Pneumococcal responses are similar in Papua New Guinean children aged 3-5 years vaccinated in infancy with pneumococcal polysaccharide vaccine with or without prior pneumococcal conjugate vaccine, or without pneumococcal vaccination

Abstract

Trial design: In an earlier trial, Papua New Guinean (PNG) children at high risk of pneumococcal disease were randomized to receive 0 or 3 doses of 7-valent pneumococcal conjugate vaccine (PCV7), followed by a single dose of 23-valent pneumococcal polysaccharide vaccine (PPV23) at 9 months of age. We here studied in a non-randomized follow-up trial the persistence of pneumococcal immunity in these children at 3-5 years of age (n = 132), and in 121 community controls of a similar age with no prior pneumococcal vaccination.

Methods: Circulating IgG antibody titers to all PCV7 and PPV23-only serotypes 2, 5 and 7F were measured before and after challenge with 1/5th of a normal PPV23 dose. Serotype-specific memory B-cells were enumerated at 10 months and 3-5 years of age for a subgroup of study children.

Results: Serotype-specific IgG antibody titers before and after challenge were similar for children who received PCV7/PPV23, PPV23 only, or no pneumococcal vaccines. Before challenge, at least 89% and 59% of children in all groups had serotype-specific titers ≥ 0.35μg/ml and ≥ 1.0 μg/ml, respectively. Post-challenge antibody titers were higher or similar to pre-challenge titers for most children independent of pneumococcal vaccination history. The rise in antibody titers was significantly lower when pre-challenge titers were higher. Overall the relative number of serotype-specific memory B-cells remained the same or increased between 10 months and 3-5 years of age, and there were no differences in serotype-specific memory B-cell numbers at 3-5 years of age between the three groups.

Conclusions: Immunity induced by PCV7 and/or PPV23 immunization in infancy does not exceed that of naturally acquired immunity in 3-5-year-old children living in a highly endemic area. Also, there was no evidence that PPV23 immunization in the first year of life following PCV7 priming induces longer-term hypo-responsiveness.

Trial registration: Clinicaltrials.gov NCT01414504 and NCT00219401.

Conflict of interest statement

Competing Interests: Anita H.J. van den Biggelaar has received support from Pfizer Australia and GSK Australia to attend conferences. Peter C. Richmond is a former member of vaccine advisory boards for Wyeth and CSL Ltd; has received institutional funding for investigator-initiated research from GlaxoSmithKline (GSK) Biologicals and Merck; and has received travel support from Pfizer and Baxter to present study data at international meetings. William S. Pomat has received funding from Pfizer Australia to attend a conference. Deborah Lehmann was a member of the GSK Australia Pneumococcal-Haemophilus influenzae-Protein D conjugate vaccine (“Synflorix”) Advisory Panel; has received support from Pfizer Australia and GSK Australia to attend conferences; has received an honorarium from Merck Vaccines to give a seminar at their offices in Pennsylvania and to attend a conference; and is an investigator on an investigator-initiated research grant funded by Pfizer Australia. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Figures

Fig 1. Flowchart for children in the study.

A flowchart of the completed preceding neonatal PCV7 trial is published elsewhere [8]. A total of 132 of 259 children who participated in the previous PCV7 study and who were vaccinated with PPV23 at 9 months of age were included in this study. One hundred and twenty seven children could not be enrolled for reasons summarized in Fig 1, including death; being too old according to pre-defined inclusion criteria; illness; migration to an area outside the study’s reach capacities; not located; and refusal. A total of 121 of 136 potential community controls who were assented to participate in the study were included in the final analysis: of the 15 not included, three children were over age; three did not consent; three could not be relocated and blood collection pre-challenge was not successful for six children. Post-challenge data were not available for 41 children for reasons summarized. N is Neonatal PCV7 group; I is Infant PCV7 group; C is control group (no PCV7).

Fig 2. Pneumococcal serotype-specific IgG antibody titers before and after challenge.

Serum antibody titers were assessed in 3-5-year-old children who had received PCV7 and PPV23 as infants (white bars; n = 100 /n = 86), who had received only PPV23 as infants (grey bars; n = 32 /n = 28), or who had not received pneumococcal vaccines (striped bars; n = 121 pre-challenge/ n = 98 post-challenge) (A) before and (B) after challenge with a low dose of PPV23. Data are presented as geometric mean titers and 95% confidence intervals. Serotype-specific geometric mean titers before or after challenge were compared between each group using Mann-Whitney U test. * p

Fig 3. Individual pneumococcal serotype-specific IgG antibody titers before and after challenge.

Graphs present scatterplots of pneumococcal serotype-specific IgG antibody titers pre- and 1 month post-challenge with a low dose of PPV23 for individual children in the groups not vaccinated with any pneumococcal vaccines (grey triangles), vaccinated with PCV7 and PPV23 (black circles), and vaccinated with PPV23 only (open squares). Serotypes with an asterisk (*) are included in PPV23 only, while other serotypes are included in both PCV7 and PPV23. For children whose antibody titers are higher post- than pre-challenge (increase in antibody titer) data points lie above the line; for children with similar titers before and after challenge data points cluster around the reference line; and for children whose antibody titers were lower 1month after challenge than before data points lie under the reference line. The p-values included in the graphs correspond with non-parametric analysis of paired pre- and post-challenge responses within the treatment groups (Wilcoxon Signed Rank Test).

Fig 4. Individual pneumococcal serotype-specific IgG antibody titers following PPV23 vaccination at 9 months versus low-dose challenge at 3–5 years of age.

Graphs present scatterplots of pneumococcal serotype-specific IgG antibody titers measured in individual children 1 month after PPV23 vaccination (vaccinated at 9 months of age) (x axis) and 1 month after challenge with a low dose of PPV23 at 3–5 years of age (y axis), in those who had received 3 doses of PCV7 before the PPV23 vaccine (primed; grey circles), or only received PPV23 (unprimed; black diamonds). Serotypes with an asterisk (*) are included in PPV23 only, while the other serotypes are included in both PCV7 and PPV23. The p-values included in the graphs correspond with non-parametric analysis of paired responses within the treatment groups (Wilcoxon Signed Rank Test).

Fig 5. Pneumococcal serotype-specific memory B-cell responses.

Serotype-specific Antibody Forming Cells (AFCs) per 1x106 cultured PBMCs were measured at 10 months of age (1 month after PPV23 vaccination) and pre-challenge at 3–5 years of age in a subset of children vaccinated with PCV7 and PPV23 (white bars) or PPV23-only (grey bars), and pre-challenge at 3–5 years of age in a subset of children not vaccinated with any pneumococcal vaccines (striped pattern). Serotypes with an asterisk (*) are included in PPV23 only, while other serotypes are included in both PCV7 and PPV23. Data are presented as means and 95% confidence intervals. No significant differences were found between groups at 10 months or 3–5 years of age (tested using Mann-Whitney U test). Differences in responses at 10 months versus 3–5 years of age within a group were tested using Wilcoxon Signed Rank Test, and where significant differences were found this has been indicated in the graph.