Waning protection after immunization with serogroup C meningococcal vaccines in infancy and early childhood has been associated with a fall in serum bactericidal antibody concentrations. Despite the immunologic memory induced by these vaccines, rapid progression of meningococcal disease would not allow the organism to mount an anamnestic immune response.1,2 Protection correlates with the circulating antibody concentration. A booster dose, introduced in the second year of life, induces a substantial rise in bactericidal antibody titers.3,4
Seroepidemiologic studies have shown that 3–6 years after a single dose of conjugated meningococcal serogroup C (MenC) vaccine, the percentage of subjects protected with serum bactericidal antibody (SBA) titers ≥1:8 decreases with the age when the vaccine was given.5,6
The kinetics of the seroprotection after a booster dose is not well known. There are no long-term studies to assess the persistence of antibodies. In 1 clinical trial,3 the SBA geometric mean titers (GMTs) decreased by more than 97% in the first 18 months after the booster dose. A higher rate of persisting protective SBA-MenC titers was observed in those subjects who had higher SBA-MenC GMTs after booster vaccination.3
We have recently described the immune response to a booster dose in children primed and boosted with 2 MenC vaccines.4 The antibody titers reached were strongly depended on the vaccine used for priming; GMTs were 3.5 times higher if the vaccine used was conjugated with tetanus toxoid (MenC-TT) compared with CRM197 (MenC-CRM) conjugated vaccine formulation. Although the MenC vaccine used for priming has been described to affect the response to Haemophilus influenzae type b (Hib) vaccines given concomintantly,7 we did not find any difference after boosting with either MenC vaccine.4
The objective of this study was to assess the persistence of the seroprotection against MenC and Hib 1 year after the booster dose and to analyze the factors that might influence seroprotection.
This study was designed as a multicenter, randomized, open-label, clinical trial, described in a previous publication.4
Children aged 14 to 18 months who completed the primary vaccination series before their 8th month with either MenC-TT or MenC-CRM were randomized to receive one of these vaccines as a booster. The exclusion criteria were having an acute or severe chronic disease or hypersensitivity to any of the vaccine components including antibiotics, a history of invasive disease and being treated with any immunosuppressant drug.
The Ethics Committee of DGSP/CSISP, Valencia, approved the study, and informed written consent was signed by the parents or guardians before entering in the study.
A blood sample was collected before the booster dose, and 1 month and 12 months (±3 weeks) after the booster. The results of this last sample are described here.
Sera were analyzed at the Manchester Vaccine Evaluation Department of the Health Protection Agency, UK. Functional MenC antibody titers were determined using the SBA assay. The SBA target strain was MENC11 (C:16:P1.7–1,1), and the complement source was baby rabbit sera (Pel-Freeze Incorporated, Rodgerson, AZ). SBA titers are expressed as the reciprocal of the final serum dilution equivalent to 50% killing at 60 minutes. Hib specific antibodies (IgG) were quantified using standardized ELISA at the Immunoassay Laboratory, Health Protection Agency, Porton Down, UK. The standard sera used were the International anti-Hib Quality Control Serum Center for Biologics and Evaluation Research (CBER) 1983.
Antibody titers were log transformed; geometric mean titers (GMT) and concentrations (GMC) with 95% confidence intervals were calculated. Mann-Whitney U test was used to evaluate significant differences between antibody assays at each time point. Children were considered seroprotected when MenC SBA titers were ≥1:8, and anti-Hib antibodies were ≥0.15 μg/mL.
Of the 389 subjects randomized in the clinical trial, 334 (85.9%) had blood drawn 12 months after the booster dose. One month after the booster dose all but 2 children had reached seroprotection titers (Table 1). One year later, 61.5% of subjects primed with MenC-CRM who received a booster with the same vaccine retained seroprotective values, whereas 92.8% of subjects primed and boosted with MenC-TT retained seroprotective titers. SBA titers of ≥1:128 were measured in 49.5% and 91.3% of subjects, respectively. The seroprotection rate was dependent not only on which vaccine was used for priming (MenC-CRM versus MenC-TT), but also on which vaccine was used for the booster dose. Sixty-nine percent of the children primed with MenC-CRM had SBA titers ≥1:8, compared with 87.2% of those primed with MenC-TT (P < 0.01), with GMTs of 60.0 (95% CI: 43.8–82.2) and 283.8 (95% CI: 204.3–394.3), respectively.
In children initially primed with MenC-CRM, 61.5% of those who received a booster with the same vaccine, and 75.5% of those boosted with MenC-TT had seroprotective SBA titers (P < 0.05) 12 months after the booster dose. Among children who were primed with MenC-TT, 92.8% of those boosted with the same vaccine, and 81.9% of those boosted with MenC-CRM (P = 0.055) were still seroprotected 12 months after the vaccine was administered.
The SBA GMTs among groups also varied depending on which vaccine was used for booster. Children primed with MenC-CRM had SBA GMTs of 45.1 (95% CI 28.5–71.3) if boosted with the same vaccine and 77.4 (95% CI: 50. 1–119.7) if boosted with MenC-TT (P = 0.066). Among children primed with MenC-TT, the SBA GMTs were 199.3 (95% CI: 119.8–331.5) if boosted with MenC-CRM compared with 410.5 (95% CI: 273.4–616.3) if boosted with MenC-TT (P < 0.05) (Fig., Supplemental Digital Content 1, http://links.lww.com/INF/A426).
Three of the 283 subjects from whom a blood sample was drawn for Hib antibodies did not maintain anti-Hib concentrations ≥0.15, which is considered a correlation of protection, 12 months post booster. One such case occurred in 3 of the 4 treatment groups. There was no difference in anti Hib GMC between children initially vaccinated with MenC-CRM (3.4 μg/mL; 95% CI: 2.8–4.1) versus those primed with MenC-TT (3.6 μg/mL; 95% CI: 2.9–4.4), nor was the anti-Hib concentration dependent of which vaccine was used for booster (Table, Supplemental Digital Content 2, http://links.lww.com/INF/A427).
In the 12 months after administration of a Men C booster vaccine to toddlers (aged 14–18 months), a rapid decrease in SBA titers was observed. In blood samples taken 12 months (+3 weeks) after the booster vaccination, 1 in 4 children were not seroprotected as measured by SBA.
A booster vaccination was recommended to children who had been primed during their first year of life, as it had previously been shown that immunogenicity decreased in these children after their first birthday.1,2 It was estimated that a single booster dose would protect children for a longer period and that additional vaccinations would not be required.
In a previous study we showed the immunologic effect 4 weeks after the booster dose,4 in the current article we describe the follow-up of these children. One month after the booster vaccine, most of the subjects had seroconverted to SBA ≥1:128 and had attained high SBA titers, with differences depending on which vaccine had been used for the primary vaccination series; subjects who had been primed with the MenC-TT vaccine attained SBA titers 3.5 times higher than those primed with the MenC-CRM vaccine.4 One year later, the SBA titers were shown to have decreased substantially, although the SBA GMTs remained higher than before the booster vaccination and a large percentage of subjects retained seroprotective levels. A decrease in the percentage of children with SBA ≥1:8 might reflect a decrease in the number of children protected with advancing age.
At 12 months postbooster vaccination, seroprotection rates and SBA titers were dependent on which vaccine had been used for the primary and booster vaccinations. The highest percentage of subjects was seroprotected when MenC-TT vaccines had been used for all (prime and booster) vaccinations.
The decrease in seroprotection has also been described in another study in which the investigators used a combination vaccine (Hib-MenC3) and found that SBA titers fell up to 95% in the first 18 months after administration of a booster dose given in the second year of life. Also, although 91% to 100% of the children who received a single vaccine dose in their second year of life8 became seroprotected with an SBA titer of ≥1:8, at 4 years of age the seroprotection rates in these children were low.9 These findings seem to indicate that seroprotection decreases over time after a single dose of MenC vaccine in preschool-aged (1–2-year-old) children.
Findings from this study may influence future MenC vaccination policies. If SBA titers and seroprotection rates decrease in this way, a large proportion of young children could be at risk for developing MenC infection. However, if herd immunity is established, this will not translate into increased infection rates. Most of the adolescents in Europe, in countries where a catch-up program was established, are still seroprotected6; however, as children vaccinated in infancy, with or without a booster dose, reach adolescence, a possible resurgence of MenC circulation among this group is possible, as the protective herd immunity disappears. A booster dose during early adolescence could be required6; however, this was not predicted in a mathematical model indicating that high levels of indirect protection against meningococcal group C diseases are likely to persist even if the vaccine only provides 3 years of protection against carriage.10
The authors thank all the participants in the clinical trial and the investigators collecting data.
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