Safety and immunogenicity of neonatal pneumococcal conjugate vaccination in Papua New Guinean children: a randomised controlled trial

Abstract

Background: Approximately 826,000 children, mostly young infants, die annually from invasive pneumococcal disease. A 6-10-14-week schedule of pneumococcal conjugate vaccine (PCV) is efficacious but neonatal PCV may provide earlier protection and better coverage. We conducted an open randomized controlled trial in Papua New Guinea to compare safety, immunogenicity and priming for memory of 7-valent PCV (PCV7) given in a 0-1-2-month (neonatal) schedule with that of the routine 1-2-3-month (infant) schedule.

Methods: We randomized 318 infants at birth to receive PCV7 in the neonatal or infant schedule or no PCV7. All infants received 23-valent pneumococcal polysaccharide vaccine (PPV) at age 9 months. Serotype-specific serum IgG for PCV7 (VT) serotypes and non-VT serotypes 2, 5 and 7F were measured at birth and 2, 3, 4, 9, 10 and 18 months of age. Primary outcomes were geometric mean concentrations (GMCs) and proportions with concentration ≥ 0.35 µg/ml of VT serotype-specific pneumococcal IgG at age 2 months and one month post-PPV.

Results: We enrolled 101, 105 and 106 infants, respectively, into neonatal, infant and control groups. Despite high background levels of maternally derived antibody, both PCV7 groups had higher GMCs than controls at age 2 months for serotypes 4 (p<0.001) and 9V (p<0.05) and at age 3 months for all VTs except 6B. GMCs for serotypes 4, 9V, 18C and 19F were significantly higher (p<0.001) at age 2 months in the neonatal (one month post-dose2 PCV7) than in the infant group (one month post-dose1 PCV7). PPV induced significantly higher VT antibody responses in PCV7-primed than unprimed infants, with neonatal and infant groups equivalent. High VT and non-VT antibody concentrations generally persisted to age 18 months.

Conclusions: PCV7 is well-tolerated and immunogenic in PNG neonates and young infants and induces immunologic memory to PPV booster at age 9 months with antibody levels maintained to age 18 months.

Trial registration: ClinicalTrials.gov NCT00219401.

Figure 1. Flow diagram of the study .

Flow diagram indicating number of women who assented and children enrolled into the study, randomized to neonatal or infant PCV7 or control groups and number excluded or lost to follow-up in the course of the study. PCV = 7-valent pneumococcal conjugate vaccine; N = Neonatal group; I = Infant group; C = control group; LTFU = lost to follow-up (includes not located, withdrew consent, migration). Numbers (n) are total excluding LTFU and protocol violations.

Figure 2. Risk for hospitalization.

Gender-adjusted incidence rates of hospitalization (±95% confidence intervals) during the 1^st month, 1–<4 months (PCV immunization ongoing), 4–<10 months (PCV immunization completed), and 10–18 months (post-PPV) of life for the neonatal PCV (green bars), infant PCV (red bars) and control group (blue bars).

Figure 3. Age-specific geometric mean serotype-specific antibody concentrations pre-and post-PCV7 at 0-1-2 or 1-2-3-months or no PCV7.

Geometric mean (GM) concentrations and 95% confidence intervals of serotype-specific IgG antibodies for PCV7 serotypes and non-PCV7 serotypes 2, 5 and 7F in the neonatal (•) (PCV7 at birth, 1 and 2 months), infant (□) (PCV7 at 1, 2, and 3 months) and control group (▵) (no PCV7). All children received PPV at 9 months of age.

Figure 4. Geometric mean fold rise in antibody for PCV7-serotypes following PPV at age 9 months.

To demonstrate immunological memory, PPV was administered at 9 months of age and the mean (and 95% CI) fold changes in PCV7-serotype-specific GMCs were calculated and compared for the neonatal (•), infant (□) and control group (▴), with significant differences between groups (p<0.05) indicated with *.