A 2-Dose Schedule of 13-Valent Pneumococcal Conjugate Vaccine (PCV13) Given to Children with Sickle Cell Disease Previously Immunized with 23-Valent Pneumococcal Polysaccharide Vaccine (PPSV23): Results of a Phase 3 Study

Children with sickle cell disease (SCD) have a significantly increased risk of invasive pneumococcal disease (IPD) and mortality, primarily attributable to functional asplenia. Penicillin prophylaxis and PPSV23 have been shown to dramatically reduce those risks, but strain resistance to penicillin has increased. Furthermore, PPSV23 is less effective in children <2 years and the protection declines within 3 years after administration. The introduction in 2000 of the 7-valent conjugate vaccine (PCV7) induced a further reduction of IPD in children with SCD, but was accompanied by the emergence of non-PCV7 serotypes-related IPD, especially 19A. A new PCV13 incorporating the new serotypes 1, 3, 5, 6A, 7F and 19A to those in PCV7 was recently licensed. This study was designed to determine whether PCV13 has the potential to offer immunologic benefit to children with SCD.

We conducted a phase 3, open-label, single-arm study to evaluate the safety, tolerability, and immunogenicity of 2-doses of PCV13 given 6 months apart to children 6 to less than 18 years of age with SCD previously immunized with PPSV23 more than 6 months prior to study entry. Blood samples were collected prior to and 1 month after each dose. Serotype-specific immunoglobulin (IgG) geometric mean concentrations (GMCs) and fold rises (GMFRs) were determined. Local pain, redness and swelling, and fever, vomiting, diarrhea, headache, fatigue, muscle pain and joint pain were recorded in an ediary for 7 days after each dose. Serious adverse events (SAEs) were reported throughout the study.

We enrolled 158 subjects; 51.9% were males. All subjects were previously vaccinated with PPSV23; 12 subjects had received 2 to 6 doses. The mean age at enrollment was 13.3 (±3.08) years. All subjects received dose 1; 146 subjects received dose 2. One of the 12 subjects who did not complete the vaccination phase withdrew due to local pain and systemic events reported after dose 1.

Subjects responded very well to a single dose of PCV13 (see Table). The prevaccination/postdose 1 IgG GMFRs ranged from 1.73 (serotype 5) to 7.01 (serotype 4). The antibodies declined over 6 months and subjects responded well to a second dose of PCV13; however the IgG GMCs were generally lower than after the first dose (see Table). The postdose 2/postdose 1 IgG GMFRs were <1.0 for all serotypes except 19F and the 95% confidence intervals did not include 1.0 except for serotypes 6A, 6B, 19F and 23F, suggesting the postdose 2 responses were significantly lower than postdose 1.

91.7% and 88.5% of subjects reported local reactions, and 87.5% and 89.3% of subjects reported systemic events after dose 1 or dose 2, respectively. Most of the SAEs were due to vaso occlusive crisis and only one was assessed by the investigator as related to the study vaccine. No deaths occurred.

Children with SCD previously vaccinated with PPSV23 responded well to PCV13. A second dose did not enhance the immune response, likely due to the short interval (6 months) and high levels of persisting antibody. Pending analysis of functional antibody responses assessed by opsonophagocytic activity (OPA) will further describe the immune responses of PCV13 in this population.

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