Heptavalent pneumococcal conjugate vaccine immunogenicity in very-low-birth-weight, premature infants

Abstract

Background: The heptavalent pneumococcal CRM197 conjugate vaccine (PCV-7) has been incompletely studied in very-low-birth-weight (< or =1500 g) infants.

Objective: To assess PCV-7 immunogenicity in very-low-birth-weight, premature infants. We hypothesized that the frequency of postvaccine antibody concentrations > or =0.15 microg/mL would vary directly with birth weight.

Methods: This was a multicenter observational study. Infants 401 to 1500 g birth weight and <32 0/7 weeks gestation, stratified by birth weight, were enrolled from 9 National Institute of Child Health and Human Development Neonatal Research Network centers. Infants received PCV-7 at 2, 4, and 6 months after birth and had blood drawn 4 to 6 weeks following the third dose. Antibodies against the 7 vaccine serotypes were measured by enzyme-linked immunosorbent assay.

Results: Of 369 enrolled infants, 244 completed their primary vaccine series by 8 months and had serum obtained. Subjects were 27.8 +/- 2.2 (mean +/- standard deviation) weeks gestation and 1008 +/- 282 g birth weight. Twenty-six percent had bronchopulmonary dysplasia and 16% had received postnatal glucocorticoids. Infants 1001 to 1500 g birth weight were more likely than those 401 to 1000 g to achieve antibody concentrations > or =0.15 microg/mL against the least 2 immunogenic serotypes (6B: 96% vs. 85%, P = 0.003 and 23F: 97% vs. 88%, P = 0.009). In multiple logistic regression analysis, lower birth weight, postnatal glucocorticoid use, lower weight at blood draw, and Caucasian race were each independently associated with antibody concentrations <0.35 microg/mL against serotypes 6B and/or 23F.

Conclusions: When compared with larger premature infants, infants weighing < or =1000 g at birth have similar antibody responses to most, but not all, PCV-7 vaccine serotypes.

Trial registration: ClinicalTrials.gov NCT00273325.

Figure 1. Flow of study participants

Of a total of 1310 infants assessed for eligibility, 30% did not qualify (most would have been unable to return for follow-up), 42% were eligible but did not enroll (most had parents decline to give permission), and 28% were enrolled. The birth weights, gestational ages and demographic characteristics of the non-enrolled subjects were similar to those of the enrolled subjects. Overall, 66% of enrollees completed study procedures within specified windows and had serum from 4–6 weeks after the third PCV-7 dose available for the primary analysis (“on-time” cohort). Of the 125 children who were enrolled in the study, but were not included in the primary analysis cohort, 4 died between enrollment and the blood draw (2 of these died during the vaccine series and 2 before vaccines were begun), 7 withdrew, 14 were lost to follow-up, 54 did not complete the course of vaccines and blood draws, and 9 had inadequate blood samples (5 had had blood drawn within the prescribed window and 4 outside it). This left 37 children with specimens for a secondary analysis.

Figure 2. Pneumococcal antibody concentrations at 4–6 weeks after the third PCV-7 dose by birth weight

Serotypes 6B (A) and 23F (B) are shown. Each plot includes the 244 subjects in the primary analysis cohort. Diamonds represent individual values and lines show least mean squares regression and 95% confidence intervals. The dashed lines represent the WHO reference antibody concentration (0.35 µg/mL). In both cases, although the association between antibody concentration and birth weight was significant (6B P=0.006, 23F P=0.02), ≤3% of variability in antibody concentration was attributable to birth weight (R² ≤0.03). Similar results were found if antibody concentrations were plotted against gestational age (not shown).

Figure 3. Multiple logistic regression for pneumococcal antibody concentration ≥0.35 µg/mL at 4–6 weeks after the third PCV-7 dose

Multiple logistic regression was performed on 243 available subjects in the primary analysis cohort using the independent variables shown on the plots (one subject had missing weight data). The dependent variable was an antibody concentration ≥0.35 µg/mL. Results are depicted for serotypes 6B (A) and 23F (B). The X axis shows the odds ratio for the effect of each variable, adjusted for all of the other independent variables. Diamonds depict odds ratios and whiskers represent 95% confidence intervals.