Invasive meningococcal disease (IMD) is caused by the bacterium Neisseria meningitidis and commonly presents as serious or life-threatening meningitis and septicemia in children and adolescents, with a fatality rate of up to 10% in affected individuals.1 , 2 Virtually all IMDs are caused by 6 serogroups: A, B, C, W, X and Y.3–6 The epidemic potential and geographic distribution of the meningococcal serogroups responsible for sporadic disease outbreaks differ widely.6 , 7 In Europe, serogroup B accounts for most IMD cases and an increase in serogroup W-caused disease has been observed recently,8 , 9 while in the United States, cases are most frequently caused by serogroups B, C and Y.4 , 5
Meningococcal vaccination has reduced the incidence of overall IMDs; however, serogroup B remains predominant in both Europe and North America.8 Several quadrivalent meningococcal conjugate vaccines are currently available against serogroups A, C, Y and W (MenACWY), using different carrier proteins: CRM197 (MenACWY-CRM; Menveo, GSK, Italy), diphtheria toxoid or tetanus toxoid.10–13 Only recently, 2 vaccines have been approved for use against serogroup B.4 , 14 , 15
Meningococcal vaccination recommendations for young children, teens and young adults vary by country and region. In the United States, children 11–12 years of age routinely receive a single dose of MenACWY vaccine, with a booster dose at 16–19 years.16 The use of meningococcal serogroup B vaccines is recommended in at-risk individuals ≥10 years of age, and adolescents and young adults 10–25 years of age may receive 2- or 3-dose series between 16 and 23 years.17 However, an ABCWY vaccine would protect against the 5 most common clinically important N. meningitidis serogroups while simplifying dosing regimens, thereby improving vaccine uptake and coverage. Recently, the investigational MenABCWY vaccine, including glycoconjugate components of serogroups A, C, W, Y, as well as recombinant serogroup B proteins and outer membrane vesicle (OMV) components has been developed. MenABCWY is immunogenic in children, adolescents and adults, with an acceptable safety profile, and is predicted to be protective against currently circulating serogroup B strains.18–21
In a primary phase 2, randomized, observer-blind clinical trial, a 2-dose primary series of 2 different MenABCWY formulations were previously shown to be well tolerated and immunologically noninferior compared with 1 dose of the MenACWY-CRM vaccine, and to elicit robust immune responses against serogroup B strains in children and young adults 10–25 years of age.22 These results warrant further investigation on the use of a 2-dose MenABCWY vaccination to replace routine immunization against MenACWY at 11–12 years of age, while also providing protection against serogroup B-caused disease during early adolescence.
Here, we report the results of an extension study, conducted to assess the immune response elicited by a booster dose of MenABCWY administered at 24 months after primary vaccination with MenABCWY, a licensed serogroup B vaccine (4CMenB; Bexsero, GSK, Italy) or the licensed quadrivalent MenACWY-CRM vaccine in the parent study, and to evaluate antibody persistence at 24 and 36 months after the primary series.
A summary contextualizing the results and potential clinical research relevance and impact is displayed in the Focus on Patient section (Fig. 1) for the benefit of Health Care Professionals.
MATERIALS AND METHODS
Study Design and Participants
This phase 2, randomized, placebo-controlled, observer-blind extension study was conducted in 8 centers in the United States and 5 centers in Poland, between December 2013 and April 2015.
Healthy children and young adults 10–25 years of age were assessed if they had received study vaccination and completed the final clinic visit in the primary study.22 Those with a history of administration of any other meningococcal vaccine, administration of any vaccine within 30 days before and after study vaccine, confirmed or suspected disease caused by N. meningitidis and contact with or exposure to N. meningitidis infection within 60 days of enrolment in the extension study were excluded. Pregnant or nursing women were not eligible for inclusion.
In the primary study (NCT01272180), participants were randomized into 4 groups to receive an investigational vaccine formulated with either 25 μg OMV (MenABCWY) or 6.25 μg OMV (MenABCWY¼), 4CMenB vaccine (2 doses, administered 2 months apart), or placebo followed by 1 dose of MenACWY-CRM vaccine.22 In this extension study, an additional dose was administered at 24 months after the completion of the primary series. Participants previously vaccinated with MenABCWY or MenABCWY¼ were randomized (1:1) to receive either the same formulation or placebo (ABCWY groups). Participants who had received a primary series of 4CMenB vaccine were randomized (1:1) to receive a booster dose of MenABCWY or MenABCWY¼ (4CMenB groups), and those who received a primary dose of MenACWY-CRM vaccine were randomized (1:1:1) to receive a booster dose of MenABCWY, MenABCWY¼ or placebo (ACWY groups) (Supplemental Digital Content 1, http://links.lww.com/INF/C934).
The randomization was performed using a web-based system. All study personnel and participants were blinded to vaccine assignment apart from designated clinical research associates who were responsible for preparing and administering the vaccines.
The study was undertaken according to the International Conference on Harmonization guidelines for good clinical practice, applicable local regulations and the Declaration of Helsinki. The protocol and protocol-related documents were approved by Independent Ethics Committees before study initiation. All participants or their parent/legal guardian provided informed written consent for inclusion in the extension study. In addition, all participants 10–18 (United States) or 12–18 years of age (Poland) were informed about the study and assented to participation in the trial by personally signing and dating the informed assent form as required by local regulations. The study is registered at www.Clinicaltrials.gov (NCT01992536).
The primary immunogenicity objectives evaluated (1) immune responses against serogroups A, C, W and Y, in terms of the percentage of participants with seroresponses as measured by serum bactericidal assay using exogenous human complement (hSBA) and (2) against serogroup B strains in terms of the percentage of participants with high-throughput hSBA titers ≥5, at 1 month postbooster vaccination, in groups previously receiving the same MenABCWY formulation. Secondary immunogenicity objectives assessed immune responses against all vaccine antigens, at 1 month after boosting with MenABCWY and assessed antibody persistence at 24 and 36 months after primary vaccination. The safety and reactogenicity of the study vaccines were also evaluated, including new onset of chronic diseases (NOCDs) recorded since completion of primary vaccination to the end of the extension study.
A dose of 0.5 mL MenABCWY22 was administered intramuscularly into the deltoid muscle of the nondominant arm. Placebo was a saline solution for injection. Vaccine lot numbers are provided in Supplemental Digital Content 1, http://links.lww.com/INF/C934.
Serum samples were collected from all participants before receiving the booster dose (extension baseline), and at 1 month and 1 year postbooster. Immunogenicity assessments were conducted as previously described22 by GSK Clinical Laboratory Sciences, Marburg, Germany. Briefly, immune responses were assessed by high-throughput serum hSBA23 against 4 test strains for serogroups A, C, W and Y, and against 4 test strains for serogroup B, 1 for each of the vaccine antigens: M14459 [factor H binding protein (fHbp)], M01-0240364 [Neisserial adhesin A (NadA)], M07-0241084 [Neisseria heparin binding antigen (NHBA)] and NZ98/254 [porin A protein (PorA)]. Characteristics of the serogroup B test strains (expression of fHbp, NadA and NHBA antigens and genotypic match to the vaccine PorA antigen), together with similar data for serogroup A, C, W and Y test strains are described in Supplemental Digital Content 1, http://links.lww.com/INF/C934 includes the Meningococcal Antigen Typing System relative potency values expressed relative to the reference strain for each antigen.24 Each test strain is representative of circulating strains in the United States and was tested for specificity to the primary target antigen of bactericidal killing, using human complement serum bactericidal inhibition assays with the target recombinant protein vaccine component, as required by the Food and Drug Administration guidelines for qualification and validation of the assay.25
Seroresponse was defined as the proportion of participants with ≥4-fold increase in hSBA titers from a baseline titer ≥4, or a titer ≥8 from a baseline titer <4 for serogroups A, C, W and Y, and as the proportion of participants with hSBA titers of ≥5 for serogroup B, at 1 month postbooster vaccination. Antibody persistence was assessed at 1 year postbooster dose, as the proportion of participants with hSBA titers ≥8 for serogroups A, C, W and Y and with hSBA titers ≥5 for serogroup B strains. Geometric mean titers (GMTs) for serogroups A, B, C, W and Y (at all timepoints) and increases in GMTs relative to the extension baseline [geometric mean ratios (GMRs)] were also evaluated.
Participants were observed for 30 minutes after each vaccination and participants or parents/guardians used diary cards to record solicited local and systemic adverse events (AEs) up to 7 days postvaccination. All solicited AEs were graded by severity (from mild to severe) and were reported as unsolicited AEs if they continued beyond the 7-day period. Unsolicited AEs were recorded for 30-day postvaccination on diary cards. Serious AEs (SAEs) and NOCDs were reported for 1 year postbooster dose. Investigators recorded whether they considered AEs to be related to the study vaccines.
Sample size considerations were described for the primary study.22
The response rates against serogroups A, B, C, W and Y were summarized by vaccine group with 2-sided 95% Clopper-Pearson confidence intervals (CIs). Extension baseline GMTs and GMRs were constructed by exponentiation of the corresponding log-transformed means (and mean differences from extension baseline in log-transformed titers) and their 95% CIs for the log-transformed means obtained from a 2-way analysis of variance with vaccine group and center as factors in the model. Titers below the limit of detection were set to half that limit for the purposes of analysis. The log-transformed antibody titers were analyzed without any statistical adjustment. The frequency of solicited and unsolicited AEs was tabulated with 95% CIs.
All participants in the extension study randomized and vaccinated were included in the full analysis set (FAS). Immunogenicity analyses were conducted on the FAS for immunogenicity (pre- and 1 month postbooster) and persistence (24 and 36 months postprimary vaccination), including participants from the FAS at days 30 and 365, respectively, who provided an evaluable serum sample. Safety assessments were performed on all vaccinated participants.
Because only the MenABCWY formulation was selected for further development, all data for the groups receiving MenABCWY¼ in either the primary or the extension study are presented only as supplementary information (Supplemental Digital Content 2, http://links.lww.com/INF/C935).
From the 419 participants who had completed the primary trial,22 414 were eligible for the extension study, 194 were enrolled and 190 received a booster or placebo dose. The disposition of participants is shown in Figure 2. The mean age of the participants was 18.4 ± 5.08 years and all demographic characteristics were balanced between the vaccine groups (Supplemental Digital Content 3, http://links.lww.com/INF/C936).
Serogroups A, C, W and Y
At 1 month postbooster vaccination, in the ABCWY/ABCWY group, the booster seroresponse rates were 96%, 85%, 85% and 96%, against serogroups A, C, W and Y, respectively. Seroresponse rates were 100%, 100%, 82% and 73% in the 4CMenB/ABCWY group and 84%, 95%, 83% and 95%, in the ACWY/ABCWY group, against serogroups A, C, W and Y, respectively (Table 1). At 1 month postbooster, the percentage of participants with hSBA titers ≥8 for any of the 4 serogroups was 100% for all groups receiving MenABCWY, except for group 4CMenB/ABCWY (82%), while no increase from extension baseline values was observed in the ACWY/placebo group (Fig. 3A). In all groups receiving a booster dose of MenABCWY, GMTs for serogroups A, C, W and Y increased from the extension baseline, with GMRs of 76, 29, 23 and 45, respectively, in the ABCWY/ABCWY group. GMTs remained at extension baseline levels in the groups receiving placebo (Supplemental Digital Content 3, http://links.lww.com/INF/C936).
At 1-year postbooster vaccination with MenABCWY, the percentages of participants with hSBA titers ≥1:8 were ≥67%, ≥82% and ≥91%, for serogroups A, C and W, respectively. For serogroup Y, ≥95% of participants in the ABCWY/ABCWY and ACWY/ABCWY groups, and 45% in the 4CMenB/ABCWY group had hSBA titers ≥8. At the same time point, in the ACWY/placebo group, 35%–65% of participants had hSBA titers ≥8 for each of the 4 serogroups, similarly to values at extension baseline (Fig. 3A). With few exceptions, GMTs tended to decrease from 1 month to 1 year postbooster vaccination in the ABCWY/ABCWY, 4CMenB/ABCWY and ACWY/ABCWY groups but remained higher (by ≥2.99-fold) than at extension baseline, for all serogroups. In the ACWY/placebo group, GMTs remained similar to extension baseline levels (Supplemental Digital Content 3, http://links.lww.com/INF/C936).
At 1 month postbooster, the percentage of participants with hSBA titers ≥5 against serogroup B test strains increased from extension baseline only in groups receiving MenABCWY, to values of ≥82% in the ABCWY/ABCWY and 4CMenB/ABCWY [except for the strain M07-0241084 (NHBA)] (Table 2). GMTs for serogroup B strains increased from the extension baseline to 1 month postbooster vaccination with MenABCWY, with GMR values ranging from 9.72 to 525 in the ABCWY/ABCWY and 4CMenB/ABCWY groups. At the same time point, GMRs for serogroup B strains in groups receiving placebo were ≤1.52 (Table 2).
At 1-year postbooster vaccination, the percentage of participants with hSBA titers ≥5 against serogroup B test strains in the ABCWY/ABCWY and 4CMenB/ABCWY groups was ≥57% for fHbp, NHBA and NadA and ≥29% for PorA. At the same time point, 14%–29% of participants in the ACWY/ABCWY group and 6%–35% in the ACWY/placebo group had hSBA titers ≥5 against serogroup B test strains (Fig. 3B).
At least 1 local solicited AE was reported by 81%–100% of participants receiving MenABCWY and 21%–25% of those receiving placebo. The most frequently reported solicited local AE was pain in all groups, including ABCWY/ABCWY (77%), ABCWY/placebo (25%), 4CMenB/ABCWY (100%), ACWY/ABCWY (90%) and the ACWY/placebo (89%) groups (Supplemental Digital Content 4, http://links.lww.com/INF/C937). Any solicited systemic AE was reported by 46%–71% of participants receiving MenABCWY and 26%–38% of those receiving placebo. The most frequent systemic solicited AEs were fatigue in the ABCWY/ABCWY (35%) and 4CMenB/ABCWY (45%) groups, and headache in the 4CMenB/ABCWY (45%) and ACWY/ABCWY (57%) groups. The incidence of severe solicited AEs was low across all groups, for both local and systemic reactions (Supplemental Digital Content 4, http://links.lww.com/INF/C937).
At least 1 unsolicited AE was reported by 22%–29% of participants receiving MenABCWY and 9%–21% of participants receiving placebo, regardless of the primary vaccination (Supplemental Digital Content 4, http://links.lww.com/INF/C937). During the extension study, 9 NOCDs were reported by 9 participants across the vaccine groups; none of them were considered as related to vaccination. There were 5 SAEs reported by 5 participants: limb injury (group ACWY/ABCWY¼), syncope (group ABCWY¼/ABCWY¼), appendicitis (group ABCWY/MenABCWY¼), asthma (group ACWY/placebo) and facial bone fracture (group ABCWY¼/placebo). None of these SAEs were assessed as related to vaccination. Four participants became pregnant during the study, with the pregnancies resulting in live births with no congenital abnormalities. One participant became pregnant on study day 343 after withdrawing from the study, and gave birth at study day 614 to a live infant with congenital abnormalities. The principal investigator suspected to be VACTERL association (Vertebral defects, Anal atresia, Cardiac defects, Tracheo-Esophageal fistula, Renal anomalies, and Limb abnormalities) but with no genetic evidence due to subject being intractable after withdrawal from the study. No deaths were reported during the study.
This MenABCWY vaccine study assessed the immune responses elicited by a booster dose of the combination MenABCWY vaccine after primary immunization with either MenABCWY or 2 separate licensed vaccines (MenACWY-CRM and 4CMenB). A booster dose of MenABCWY induced a robust immune response at 24 months postprimary vaccination. Only subjects given a B component vaccine as the primary series showed any notable immune response at 1 month postbooster dose against the serogroup B reference strains. Antibody persistence for all 5 meningococcal serogroups at 24 months from primary vaccination was similar between groups primed with MenABCWY and those receiving licensed vaccines.
At the extension study baseline, 24 months after the primary series, immune responses against all meningococcal serogroups had substantially decreased from the completion of the primary series22 in all of the vaccine groups. Robust immune responses were observed at 1 month postboosting with MenABCWY vaccine, regardless of the vaccine used for the primary series.
A higher seroresponse rate was observed postbooster dose in the 4CMenB/ABCWY group than in the ABCWY/ABCWY and ACWY/ABCWY groups against serogroup A and C, while the seroresponse rate against serogroup Y was higher in the ABCWY/ABCWY and ACWY/ABCWY groups. At 1 month postbooster, hSBA GMTs for serogroup A seemed lower in groups primed with either MenABCWY or MenACWY-CRM than in 4CMenB-primed individuals. Although the small sample sizes preclude any conclusion, these results are consistent with previous observations that preexisting antibody levels might impact immune response to vaccination against serogroup A, especially for conjugated vaccines.26
In the ABCWY/ABCWY group, persistence of the immune response tended to be higher for serogroups C, W and Y than for serogroup A at the extension baseline and at 1-year postbooster vaccination. This trend seems to be consistent with previous observations for a vaccination schedule of 2 + 1 doses of MenABCWY administered at 0, 2 and 6 months in adolescents.27 The slightly higher antibody levels at the extension baseline for serogroups C, W and Y compared with serogroup A in participants primed with 4CMenB components is consistent with previous reports showing that hSBA titers for serogroup A exhibit a drop within the first 6 months postvaccination, although the same is not observed for titers assessed by SBA using baby rabbit complement.28–30 At 1-year postbooster, the rate of antibody persistence against serogroups A, C, W and Y was ≥67% in the ABCWY/ABCWY group, ≥85% in the ACWY/ABCWY group and ≥45% in the 4CMenB/ABCWY group who received a primary series covering only serogroup B strains.
The percentage of participants with hSBA titers ≥5 against serogroup B strains was comparable between the ABCWY/ABCWY and the 4CMenB/ABCWY groups at 1 month after booster vaccination. This trend seemed to continue beyond the 1 month postbooster timepoint, with lower responses being observed in the ACWY/ABCWY group. At 1 year postbooster, the persistence of immune response for serogroup B varied between strains, with 29% (PorA strain) and ≥57% for the other strains in the ABCWY/ABCWY group having hSBA titers ≥5. The rate of persistence against serogroup B strains at 1 year postbooster in the 4CMenB/ABCWY group was 45%–100%, and in the ACWY/ABCWY group was 14%–29%. However, the small sample size precludes any statistical significance of this observation.
Overall, all of the prime-boost schedules were well tolerated. In all groups receiving a booster dose of MenABCWY, the most frequent local solicited AE was injection site pain, and the most frequent systemic solicited AEs were headache and fatigue. These results are similar to those observed after primary doses of MenABCWY in the primary study22 and with different investigational formulations.31 The incidence of solicited AEs seemed lower than that observed after administration of a third dose of MenABCWY at 180 days postprimary vaccination, in a previous study in adolescents.27 Unsolicited AEs were reported with a comparable incidence to that noted in the primary study, assessing that the safety profile of the MenABCWY vaccine was comparable with that of the licensed MenACWY-CRM and 4CMenB vaccines.27 There were no SAEs in the active booster groups and no deaths reported during the study. None of the NOCDs reported from the completion of the primary vaccination series to the end of the extension study were considered related to vaccination.
The main limitation of the study was the small sample size in each group, and the descriptive nature of the analyses, which restricts the generalization of our results. Due to potential site-specific differences in the reconstitution technique, the final volume injected might have varied between the sites, as previously described.22 The main strength of the study was that the assessed schedule fits current recommendation for meningococcal vaccination. Future studies investigating the MenABCWY vaccine should include a MenACWY control group, particularly because such a comparison would provide important data on the protection afforded against serogroup B in adolescents younger than 16–19 years, the age at which immunization is currently recommended.
The data in this study provide evidence that the MenABCWY vaccine elicits a robust antibody response and is well tolerated in prime-boost schedules consisting of primary vaccination with 2 licensed immunogenic vaccines covering 5 meningococcal serogroups, and which are already included in vaccination schedules worldwide (MenACWY-CRM and 4CMenB). The use of MenABCWY as a 2-dose primary vaccination in children 11–12 years of age followed by a booster dose administered 12 months later to replace separate administration of quadrivalent MenACWY and serogroup B vaccines would have the benefit of providing protection against all 5 clinically relevant meningococcal serogroups at an earlier age than that afforded by current recommendations. The further clinical development of a combination pentavalent MenABCWY vaccine is warranted, in view of its potential to simplify vaccine regimens and improve meningococcal vaccination coverage.
Menveo and Bexsero are trademarks of GSK group of companies.
The authors thank all of the participants, their families and the study staffs at the research centers for contributing to this study. The authors would like to acknowledge Hanna Czajka and Wendy Daly for their participation in the conduct of this study, as well as Linda Han, Julie Densmore and Gordon Brestrich for their contribution to the study.
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meningococcal; vaccine; booster; serogroups ABCWY
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