Hyporesponsiveness to re-challenge dose following pneumococcal polysaccharide vaccine at 12 months of age, a randomized controlled trial

Abstract

Background: To evaluate the immunological impact of the 23-valent pneumococcal polysaccharide vaccine (23vPPS) at 12 months, for children who have received zero to three infant doses of seven-valent pneumococcal conjugate vaccine (PCV), on responses to a subsequent exposure to a small dose of 23vPPS (mPPS).

Methods: Five hundred and fifty-two Fijian infants were stratified by ethnicity and randomized into eight groups to receive zero, one, two, or three PCV doses at 14 weeks, six and 14 weeks, or six, ten, and 14 weeks. Within each group, half received 23vPPS at 12 months and all received mPPS at 17 months. Sera were taken prior and one month post-mPPS.

Findings: By 17 months, geometric mean antibody concentrations (GMC) to all 23 serotypes in 23vPPS were significantly higher in children who had received 23vPPS at 12 months compared to those who had not. Post-mPPS, children who had not received the 12 month 23vPPS had a significantly higher GMC for all PCV serotypes compared with those who had (each p<0.02). For the non-PCV serotypes, children who had not received the 12 month 23vPPS had significantly higher GMC for six of 16 non-PCV serotypes (7F, 9N, 12F, 19A, 22F, 33F) than those who did (each p<0.02). After adjusting for the pre-mPPS level, exposure to 23vPPS was associated with a lower response to mPPS for all serotypes (each p<0.001).

Interpretation: Despite higher antibody concentrations at 17 months in children who had received 23vPPS at 12 months, the response to a re-challenge was poor for all 23 serotypes compared to children who had not received the 12 month 23vPPS.

Trial registration: ClinicalTrials.gov NCT00170612.

Figure 1. CONSORT chart of the screened and enrolled children to 18 months of age, showing the number having the pre-mPPS blood test¹, mPPS at 17 months of age², and blood test one month post-mPPS³

Withdrawals: 34 moved out of the study area, 16 failed to return for follow up, 13 refused a study procedure, nine developed an exclusion criterion, nine were withdrawn due to a protocol amendment, for six no reason was given, two had protocol violations, and one died from causes unrelated to receipt of the study vaccine.

Figure 2. Serotype-specific IgG GMC (μg/mL) to PCV serotypes at 17 months of age pre- (Figure 2a) and one month post-mPPS (Figure 2b) in children who did or did not receive the 12 month 23vPPS. Data from infants receiving 0,1,2,or 3 PCV doses have been combined in these graphs

Figure 3. Serotype-specific IgG GMC (μg/mL) to non-PCV serotypes at 17 months of age pre- (Figure 3a) and one month post-mPPS (Figure 3b) in children who did or did not receive the 12 month 23vPPS. Data from infants receiving 0,1,2,or 3 PCV doses have been combined in these graphs

Figure 4. Pre- and one month post-mPPS log antibody concentrations for non-PCV serotypes 1, 5, 7F, and 19A in those that did (+) and did not (o) receive 23vPPS at 12 months of age. Data from infants receiving 0,1,2,or 3 PCV doses have been combined in these graphs

Footnote: A 45-degree line, which indicates no change before and after the re-challenge, is super-imposed. The pre- and post-mPPS log antibody concentrations of those who received 23vPPS at 12 months mostly fell along the 45-degree line, indicating no response to mPPS. In contrast, most children who did not receive 23vPPS had an increase in antibody concentration, as indicated by the data points falling above the 45-degree line. The distribution of pre-mPPS log antibody concentrations of those that did and did not receive the 12 month 23vPPS mainly overlapped in the range between −2 to 0 for serotype 1. Within this range, it is clear that at any given log antibody concentration pre-mPPS, children who had not received the 23vPPS at 12 months had higher log antibody concentrations one month post-mPPS.

Figure 5. Pre- and one month post-mPPS log antibody concentrations for serotype 4 for children who did (+) or did not (o) receive 23vPPS at 12 months of age and by the number of PCV doses in the primary series (Figure 5a)

Figure 6. Pre- and one month post-mPPS log antibody concentrations for serotype 6B for children who did (+) or did not (o) receive 23vPPS at 12 months of age and by the number of PCV doses in the primary series (Figure 6a)