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Clin Vaccine Immunol. Mar 2011; 18(3): 483–486.
Published online Dec 22, 2010. doi:  10.1128/CVI.00304-10
PMCID: PMC3067382

Immunogenicity and Safety of a Multicomponent Meningococcal Serogroup B Vaccine and a Quadrivalent Meningococcal CRM197 Conjugate Vaccine against Serogroups A, C, W-135, and Y in Adults Who Are at Increased Risk for Occupational Exposure to Meningococcal Isolates[down-pointing small open triangle]

Abstract

Laboratory staff who work with meningococcal isolates are at increased risk for developing invasive disease relative to the general population. This was the first study of laboratory workers who received both a conjugate vaccine against meningococcal serogroups A, C, W-135, and Y (Men ACWY-CRM, Menveo) and an investigational multicomponent vaccine against serogroup B containing factor H binding protein, neisserial adhesin A, Neisseria heparin binding antigen, and New Zealand strain outer membrane vesicles (4CMenB). Healthy adults (18 to 50 years of age) received three doses of 4CMenB at baseline, 2 months, and 6 months followed by a single dose of MenACWY-CRM 1 month later. Immunogenicity was assessed via serum bactericidal assay using human complement (hSBA) at 1 month postvaccination; solicited reactogenicity and adverse events were monitored. Fifty-four participants enrolled. Bactericidal immune responses were evident after each dose of 4CMenB, as assessed by hSBA geometric mean titers and percentages of subjects with hSBA titers of ≥4 against the test strains or a 4-fold rise in titer over baseline. At 1 month postvaccination, most MenACWY-CRM recipients had hSBA titers of ≥8 against serogroups A, C, W-135, and Y. Few participants discontinued due to an adverse event or vaccine reaction. Rates of solicited reactions were lower after MenACWY-CRM than after 4CMenB administration. Sequential administration of 4CMenB and MenACWY-CRM provided robust evidence of an immune response against serogroups A, B, C, W-135, and Y in laboratory workers routinely exposed to meningococcal isolates.

Invasive meningococcal disease can cause devastating disability or death in a matter of hours. Although the most commonly affected groups are infants and young children, adults also contract invasive disease, and recommendations in some countries include vaccinating at-risk adults with asplenia, complement deficiency, or occupational exposure to meningococci (5-7, 12).

Laboratory scientists and other workers who routinely work with meningococcal strains are at increased risk for contracting invasive meningococcal disease relative to the general population (4-7, 12). In a 2002 study, the U.S. Centers for Disease Control and Prevention (CDC) estimated that the attack rate among laboratory workers was 13 per 100,000 population, severalfold higher than that in the general population, which was approximately 0.3 per 100,000 in 2007 (7). The CDC found that approximately half of all laboratory-acquired invasive meningococcal disease between 1996 and 2000 was caused by serogroup B, while the other half was caused by serogroup C (5). Although disease caused by serogroup C has long been considered vaccine preventable, no vaccine against serogroup B strains has been licensed in the United States. Thus, current recommendations to protect laboratory workers include handling precautions to limit exposure (4).

We report the results of the first study of laboratory workers who received both a meningococcal conjugate vaccine against serogroups A, C, W-135, and Y (Menveo, MenACWY-CRM) and a multicomponent vaccine against meningococcal serogroup B (4CMenB), which has been previously described (2, 10). 4CMenB has shown clinical immunogenicity against multiple serogroup B strains in published studies of infants (9, 18).

MATERIALS AND METHODS

This was a phase 2, open-label study performed following good clinical practice and the principles outlined in the Declaration of Helsinki. Approval was obtained from the appropriate local ethics committees before the study start; all participants provided written informed consent before enrollment.

Participants.

Eligible vaccinees were healthy adults between 18 and 50 years of age who were routinely exposed to Neisseria meningitidis in appropriately controlled laboratory settings and who could follow study procedures and complete study visits. Exclusion criteria at enrollment were antibiotic treatment within 6 days, significant acute or chronic infection within 7 days, exposure to anyone with laboratory-confirmed N. meningitidis infection within 60 days, any chronic or progressive disease, or known impairment of the immune system. Recreational drug use, allergy to any vaccine component, obesity, and receiving vaccines or other study agents within 90 days of enrollment or during the study were also exclusions. Female vaccinees were to be medically sterile or negative in a pregnancy test, not breast-feeding, and using birth control measures for at least 2 months before and for the duration of the study.

Study vaccines.

4CMenB was provided in prefilled syringes and contained 50 μg of each of the purified antigens neisserial adhesin A (NadA), factor H binding protein (fHbp) (fused with genome-derived neisserial antigen [GNA] 2091), and Neisseria heparin binding antigen (NHBA) (fused with GNA 1030) and 25 μg of outer membrane vesicles (OMV) from N. meningitidis NZ98/254. Each vial also contained 1.5 mg aluminum hydroxide, 3.12 to 3.26 mg NaCl, and 10 mM histidine and water up to 0.5 ml for injection. The purified antigens have been previously described (2, 10).

MenACWY-CRM was provided as a lyophilized serogroup A component to be reconstituted with a liquid serogroup CWY component. The reconstituted MenACWY-CRM vaccine contained 10 μg of serogroup A polysaccharide and 5 μg each of serogroups C, W-135, and Y polysaccharide conjugated with CRM197 (cross-reactive material 197). The liquid component also contained 4.5 mg sodium chloride, 12.5 mg sucrose, 5 mM potassium dihydrogen phosphate, 10 mM sodium phosphate buffer, and water to make up the injection volume to 0.5 ml.

Each participant was to receive three doses of 4CMenB at baseline, 2 months, and 6 months and a single dose of MenACWY-CRM 1 month later. Both vaccines were given intramuscularly to the deltoid of the nondominant arm.

Safety.

Study personnel monitored participants for 30 min postvaccination for immediate reactions. Solicited injection site reactions (pain, erythema, and induration), systemic reactions (nausea, malaise, myalgia, arthralgia, headache, and fever), and any adverse events were collected for 7 days following each vaccination on diary cards. Medically attended adverse events, adverse events leading to premature withdrawal, and serious adverse events were collected after each vaccination and throughout the study period, including a follow-up 6 months after the last dose of study vaccine. Adverse events were assessed by the investigator for relationship to study vaccination and for severity using a predefined scale in which “severe” indicated an inability to perform daily activities, “moderate” indicated limitations of daily activities, and “mild” indicated no limitation of daily activities.

Immunogenicity.

Blood samples were obtained for serology testing at baseline and 1 month after each study vaccination as well as immediately before the third dose of 4CMenB. All immunogenicity endpoints were exploratory, and analyses included the per-protocol population who provided evaluable sera between 26 and 37 days after an individual vaccine dose. These included the percentage of participants with titers of ≥4 and ≥8 in a serum bactericidal assay using human complement (hSBA) against serogroups A, C, W-135, and Y, as well as against a panel of three meningococcal serogroup B reference strains, which were chosen to evaluate bactericidal activity to the three vaccine antigens NadA (strain 5/99), fHbp (strain 44/76-SL), and PorA P1.4 (strain NZ98/254), as previously described (11). Serogroup B strain NZ98/254 was chosen to assess the immunogenicity of the PorA P1.4 component of the OMV, which is the immunodominant protein and primary target for bactericidal antibodies in the vesicle. The starting dilutions in the hSBA were 1:4 for serogroups A, C, W-135, and Y and 1:2 for serogroup B strains. Methods were described previously (3, 9, 15, 16, 18, 19).

Immunogenicity assessments included geometric mean titer, geometric mean ratio of hSBA responses postvaccination compared with baseline for all serogroups, and 4-fold rise in hSBA titers against the three serogroup B strains.

Statistical methods.

The planned sample size was 250. Statistical analyses were exploratory. The percentages of subjects with a bactericidal titer of ≥4 or ≥8 in hSBA were tabulated with associated 95% Clopper-Pearson confidence intervals (CIs), as were the percentages of subjects with no detectable bactericidal titers at baseline (<4 in hSBA) who had a detectable titer during the study. Values below the limit of detection were set at one-half the limit of detection for all analyses. Geometric mean titers, geometric mean ratios, and associated 95% CIs were computed for each visit and meningococcal B strain and for serogroups A, C, W and Y by exponentiating (base 10) the means of the log-transformed (base 10) titers and their 95% CIs from PROC UNIVARIATE. Analysis was performed by Novartis Vaccines, using SAS software version 9.1 or higher.

RESULTS

Participants.

The study was conducted between July 2007 and November 2009 at one clinical center in Italy and one in Germany. Fifty-four participants enrolled; 96% were Caucasians, their mean weight was 71.5 kg, and gender was evenly balanced. The overall per-protocol population included 46 4CMenB recipients and 23 MenACWY-CRM recipients (Fig. (Fig.1).1). Demographic characteristics were similar for the enrolled and per-protocol populations.

FIG. 1.
Participant flow chart.

Immunogenicity.

Immune responses were evident after each dose of 4CMenB, as assessed by geometric mean titers and percentages of subjects with hSBA titers of ≥4 or ≥8 or achieving a 4-fold rise over baseline hSBA titers (Table (Table1).1). For all immunogenicity endpoints, waning was evident 4 months after the second dose of vaccine. Among participants with a baseline hSBA titer of <4 against one or more serogroup B strains, at least 89% had titers of ≥4 after the second dose and at least 90% had titers of ≥4 after the third dose of 4CMenB (data not shown).

TABLE 1.
Immunogenicity endpoints by strain at 1 month postvaccination with multicomponent meningococcal serogroup B vaccinea

One month after receiving MenACWY-CRM, the majority of participants had hSBA titers of ≥8 against meningococcal serogroups A, C, W-135, and Y (Table (Table22).

TABLE 2.
Immunogenicity parameters at 1 month postvaccination with a quadrivalent meningococcal conjugate vaccine (MenACWY-CRM)

Reactogenicity and tolerability.

Fifty-three adults received at least one study vaccination and were included in the safety analysis.

4CMenB was associated with injection site reactogenicity in all participants (Fig. (Fig.2a).2a). Systemic reactions were less frequent than injection site reactions, with over half of vaccinees reporting malaise and fewer reporting other systemic reactions (Fig. (Fig.2b).2b). Three participants reported fever, 4 or 5 participants remained home after each dose of 4CMen B, and 5 to 10 required antipyretic or analgesic medication. Most solicited reactions were transient and resolved within the first 3 days after vaccination; several reactions of induration were ongoing at day 7 postvaccination.

FIG. 2.
(a) Solicited injection site reactions following multicomponent meningococcal serogroup B vaccine by dose within 7 days of study vaccine. (b) Solicited systemic reactions following multicomponent meningococcal serogroup B vaccine by dose within 7 days ...

Solicited reactions were less common after receipt of MenACWY-CRM (Fig. (Fig.2c)2c) than after any dose of 4CMenB. The majority of the reactions to MenACWY-CRM occurred within the first 3 days postvaccination, and few continued up to day 7. Two participants reported fever.

Overall, 24 participants (45%) experienced at least one adverse event and 7 (13%) were possibly related to the vaccination; the most commonly reported adverse events were nasopharyngitis (n = 6) and rhinitis (n = 3). No serious adverse event or death was reported. One participant withdrew due to syncope and one due to nasopharyngitis; neither was considered related to vaccine by investigators. One participant withdrew consent after becoming pregnant.

DISCUSSION

We present the results of the first study of 4CMenB plus MenACWY-CRM, given sequentially to laboratory workers who routinely encounter meningococcal isolates. No other study has considered the sequential effects of a serogroup B vaccine and a quadrivalent vaccine against serogroups A, C, W-135, and Y, making these results of potential interest for other study populations.

Immune responses to serogroup B strains were higher than anticipated after an initial dose of 4CMenB. Between 64% and 88% of participants had hSBA titers of ≥4 or a 4-fold rise in hSBA titer from baseline after a single dose of 4CMenB, while between 69% and 100% had similar evidence of immune responses after three doses of vaccine. It is possible that these vaccinees had been previously primed through their routine handling of meningococcal isolates. Immune responses to a single dose of MenACWY-CRM were generally consistent with findings in previously published studies with adults (15), with 83 to 100% of participants having an hSBA titer of ≥8 against serogroups A, C, W-135, and Y.

While every participant reported some type of injection site reaction to 4CMenB, only about 25% of vaccinees reported an injection site reaction to MenACWY-CRM. Results for MenACWY-CRM were consistent with those in previously published studies where participants were blinded to vaccine (16, 19). However, somewhat more reactogenicity was reported than in previous studies of New Zealand OMV vaccine or preliminary results of trials of 4CMenB in adults presented at scientific meetings (13; P. M. Dull et al., presented at the International Pathogenic Neisseria Congress, Banff, Alberta, Canada, 2010). It is possible that the open-label study design confounded results; further study of 4CMenB is ongoing.

The small sample size and open-label design of this study also limit the applicability of these results to other situations and populations. A substantial body of literature describes MenACWY-CRM, which is licensed in the United States and Europe, and published findings with 4CMenB are limited to small-scale phase 2 studies with infants (9, 18). Further study of 4CMenB in adolescent and adult populations is needed. Despite the obvious limitations of the current study, relatively few studies with any type of compromised or at-risk population receiving meningococcal vaccines have been published, and most of these have considered the effects of polysaccharide-based vaccines in groups with innate or acquired immune deficiencies (1, 14, 17). Therefore, the current results provide an important step in considering the potential use of both outer membrane protein vaccines against serogroup B and polysaccharide conjugate vaccines against other serogroups in a population at an increased risk for exposure to pathogenic isolates.

Another limitation of the current study is a lack of information about the NHBA component of 4CMenB; further study is necessary to provide this information. As shown in an earlier publication detailing strain selection for phase 3 evaluation of 4CMenB (11) as well as phase 2 studies with infants, (9, 18), additional work to translate findings to coverage is needed (8). Preliminary data have indicated that a potential hSBA test strain for NHBA was available for use in studies of infant sera (Dull et al., presented at the International Pathogenic Neisseria Congress, Banff, Alberta, Canada, 2010), and a meningococcal antigen typing system has been proposed to predict killing of individual strains in the hSBA (8).

In the current study, investigational 4CMenB provided evidence of immune responses in a population that could be considered more vulnerable to contracting disease because of potential environmental hazards. Given the possibility of deaths of laboratory workers due to invasive disease caused by serogroup B, these results are promising for laboratory workers in countries where MenACWY-CRM is licensed and for further study of 4CMenB.

Acknowledgments

Participants were enrolled into the trial and clinical evaluations were made by M. Giotti and M. Goedecke. Michaelangelo Barone, Astrid Borkowski, and Laura Tomani monitored the study. Ellen Ypma and Kay Vienken provided scientific guidance for study design and conduct. Lisa DeTora provided editorial and scientific guidance on the manuscript. Shruti Priya Bapna provided essential writing and graphic support. J. Anne Welsch provided editorial support.

All authors are employees of Novartis Vaccines and Diagnostics. The sponsor's unique identifier for this study is V72P4, and the clinicaltrials.gov registration number is NCT00560313.

Footnotes

[down-pointing small open triangle]Published ahead of print on 22 December 2010.

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