Meningococcal disease (MD) is an important cause of septicemia and meningitis, and a major public health challenge worldwide.1,2 People living with human immunodeficiency virus (HIV) infection have an increased risk for MD. Studies have demonstrated a five to ten times higher risk of MD among HIV-infected (HIVI) children and almost ten-fold higher among adolescents and adults when compared with HIV-uninfected individuals (HIVU).3,4 Furthermore, HIVI children and adolescents have lower vaccine response rates despite being on combination antiretroviral therapy (cART).5–7 Vaccine-induced antibodies also may wane more quickly in persons with HIV than in healthy individuals, indicating that immune reconstitution was not sufficient to ensure long-term protection and highlighting the importance of evaluating long-term immunogenicity to meningococcal vaccines and factors that may be associated with a better response.8,9

The persistence of antibodies after meningococcal serogroup C (MCC) conjugate vaccines has been studied in many high-risk populations with different degrees of immunosuppression, but there are few studies in HIVI.10–12

The aims of this study were: (1) to assess the persistence of serum bactericidal antibody against MCC, using human complement (hSBA) in HIVI children and adolescents, 12–18 months after a single dose of MCC, and compared with HIVU participants; and (2) to evaluate factors associated with antibody persistence.

A total of 154 HIVI and 50 HIVU participants were enrolled in the study. Nine individuals in the HIVI group were excluded at the 12–18 month visit (six were lost to follow-up, one was transferred to another state, and one was on prolonged use of antibiotics); data was available for 195 participants. Females comprised 52% of the participants, with no differences between groups (p=0.11). The median age at enrollment was 11 years: 12 years for HIVI and 10 years for HIVU participants (p=0.02; Table 1).

There were no differences in median body mass index Z-scores between HIVI and HIVU, 0.39 and −0.14, respectively (p=0.17). The HIVU group had a higher median number of individuals living in the same household (five vs. four; p<0.01). Although the median family income in both groups was less than one Brazilian minimum wage, when the distribution of this variable was considered, the HIVU group had a significantly lower family income (p=0.01). A total of 89% of HIVI participants were receiving cART, 124 of whom started cART before entry and five, after entry. The median time of cART use was 7.5 years (IQ range=5.9–9.9 years). A total of 59 (41%) had a history of Centers for Diseases Control and Prevention (CDC) HIV clinical classification class C conditions and 85 (44%) had undetectable VL at entry.

Overall, 14.9% (29/195) had baseline (before immunization) hSBA >1:4, with a higher proportion among the HIVU (30% vs. 9.7%; p=0.01). Among those with baseline hSBA >1:4, the mean family income was 0.17 Brazilian minimum wage.

At 12–18 months post-immunization, 53 (27.2%) retained seroprotective SBA titers: 24.1% among HIVI and 36% among HIVU (p=0.14). Of the 29 individuals who had baseline immunity, 21 (72%) retained protective hSBA titer at 12–18 months visit. Although the baseline immunity rate was higher among HIVU, more HIVI remained with hSBA >1:4, if they had previous immunity at entry (8/15 for HIVU vs.13/14 for HIVI group, p=0.04).

There was no difference in the seroprotective rate by age at entry (p=0.08) or length of time between vaccination and 12–18 months visits (p=0.57).

The main variable associated with hSBA persistence 12–18 months after MCC for the total population, as well as for the HIVI, was baseline hSBA >1:4; however, older age and higher body mass index were also associated with hSBA persistence in the total population. Undetectable VL at entry and income were also important among HIVI group (Table 2). On the logistic regression model, baseline hSBA >1:4 was the main significant variable on the model of the total population; the same was observed on the model of the HIVI group. In the latter group, undetectable VL at entry (at the immunization) also presented a trend of significance (Table 2).

The persistence of MCC bactericidal antibodies 12–18 months after immunization in Brazilian children and adolescents with and without HIV infection was low (27.2%), and lower in HIVI individuals, although not statistically significant. The antibody persistence rate was in accordance with that observed on the literature (19–57%).12,15–17

The main variable associated with persistence of MCC antibodies was hSBA titer at entry ≥1:4. For individuals who had baseline immunity, the single dose vaccine was at least the second contact with this agent, and the prime immunization would be considered a booster.18

To the best of the authors’ knowledge, this is the first study of MCC antibody persistence in HIVI children and adolescents. Siberry et al. followed-up 45 children aged 2–10 years, up to 72 weeks after two doses of meningococcal ACWY immunization.19 They observed a 45% persistence rate of the N. meningitidis C antibodies, defined as rabbit SBA ≥1:128; Black patients had higher rates of long-term immunity. Indeed, in the multivariate analysis, a socioeconomic proxy variable, income, was associated with immune persistence. The authors hypothesize that patients with lower socioeconomic level were exposed to a crowded environment, and therefore had more chance to having been exposed to serogroup C N. meningitidis. Nonetheless, genetic factors must also play a role on the association of lower socioeconomic level and decreased immune persistence.

Based on the present results, protective SBA titer gradually waned over time, and at least two doses of MCC are necessary to maintain protection against N. meningitidis in participants aged 2–18 years. Furthermore, optimal immune response to MCC among HIVI may coincide with undetectable VL, which would have implications for the timing of immunization in this group.

In other pediatric studies, antibody persistence was higher among older the patients at immunization.12,16,17,20–24 This phenomenon was not observed in the present study, following adjustment for other variables, such as baseline immunity. However, HIV infection was not significantly associated with lack of antibody response after 12–18 months of the immunization as expected. Considering that the HIVI group had a worse MCC immune response 1–2 months after immunization,13 and since the HIVI group was older than the HIVU group and had higher socioeconomic status, perhaps these variables played a role in determining the lack of difference between HIVI and HIVU groups or in age. Probably, the study sample size was not large enough to discern differences in some groups’ covariates.

In conclusion, it was demonstrated that one dose of MCC vaccine was not sufficient to maintain immune protection at 12–18 months among both HIVI and HIVU, even among HIVI with preserved or restored immunity. Studies that evaluate new approaches to vaccination must be pursued. In order to maintain immune response among the HIVI individuals, it is probably important to immunize these individuals with undetectable VL.

The study was funded by grants from Fogarty International Center of the National Institutes of Health to CBH (Grant No. 5R01 TW008397) and from Foundation for Research Support of the State of Rio de Janeiro (FAPERJ, Grant No. #E-26/112.645/2012) to LGM. This work was also supported in part by a grant from the Fogarty International Center Global Infectious Diseases Research Training Program, National Institutes of Health, to the University of Pittsburgh (Grant No. D43TW006592). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

The authors declare no conflicts of interest.