In 6-, 12-, and 18-month-old children, two doses of tetravalent polysaccharide vaccine gave poor responses against menC, menW, and menY; however, for menA, two doses resulted in 42% putatively protected children (SBA titer, ≥8) at 18 months of age. A high percentage of 2-year-old children were putatively protected following a single dose of menA polysaccharide, and a similar percentage was observed for menY for the 4-year-old group but not for younger groups. However, for menC and menW poor responses were still evident at 4 years of age. The SBA responses observed for menC, menW, and menY, although poor compared to the responses observed for menA, do appear to be age dependent, and an increase in the proportions of children with SBA titers of ≥8 was seen in individuals who were 24 months old or older. An SBA titer of ≥8 determined by an assay using baby rabbit complement has been proposed as a short-term putative correlate of protection following menC conjugate vaccination (3
). For menA the only proposed correlate of protection is from the Finnish efficacy trials of menA polysaccharide vaccine and is 2 μg/ml of immunoglobulin as determined by radioimmunoassay (22
). There are currently no putative correlates of protection for menW or menY.
Prior to vaccination, an age-dependent increase in the proportion of children with SBA titers of ≥8 was observed for menA, menW, and menY but not for menC. There are no previous studies to compare the data for menW and menY; however, the menC data are similar to data for age-matched United Kingdom children, in which no increase in the proportion with SBA titers of ≥8 was observed (32
). However, the setting of the study does appear to have an influence, as in age-matched United States children a general increase in the percentage with menC SBA titers of ≥4 (using human complement) was observed (14
). An age-dependent increase in the percentage with SBA titers of ≥4 was also observed in United States children for menA (14
), which is similar to the data in this study for Saudi children.
A Finnish study (27
) that looked at the immunogenicity of one dose of tetravalent polysaccharide vaccine revealed over 90% responders for menA (≥fourfold increase in the SBA titer or from undetectable to detectable SBA titer) in children 6 to 23 months of age. For menC, menW, and menY in the 18- to 23-month age group there were 90, 85, and 79% responders, respectively. These data are not directly comparable with the data reported here as only one dose of vaccine was used in the Finnish study and two doses were used for the <24-month-old children in the present study. It is well documented that repeated doses of menC polysaccharide lead to hyporesponsiveness (13
); however, to date, there have been no reported studies for menW and menY. This could not be categorically ascertained in the present study, as blood was not collected following the first dose for children who were <24 months of age. However, the proportions of individuals with SBA titers of ≥8 postvaccination for children who were 6 to 18 months old were similar for menC, menW, or menY, and the values for children who were ≥24 months old were significantly greater, suggesting that menW and menY polysaccharides behave like the menC polysaccharide rather than the menA polysaccharide, for which a steady increase in the proportion of individuals with SBA titers of ≥8 was observed with increasing age. Repeated doses of menA polysaccharide lead to boosting in adults (17
), but it is still unclear if this occurs in young children or if, similar to the response to repeated doses of menC polysaccharide, hyporesponsiveness is induced. An inherent problem when ≥fourfold increases in the SBA titer prevaccination to postvaccination are used is the presence of SBA titers in the prevaccination samples. This biases the number of responders; for example, 40% of 24-month-old children have greater SBA titers (≥128) prevaccination. The percentage of individuals seroconverting for menC in the Finnish study (90% for the 18- to 23-month-old children) also seems very high, especially as menC polysaccharide has not been reported to protect children who are <2 years of age (2
We found that the immunogenicity of the serogroups differed as follows, from the most immunogenic to the least immunogenic: menA, menY, menW, menC. In contrast, Lepow et al. (20
) found that for children less than 5 years of age receiving one dose of a tetravalent polysaccharide, a greater percentage responded to menW and menY than to menA or menC. However, a similar number of responders to menC (40% of 2- to 5-year-old children) was observed, which is similar to our findings. This is also supported by the vaccine effectiveness reported following a mass immunization campaign against menC disease in Quebec, where the effectiveness was 41% for ages 2 to 9 years (12
). Our data for menC are also similar to those reported in a previous study of bivalent polysaccharide in young children in the United Kingdom (10
). A small French study performed with older children (ages, 3 to 13 years) and with a single dose of tetravalent polysaccharide demonstrated that all 21 children responded, as measured by a ≥fourfold increase in the SBA titer pre- to post vaccination for all four serogroups (11
Age-dependent increases in serogroup-specific IgG concentrations were observed following vaccination for menA, menW, and menY. The concentrations observed for menA were greater than the concentrations observed for the other serogroups. There is no known IgG correlate of either short- or long-term protection following polysaccharide vaccination. For menA, 2 μg/ml of anticapsular total antibody has been reported to be a correlate of protection following polysaccharide vaccination (22
). In this study ≥77% of individuals achieved an IgG concentration of >2 μg/ml in response to the menA portion of the polysaccharide vaccine. Low levels of menY-specific IgG were observed in comparison to the other serogroups. The response to the menY portion of the polysaccharide vaccine was shown to be age dependent, but only 61% and 45% of the children who were 48 months old had IgG concentrations of >1 and 2 μg/ml, respectively. However, 87% of the children in the same age group had menY SBA titers of ≥8, and 75% had a ≥fourfold increase in the SBA titer pre- to postvaccination.
In conclusion, two doses of tetravalent polysaccharide vaccine in children <24 months old gave poor protection against menC, menY, and menW; however, there was reasonable protection against menA from 18 months of age. For one dose from 24 months to 48 months there was a trend to an age-dependent response for all serogroups. These data led to discontinuation of the use of tetravalent vaccine in children less than 2 years of age in Saudi Arabia and have wider implications for the use of tetravalent polysaccharide vaccines in African countries.