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Infection and Immunity, May 2005, p. 2932-2939, Vol. 73, No. 5
0019-9567/05/$08.00+0     doi:10.1128/IAI.73.5.2932-2939.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Serologic Responses to ACYW135 Polysaccharide Meningococcal Vaccine in Saudi Children under 5 Years of Age

Y. Al-Mazrou,1 M. Khalil,2 R. Borrow,3* P. Balmer,3 J. Bramwell,3 G. Lal,3 N. Andrews,4 and M. Al-Jeffri1

Department of Preventive Medicine, Ministry of Health, Saudi Arabia,1 Medical Education and Research Center, King Fahad Specialist Hospital, Qassim, Saudi Arabia,2 Meningococcal Reference Unit, HPA North West Laboratory, Manchester Royal Infirmary, Manchester M13 9WZ, United Kingdom,3 Statistics Unit, Communicable Disease Surveillance Centre, HPA Centre for Infections, London NW9 5EQ, United Kingdom4

Received 7 December 2004/ Returned for modification 5 January 2005/ Accepted 9 January 2005


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ABSTRACT
 
An immunization campaign with meningococcal ACYW135 polysaccharide vaccine was conducted in 2003 by the Saudi Arabian Ministry of Health and included a study to evaluate the immune responses in children under 5 years of age in the Al Qassim region of Saudi Arabia. Children who were ≥24 months old were given one dose of tetravalent polysaccharide vaccine, while younger children were given two doses with an interval of 2 to 3 months. Blood samples were collected prevaccination and 1 month after the second dose for children younger than 24 months old and 1 month after the single dose for older children. Serogroup-specific antibody responses were determined by serum bactericidal antibody (SBA) assays and a tetraplex immunoglobulin G (IgG) bead assay. Significant increases in the proportions of individuals who were ≥24 months old with SBA titers of ≥8 were observed pre- to postvaccination for all serogroups. Age-dependent increases in the percentage of individuals with SBA titers of ≥8 1 month postvaccination were observed for each serogroup. Age-dependent increases in postvaccination IgG levels were observed for serogroup A (menA), serogroup W135 (menW), and serogroup Y (menY) but not for serogroup C (menC). Two doses of tetravalent polysaccharide vaccine in individuals who were ≤18 months old were poorly immunogenic for menC, menW, and menY. However, for menA, 42% of the children who were 18 months old were putatively protected with SBA titers of ≥8. A high percentage of subjects who were ≥2 years of age were putatively protected for menA; a similar level was observed for menY for children who were 4 years of age but not for younger children. However, for menC and menW poor levels of putative protection were still evident at 4 years of age.


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INTRODUCTION
 
Bacterial meningitis is a significant health problem worldwide, particularly in young children. Epidemics of serogroup A meningococcal disease occur in the meningitis belt in sub-Saharan Africa, whereas endemic serogroup B, C, and Y disease occurs in most other regions of the world. Plain polysaccharide vaccines containing either serogroups A and C or serogroups A, C, Y, and W135 have been available for several years, but the serogroup C portion has limited immunogenicity in young children (13). Meningococcal serogroup C conjugate vaccines have been introduced in the United Kingdom (and other countries) and have successfully reduced the incidence of serogroup C disease (8).

Meningococcal disease remains a serious public health issue in Saudi Arabia and occurs in the form of epidemics, usually coinciding with the Hajj and Umra seasons, when 4 million pilgrims visit each year. In 1987, following meningococcal epidemics caused by menA, the Saudi Arabian authorities issued a requirement that all persons applying for Hajj or Umra should be vaccinated with the bivalent A/C vaccine (7). Children under 2 years of age were given monovalent serogroup A vaccine. During the years 2000 to 2002 there was a shift in the epidemic pattern of meningococcal disease during the Hajj season, and there was a predominance of Neisseria meningitis menW (15, 25). Globally, an increase in menW disease occurred during the same period. Epidemics of menW disease occurred in Burkina Faso (4, 5), and significant numbers of Hajj-related cases were observed globally due to returning pilgrims (28). Characterization of the menW strains isolated both from Burkina Faso and countries experiencing Hajj-related menW disease demonstrated that they were mainly the same strain, W135:2a:P1.5,2 belonging to the ET-37 clonal complex (5, 24, 29). It is likely that the outbreak in 2000 and the global increase in menW disease were due to expansion of the ET-37 clone that has been in circulation since at least 1970 (24). New genetic lineages of menW that are independent of the Hajj-related strain have been reported (30).

In 2002 the Saudi Ministry of Health decided to use the ACYW135 polysaccharide vaccine to cover menW and menY (6). The vaccine was recommended for those coming for Hajj and for school children in Saudi Arabia. However, it was observed that 58% of reported meningococcal disease occurred in children below the age of 5 years and that 39% occurred in children below the age of 2 years (1). Therefore, in preparation for the Hajj season the Ministry of Health decided to launch a campaign with ACYW135 polysaccharide vaccine, targeting children who were 6 months to 5 years old. The campaign was conducted in 2003 and included a study to evaluate the immune responses to ACYW135. Serum bactericidal antibody (SBA) titers following two doses of tetravalent polysaccharide vaccine in children under 2 years of age have not been previously reported.

(This work was presented in part at the Pathogenic Neisseria Conference, Milwaukee, Wis., September 2004.)


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MATERIALS AND METHODS
 
Overall design. A follow-up study to evaluate the immunogenicity to tetravalent polysaccharide ACYW135 vaccine given to children up to 5 years old during the campaign was performed. The following six age groups were included in the study: 6, 12, 18, 24, 36, and 48 months. The age range was ±2 weeks for each age group. Children under 24 months of age were vaccinated with two doses with an interval of 2 to 3 months, while older children were vaccinated with one dose. After guardian consent was obtained, blood samples were collected before the first dose and 1 month after the second for children under 2 years old and before the single dose of vaccine and 1 month later for children 2 years old and older. Ethical approval for the study was obtained from the Ethical Committee, Saudi Ministry of Health.

Study population. The study was conducted in the Al Qassim region in the central part of Saudi Arabia, 350 km north of Riyadh and 1,000 km northeast of Mecca. The study was conducted through Primary Health Care (PHC) centers. Five centers were selected randomly from the list of PHC centers in Qassim. Children were recruited randomly from the catchment area of each center, with a planned 100 children in each age group to allow for the expected dropout. The inclusion criteria were as follows: Saudi nationals who were 6 months to 5 years old, with ±2 months allowed for each target age group, and agreement to participation by the guardian. The exclusion criteria included a history of chronic illness, a history of prior meningococcal vaccination, and a prior history of any meningococcal disease or meningitis of other etiology.

Vaccine. The vaccine used in the national campaign was Mencevax ACWY (GSK, Rixensart, Belgium). This vaccine contained 50 µg of each of the four polysaccharides. The vaccine used is licensed for use in children who are more than 2 years old. The study included infants for whom the vaccine is not licensed.

Serology. Serogroup-specific antibody responses were determined by SBA assays as described elsewhere (23) using baby rabbit complement (Pel-Freeze Incorporated, Rodgerson, AZ) as an exogenous source of complement. The following strains were used: for menA, F8238 (A:4:P1.20,9); for menC, C11 (C:16:P1.7-1,1); for menW, M,01.0240070 (W135:NT:P1.18-1,3); and for menY, M,00.0242975 (Y:2a:P1.5,2). SBA titers were expressed as the reciprocal of the final serum dilution giving ≥50% killing at 60 min for menC, menW, and menY and at 90 min for menA. For computational purposes, titers of <4 were assigned a value of 2. A subject with an SBA titer of ≥8 was defined as putatively protected (3).

Serogroup-specific immunoglobulin G (IgG) concentrations were determined as previously described using a tetraplex IgG bead assay (19). The calibration factors of the standard CDC1992 serum for menC-specific IgG used were 91.8 and 24.1 µg/ml for menA and menC, respectively (16), and 25.23 and 28.92 µg/ml for menW and menY, respectively (18). Results were expressed in µg/ml, and the lower limits of detection for menA, menC, menW, and menY were 0.08, 0.06, 0.065, and 0.075 µg/ml, respectively.

Statistical analysis. Serogroup-specific IgG concentrations (GMCs) with 95% confidence intervals were calculated for each group at each sampling time. The proportions with IgG titers of >1 and 2 µg/ml were calculated for each age group, and values for different ages were compared using a chi-square test or Fisher's exact test as appropriate and tested for trend by age. The proportions of individuals with SBA titers of ≥8 were calculated and compared between age groups using a chi-squared test and test for trend by age. The significance of changes in the proportions of individuals with SBA titers of ≥8 pre- to postvaccination was calculated using McNemar's exact test. Paired t tests were used to compare IgG titers pre- to postvaccination.


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RESULTS
 
Sample compliance. Table 1 summarizes the distribution of the recruited children by age group. A high dropout level was noticed in younger age groups, mainly due to refusal to give blood samples, especially in the second visits. Due to the large number of assays required and the limited serum volumes, some samples were not sufficient to test for all serogroups; therefore, the numbers of results for each age group vary by serogroup.


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  		TABLE 1. Compliance with sampling and numbers of paired sera sent for serology by age group

Serum bactericidal antibody titers. The SBA titers were not normally distributed because a large proportion of the values were <4. Therefore, the SBA data were analyzed by examining the proportions of individuals with SBA titers with ≥eight- or fourfold increases from pre- to postvaccination (Table 2). The percentages of individuals at different SBA cutoffs are shown in Fig. 1.


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  		TABLE 2. Proportions of individuals for serogroups A, C, Y, and W135 by age group with serum bactericidal antibody titers of ≥8 before and 1 month following vaccination with tetravalent polysaccharide vaccine and ≥fourfold increases pre- to postvaccination



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  		FIG. 1. Percentages of subjects before and 1 month following vaccination at serum bactericidal titer cutoffs of <8, 8 to 128, and >128.

Significant increases (P < 0.001) in the proportions of individuals who were ≥24 months old with SBA titers of ≥8 were observed pre- to postvaccination for all serogroups. If the data for 6- to 18-month-old children were combined, increases in the numbers of individuals with SBA titers of ≥8 were observed pre- to postvaccination (for menA, P = 0.01; for menC, P = 0.03; for menW, P < 0.001; for menY, P = 0.01).

Age-dependent increases in both prevaccination and postvaccination SBA titers were suggested by the percentages of individuals with different SBA titers shown in Fig. 1 and were confirmed by analysis of the proportions of individuals with SBA titers of ≥8 both pre- and postvaccination for all serogroups (P ≤ 0.005) with the exception of prevaccination menC (P = 0.42). For all serogroups there was an increase in the percentage of individuals with a ≥fourfold increase in the SBA titer pre- to postvaccination with increasing age (P < 0.001 for all serogroups).

Meningococcal serogroup-specific IgG. The serogroup-specific IgG GMCs and 95% confidence intervals are shown in Table 3. The levels of menA-specific IgG were higher than the levels for the other serogroups. Significant increases (P < 0.05) were seen from pre- to postvaccination in all age groups for each serogroup except menW-specific IgG at 6 months.


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  		TABLE 3. Serogroup-specific IgG concentrations for serogroups A, C, Y, and W135 by age group before and 1 month following vaccination with tetravalent polysaccharide vaccine

Analysis of serogroup-specific IgG concentrations by age showed that, unlike the SBA titers, there were no age-dependent increases in prevaccination concentrations for any serogroup. Postvaccination there were clear increases with age in GMCs for menA and menY (P ≤ 0.001) and a small increase for menW (P = 0.02). There was no increase with age for menC (P = 0.96).

The proportions of individuals with serogroup-specific IgG levels greater than a range of concentrations (0.25 to 500 µg/ml) pre- and postvaccination are shown as reverse cumulative distributions in Fig. 2. For menA and menC there were similar proportions of individuals with IgG concentrations of >1 or 2 µg/ml both pre- and postvaccination, which is reflected in the similar distribution frequencies shown in Fig. 2A and B. For menW and menY there were lower proportions of individuals with IgG concentrations of >1 or 2 µg/ml than there were for menA or menC. For menY, only 61% and 45% of the individuals who were 48 months old achieved concentrations of >1 and 2 µg/ml following vaccination, respectively, compared to 97% and 89% for menA.






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  		FIG. 2. Serogroup-specific IgG concentrations for serogroups A (A), C (B), W135 (C), and Y (D) by age group, before and 1 month following vaccination with tetravalent polysaccharide vaccine.

An age-dependent increase in the proportions of individuals achieving a concentration of >1 µg/ml was observed only for menY postvaccination (P < 0.001), confirming the age-dependent response illustrated in the reverse cumulative distribution plot (Fig. 2D).


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DISCUSSION
 
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, 9). 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, 26). 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, 21); 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, 31).

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, 26). 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.


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ACKNOWLEDGMENTS
 
We thank the children and parents who participated in this study and the staff at the PHC centers who were involved. We thank Elizabeth Miller, Immunisation Division, CDSC, Health Protection Agency, Colindale, United Kingdom, for critical reading of the manuscript.

This study was funded in part by GlaxoSmithKline, Rixensart, Belgium.


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FOOTNOTES
 
* Corresponding author. Mailing address: Meningococcal Reference Unit, HPA North West Laboratory, Manchester Royal Infirmary, Manchester, United Kingdom. Phone: 44 161 276 6793. Fax: 44 161 276 6792. E-mail: ray.borrow{at}hpa.org.uk. Back

Editor: D. L. Burns


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Infection and Immunity, May 2005, p. 2932-2939, Vol. 73, No. 5
0019-9567/05/$08.00+0     doi:10.1128/IAI.73.5.2932-2939.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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