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

Abstract

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.

FIGURE 1.

Effect of primary PCV dosing schedule on GMC by serotype. A) 2-dose versus 3-dose primary schedule on postprimary (~7 months) GMC; B) 2-dose versus 3-dose primary schedule on preboost (~12 months) GMC; C) effect of 2-dose versus 3-dose primary schedule on postboost (~13 months) GMC; D) effect of delaying age at first dose by 1 month on postprimary (~7 months) GMC; E) effect of increasing the interval between doses from 1 to 2 months on postprimary (~7 months) GMC and F) effect of delaying age at last dose by 1 month on postprimary (~7 months) GMC. Adjusted for age at first dose, geographic region, PCV product, coadministration of DTaP versus DTwP and laboratory method (GSK vs. Wyeth/other). N is the number of study arms. Asterick indicates that the significant ST1 finding in Figure 1B is due to 1 study where the two 2-dose arms had lower GMCs than the two 3-dose arms. Otherwise, when looking at other studies, there is no difference.

FIGURE 2.

Log GMC by serotype, geographic region and number of primary series PCV doses. PCV product is indicated by manufacturer [W, Wyeth (Pfizer); G, GSK; A, Aventis; M, Merck] and valency (ie, number of serotypes it contains) on the x-axis, and by (o) for licensed or precursor or (+) for unlicensed product.

FIGURE 3.

Effect of PCV booster dose in second year of life on GMC by serotype. A) Change in GMC pre- to postbooster; B) Change in GMC from postprimary (~7 months) to postbooster (~13 months).

FIGURE 4.

Difference in post-third dose GMC when changing from 3+0 (GMC at 6 months) to 2+1 (GMC at 15 months) PCV schedule.

FIGURE 5.

After postdose-3 log GMC, by serotype and PCV schedule: 2+1 (postbooster) versus 3+0 (postprimary). PCV product is indicated by manufacturer and valency (ie, number of serotypes it contains). W, Wyeth (Pfizer); G, GSK; A, Aventis; M, Merck.

FIGURE 6.

Proportion of children achieving >0.35 μg/mL (or >0.2 μg/mL if GSK ELISA used), by serotype, number of doses in primary series and immunization schedule. Each bar represents results from one study arm. Schedule is noted on the y-axis in months (m) or weeks (w). Error bars are 95% confidence intervals.