules (3+0) without a booster dose, 11 "2+1" (2 primary plus booster) and 42 "3+1" schedules. The GMC after the primary series was higher following 3-dose schedules compared with 2-dose schedules for all serotypes except for serotype 1. Pre- and postbooster GMCs were generally similar regardless of whether 2 or 3 primary doses were given. GMCs were significantly higher for all serotypes when dose 3 was administered in the second year (2+1) compared with ≤6 months of age (3+0). CONCLUSIONS: While giving the third dose in the second year of life produces a higher antibody response than when given as part of the primary series in the first 6 months, the lower GMC between the 2-dose primary series and booster may result in less disease protection for infants in that interval than those who completed the 3-dose primary series. Theoretical advantages of higher antibodies induced by giving the third dose in the second year of life, such as increased protection against serotype 1 disease, longer duration of protection or more rapid induction of herd effects, need to be evaluated in practice.

The differential impact of coadministered vaccines, geographic region, vaccine product and other covariates on pneumococcal conjugate vaccine immunogenicity.

BACKGROUND: Antipneumococcal capsular polysaccharide antibody concentrations are used as predictors of vaccine efficacy against vaccine serotype (ST) pneumococcal disease among infants. While pneumococcal conjugate vaccines (PCV) are recommended globally, factors associated with optimal PCV immune response are not well described. We aimed to systematically assess local setting factors, beyond dosing schedule, which may affect PCV antibody levels. METHODS: We conducted a literature review of PCV immunogenicity, abstracting data from published reports, unpublished sources, and conference abstracts from 1994 to 2010 (and ad hoc 2011 reports). Studies included in this analysis evaluated ≥ 2 primary doses of PCV before 6 months of age in non-high-risk populations, used 7-valent or higher PCV products (excluding Aventis-Pasteur and Merck products) and provided information on geometric mean concentration (GMC) for STs 1, 5, 6B, 14, 19F or 23F. Using random effects meta-regression, we assessed the impact of geographic region, coadministered vaccines and PCV product on postprimary GMC, adjusting for dosing schedule and ELISA laboratory method. RESULTS: Of 12,980 citations reviewed, we identified 103 vaccine study arms for this analysis. Children in studies from Asia, Africa and Latin America had significantly higher GMC responses compared with those in studies from Europe and North America. Coadministration with acellular pertussis DTP compared with whole-cell DTP had no effect on PCV immunogenicity except for ST14, where GMCs were higher when coadministered with acellular pertussis DTP. Vaccine product, number of PCV doses, dosing interval, age at first dose and ELISA laboratory method also affected the GMC. CONCLUSIONS: PCV immunogenicity is associated with geographic region and vaccine product; however, the associations and magnitude varied by ST. Consideration of these factors is essential when comparing PCV immunogenicity results between groups and should be included in the evidence base when selecting optimal PCV vaccine schedules in specific settings.

Methods for a systematic review of pneumococcal conjugate vaccine dosing schedules.

BACKGROUND: Streptococcus pneumoniae causes a considerable amount of morbidity and mortality in children <5. However, pneumococcal conjugate vaccines (PCVs) can prevent much of this burden. Until recently, PCVs were mostly available only in developed countries using a variety of dosing schedules. As more lower income countries make decisions to introduce PCV into their national immunization programs, an optimal schedule with which to administer PCV has become a key policy question. METHODS: We performed a systematic review of English literature published from 1994 to 2010 on the effects of PCV dosing schedules on immunogenicity, nasopharyngeal carriage, invasive pneumococcal disease and pneumonia. Data were independently double abstracted and cleaned for analysis. Descriptive analyses were performed. RESULTS: We identified 12,980 citations from the literature search (12,976) and secondary means (44). Double review of titles and abstracts yielded 769 articles that underwent full data abstraction. Of these, 350 were further analyzed and are presented in separate reports in this supplement. CONCLUSIONS: This article presents the methods utilized in our systematic review. Because of the heterogenity of the study methods of the reports identified by this review, we did not conduct formal meta-analyses. However, these methods allow us to present a full landscape of the literature on PCV dosing schedules.