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Hum Vaccin. Nov 2010; 6(11): 881–887.
PMCID: PMC3060384
Persistence of immune responses after a single dose of Novartis meningococcal serogroup A, C, W-135 and Y CRM-197 conjugate vaccine (Menveo®) or Menactra® among healthy adolescents
Christopher J Gill,corresponding author1 Roger Baxter,2 Alessandra Anemona,1 Giuseppe L Ciavarro,1 and Peter M Dull1
1Novartis Vaccines and Diagnostics; Cambridge, MA USA
2Kaiser Permanente Vaccine Study Center; Oakland, CA USA
corresponding authorCorresponding author.
Correspondence to: Christopher Gill; Email: christopher.gill/at/novartis.com
Received April 2, 2010; Revised June 16, 2010; Accepted June 27, 2010.
Abstract
The persistence of human bactericidal activity (hSBA) responses in adolescents was assessed 22 months after vaccination with one dose of Menveo® (MenACWY-CRM; Novartis) or Menactra® (MCV4) (sanofi pasteur). The proportion of subjects with hSBA titers ≥8 was significantly higher among recipients of MenACWY-CRM than MCV4 for serogroups A, W-135 and Y.
Key words: meningococcal disease, CRM-197, Menveo, Menactra, conjugate vaccine, neisseria meningitidis
The onset of invasive meningococcal disease may occur too rapidly to allow for established immune memory to respond.1 In the United Kingdom, individuals who received meningococcal serogroup C conjugate but who also developed invasive disease despite strong evidence of immune memory, had low serum bactericidal antibody titers.2 Similar findings have been observed among Hib vaccine failures,3 a circumstance that highlights the importance of persistence of immune responses after vaccination. Complement-mediated bacteriolysis of meningococci, measured by serum bactericidal assay is the established correlate of protection against invasive meningococcal disease.4,5
In a Phase III trial, healthy adolescents and adults received a single dose of quadrivalent meningococcal CRM197 conjugate vaccine (MenACWY-CRM, Menveo®) or a quadrivalent meningococcal diphtheria toxoid conjugate vaccine (MCV4, Menactra® sanofi pasteur). The proportion of MenACWY-CRM vaccinees with seroresponse, the primary immunogenicity measure, was statistically non-inferior compared with MCV4 vaccinees for all four serogroups, with evidence of statistically superior responses to some serogroups for primary and secondary immunogenicity measures.6,7 A pre-planned persistence (and still ongoing) study was initiated to assess immune responses up to seven years post-vaccination in adolescents. We present data from the first assessment, which was planned at 21 months postvaccination.
Of the 2,118 adolescents who completed the initial trial and were included in the per protocol population, 278 MenACWY-CRM recipients and 191 MCV4 recipients enrolled in the persistence study, as did 128 vaccine-naïve controls (Fig. 1). Of these, 33 failed entry criteria (31 in the control group were inappropriately age matched, 2 in the MenACWY-CRM) and 4 did not provide hSBA results (1 MenACWY-CRM and 3 MCV4 vaccinees).
Figure 1
Figure 1
Study population flow diagram.
Baseline characteristics (Table 1), were well balanced among groups. The mean age was 15.5 years (SD ±2.4) and 55% (328/597) were young men or boys. Overall, 81% (483/597) of participants were Caucasian, 8% (49/597) were Hispanic, 5% (31/597) were Black and 3% (20/597) were Asian (Table 1). A comparison of the primary responses measured in the base trial, and the subset who participated in the persistence trial, showed that the subset was very representative of the full cohort (Table 2).
Table 1
Table 1
Demographic characteristics at baseline
Table 2
Table 2
Representativeness of hSBA Geometric Mean Titers obtained at one month post vaccination comparing participants in the base study with the subset who participated in the persistence study.
The median follow-up for previous vaccinees was 22 months. Both previously vaccinated groups had evidence of higher immune responses than did naïve controls for all four serogroups, as assessed by hSBA titers ≥8 (Fig. 2A) and hSBA GMTs (Fig. 2B). A significantly higher proportion of MenACWY-CRM recipients than MCV4 recipients had persisting hSBA titers ≥8 for serogroups A, W-135 and Y and higher GMTs for serogroups A and Y (Figs. 2A and B). Among all previous vaccine recipients, the steepest declines in the proportion of participants with hSBA titers ≥8 were evident for serogroup A: 75% to 36% in the MenACWY-CRM group and 67% to 25% in the MCV4 group.
Figure 2
Figure 2
Figure 2
Figure 2
Immune responses to MenACWY-CRM or MCV4 at 1 and 22 months post vaccination. *MenACWY-CRM noninferior to MCV4. **MenACWY-CRM statistically higher than MCV4. Percentage of participants with human SBA titers ≥8 at 1 month post vaccination in the (more ...)
In the subset of participants evaluated by rSBA, 95–100% had rSBA titers ≥8 and 91–100% had titers ≥128 at 1 month post-vaccination. At 22 months, these proportions had fallen in both vaccine groups: 60–97% had titers ≥8 and 49–94% had titers ≥128, with higher percentages evident among MenACWY-CRM versus MCV4 recipients (Table 3). The rSBA GMTs at 22 months were significantly higher among MenACWY-CRM recipients compared with MCV4 recipients for serogroups W-135 and Y, and similar for serogroups A and C (Fig. 2C).
Table 3
Table 3
Proportion of subjects with rSBA titers =8 and =128, at 1 and 22 months post-vaccination with MenACWY-CRM or MCV-4
Adolescents who received a single dose of MenACWY-CRM had evidence of enduring immune responses a median of 22 months after a single dose of vaccine. The proportions of participants with hSBA titers ≥8 among MenACWY-CRM recipients were significantly higher than in the vaccine-naïve control group for all serogroups and for serogroups A, W-135 and Y compared with recipients of MCV4. A similar pattern of statistical differences between the two vaccines was seen 1 month post-vaccination.6 While higher GMTs immediately following vaccination are of uncertain clinical relevance generally, in this study, higher GMTs established initially corresponded with statistically higher proportions of subject exceeding the protective threshold of hSBA titers ≥8 nearly two years later. Overall, the percentage of subjects with hSBA titers ≥8 ranged from 54–84% for serogroups C, W and Y and 25–36% for serogroup A. Although the between-group statistical differences in persistence are clearly apparent, the interpretation of these results with respect to duration of disease protection is complicated. Additionally, while presence of bactericidal antibodies has been associated with protection against disease caused by serogroup C, and by inference other serogroups, the absence of bactericidal antibodies may not indicate susceptibility.5,8
Studies of complement sources for use in assays evaluating meningococcal vaccines have been of interest since the development of the serogroup C meningococcal conjugate vaccines.2,4,5,911 As expected based on existing knowledge about the differences in human and rabbit as sources of complement for bactericidal assays, the titers measured by rSBA greatly exceeded those generated by hSBA.12 Previous studies have found a lack of correlation between hSBA and rSBA results;12 however, our data did not detect any instances where the rSBA results contradicted the hSBA results. For serogroups A, W-135 and Y, MenACWY-CRM recipients were significantly more likely than MCV4 recipients to have evidence of bactericidal antibodies almost 2 years after vaccination, regardless of the complement source used, while the proportions of subjects achieving rSBA or hSBA titers ≥8 were similar for serogroup C in recipients of both vaccines. While serogroup C disease remains of particular epidemiologic concern globally, in several countries including the United States, serogroup Y has emerged as a significant contributor to invasive disease incidence.13
One limitation of this study is that the population represented only a subset of the full cohort of subjects vaccinated in the initial study.6 Nevertheless, the consistency of results among the cohorts included in the persistence study and those in the primary study indicate that the immune responses of the subset were representative of the full cohort, minimizing concerns about selection bias. Another limitation of the current report is that it did not identify the critical point at which protection was no longer evident. Predefined assessments in future years are intended to provide this information. In addition, it was observed that the naïve controls were, on average, slightly younger than the age matched subjects from the parent study. This can be explained by the fact that the controls were enrolled to match within a range of ages relative to the vaccinated subjects, but because of the routine utilization of MCV4 in adolescents as per ACIP guidelines,14 it was relatively more difficult to identify controls at the higher ends of the range than at the lower end. The consequence is that this could have the effect of slightly underestimating the background rate of naturally acquired immunity to meningococcal disease, though given the slow pace by which natural immunity is acquired over time,15 it seems unlikely that this would be a significant limitation.
In summary, recipients of the MenACWY-CRM was immunogenic at the post-primary (1 month) and demonstrated strong persistence at a median of 22 months post vaccination, and led to a statistically higher proportion of subjects with hSBA titers ≥8 for serogroups A, W-135 and Y than did MCV4. Given that hSBA titers have been correlated with protection against invasive meningococcal disease due to serogroup C,5,16 these results may infer a potential advantage of the MenACWY-CRM vaccine over time, and may be relevant in determining the need for, and/or timing of a booster dose of meningococcal vaccine for older adolescents.
Study population.
Participants in the initial trial (V59P13)6 were healthy adolescents 11–18 years of age. Those with an evaluable serologic response and no major protocol deviations, who met all inclusion/exclusion criteria, and had no medical conditions that could interfere with immunogenicity assessment, were invited to participate in the persistence study. An age-matched vaccine-naïve control group was enrolled concurrently.
Study design.
A list of eligible subjects was compiled separately for MenACWY-CRM and MCV4 and sorted by subject identification number, as in the original study; to avoid selection bias, sites were instructed to approach subjects sequentially to solicit enrollment into the extension study, starting from the top of the list. In an effort to maintain an approximate balance between the group sizes for the extension study, sites were requested to attempt to match their enrollment of MenACWY-CRM subjects with MCV4 subjects as far as reasonably possible. Eligible participants underwent a single blood draw 21 months after the vaccination; age-matched controls were offered a dose of licensed MCV4 (MenACWY-CRM was not yet licensed) after providing a blood sample.
Serology.
The serum bactericidal assay using human complement (hSBA) is the original correlate of protection against meningococcal disease. Assays using rabbit complement (rSBA) are also used and have been the basis for licensure of several meningococcal vaccines.9 A blinded analysis by hSBA was performed by Novartis Vaccines serology laboratory in Marburg, Germany, using methods as previously described.6 Sera from 100 participants included in the per-protocol analysis from each of the active groups and 50 from the control group were randomly selected to undergo further testing with rSBA, which was performed by the Vaccine Evaluation Unit of the Health Protection Agency, Manchester Royal Infirmary, UK (Dr. Ray Borrow), as previously described.6 The lab staff conducting the hSBA and the rSBA testing were blinded to group allocation.
Statistical methods.
The primary objective of this study was to determine the percentage of participants with an hSBA titer ≥8. An attrition of 50% was assumed between the first persistence time point at 2 years and the last at 7 years. Thus, the target enrollment goal was 200 MenACWY-CRM and 200 MCV4 subjects from the parent study, and 100 naïve subjects at each time point. With a sample size of 100 subjects per group there is at least 80 power to detect a 20% percent point difference between two groups assuming the percentage of subjects with hSBA titer ≥8 in the MenACWY-CRM group is equal to 70%.
The primary endpoint was the proportion of participants with evidence of seroprotection (defined as an hSBA titer ≥8) among recipients of an active vaccine in the initial study.6 Persistence of immune response was also evaluated by hSBA geometric mean titers (GMTs) and comparisons were made for all assessments with vaccine-naïve subjects. An analysis of hSBA titers ≥4 was also planned (data not shown). For rSBA, the proportions of each study group with titers ≥8 and ≥128, per convention,12 were calculated as were GMTs. Between-group comparisons were made with two-sided 95% Clopper-Pearson confidence intervals. The GMTs were constructed by exponentiating the least square means of the logarithmically transformed (base 10) titers and their 95% CIs from a one-way analysis of variance model (ANOVA) with factors for vaccine group. Data were analyzed using SAS version 9.1 (SAS Institute Inc., Cary, NC USA).
Acknowledgements
Lisa Jackson, Wilson Andrews, Stan Block, Blaise Congeni, Keith Reisinger, Edward Rothstein, Richard Rupp, Shelly David Senders and Shane Christiansen enrolled participants into the study and made assessments. Lisa Danzig participated in the initial study and provided early guidance. Annette Karsten performed and supervised hSBA testing at Novartis Vaccines in Marburg, Germany. Lisa DeTora provided editorial and content guidance.
Footnotes
Financial Support
The study was funded by Novartis Vaccines and Diagnostics. ClinicalTrials.gov Identifier: NCT00856297.
Conflicts of Interest
C.J.G. (clinical), A.A. (biostatistics), G.L.C. (clinical), P.M.D. (clinical) are members of the clinical development team for Menveo® at Novartis Vaccines. RB has received research grants from Merck, sanofi pasteur, Protein Sciences, GlaxoSmithKline, Chiron Novartis and MedImmune.
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