Pneumococcal serotype-specific antibodies persist through early childhood after infant immunization: follow-up from a randomized controlled trial

Abstract

Background: In a previous UK multi-center randomized study 278 children received three doses of 7-valent (PCV-7) or 13-valent (PCV-13) pneumococcal conjugate vaccine at 2, 4 and 12 months of age. At 13 months of age, most of these children had pneumococcal serotype-specific IgG concentrations ≥ 0.35 µg/ml and opsonophagocytic assay (OPA) titers ≥ 8.

Methods: Children who had participated in the original study were enrolled again at 3.5 years of age. Persistence of immunity following infant immunization with either PCV-7 or PCV-13 and the immune response to a PCV-13 booster at pre-school age were investigated.

Results: In total, 108 children were followed-up to the age of 3.5 years and received a PCV-13 booster at this age. At least 76% of children who received PCV-7 or PCV-13 in infancy retained serotype-specific IgG concentrations ≥ 0.35 µg/ml against each of 5/7 shared serotypes. For serotypes 4 and 18C, persistence was lower at 22-42%. At least 71% of PCV-13 group participants had IgG concentrations ≥ 0.35 µg/ml against each of 4/6 of the additional PCV-13 serotypes; for serotypes 1 and 3 this proportion was 45% and 52%. In the PCV-7 group these percentages were significantly lower for serotypes 1, 5 and 7F. A pre-school PCV-13 booster was highly immunogenic and resulted in low rates of local and systemic adverse effects.

Conclusion: Despite some decline in antibody from 13 months of age, these data suggest that a majority of pre-school children maintain protective serotype-specific antibody concentrations following conjugate vaccination at 2, 4 and 12 months of age.

Trial registration: ClinicalTrials.gov NCT01095471.

Conflict of interest statement

Competing Interests: This work was partly supported by Pfizer Vaccine Research. AJP, AF, MDS, PTH and SNF act as chief or principal investigators for clinical trials conducted on behalf of their respective NHS Trusts and/or Universities, sponsored by vaccine manufacturers including Pfizer who make Prevenar 13, but receive no personal payments from them. AJP, AF, MDS, PTH and SNF have participated in advisory boards for vaccine manufacturers, but receive no personal payments for this work. JT, MDS, SNF, and PTH have received financial assistance from vaccine manufacturers to attend conferences. All grants and honoraria are paid into accounts within the respective NHS Trusts or Universities, or to independent charities. All other authors: no potential conflicts. There are no further patents, products in development or marketed products to declare. This does not alter the authors’ adherence to all the PLOS ONE policies on sharing data and materials, as detailed online in the guide for authors.

Figures

Figure 1. Flow chart of participants through the study.

Figure 2. Standardized number of serotypes above thresholds.

Box plots of standardized number of serotypes above thresholds (IgG ≥0.35 µg/ml and OPA titers ≥8) at 3.5 years in each of the groups [standardized to 13 serotypes]. The median is shown as a line across the box with the box representing the lower and upper quartiles. Whiskers extend to the maximum or minimum values within 1.5 times the IQR above and below the 3rd and 1st quartile, respectively. Points outside this range are represented as dots.

Figure 3. Proportion of participants with serotype-specific IgG concentrations and OPA titers above thresholds.

Proportion of participants with serotype-specific IgG concentrations and OPA titers above a threshold of 0.35 µg/ml and 8, respectively, for each of the serotypes before (40 months, 40 mo) and after (41 months, 41 mo) the PCV-13 booster. Shown are mean values along with their 95% confidence intervals. Red lines are shown at the bottom if p-values from chi-square test of proportions between the groups were significant (p-values ≤0.05, ≤0.01, ≤0.001, and ≤0.0001 are represented by 1, 2, 3, and 4 lines).

Figure 4. Serotype-specific IgG GMCs and OPA GMTs.

Box plots of IgG GMCs and OPA GMTs for each of the serotypes before (40 months, 40 mo) and after (41 months, 41 mo) the PCV-13 booster. The median is shown as a line across the box with the box extending to the lower and upper quartiles, respectively. The whiskers extend to the maximum or minimum values within 1.5 times the IQR above and below the 3rd and 1st quartile, respectively. Points outside this range are represented as dots. Means are shown as a diamonds and t-test were performed for each serotype at each time point between the groups with p-values being represented as red lines if significant (1, 2, 3, and 4 lines if p≤0.05, ≤0.01, ≤0.001, and ≤0.0001, respectively).