Volume 14, Issue 10 , Pages e868-e875, October 2010
Safety and immunogenicity of an investigational quadrivalent meningococcal CRM197 conjugate vaccine, MenACWY-CRM, compared with licensed vaccines in adults in Latin America
Article Outline
Summary
Background
This study compared the investigational quadrivalent meningococcal CRM197 conjugate vaccine, MenACWY-CRM, with licensed quadrivalent polysaccharide (MPSV4) and conjugate (MenACWY-D) meningococcal vaccines.
Methods
In this phase III multicenter study, 2505 adults (aged 19–55 years) were randomized to receive either MenACWY-CRM or MenACWY-D, and 326 adults (aged 56–65 years) were randomized to receive either MenACWY-CRM or MPSV4. Sera obtained pre-vaccination and at 1-month post-vaccination were tested for serogroup-specific serum bactericidal activity using human complement (hSBA) for immunogenicity non-inferiority and superiority analyses.
Results
The vaccines in all groups were well tolerated. In the 19–55 years age group, post-vaccination geometric mean titers (GMTs) were consistently higher for MenACWY-CRM than for MenACWY-D for all four serogroups. MenACWY-CRM was non-inferior to MenACWY-D for all serogroups, and superior for serogroup Y. In the 56–65 years age group, post-vaccination GMTs were 1.2- to 5.4-fold higher for MenACWY-CRM than for MPSV4 for the four serogroups.
Conclusions
MenACWY-CRM is well tolerated and immunogenic in adults aged 19–65 years, with at least non-inferior immunogenicity compared with the currently licensed meningococcal vaccines.
Keywords: Adult, Meningococcal, Conjugate vaccine, Meningococcal polysaccharide vaccine
1. Introduction
Meningococcal disease caused by Neisseria meningitidis is a major cause of morbidity and mortality worldwide.1 The highest incidence of meningococcal disease is in infants aged <
12 months, and a second peak in incidence often occurs in adolescents.2 Although the incidence of meningococcal disease is highest in infants, 50% of meningococcal disease in Europe3 and 62% of meningococcal disease in the USA occurs among persons aged ≥10 years and ≥11 years, respectively.2 In other regions, such as Latin America, the adolescent peak is not so obvious, with approximately 25% of meningococcal disease cases occurring among persons ≥15 years of age.4 Furthermore, case-fatality rates are higher in young adults aged 15–24 years (22.5%) and in adults aged >25 years (16.5%), than in children aged <15 years (4.6%).5
The global epidemiology of meningococcal serogroups is dynamic and unpredictable, and can differ by region. In 2007, USA Active Bacterial Core Surveillance data showed that meningococcal serogroups B, C, and Y accounted for 25%, 30%, and 37% of isolates in that year, respectively,6 with a markedly increased contribution from serogroup Y, which was <5% in the early 1990s.7 Similarly, in Colombia between 1994 and 2002, and between 2003 and 2006, serogroup Y increased from accounting for 2.2% of all invasive meningococcal disease to over 29.5%.8 Epidemics in Africa and elsewhere in the world have most frequently been caused by serogroup A, and more recently serogroup W-135.9 The recent emergence of serogroup W-135 was underscored by an outbreak in 2000 that was associated with the Hajj – this was the first recognition of the potential for outbreak in this serogroup.10 In Brazil, the prevalence of serogroup W-135 increased significantly in the period 2003–2005.11 An unprecedented incidence of serogroup X was reported in Niger, Africa in 2006.12 Serogroups B and C are predominant in most regions, including Europe and Latin America.13
The variability in the expression of serogroup B immunodominant surface proteins, coupled with the poor immunogenicity of the capsular polysaccharides, has prevented the successful introduction of a broadly protective serogroup B meningococcal vaccine.14 This will take some years and until this is possible, the best option for protection is offered by quadrivalent (meningococcal serogroups A, C, W-135, and Y) vaccination. Of the two types of licensed quadrivalent meningococcal vaccine, only the plain polysaccharide vaccine is licensed outside North America, and it remains the only vaccine anywhere in the world that is licensed for adults aged >55 years. Such unconjugated meningococcal polysaccharide vaccines have been shown to be well tolerated and immunogenic in children >2 years of age and adults,13 but are poorly immunogenic in children aged <2 years.15 Polysaccharide vaccines do not promote T cell-dependent responses, and therefore do not induce immunologic memory.16, 17 They also provide a limited duration of protection18 and do not confer sustainable reduction of nasopharyngeal carriage of N. meningitidis.19, 20
In comparison, conjugated meningococcal vaccines have been shown to contribute to the control of meningococcal infection by indirect protection or herd immunity, by reducing the attack rate in the unvaccinated population,21 and can generate T cell-dependent responses, therefore inducing immunologic memory.22
An investigational quadrivalent meningococcal conjugate vaccine (MenACWY-CRM, Novartis Vaccines, Bellaria-Rosia, Italy), which includes Corynebacterium diphtheriae cross-reactive material (CRM197), a naturally occurring non-toxic mutant of diphtheria toxin, has been shown to be well tolerated and immunogenic in infants,23, 24 children,25 and adolescents.26 In two studies carried out in adolescents in the USA, MenACWY-CRM elicited a non-inferior immune response compared with an unconjugated meningococcal polysaccharide vaccine, Menomune (MPSV4; Sanofi Pasteur Inc., Swiftwater, PA, USA),26 and generated higher antibody titers to all four serogroups than with a polysaccharide–protein conjugate vaccine, Menactra (MenACWY-D; Sanofi Pasteur Inc., Swiftwater, PA, USA), conjugated to denatured diphtheria toxoid carrier proteins.27
In the present study in Latin America, the safety and immunogenicity of MenACWY-CRM were compared with the licensed vaccines to establish non-inferiority: MenACWY-D in subjects aged 19–55 years and MPSV4 in subjects aged 56–65 years (as MenACWY-D is not licensed for use in subjects >55 years of age).
2. Methods
A phase III, observer-blind, multicenter, randomized, controlled study was conducted in Argentina and Colombia to evaluate the safety and immunogenicity of MenACWY-CRM in healthy subjects aged 19–65 years. Ethics committee approval of the protocol was obtained before enrollment, and written informed consent was obtained from each subject. The study was performed in accordance with the current Good Clinical Practice and International Conference on Harmonisation guidelines.
2.1. Subjects
Subjects were approached via posters displayed in medical clinics. Healthy subjects aged 19–65 years were eligible for inclusion in the study. Subjects were excluded from the study if they had previously received meningococcal vaccine; had been vaccinated with any licensed vaccines ≤1 month before enrollment; had a previous or suspected disease caused by N. meningitidis; had received any investigational agents or vaccines ≤90 days before enrollment; had any serious acute, chronic, or progressive disease; or had a known or suspected impairment/alteration of immune function.
2.2. Vaccines and vaccinations
A total of 2831 subjects were enrolled and randomized in the study. Of these, 2505 subjects aged 19–55 years were randomly assigned to receive either MenACWY-CRM or MenACWY-D. Immunogenicity testing was performed for the first 200 subjects in both the 19–34 years and the 35–55 years age groups; these subjects were randomized in a 1:1 ratio. The subsequent subjects were randomized in a 2:1 ratio to receive MenACWY-CRM or MenACWY-D. The 326 subjects aged 56–65 years were randomized in a 2:1 ratio to receive either MenACWY-CRM or MPSV4, and the first 225 subjects were tested for immunogenicity.
All subjects received a single dose (0.5ml) of one of the three vaccines, administered intramuscularly in the left upper deltoid area (MenACWY-CRM or MenACWY-D), or subcutaneously in the left upper arm (MPSV4). Each dose of MenACWY-CRM consisted of two components: 10μg of lyophilized meningococcal serogroup A capsular polysaccharide, conjugated to CRM197 (MenA), and 5μg of capsular polysaccharide of serogroups C, W-135, and Y, conjugated to CRM197 in 0.5ml of phosphate-buffered saline, which was used to reconstitute the lyophilized MenA component, pre-vaccination. Blinding was maintained by using designated nurses or physicians to administer the study vaccines to the subjects, while the investigators and other investigative site personnel remained blinded.
2.3. Safety monitoring
Each subject was observed for 30min post-vaccination for any local or systemic reactions, or anaphylaxis. Oral or axillary temperature was recorded, and subjects were given diary cards to record solicited local (pain, erythema, and induration) or systemic (chills, nausea, malaise, myalgia, arthralgia, headache, and rash) reactions that occurred between day 1 and day 7. Any adverse events (AEs) requiring medical attention were recorded for 1 month post-vaccination, and any medically significant and serious AEs (SAEs) were recorded for 6 months post-vaccination.
2.4. Serology
Blood samples (20ml) were obtained pre-vaccination and at 1-month post-vaccination. The immunogenicity of the study vaccines was evaluated by serum bactericidal activity using human complement (hSBA) for meningococcal serogroups A, C, W-135, and Y according to methods described previously.24
For comparisons of the immunogenicity of the vaccines, three immunologic endpoints were defined. For each serogroup, these endpoints included the post-vaccination hSBA geometric mean titer (GMT), the proportion of subjects with a post-vaccination hSBA titer ≥1:8, and the proportion of seroresponders. Seroresponse was a composite endpoint that incorporated two categories of pre-vaccination immune status: for initially seronegative subjects, i.e., with a baseline hSBA titer <1:4, seroresponse was defined as a post-vaccination hSBA titer of ≥1:8; for those initially seropositive, with a baseline hSBA titer ≥1:4, seroresponse was defined as at least a 4-fold increase in the pre-vaccination titer.
2.5. Statistical methods and analyses
The immunogenicity of MenACWY-CRM was considered non-inferior to the immunogenicity of MenACWY-D for any of the four serogroups, if the lower limit (LL) of the two-sided 95% confidence interval (CI) around the difference (MenACWY-CRM minus comparator) in the percentage of subjects achieving a seroresponse or percentage of subjects with an hSBA titer ≥1:8 for that serogroup was greater than −10%; superiority was defined as an LL greater than 0%. Similarly, for GMTs, non-inferiority was based on the LL of the two-sided 95% CI around the ratio of the geometric means (MenACWY-CRM:comparator) >0.5; superiority was defined as an LL >1.0.
The vaccine group differences in the percentage of subjects achieving a seroresponse or an hSBA titer ≥1:8 were calculated using binomial distribution. When constructing two-sided 95% CI for the difference between MenACWY-CRM and the comparator in the proportion of subjects with a response, the associated 95% CI was constructed using the differences of two percentages based on the Chi-square method.28 Vaccine group ratios of GMTs, along with the 95% CI for the ratio, were based on the estimate of the difference in least square means from an analysis of variance which included vaccine group and center as fixed effects in the model. Titers were transformed to a log10 basis for the analyses and the results were then back-transformed to provide the GMTs and associated difference and CI.
The study was powered to assess non-inferiority in the 19–55 years age cohort; the analysis of the 56–65 years age cohort was exploratory. The per protocol population was used for the analyses and consisted of subjects who received a vaccine, provided evaluable sera pre- and post-vaccination, and had no major protocol violations, which may have precluded the assessment of immunogenicity (i.e., corticosteroid use). Statistical analyses were performed using SAS software, version 9.1 or higher (SAS Institute, Cary, NC, USA).
3. Results
3.1. Subject characteristics
Subject demographics were well matched between all groups (Table 1, Table 2). Of the 2831 subjects enrolled, 2785 completed the study in line with the protocol (Figure 1). Overall, 46 subjects withdrew from the study; six withdrew consent, 28 were lost to follow-up, 11 were enrolled inappropriately, and one died (unrelated to the study vaccines).
Table 1. Subject demographics for the total enrolled population
| 19–55 years of age | 56–65 years of age | |||
|---|---|---|---|---|
| MenACWY-CRM (n=1606) | MenACWY-D (n=899) | MenACWY-CRM (n=217) | MPSV4 (n=109) | |
| Mean age, years (SD) | 34.6 (10.1) | 34.8 (10.4) | 60.1 (2.7) | 60.1 (2.6) |
| Male, n (%) | 514 (32) | 272 (30) | 54 (25) | 30 (28) |
| Ethnicity, n (%) | ||||
| Asian | 1 (<1) | 1 (<1) | 1 (<1) | 0 |
| Black | 135 (8) | 109 (12) | 18 (8) | 8 (7) |
| Caucasian | 249 (16) | 127 (14) | 38 (18) | 23 (21) |
| Hispanic | 1217 (76) | 658 (73) | 158 (73) | 77 (71) |
| Other | 4 (<1) | 3 (<1) | 2 (<1) | 1 (<1) |
Table 2. Subject demographics for the per protocol immunogenicity population
| 19–55 years of age | 56–65 years of age | |||
|---|---|---|---|---|
| MenACWY-CRM (n=183) | MenACWY-D (n=184) | MenACWY-CRM (n=84) | MPSV4 (n=41) | |
| Mean age, years (SD) | 36.5 (11.2) | 36.4 (10.9) | 60.0 (2.5) | 59.6 (2.3) |
| Male, n (%) | 32 (17) | 42 (23) | 15 (18) | 9 (22) |
| Ethnicity, n (%) | ||||
| Asian | 0 (0) | 0 (0) | 0 (0) | 0 (0) |
| Black | 52 (28) | 57 (31) | 15 (18) | 7 (17) |
| Caucasian | 0 (0) | 0 (0) | 0 (0) | 0 (0) |
| Hispanic | 131 (72) | 127 (69) | 69 (82) | 34 (83) |
| Other | 0 (0) | 0 (0) | 0 (0) | 0 (0) |
| Baseline hSBA titer ≥1:8 | ||||
| A | 8 | 10 | 11 | 7 |
| C | 21 | 25 | 21 | 17 |
| W-135 | 60 | 66 | 67 | 67 |
| Y | 22 | 29 | 20 | 27 |
Figure 1.
Subject disposition flowchart.
MenACWY-CRM, quadrivalent meningococcal CRM197 conjugate vaccine; MenACWY-D, quadrivalent meningococcal polysaccharide-protein conjugate vaccine; MPSV4, unconjugated quadrivalent meningococcal polysaccharide vaccine; SAE, serious adverse event.
aInappropriate enrollments included: subject with a pacemaker; vaccination received 15 days before the day of enrollment; subject had doubts about previous meningococcal vaccination; subject was pregnant.
bInappropriate enrollments included: subject had Sheehan's syndrome; subject planning to leave study area before the end of the study period; subject had doubts about previous meningococcal vaccination; subject did not want to use any contraception method; subject was pregnant; subject taking methotrexate due to rheumatoid arthritis; subject had supraventricular tachycardia.
cUnrelated to the study vaccine.
3.2. Safety and tolerability
3.2.1. Local reactionsFrequencies of subjects reporting any local reaction were similar in both age groups; 46% of MenACWY-CRM and 50% of MenACWY-D recipients in the 19–55 years age group, and 43% of MenACWY-CRM and 40% of MPSV4 recipients in the 56–65 years age group, experienced local reactions (Table 3). The most frequently reported local reaction was pain, reported by 40% of MenACWY-CRM recipients and 44% of MenACWY-D recipients in the 19–55 years age group, and 32% of MenACWY-CRM and 31% of MPSV4 recipients in the 56–65 years age group.
Table 3. Solicited local and systemic reactions at 7-days post-vaccination with MenACWY-CRM or MenACWY-D in subjects aged 19–55 years, and MenACWY-CRM or MPSV4 in subjects aged 56–65 years
| Reactogenicity | Subjects, n (%) | |||
|---|---|---|---|---|
| 19–55 years of age | 56–65 years of age | |||
| MenACWY-CRM (n=1588) | MenACWY-D (n=882) | MenACWY-CRM (n=216) | MPSV4 (n=109) | |
| Any local reaction | ||||
| Any | 729 (45.9) | 439 (49.8) | 92 (42.6) | 44 (40.4) |
| Severe | 60 (3.8) | 37 (4.2) | 12 (5.6) | 2 (1.8) |
| Pain | ||||
| Any | 632 (39.8) | 392 (44.4) | 69 (31.9) | 34 (31.2) |
| Severe | 41 (2.6) | 29 (3.3) | 8 (3.7) | 2 (1.8) |
| Erythema | ||||
| Any | 207 (13.0) | 105 (11.9) | 41 (19.0) | 13 (12.0)a |
| >50 mm | 17 (1.1) | 7 (0.8) | 6 (2.8) | 0 (0) |
| Induration | ||||
| Any | 179 (11.3) | 115 (13.0) | 39 (18.1) | 17 (15.7)a |
| >50 mm | 13 (0.8) | 10 (1.1) | 4 (1.9) | 0 (00) |
| Any systemic reaction | ||||
| Any | 616 (38.8) | 375 (42.5) | 84 (38.9) | 44 (40.4) |
| Severe | 95 (6.0) | 46 (5.2) | 14 (6.5) | 9 (8.3) |
| Chills | ||||
| Any | 124 (7.8) | 70 (7.9) | 26 (12.0) | 6 (5.5) |
| Severe | 19 (1.2) | 5 (0.6) | 5 (2.3) | 3 (2.8) |
| Nausea | ||||
| Any | 112 (7.1) | 77 (8.7) | 20 (9.3) | 8 (7.3) |
| Severe | 10 (0.6) | 4 (0.5) | 2 (0.9) | 1 (0.9) |
| Malaise | ||||
| Any | 309 (19.5) | 186 (21.1) | 50 (23.1) | 20 (18.3) |
| Severe | 43 (2.7) | 12 (1.4) | 9 (4.2) | 6 (5.5) |
| Myalgia | ||||
| Any | 197 (12.4) | 131 (14.9) | 39 (18.1) | 11 (10.1) |
| Severe | 25 (1.6) | 10 (1.1) | 3 (1.4) | 5 (4.6) |
| Arthralgia | ||||
| Any | 118 (7.4) | 76 (8.6) | 25 (11.6) | 11 (10.1) |
| Severe | 16 (1.0) | 7 (0.8) | 2 (0.9) | 4 (3.7) |
| Headache | ||||
| Any | 421 (26.5) | 254 (28.8) | 52 (24.1) | 30 (27.5) |
| Severe | 49 (3.1) | 26 (2.9) | 6 (2.8) | 5 (4.6) |
| Fever (≥38°C) | ||||
| Any | 56 (3.5)b | 31 (3.5) | 6 (2.8) | 3 (2.8) |
| ≥39°C | 14 (0.9) | 9 (1.0) | 4 (1.9) | 1 (0.9) |
| Other | ||||
| Analgesic/antipyretic used | 250 (15.7) | 148 (16.8)c | 25 (11.6) | 14 (12.8) |
| Stayed at home | 75 (4.7)d | 46 (5.2)e | 14 (6.5)f | 6 (5.6)a |
The percentages of subjects reporting erythema and induration were similar between vaccine groups and within age groups (erythema: 19–55 years of age – MenACWY-CRM 13%, MenACWY-D 12%; 56–65 years of age – MenACWY-CRM 19%, MPSV4 12%. Induration: 19–55 years of age – MenACWY-CRM 11%, MenACWY-D 13%; 56–65 years of age – MenACWY-CRM 18%, MPSV4 16%).
Fewer than 5% of recipients of any vaccine in both age groups reported a local reaction as severe or >50mm.
The percentages of subjects reporting any systemic reaction were also similar between vaccine groups and within age groups (19–55 years of age: MenACWY-CRM 39%, MenACWY-D 43%; 56–65 years of age: MenACWY-CRM 39%, MPSV4 40%) (Table 3). Across the vaccine groups, the most commonly reported systemic reactions were headache, malaise, and myalgia. In the 19–55 years age group, these were reported by 27%, 19%, and 12%, respectively, of MenACWY-CRM recipients, and by 29%, 21%, and 15%, respectively, of MenACWY-D recipients (Table 3). In the 56–65 years age group, these were reported by 24%, 23%, and 18%, respectively, of MenACWY-CRM recipients, and by 28%, 18%, and 10%, respectively, of MPSV4 recipients (Table 3).
3.2.3. Adverse eventsIn the 19–55 years age group, the percentage of subjects experiencing any unsolicited AEs was similar between vaccine groups (MenACWY-CRM 19%; MenACWY-D 21%). In the 56–65 years age group, the percentage of subjects experiencing any unsolicited AEs was slightly higher for MenACWY-CRM recipients (25%) than MPSV4 recipients (15%). The percentage of subjects experiencing possibly or probably related AEs was similar between the vaccine and age groups (9%) except for MenACWY-CRM (15%) in the 56–65 years age group.
One SAE occurred that was considered by the study investigator to be possibly related to the study vaccination. This was in a 34-year-old woman who had a spontaneous abortion 44 days after vaccination with MenACWY-CRM. She had a negative urine pregnancy test at the time of study entry. In the 56–65 years age group, one death occurred due to hypovolemic shock following a surgical procedure and was not considered vaccine-related.
3.2.4. ImmunogenicityThe immune responses to MenACWY-CRM were generally higher in both age groups when compared with the respective comparator vaccines.
3.2.5. 19–55 years age groupThe seroresponse rate endpoint estimates were numerically higher in the MenACWY-CRM group than in the MenACWY-D group for all serogroups (A: 78% vs. 77%; C: 83% vs. 81%; W-135: 66% vs. 53%; Y: 80% vs. 58%) (Table 4). Non-inferiority of the immune response, assessed as the number of subjects with a seroresponse to MenACWY-CRM compared with the number achieving a seroresponse to MenACWY-D, was demonstrated for all four serogroups, and superiority criteria were met for serogroups W-135 and Y (Table 4).
Table 4. Immunogenicity against meningococcal serogroups A, C, W-135, and Y at 1-month post-vaccination with MenACWY-CRM or MenACWY-D in subjects aged 19–55 years
| Serogroup | Seroresponse | hSBA titer ≥1:8 | Geometric mean titer | ||||||
|---|---|---|---|---|---|---|---|---|---|
| MenACWY-CRM | MenACWY-D | Group difference (95% CI) | MenACWY-CRM | MenACWY-D | Group difference (95% CI) | MenACWY-CRM | MenACWY-D | Post-vaccination group ratio (95% CI) | |
| A | 78 (n=179) | 77 (n=182) | 0 (−8–9)a | 81 (n=179) | 80 (n=182) | 1 (−7–9)a | 77 (n=179) | 52 (n=182) | 1.5 (0.98–2.3)c |
| C | 83 (n=180) | 81 (n=183) | 2 (−6–10)a | 88 (n=180) | 92 (n=183) | −5 (−11–2) | 114 (n=180) | 88 (n=183) | 1.3 (0.85–1.97)c |
| W-135 | 66 (n=178) | 53 (n=180) | 12 (2–22)b | 98 (n=178) | 93 (n=180) | 5 (1–10)b | 159 (n=178) | 112 (n=180) | 1.42 (0.99–2.03)c |
| Y | 80 (n=181) | 58 | 22 (13–31)b | 88 (n=181) | 76 | 11 (4–19)b | 95 (n=181) | 40 | 2.37 (1.56–3.6)d |
The GMTs showed a large increase for all four serogroups in both vaccine groups, but were consistently higher in the MenACWY-CRM group (A: 77 vs. 52; C: 114 vs. 88; W-135: 159 vs. 112; Y: 95 vs. 40), and the ratio of GMTs met the pre-specified criteria for non-inferiority for all four serogroups, and met the criteria for superiority for serogroup Y (Table 4 and Figure 2).
Figure 2.
Reverse cumulative distribution of hSBA titers in subjects (A)–(D) 19–55 years of age or (E)–(H) 56–65 years of age against meningococcal serogroups A, C, W-135, and Y, pre-vaccination and 1-month post-vaccination with MenACWY-CRM, MenACWY-D, or MPSV4.
hSBA, serum bactericidal activity using human complement; MenACWY-CRM, quadrivalent meningococcal CRM197 conjugate vaccine; MPSV4, unconjugated quadrivalent meningococcal polysaccharide vaccine.
When assessed as the proportion of subjects with an hSBA titer ≥1:8 at 1-month post-vaccination, the immune response to MenACWY-CRM met the criteria for non-inferiority compared with MenACWY-D for serogroups A, W-135, and Y, and met the criteria for statistical superiority for serogroups W-135 and Y (Table 4).
3.2.6. 56–65 years age groupThe percentage of seroresponders was consistently higher in the MenACWY-CRM group than in the MPSV4 group, for all serogroups (A: 86% vs. 61%; C: 83% vs. 73%; W-135: 61% vs. 54%; Y: 77% vs. 54%) (Table 5). Geometric mean titers were also consistently higher in the MenACWY-CRM group than in the MPSV4 group for all serogroups (A: 111 vs. 21; C: 196 vs. 86; W-135: 164 vs. 132; Y: 121 vs. 28) with GMTs several-fold higher (5-fold higher for serogroup A) in the MenACWY-CRM group than in the MPSV4 group (Table 5).
Table 5. Immunogenicity against meningococcal serogroups A, C, W-135, and Y at 1-month post-vaccination with MenACWY-CRM or MPSV4 in subjects aged 56–65 years
| Serogroup | Seroresponse | hSBA titer ≥1:8 | Geometric mean titer | ||||||
|---|---|---|---|---|---|---|---|---|---|
| MenACWY-CRM | MPSV4 (n=41) | Group difference (95% CI) | MenACWY-CRM (n=84) | MPSV4 (n=41) | Group difference (95% CI) | MenACWY-CRM (n=84) | MPSV4 (n=41) | Post-vaccination group ratio (95% CI) | |
| A | 86 (n=83) | 61 | 25 (9–41) | 87 (n=83) | 63 | 23 (8–40) | 111 (n=83) | 21 | 5.4 (2.47–12) |
| C | 83 | 73 | 10 (−4–27) | 90 | 83 | 8 (−4–23) | 196 | 86 | 2.27 (1.05–4.95) |
| W-135 | 61 (n=82) | 54 (n=39) | 7 (−11–26) | 94 (n=82) | 95 (n=39) | −1 (−9–11) | 164 (n=82) | 132 (n=39) | 1.24 (0.64–2.42) |
| Y | 77 | 54 | 24 (6–41) | 88 | 68 | 20 (5–36) | 121 | 28 | 4.25 (1.89–9.56) |
Using the criteria of subjects with an hSBA titer ≥1:8, the immune response was higher in the MenACWY-CRM group than in the MPSV4 group for serogroups A, C, and Y (Table 5).
4. Discussion
The investigational quadrivalent meningococcal conjugate vaccine, MenACWY-CRM, was well tolerated and had comparable, or statistically higher, immune responses compared with the two currently licensed quadrivalent meningococcal vaccines available for adults aged 19 to 65 years (MenACWY-D for subjects 11–55 years of age and MPSV4 for subjects 56–65 years of age). The results from this study are consistent with other recently reported data, in which the immunogenicity of MenACWY-CRM and MenACWY-D were compared.27
MenACWY-D (Menactra), the only other licensed quadrivalent meningococcal conjugate vaccine, is currently licensed for use in subjects aged 2–55 years in Canada and the USA. While the clinical relevance of the findings requires further study, in subjects aged 19–55 years, the immune response following vaccination with MenACWY-CRM nevertheless demonstrated favorable immunogenicity compared with that of MenACWY-D, for each of the clinical endpoints. These findings may reflect differences in the carrier proteins used for conjugation: CRM197 and diphtheria toxoid, respectively. These results are consistent with those observed in infants and toddlers vaccinated with Haemophilus influenzae type b (Hib),29 in which a vaccine using the diphtheria toxoid as the carrier protein was less immunogenic than a vaccine using CRM197. However, diphtheria toxoid is no longer used as a carrier protein in any currently licensed infant vaccines. Other differences between the vaccines include selective sizing of the oligosaccharides before conjugation (MenACWY-CRM) and the conjugation chemistry employed.30
The only available quadrivalent meningococcal vaccines for use outside North America are unconjugated polysaccharide vaccines, and at this time they are the only vaccines licensed for use in persons >55 years of age. Here, we have shown that immune responses following vaccination with MenACWY-CRM were higher for most meningococcal serogroups compared with those following vaccination with MPSV4 (Menomune) in subjects aged 56–65 years. This difference was particularly notable for serogroups A and Y, where GMTs induced by MenACWY-CRM exceeded those induced by MPSV4 by more than 4-fold (111 vs. 21 for serogroup A; 121 vs. 28 for serogroup Y). The clinical relevance of higher GMTs is unclear, but it is worth noting that higher proportions of participants achieved the putative seroprotective hSBA titer ≥1:8 against serogroups W-135 and Y in the 19–55 years age group, and serogroups A and Y in the 56–65 years age group, compared with the vaccines currently available for these populations. Although most subjects >55 years of age are presumably not naïve to these meningococcal antigens, these results are consistent with those from several other studies of vaccination of adults or the elderly with conjugate (pneumococcal or H. influenzae) vaccines relative to their unconjugated purified polysaccharide vaccine counterparts.31, 32, 33 Outside Canada and the USA, the meningococcal quadrivalent polysaccharide vaccine is the only vaccine available that provides broad serogroup protection against meningococcal disease, particularly in high risk groups such as travelers and the military. Given the dynamic epidemiology of meningococcal disease and the limitations of the polysaccharide vaccine previously discussed, broad protection for all ages is important, as one cannot rely on vaccines that only target local epidemiology to protect against serogroups encountered in other countries. These data indicate that MenACWY-CRM may provide an enhanced immune response to the currently available options.
There are three currently licensed meningococcal serogroup C conjugate vaccines (Meningitec, Wyeth Vaccines, Philadelphia, PA, USA; Menjugate, Novartis Vaccines, Siena, Italy; and NeisVac-C, Baxter Healthcare, Beltsville, MA, USA) that are available for use in children <2 years of age. However, there is no quadrivalent vaccine, either conjugate or polysaccharide, available for use in this age group (which has the highest incidence of meningococcal disease). MenACWY-CRM has previously been shown to be immunogenic and well tolerated in infants from 2 months of age,23, 24 children,25 adolescents,26 and adults from 19 to 65 years of age in this study. As such, and in view of the non-inferiority to the current options demonstrated in this report, it is significant that a vaccine which has been shown to be immunogenic in all age groups from infants to the elderly is non-inferior to a vaccine only licensed for the 2–55 years age group. MenACWY-CRM has the potential to expand meningococcal protection from currently available options for age and serogroup, and provide a public health benefit over and above currently available vaccines.
Conflict of interest: D. Stamboulian, G. Lopardo, P. Lopez, and C. Cortes-Barbosa have no conflicts of interest to declare. A. Valencia declares that she has received consulting fees and investigation honoraria from GlaxoSmithKline in the last two years and consulting fees from Abbott Laboratories. L. Bedell, A. Karsten, and P.M. Dull were all Novartis Vaccines employees at the time of the study.
Acknowledgements
This study was supported by Novartis Vaccines. Medical writing support was provided by Sarah Angus during the preparation of this paper, supported by Novartis Vaccines.
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PII: S1201-9712(10)02419-7
doi:10.1016/j.ijid.2010.03.017
© 2010 International Society for Infectious Diseases. Published by Elsevier Inc. All rights reserved.
Volume 14, Issue 10 , Pages e868-e875, October 2010
