Meningococcal Serogroup A Avidity Indices as a Surrogate Marker of Priming for the Induction of Immunologic Memory after Vaccination with a Meningococcal A/C Conjugate Vaccine in Infants in the United Kingdom

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] Existing evidence for the induction of immunologic memory, which is based on the magnitude of the serum bactericidal antibody (SBA) and serogroup-specific IgG response to a serogroup A unconjugated polysaccharide challenge dose, is conflicting. In studies using a MACC vaccine that were undertaken among infants and toddlers in The Gambia, the serogroup A portion did not appear to induce immunologic memory [3]. However, in the United Kingdom, the same bivalent MACC vaccine did induce immunologic memory in infants at 2, 3, and 4 months of age, as demonstrated by a clear booster response after administration of a 10-μg dose of unconjugated serogroup A polysaccharide [4] Using existing serum samples from the UK trial [4, 5], we measured avidity indices after administration of each of the 3 primary doses and before and after administration of the serogroup A polysaccharide booster at 14 months of age. The study population and their vaccination and blood sampling schedules have been described elsewhere [4, 5]. Antibody responses in the study population were compared with those in children who had not been previously vaccinated, who received a full 50-μg dose of unconjugated serogroup A polysaccharide as part of a combined meningococcal serogroup A/C polysaccharide (MACP) vaccine given during an outbreak of meningococcal serogroup C disease in 2 UK day nurseries (vaccination details and blood samples have been described elsewhere) [6] Table 1 shows the SBA geometric mean titers (GMTs), IgG geometric mean concentrations (GMCs), and geometric mean avidity indices (GMAIs) for the study and control groups. The SBA GMT and IgG GMC of the study group increased after each dose of conjugate was administered, decreased in the following 9 months, and increased again after challenge with MACP. The GMAI, however, increased progressively over time, being significantly higher after 3 doses of conjugate vaccine than after 1 dose (P=.00011) and higher in the pre– and post–polysaccharide challenge serum samples than after the third dose of conjugate vaccine (P=.0025 and P<.0001, respectively). The GMAI of the study group after the third MACC dose and after the MACP booster was significantly higher than that of the control group, in which children were given a single dose of MACP (P=.004 and P<.0001, respectively). The SBA responses in the study group were 30-fold higher than those in the control group after the MACP booster, despite the 5-fold lower dose of serogroup A polysaccharide that they received Meningococcal serogroup A serum bactericidal titers, serogroup A–specific IgG antibody levels, and geometric mean avidity indices (GMAIs) for study and control groups This study has confirmed that the serogroup A portion of a MACC vaccine induces immunologic memory in infants in the United Kingdom. Our previously reported evidence of induction of memory, based on the magnitude of the antibody responses to a polysaccharide booster [4], was confirmed by measuring maturation of antibody avidity. Our results support the use of antibody avidity as a surrogate marker for immunologic priming for memory to meningococcal serogroup A vaccine, as with meningococcal serogroup C [1], Haemophilus influenzae type b [2], and pneumococcal conjugate [7] vaccines. The low-avidity IgG antibodies found in the naive control group after MACP vaccination confirms that, in the absence of priming with a conjugate vaccine, unconjugated serogroup A polysaccharide does not stimulate memory B cells in young children. The decline to low or undetectable SBA and IgG antibody levels within a year after completion of primary MACC immunization (table 1) indicates that long-term protection can be achieved only if children are primed for memory responses and can rapidly produce specific IgG of relatively high avidity on encounter with the appropriate antigen Further studies to investigate the kinetics of the serum and mucosal antibody responses after nasal challenge with meningococcal serogroup A antigen are warranted. In addition, it is unclear why immunologic memory is not induced in children immunized with the same MACC vaccine in The Gambia, as determined by the magnitude of the booster response to a polysaccharide challenge [3]. Investigation of avidity maturation in this population may be informative