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 threedose 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.