To our knowledge, this is the first study to demonstrate immunologic hyporesponsiveness to serogroup W135 and confirms previous reports of serogroup C immunologic hyporesponsiveness following a 1/5 dose of PsACWY vaccine in toddlers who had previously been vaccinated with a full dose of PsACWY (10 months earlier) compared to naïve subjects who received only a 1/5 dose of PsACWY.
It is well documented that repeated doses of meningococcal C polysaccharide lead to immune hyporesponsiveness, but to date, no studies have reported hyporesponsiveness to W135 polysaccharide in this age group. It is well known that the immune systems of young children cannot process polysaccharide antigens in a manner for stimulating an effective response (16
). Poor SBA responses 28 days following a full dose of PsACWY vaccine at 12 to 23 months of age were observed in this study. One month following a full dose of PsACWY vaccine, there was no significant difference between group W135 SBA GMTs of the four vaccine groups, highlighting the poor immunogenicity of the group W135 portion of the vaccine in this age group. The poor immune response observed in this age group is consistent with the response to two doses of the same vaccine in Saudi Arabian children aged <18 months (1
). In contrast to the results reported here and in the study conducted by Al-Mazrou et al. (1
), an earlier Finnish study reported a large proportion of responders (a responder was defined as an individual showing a ≥4-fold increase in SBA titer) following one dose of PsACWY vaccine in children of 6 to 23 months of age (11
). For groups C and W135, 90% and 85% of subjects, respectively, were classified as responders.
Immunized persons with hyporesponsiveness can respond with serum antibody to revaccination with meningococcal polysaccharide or conjugate vaccine, although the magnitudes of their responses are lower than those for individuals of similar ages immunized for the first time. The clinical significance of hyporesponsiveness or the mechanism underlying this reduced antibody response is unknown but has been suggested to be due to B cells becoming anergic from continuous exposure to low doses of polysaccharide or to repeated vaccination stimulating naturally primed memory B cells to become antibody-producing plasma cells without regeneration of the memory B cell population. The group W135 SBA GMTs on days 7 and 28 following vaccination with a 1/5 dose of PsACWY vaccine in subjects who had received prior PsACWY vaccination (group 4) were significantly lower than the responses observed for PsACWY-naïve subjects (group 2).
Group W135 immunologic hyporesponsiveness has previously been reported for those over the age of 2 years at initial vaccination. A reduced response to a second full dose of PsACWY vaccine was observed in a Ugandan cohort (aged 2 to 19 years) compared to the response following the first dose, 1 year earlier (10
). The group C response was also lower in the subjects who had received prior PsACWY vaccination than in naïve subjects, consistent with previously reported studies (8
For both serogroups W135 and C, the SBA GMT of naïve individuals was significantly higher at 7 days postvaccination than that of subjects who had received prior PsACWY vaccination, and a significant decline was observed from day 7 to day 28. This decline was also true for the group W135 SBA GMT of those subjects who had received prior PsACWY vaccine, but the magnitude of the difference was much lower than that for naïve subjects. The group A responses of this cohort following PsA-TT or PsACWY vaccination were also higher on day 7 than on day 28 (15
). The decline in SBA GMTs from day 7 to 28 may be attributed to the presence of group-specific IgM, but the serogroup A-specific IgG of this cohort was also seen to decline significantly (15
). Measurement of serogroup C- and W135-specific IgM and IgG in this cohort would provide further information on this observation. Similar findings were reported from two studies of a licensed meningococcal group A, C, W135, and Y conjugate vaccine in children aged 4 to 6 years (12
) and in adolescents (6
). Keyserling et al. (6
) speculated that the higher SBA GMT observed at day 8 in adolescents could be due to an early onset of high-avidity IgG antibodies. Pichichero et al. (12
) measured group-specific IgG and evaluated the IgG avidity via avidity indices. There were no differences in either IgG or the avidity indices measured on days 8 and 28 following vaccination for all groups.
The serogroup C and W135 SBA responses following polysaccharide vaccination have been shown to be age dependent. An age-dependent response to group W135 polysaccharide was evident in this study, with the SBA GMT 1 month following a 1/5 dose of PsACWY vaccine at 20 to 33 months of age being 3.7-fold higher than the response to a full dose at 12 to 23 months of age. The group W135 SBA GMTs at 10 months post-primary vaccination show that this difference in response is not attributable to natural immunity. The response to the group C component following a 1/5 dose was comparable to that after a full dose at a younger age. A previous study demonstrated that the immune responses to group C and W135 polysaccharides were poor up until the age of 4, with an age-dependent increase in the number of subjects with SBA titers of ≥8 (1
This study confirms previously reported data showing that the immune responses to group A, C, and W135 polysaccharides differ (1
), as the group A response following a full dose of PsACWY at 12 to 23 months of age was considerably higher (15
) than those seen here for groups C and W135.
In conclusion, we observed poor immune responses to both the group C and W135 portions of the PsACWY vaccine in those of <3 years of age, and we question the use of meningococcal polysaccharide vaccines (full or fractional dose) in this age group for the prevention of group C or W135 disease. Immunologic hyporesponsiveness was observed following a full dose of PsACWY vaccine at 12 to 23 months of age with subsequent vaccination with a 1/5 dose of PsACWY 10 months later compared to the response in PsACWY-naïve subjects receiving a 1/5 dose of PsACWY vaccine. The clinical relevance of immunologic hyporesponsiveness is unknown, but due to the rapid onset of meningococcal disease, circulating antibody is thought to be crucial in the protection against disease.