Ray Borrow

Although efficacy has never been demonstrated in children, 23-valent pneumococcal vaccine (PPV23) consisting of multiple unconjugated capsular polysaccharides has long been recommended for many children in high risk groups. Even since licensure of lower valency conjugated vaccines for which efficacy data are strong, PPV23 has continued to be recommended as part of a combined schedule and for children aged >5 years. Children with chronic renal diseases are representative of broader high risk groups having susceptibility both related to primary disease and immunosuppressive treatment. The authors immunised PCV7-naïve children with seven valent conjugate vaccine (PCV7) and 6 m later with a test dose (0.1 ml) of 23valent polysaccharide vaccine (challenge). Serum was collected immediately before (V1 and V3) and 28–42 days after (V2 and V4) each vaccine dose and assayed (Luminex bead) for IgG antibody to PCV7 serotypes (ST). 75 children (51 male) aged 2.6–18.7 years (mean 11.5) were enrolled in three UK centres. 42 were post-renal transplant and 19 had chronic renal failure, of whom eight were on renal replacement therapy and two were awaiting transplant. Two had glomerulonephritis with low C3 and/or C4 and 14 had nephrotic syndrome that was steroid resistant and/or frequently relapsing. Geometric mean concentrations (n=55, μg/ml) at the four study visits (V) are shown in the table. Serum antibody responses to PCV7 showed mean 14.1-fold rises (range 5.8–19.1 for the seven serotypes). 75% (ST4) to 88% (STs 18C and 23F) achieved serum concentrations ≥0.35 μg/ml. After falling to mean 0.5 of post immunisation, a mean twofold titre rise (range 1.5–2.4) occurred after challenge, suggesting immunological memory. Children (n=10) who had received PPV23 prior to the study had much lower responses to PCV7 (p=0.01) suggesting hyporesponsiveness but had similar fold-rises (p=0.52) on PPV23 challenge. PCV7 was highly immunogenic in these immunocompromised children. These results confirm that, after inducing short-lived antibody responses, PPV23 induces hyporesponsiveness to pneumococcal antigens. With the availability of 10- and 13-valent conjugate vaccines, in the absence of evidence of benefit and in the presence of evidence of potential harm, consideration should now be given to cessation of use of PPV23 in childhood.

To the Editor—Richmond et al. [1] reported the use of avidity indices as a marker of immunologic priming after administration of meningococcal serogroup C conjugate vaccine in toddlers in the United Kingdom. Antibody avidity, the strength with which a multivalent antibody binds to a complex antigen, increases over time after primary immunization with a T cell–dependent antigen. Memory responses are characterized by the production of high-avidity antibody, and, therefore, avidity indices can be used as a surrogate marker for the generation of memory [2]. We report the use of avidity indices to investigate memory responses to the serogroup A component of a meningococcal serogroup A/C conjugate (MACC) vaccine, using the method described by Richmond et al. [1]

The antibody data supporting the use of meningococcal serogroup C conjugate (MCC) vaccines in the United Kingdom were generated by serum bactericidal assay (SBA) using rabbit complement (rSBA). This may give higher titers than those obtained with human complement (hSBA), for which the “gold standard” correlate of protection for meningococcal C disease is a titer of ≥4. Comparison of rSBA and hSBA titers in sera from unvaccinated adults with an rSBA titer of ≥8 showed that for 93% (27 of 29) the titer was ≥4 by hSBA, confirming natural protection. Furthermore, sera from MCC vaccinees showed that an rSBA titer of <8 or ≥128 discriminated susceptibility and protection well (85% with rSBA titers of <8 had hSBA titers of <4, and 99% with rSBA titers of ≥128 had hSBA titers of ≥4). However, discrimination was poor in the rSBA titer range 8 to 64, with only 60% having hSBA titers of ≥4. In such cases we propose that protection can be assumed if there is a fourfold rise in titer between pre- and postvaccination sera or if there is a characteristic booster response to a polysaccharide challenge dose with, if available, evidence of antibody avidity maturation or an hSBA titer of result ≥4. Applying these criteria to toddlers, 10 to 40% of whom had titers in the range 8 to 64 after a single dose of MCC vaccine, showed that 94% had a fourfold rise in titer, including 98% of those in the titer range 8 to 64. In addition, of those with titers of <128 post-MCC vaccination, 90% had titers of ≥128 after a 10-μg polysaccharide booster dose, compared with only 7% of unprimed age-matched toddlers given a full 50-μg dose. Furthermore, the increase in geometric mean avidity index pre- and postbooster was independent of post-primary MCC titer. These results indicated that the majority of toddlers with an rSBA titer between 8 and 64, and some of those with an hSBA result of <4, have mounted a protective immune response with the induction of immunological memory.