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Antibody persistence to meningococcal serogroups A, C, W and Y in toddlers two years after vaccination with a quadrivalent meningococcal ACWY-tetanus toxoid conjugate (MenACWY-TT) vaccine as measured by bactericidal antibody assays using rabbit or human complement
Trials in Vaccinology 3 (2014) 121–126
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Antibody persistence to meningococcal serogroups A, C, W and Y in toddlers two years after vaccination with a quadrivalent meningococcal ACWY-tetanus toxoid conjugate (MenACWY-TT) vaccine as measured by bactericidal antibody assays using rabbit or human complement q Timo Vesikari a,⇑, Aino Forsten a, Veronique Bianco b, Marie Van der Wielen b, Jacqueline M. Miller c a
Vaccine Research Center, University of Tampere Medical School, Tampere, Finland GlaxoSmithKline Vaccines, Av Fleming 20, Parc de la Noire Epine, 1300 Wavre, Belgium c GlaxoSmithKline Vaccines, 2301 Renaissance Boulevard, RN0220, King of Prussia, PA 19406, United States b
a r t i c l e
i n f o
Article history: Received 19 March 2014 revised 26 June 2014 Accepted 26 June 2014
Keywords: Quadrivalent meningococcal conjugate vaccine Antibody persistence Neisseria meningitidis Serum bactericidal activity
a b s t r a c t Long term protection against invasive meningococcal disease relies on persistence of bactericidal antibodies. We studied the persistence of serum bactericidal antibodies using rabbit and human complement (rSBA, hSBA assays) two years after vaccination with a meningococcal serogroup A, C, W, Y tetanus toxoid conjugate vaccine (MenACWY-TT, N = 253) or a licensed monovalent serogroup C conjugate vaccine (MenC-CRM197, N = 42) in Finnish toddlers who were aged 12–23 months at the time of vaccination. In 97.8–98.9% of subjects receiving MenACWY-TT, rSBA titres P1:8 persisted against serogroups A, W and Y and 88.2% against serogroup C, which was according to exploratory analysis statistically significantly higher than in recipients of the MenC-CRM197 vaccine (69.0%). A total of 86.9% of subjects had persisting hSBA P1:8 for serogroup C, which was statistically significantly higher than the MenC-CRM group (52.6%). Exploratory analysis also showed that the year 2 hSBA-MenC geometric mean titre was statistically significantly higher in the MenACWY-TT group than the MenC-CRM group. At least 87.0% of subjects had hSBA P1:8 for serogroups W and Y at year 2, while the percentage was 23.0% for serogroup A. Using rSBA, but not hSBA, a high percentage of MenC-CRM197 recipients acquired antibody against serogroups A (82.1%), W (58.6%) and Y (80.0%). MenACWY-TT induced high level of bactericidal antibody in toddlers that persisted for at least 2 years. Ó 2014 Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http:// creativecommons.org/licenses/by-nc-nd/3.0/).
Introduction
Abbreviations: CI, confidence interval; GMT, geometric mean antibody titre; hSBA, human complement bactericidal antibody assay; MenACWY-CRM, combined N. meningitidis serogroups A, C, W and Y-CRM197 conjugate vaccine; MenACWY-DT, combined N. meningitidis serogroups A, C, W and Y-diphtheria toxoid conjugate vaccine; MenACWY-TT, combined N. meningitidis serogroups A, C, W and Y-tetanus toxoid conjugate vaccine; MenC, N. meningitidis serogroup C polysaccharide; rSBA, rabbit complement bactericidal antibody assay; SAE, serious adverse event; SD, standard deviation; TT, tetanus toxoid. q
This study has been registered at www.clinicaltrials.gov NCT00955682.
⇑ Corresponding author. Address: Vaccine Research Center, University of Tampere Medical School, Biokatu 10, FM3, FI-33014 University of Tampere, Finland. Tel.: +358 50 524 6530; fax: +358 3 364 1512. E-mail addresses: timo.vesikari@uta.fi (T. Vesikari), aino.forsten@uta.fi (A. Forsten), [email protected] (V. Bianco), [email protected] (M. Van der Wielen), [email protected] (J.M. Miller).
The highest incidence of invasive meningococcal disease occurs in infants followed by young children [1–3]. Monovalent serogroup C (MenC) conjugate vaccines have been successfully used to prevent invasive meningococcal disease in infants, toddlers and individuals up to 18 years of age since 1999 [4]. The duration of protection afforded by vaccination is not yet known, although evidence from children who experienced vaccine failure suggests that circulating antibody is needed for protection against invasive disease [5]. We previously demonstrated that a quadrivalent meningococcal conjugate vaccine with four serogroup polysaccharides, A, C, W and Y, all conjugated to tetanus toxoid (MenACWY-TT), administered to toddlers, induced high levels of bactericidal antibodies to serogroup A, W, and Y and was non-inferior to licensed
http://dx.doi.org/10.1016/j.trivac.2014.06.003 1879-4378/Ó 2014 Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/3.0/).
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monovalent meningococcal MenC conjugate vaccine (MenCCRM197) in terms of seroresponse to serogroup C [6]. We subsequently studied antibody persistence against each serogroup two years after primary vaccination, using serum bactericidal assays with either rabbit (rSBA) or human (hSBA) complement. Demonstration of a serological correlate of protection for serogroup C was done using rSBA in post-licensure effectiveness studies [7,8], whereas hSBA titres P1:4 are considered protective for serogroup C [9]. Methods In the primary vaccination study in Finland (www.clinicaltrials.gov NCT00474266), 12–23 month old toddlers randomised to receive primary vaccination with MenACWY-TT (containing 5 lg of each meningococcal serogroup A, C, W and Y polysaccharide conjugated to tetanus toxoid: N = 749), or MenC-CRM197 (Meningitec™ Pfizer Inc., containing 10 lg of MenC polysaccharide conjugated to mutant diphtheria toxoid CRM protein: N = 251) [6]. All children were invited to participate in the assessment of antibody persistence at year 2 (NCT00955682). Children were not allowed to participate if they had developed meningococcal disease or received any meningococcal vaccination since the primary vaccination study, or if they had an intervening immunocompromising condition, or had received immunoglobulin or blood products within 3 months of the study visit. The protocol and associated documents were reviewed and approved by the ethics committee of Pirkanmaa Hospital District. Written informed consent was obtained from the parents/guardians of children before study procedures were performed. Bactericidal activity was assessed at GlaxoSmithKline Vaccines’ laboratory using a serum bactericidal assay with rabbit and human complement (rSBA, hSBA, respectively) as previously described [10]. The assay cut-offs were 1:8 for rSBA and 1:4 for hSBA. For rSBA and hSBA we also considered more conservative thresholds
of 1:128 and 1:8, respectively. An hSBA titre P1:4 was demonstrated to correlate with protection in humans who developed natural immunity to serogroup C [9]. A rSBA titre of P1:8 was shown to correlate with protection in populations vaccines with monovalent serogroup C vaccines [7,11]. It is common practice to extend these thresholds to the other vaccine serogroups. The primary objective was to assess the percentage of subjects with rSBA antibody titres P1:8 for each of the four serogroups. Evaluation of antibody persistence using hSBA was a secondary objective. Serious adverse events (SAEs) considered by the investigator to be related to study procedures or GlaxoSmithKline concomitant medication were captured retrospectively at the year 2 study visit. An exploratory evaluation of the differences at each time point was performed for the percentage of subjects with rSBA-MenC antibody titres P1:8 and P1:128 and hSBA-MenC antibody titres P1:4 and P1:8 with standardised asymptotic 95% CIs and the ratio of the rSBA-MenC and hSBA-MenC GMTs with 95% CIs between the MenACWY-TT and MenC-CRM groups. A statistically significant difference was indicated if the value ‘1’ was excluded from the 95% CI on the GMT ratios or if the value ‘0’ was excluded from the 95% CI on differences between groups. Note that potential differences should be interpreted with caution considering that there was no adjustment for multiplicity for these comparisons. Statistical analyses were performed using SASÒ software version 9.2 (SAS Institute Inc., Cary, NC, United States) and ProcStatXact 8.1. Results The year 2 follow-up study took place between 25 August and 16 December 2009. There were 295 subjects who returned at year 2 (253 in the MenACWY-TT group and 42 in the MenC-CRM group). Of these, 218 subjects contributed to the According-to-protocol persistence cohort (Fig. 1). The median time since the primary
Primary vaccination at 12-23 months of age N=1000 Subjects randomised (3:3:1:1)
MenACWY-TT+MMRV N=375
MenACWY-TT→MMRV N=374
MMRV→MenC-CRM N=126
MenC-CRM→MMRV N=125
Year 2 Blood sample N=295 MenACWY-TT group N=253 (120 F, 133 M) age 40.7 (1.87) months*
MenC-CRM group N=42 (20 F, 22 M) age 41.1 (1.74) months*
65 eliminated: not eligible (2); eliminated during primary study (2); non-compliance with blood sampling schedule (59); sample not taken or quantity not sufficient (2) N=188
12 eliminated: non-compliance with blood sampling schedule (12) N=30
Year 2 ATP persistence cohort N=218 Fig. 1. Subject flow. ⁄Mean age (standard deviation); F = female, M = male. N = number of subjects in each group/cohort. Primary vaccination study: MenACWYTT + MMRV = subjects vaccinated with MenACWY-TT co-administered with MMRV; MenACWY-TT ? MMRV = subjects vaccinated with MenACWY-TT and 42 days later with MMRV; MMRV ? MenC-CRM = subjects vaccinated with MMRV and 42 days later with MenC-CRM197; MenC-CRM ? MMRV = subjects vaccinated with MenC-CRM197 and 42 days later with MMRV. Persistence study: MenACWY-TT = subjects previously primed with MenACWY-TT (with or without MMRV), i.e., pooled MenACWY-TT + MMRV and MenACWY-TT ? MMRV groups. MenC-CRM197 = subjects previously primed with MenC-CRM197 (given 42 days before or after MMRV), i.e., pooled MMRV ? MenC-CRM and MenC-CRM ? MMRV groups.
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Table 1 rSBA and hSBA antibody persistence 42 days and 2 years after vaccination with MenACWY-TT or MenC-CRM197 at 12–23 months of age (According-to-protocol cohort for persistence at Year 2). Serogroup
MenACWY-TT
rSBA
N
% P1:8 [95% CI]
% P1:128 [95% CI]
GMT [95% CI]
N
% P1:8 % [95% CI]
% P1:128 [95% CI]
GMT [95% CI]
186 181 184 186 186 188 185 188
100 [98.0; 100] 97.8 [94.4; 99.4] 100 [98.0; 100] 88.2 [82.6; 92.4] 100 [98.0; 100] 98.9 [96.2; 99.9] 100 [98.0; 100] 97.9 [94.6; 99.4]
100 [98.0; 100] 91.7 [86.7; 95.3] 94.0 [89.6; 97.0] 48.4 [41.0; 55.8] 100 [98.0; 100] 91.0 [85.9; 94.6] 100 [98.0; 100] 81.9 [75.7; 87.1]
1924 [1698; 2181] 420 [356; 496] 447 [397; 503] 98 [78; 124] 2241 [1999; 2512] 397 [342; 461] 2550 [2213; 2937] 397 [324; 486]
14 28 30 29 16 29 16 30
50.0 82.1 93.3 69.0 50.0 58.6 75.0 80.0
28.6 57.1 60.0 48.3 18.8 41.4 56.3 66.7
[8.4; 58.1] [37.2; 75.5] [40.6; 77.3] [29.4; 67.5] [4.0; 45.6] [23.5; 61.1] [29.9; 80.2] [47.2; 82.7]
22 [7; 66] 91 [46; 178] 146 [84; 255] 54 [26; 112] 22 [7; 65] 42 [19; 96] 88 [30; 262] 151 [69; 331]
N
% P1:4 [95% CI]
% P1:8 [95% CI]
GMT [95% CI]
N
% P1:4 % [95% CI]
% P1:8 [95% CI]
GMT [95% CI]
179 183 179 175 176 180 169 154
83.2 25.1 98.3 88.0 81.8 92.8 79.3 87.0
81.0 23.0 98.3 86.9 81.3 91.1 79.3 87.0
23.2 [18.7; 28.7] 3.8 [3.2; 4.5] 170.2 [143.4; 202.0] 50.2 [38.7; 65.1] 42.1 [32.4; 54.7] 77.7 [61.8; 97.6] 29.5 [22.8; 38.1] 58.1 [44.5; 75.8]
23 23 23 19 23 23 23 22
0.0 [0.0; 14.8] 8.7 [1.1; 28.0] 82.6 [61.2; 95.0] 57.9 [33.5; 79.7] 4.3 [0.1; 21.9] 0.0 [0.0; 14.8] 4.3 [0.1; 21.9] 22.7 [7.8; 45.4]
0.0 [0.0; 14.8] 0.0 [0.0; 14.8] 82.6 [61.2; 95.0] 52.6 [28.9; 75.6] 4.3 [0.1; 21.9] 0.0 [0.0; 14.8] 4.3 [0.1; 21.9] 22.7 [7.8; 45.4]
2.0 [2.0; 2.0] 2.2 [1.9; 2.4] 45.9 [21.0; 100.1] 10.4 [4.7; 22.8] 2.3 [1.8; 2.9] 2.0 [2.0; 2.0] 2.5 [1.6; 4.1] 5.0 [2.2; 11.1]
A C W Y
M1 Y2 M1 Y2 M1 Y2 M1 Y2
hSBA A C W Y
M1 Y2 M1 Y2 M1 Y2 M1 Y2
[76.9; [19.0; [95.2; [82.2; [75.3; [88.0; [72.4; [80.7;
MenC-CRM197
88.4] 32.1] 99.7] 92.4] 87.2] 96.1] 85.1] 91.9]
[74.5; [17.1; [95.2; [80.9; [74.7; [86.0; [72.4; [80.7;
86.5] 29.7] 99.7] 91.5] 86.7] 94.8] 85.1] 91.9]
[23.0; [63.1; [77.9; [49.2; [24.7; [38.9; [47.6; [61.4;
77.0] 93.9] 99.2] 84.7] 75.3] 76.5] 92.7] 92.3]
M1 = 42 days after vaccination; Y2 = 2 years after vaccination; N = number of subjects with available results. Note that in the case of insufficient sera, not all assays were able to be performed; 95% CI = 95% confidence interval.
vaccination dose was 26 months. Subjects in the two pooled treatment groups were similar in terms of age and gender (Fig. 1). rSBA antibodies Two years after primary vaccination, 97.8–98.9% of subjects in the MenACWY-TT group had persisting rSBA antibody titres P1:8 for serogroups A, W and Y, and 88.2% for serogroup C (Table 1).
For each serogroup, rSBA GMTs decreased by year 2 but remained higher than pre-vaccination levels (Table 1 and Fig. 2). The percentage of subjects in the MenC-CRM group with serogroup C rSBA titres P1:8 was 69.0% (Table 1). The rSBA-MenC GMT decreased by year 2 but remained higher than prevaccination levels (Table 1 and Fig. 2). The exploratory group comparison indicated that antibody persistence for serogroup C was significantly higher in the
Fig. 2. Reverse cumulative curves for rSBA titres at pre- and post-vaccination and at year 2 (M24) (ATP cohort for persistence at year 2).
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Fig. 3. Reverse cumulative curves for hSBA titres at pre- and post-vaccination and at year 2 (M24) (ATP cohort for persistence at year 2).
MenACWY-TT group than in the MenC-CRM group as measured by the percentage of subjects with rSBA titres P1:8. No statistically significant differences between groups were observed for the percentage with rSBA-MenC titres P1:128 or for the rSBA-MenC GMT at year 2 (exploratory analysis). After primary vaccination the percentage of MenC-CRM197 recipients with rSBA titres P1:8 was 50.0% for serogroups A and W, and 75.0% for serogroup Y. At year 2, the percentages had increased to 82.1% for serogroup A, 58.6% for W and 80.0% for Y. hSBA antibodies Two years after primary vaccination, the percentage of subjects in the MenACWY-TT group with persisting hSBA antibody titres P1:8 was 86.9% for serogroup C, 91.1% for W and 87.0% for Y, while only 23.0% retained hSBA antibody for serogroup A (Table 1). For serogroups A and C, hSBA GMTs decreased by year 2 but remained higher than pre-vaccination levels (Table 1 and Fig. 3). The percentage of subjects in the MenC-CRM group with hSBAMenC titres P1:8 was 52.6%. The hSBA-MenC GMT reduced by year 2 but remained higher than pre-vaccination levels (Table 1 and Fig. 3). The exploratory group comparison indicated that antibody persistence for serogroup C was statistically significantly higher in the MenACWY-TT group than in the MenC-CRM group in terms of the percentage of subjects with hSBA titres P1:8 and the hSBAMenC GMT. In contrast to measurements using rSBA, few subjects in the MenC-CRM group had antibody titres P1:8 against the other serogroups using hSBA: 0.0% for serogroups A and W, and 22.7% for serogroup Y.
Safety No vaccine-related SAEs were reported from the end of the primary vaccination study until the year 2 persistence visit. Discussion This study of antibody persistence in toddlers showed that antibodies as measured by rSBA persisted in the majority of subjects vaccinated with MenACWY-TT until 2 years after vaccination. Exploratory analyses conducted after the primary vaccination dose indicated that the post-vaccination rSBA-MenC GMT was statistically significantly higher in MenACWY-TT recipients than in MenC-CRM197 recipients [6]. In-line with these results, we observed a higher percentage of subjects with rSBA-MenC titres P1:8 in the MenACWY-TT group compared to the MenC-CRM group at year 2 (exploratory analysis). The results of our study using the GSK rSBA are consistent with other studies of MenACWY-TT persistence in adolescents and children where the same assay was employed [12–14]. Good antibody persistence up until 3 years after vaccination of adolescents with MenACWY-TT has been demonstrated, while in toddlers, persisting antibody levels have been observed to be similar or higher than after vaccination with licensed MenC-CRM197 [13–17]. In MenACWY-TT-primed children, hSBA antibodies for serogroups C, W and Y persisted until year 2, whereas hSBA for serogroup A declined rapidly (23.0% P 1:8 at year 2). Similar rapid decay of hSBA-MenA antibodies has been observed using other quadrivalent vaccines tested for hSBA by different laboratories: five years after vaccination of infants with three doses of
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MenACWY-CRM197 (Menveo™ Novartis) the percentage with hSBAMenA P1:8 was no higher than 4% [18]. Two years after vaccination of adolescents with MenACWY-CRM197 or MenACWY-DT, the percentage with hSBA-MenA P1:8 had decreased from 75% to 36%, and from 67% to 25%, respectively [19]. Persistence of hSBA for the other serogroups after MenACWYTT vaccination appeared comparable to other quadrivalent vaccines: 2–3 years after vaccination of 2–3 year olds with a single dose of MenACWY-DT (Menactra™ Sanofi Pasteur), 14.6% of children had hSBA P1:4 [20]; five years after 3 MenACWYCRM197 doses by 12 months of age, hSBA P1:8 for serogroups C, W and Y was observed in 27–45%, 81–84% and 42–57%, respectively [18]. In the present study we observed that rSBA antibody GMTs for serogroups A, W and Y increased at year 2 in the control group who had not received vaccination with these serogroups. The percentage of subjects with rSBA titres P1:8 for serogroups A, W and Y increased to as high as 82.1% (serogroup A) by year 2. The observed increases in rSBA probably reflects the development of natural immunity during childhood [9,21]. Natural immunity develops through production of IgM, and rabbit complement is thought to be activated by IgM as well as IgG [22,23]. By contrast, hSBA titres remained very low for serogroups A and W in MenC-CRM197 recipients, while the percentage of children with hSBA-MenY titres P1:8 increased to 22.7%. The increase in hSBA-MenY titres over time may reflect natural exposure to serogroup Y, which in Finland, along with other Scandinavian countries, causes a substantial proportion of invasive meningococcal disease [24]. Thus, the GSK rSBA and GSK hSBA assays detect natural immunity differently, with the GSK rSBA assay having a greater sensitivity than the GSK hSBA assay. It is unclear whether natural immunity as measured by GSK rSBA represents true seroprotection in contrast to the vaccine-induced immunity measured with this assay. hSBA GMTs (but not rSBA GMTs) for serogroup W and Y were also observed to increase between month 1 and year 2 in the MenACWY-TT group. Similar observations have been made by other authors after vaccination of infants with Menveo™ [25], and after vaccination of toddlers with Menactra™ [26], possibly as a result of avidity maturation, a slower antibody response, or a boosting effect due to natural exposure. Follow-up of our study cohort is planned until year 10 post-vaccination. At year 4, children were invited to receive a booster dose of the same meningococcal vaccine they had received at 12– 23 months of age (results published elsewhere). We used GSK’s rSBA until year 2 and samples collected after year 2 will be tested at a different laboratory. Thus, the present results will not be directly comparable with future persistence studies. Conclusions In conclusion, 2 years after a single dose of MenACWY-TT administered to toddlers, antibodies measured by both rSBA and hSBA assays persisted for all serogroups A, C, W and Y, with indication of higher antibody persistence for serogroup C after vaccination with MenACWY-TT than with MenC-CRM197. Sources of support GlaxoSmithKline Biologicals SA was the funding source and was involved in all stages of the study conduct and analysis. GlaxoSmithKline Biologicals SA also funded all costs associated with the development and the publishing of the present manuscript. The corresponding author had full access to the data and was responsible for submission of the publication.
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Authors’ contributions Pr Vesikari and Dr. Forsten were investigators involved in the supervision of the study, administrative, logistic and technical supports, the recruitment and the medical evaluation of subjects, the evaluation of any reported SAEs for causality, the collection and interpretation of the data, and the drafting and approval of the manuscript. Dr. J.M. Miller, Dr. M. Van der Wielen (clinical development scientists) and V. Bianco (biostatistician) are employed by GlaxoSmithKline Vaccines and were involved in all stages of the study (study design, data analyses and interpretations, drafting and approval of the manuscript). Acknowledgments The authors thank the families and children who participated in the study as well as the participating investigators and nurses without whom this study would not have been possible. We are also grateful to teams in GlaxoSmithKline Vaccines for their contribution to this study, including Markku Pulkkinen, Taneli Puumalainen and Sindia Troletti for their assistance in coordination of the study, Emmanuel Aris for input into statistical analysis, Mark Franco and Leentje Moerman for protocol writing and Pascal R Lestrate for conducting laboratory assays. We also thank Drs. Joanne Wolter (on behalf of GlaxoSmithKline Vaccines) and Virginie Durbecq (XPE Pharma & Science, on behalf of GlaxoSmithKline Vaccines) for providing writing and editorial support in preparing this manuscript. References [1] A.C. Cohn, J.R. MacNeil, L.H. Harrison, C. Hatcher, J. Theodore, M. Schmidt, et al., Changes in Neisseria meningitidis disease epidemiology in the United States, 1998–2007: implications for prevention of meningococcal disease, Clin. Infect. Dis. 50 (2010) 184–191. [2] L.H. Harrison, C.L. Trotter, M.E. Ramsay, Global epidemiology of meningococcal disease, Vaccine 27 (Suppl. 2) (2009) B51–B63. [3] S.A. Halperin, J.A. Bettinger, B. Greenwood, L.H. Harrison, J. Jelfs, S.N. Ladhani, et al., The changing and dynamic epidemiology of meningococcal disease, Vaccine 30 (Suppl. 2) (2012) B26–B36. [4] E. Miller, D. Salisbury, M. Ramsay, Planning, registration, and implementation of an immunisation campaign against meningococcal serogroup C disease in the UK: a success story, Vaccine 20 (Suppl. 1) (2001) S58–S67. [5] C. Auckland, S. Gray, R. Borrow, N. Andrews, D. Goldblatt, M. Ramsay, et al., Clinical and immunologic risk factors for meningococcal C conjugate vaccine failure in the United Kingdom, J. Infect. Dis. 194 (2006) 1745–1752. [6] T. Vesikari, A. Karvonen, V. Bianco, M. Van der Wielen, J. Miller, Tetravalent meningococcal serogroups A, C, W-135 and Y conjugate vaccine is well tolerated and immunogenic when co-administered with measles-mumpsrubella-varicella vaccine during the second year of life: an open, randomized controlled trial, Vaccine 29 (2011) 4274–4284. [7] N. Andrews, R. Borrow, E. Miller, Validation of serological correlate of protection for meningococcal C conjugate vaccine by using efficacy estimates from postlicensure surveillance in England, Clin. Diagn. Lab. Immunol. 10 (2003) 780–786. [8] R. Borrow, N. Andrews, D. Goldblatt, E. Miller, Serological basis for use of meningococcal serogroup C conjugate vaccines in the United Kingdom: reevaluation of correlates of protection, Infect. Immun. 69 (2001) 1568–1573. [9] I. Goldschneider, E.C. Gotschlich, M.S. Artenstein, Human immunity to the meningococcus. I. The role of humoral antibodies, J. Exp. Med. 129 (1969) 1307–1326. [10] S.E. Maslanka, L.L. Gheesling, D.E. Libutti, K.B. Donaldson, H.S. Harakeh, J.K. Dykes, et al., Standardization and a multilaboratory comparison of Neisseria meningitidis serogroup A and C serum bactericidal assays. The Multilaboratory Study Group, Clin. Diagn. Lab. Immunol. 4 (1997) 156–167. [11] R. Borrow, P. Balmer, E. Miller, Meningococcal surrogates of protection – serum bactericidal antibody activity, Vaccine 23 (2005) 2222–2227. [12] L. Ostergaard, M. Van der Wielen, V. Bianco, J.M. Miller, Persistence of antibodies for 42 months following vaccination of adolescents with a meningococcal serogroups A, C, W-135, and Y tetanus toxoid conjugate vaccine (MenACWY-TT), Int. J. Infect. Dis. (2012). [13] T. Vesikari, A. Forstén, D. Boutriau, V. Bianco, M. Van der Wielen, J.M. Miller, A randomized study to assess the immunogenicity, antibody persistence and safety of a tetravalent meningococcal serogroups A, C, W-135 and Y tetanus toxoid conjugate vaccine in children aged 2–10 y, Hum. Vaccin. Immunother. 8 (2012).
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[14] M. Knuf, Y. Baine, V. Bianco, D. Boutriau, J.M. Miller, Antibody persistence and immune memory 15 mo after priming with an investigational tetravalent meningococcal tetanus toxoid conjugate vaccine (MenACWY-TT) in toddlers and young children, Hum. Vaccin. Immunother. 8 (2012) 866–872. [15] T. Vesikari, A. Forstén, D. Boutriau, V. Bianco, M. Van der Wielen, J.M. Miller, Randomized trial to assess the immunogenicity, safety and antibody persistence up to three years after a single dose of a tetravalent meningococcal serogroups A, C, W-135 and Y tetanus toxoid conjugate vaccine in toddlers, Hum. Vaccin. Immunother. 8 (2012) 1892–9038. [16] T. Vesikari, A. Forstén, M. Van der Wielen, V. Bianco, J. Miller, Persistent antibody responses up to 5 years following vaccination with MenACWY-TT in toddlers and children aged 1–10 years, in: 12th European Monitoring Group on Meningococci (EMGM), Bad Loipersdorf, Austria, 17–19 September, 2013. [17] T. Vesikari, A. Forstén, V. Bianco, M. Van der Wielen, J. Miller, Antibody persistence 4 years after vaccination with a quadrivalent meningococcal ACWY tetanus toxoid conjugate vaccine in healthy toddlers, in: European Society for Paediatric Infectious Diseases, Milan, Italy, 28 May–1 June, 2013. [18] A. Khatami, M.D. Snape, E. Davis, H. Layton, T. John, L.-M. Yu, et al., Persistence of the immune response at 5 years of age following infant immunisation with investigational quadrivalent MenACWY conjugate vaccine formulations, Vaccine 30 (2012) 2831–2838. [19] C.J. Gill, R. Baxter, A. Anemona, G. Ciavarro, P. Dull, Persistence of immune responses after a single dose of Novartis meningococcal serogroup A, C, W-135 and Y CRM-197 conjugate vaccine (MenveoÒ) or MenactraÒ among healthy adolescents, Hum. Vaccin. 6 (2010) 881–887.
[20] D.M. Granoff, A. Morgan, J.A. Welsch, Persistence of group C anticapsular antibodies two to three years after immunization with an investigational quadrivalent Neisseria meningitidis-diphtheria toxoid conjugate vaccine, Pediatr. Infect. Dis. J. 24 (2005) 132–136. [21] I. Goldschneider, E.C. Gotschlich, M.S. Artenstein, Human immunity to the meningococcus. II. Development of natural immunity, J. Exp. Med. 129 (1969) 1327–1348. [22] W.D. Zollinger, R.E. Mandrell, Importance of complement source in bactericidal activity of human antibody and murine monoclonal antibody to meningococcal group B polysaccharide, Infect. Immun. 40 (1983) 257–264. [23] R.E. Mandrell, F.H. Azmi, D.M. Granoff, Complement-mediated bactericidal activity of human antibodies to poly alpha 2 ? 8 N-acetylneuraminic acid, the capsular polysaccharide of Neisseria meningitidis serogroup B, J. Infect. Dis. 172 (1995) 1279–1289. [24] M. Bröker, S. Jacobsson, M. Kuusi, D. Pace, M.J. Simões, A. Skoczynska, et al., Meningococcal serogroup Y emergence in Europe: update 2011, Hum. Vaccin. Immunother. 8 (2012) 1907–1911. [25] S.A. Halperin, F. Diaz-Mitoma, P. Dull, A. Anemona, F. Ceddia, Safety and immunogenicity of an investigational quadrivalent meningococcal conjugate vaccine after one or two doses given to infants and toddlers, Eur. J. Clin. Microbiol. Infect. Dis. 29 (2010) 259–267. [26] D.M. Granoff, A. Morgan, J.A. Welsch, Immunogenicity of an investigational quadrivalent Neisseria meningitidis-diphtheria toxoid conjugate vaccine in 2year old children, Vaccine 23 (2005) 4307–4314.
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Trials in Vaccinology journal homepage: www.elsevier.com/locate/trivac
Antibody persistence to meningococcal serogroups A, C, W and Y in toddlers two years after vaccination with a quadrivalent meningococcal ACWY-tetanus toxoid conjugate (MenACWY-TT) vaccine as measured by bactericidal antibody assays using rabbit or human complement q Timo Vesikari a,⇑, Aino Forsten a, Veronique Bianco b, Marie Van der Wielen b, Jacqueline M. Miller c a
Vaccine Research Center, University of Tampere Medical School, Tampere, Finland GlaxoSmithKline Vaccines, Av Fleming 20, Parc de la Noire Epine, 1300 Wavre, Belgium c GlaxoSmithKline Vaccines, 2301 Renaissance Boulevard, RN0220, King of Prussia, PA 19406, United States b
a r t i c l e
i n f o
Article history: Received 19 March 2014 revised 26 June 2014 Accepted 26 June 2014
Keywords: Quadrivalent meningococcal conjugate vaccine Antibody persistence Neisseria meningitidis Serum bactericidal activity
a b s t r a c t Long term protection against invasive meningococcal disease relies on persistence of bactericidal antibodies. We studied the persistence of serum bactericidal antibodies using rabbit and human complement (rSBA, hSBA assays) two years after vaccination with a meningococcal serogroup A, C, W, Y tetanus toxoid conjugate vaccine (MenACWY-TT, N = 253) or a licensed monovalent serogroup C conjugate vaccine (MenC-CRM197, N = 42) in Finnish toddlers who were aged 12–23 months at the time of vaccination. In 97.8–98.9% of subjects receiving MenACWY-TT, rSBA titres P1:8 persisted against serogroups A, W and Y and 88.2% against serogroup C, which was according to exploratory analysis statistically significantly higher than in recipients of the MenC-CRM197 vaccine (69.0%). A total of 86.9% of subjects had persisting hSBA P1:8 for serogroup C, which was statistically significantly higher than the MenC-CRM group (52.6%). Exploratory analysis also showed that the year 2 hSBA-MenC geometric mean titre was statistically significantly higher in the MenACWY-TT group than the MenC-CRM group. At least 87.0% of subjects had hSBA P1:8 for serogroups W and Y at year 2, while the percentage was 23.0% for serogroup A. Using rSBA, but not hSBA, a high percentage of MenC-CRM197 recipients acquired antibody against serogroups A (82.1%), W (58.6%) and Y (80.0%). MenACWY-TT induced high level of bactericidal antibody in toddlers that persisted for at least 2 years. Ó 2014 Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http:// creativecommons.org/licenses/by-nc-nd/3.0/).
Introduction
Abbreviations: CI, confidence interval; GMT, geometric mean antibody titre; hSBA, human complement bactericidal antibody assay; MenACWY-CRM, combined N. meningitidis serogroups A, C, W and Y-CRM197 conjugate vaccine; MenACWY-DT, combined N. meningitidis serogroups A, C, W and Y-diphtheria toxoid conjugate vaccine; MenACWY-TT, combined N. meningitidis serogroups A, C, W and Y-tetanus toxoid conjugate vaccine; MenC, N. meningitidis serogroup C polysaccharide; rSBA, rabbit complement bactericidal antibody assay; SAE, serious adverse event; SD, standard deviation; TT, tetanus toxoid. q
This study has been registered at www.clinicaltrials.gov NCT00955682.
⇑ Corresponding author. Address: Vaccine Research Center, University of Tampere Medical School, Biokatu 10, FM3, FI-33014 University of Tampere, Finland. Tel.: +358 50 524 6530; fax: +358 3 364 1512. E-mail addresses: timo.vesikari@uta.fi (T. Vesikari), aino.forsten@uta.fi (A. Forsten), [email protected] (V. Bianco), [email protected] (M. Van der Wielen), [email protected] (J.M. Miller).
The highest incidence of invasive meningococcal disease occurs in infants followed by young children [1–3]. Monovalent serogroup C (MenC) conjugate vaccines have been successfully used to prevent invasive meningococcal disease in infants, toddlers and individuals up to 18 years of age since 1999 [4]. The duration of protection afforded by vaccination is not yet known, although evidence from children who experienced vaccine failure suggests that circulating antibody is needed for protection against invasive disease [5]. We previously demonstrated that a quadrivalent meningococcal conjugate vaccine with four serogroup polysaccharides, A, C, W and Y, all conjugated to tetanus toxoid (MenACWY-TT), administered to toddlers, induced high levels of bactericidal antibodies to serogroup A, W, and Y and was non-inferior to licensed
http://dx.doi.org/10.1016/j.trivac.2014.06.003 1879-4378/Ó 2014 Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/3.0/).
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monovalent meningococcal MenC conjugate vaccine (MenCCRM197) in terms of seroresponse to serogroup C [6]. We subsequently studied antibody persistence against each serogroup two years after primary vaccination, using serum bactericidal assays with either rabbit (rSBA) or human (hSBA) complement. Demonstration of a serological correlate of protection for serogroup C was done using rSBA in post-licensure effectiveness studies [7,8], whereas hSBA titres P1:4 are considered protective for serogroup C [9]. Methods In the primary vaccination study in Finland (www.clinicaltrials.gov NCT00474266), 12–23 month old toddlers randomised to receive primary vaccination with MenACWY-TT (containing 5 lg of each meningococcal serogroup A, C, W and Y polysaccharide conjugated to tetanus toxoid: N = 749), or MenC-CRM197 (Meningitec™ Pfizer Inc., containing 10 lg of MenC polysaccharide conjugated to mutant diphtheria toxoid CRM protein: N = 251) [6]. All children were invited to participate in the assessment of antibody persistence at year 2 (NCT00955682). Children were not allowed to participate if they had developed meningococcal disease or received any meningococcal vaccination since the primary vaccination study, or if they had an intervening immunocompromising condition, or had received immunoglobulin or blood products within 3 months of the study visit. The protocol and associated documents were reviewed and approved by the ethics committee of Pirkanmaa Hospital District. Written informed consent was obtained from the parents/guardians of children before study procedures were performed. Bactericidal activity was assessed at GlaxoSmithKline Vaccines’ laboratory using a serum bactericidal assay with rabbit and human complement (rSBA, hSBA, respectively) as previously described [10]. The assay cut-offs were 1:8 for rSBA and 1:4 for hSBA. For rSBA and hSBA we also considered more conservative thresholds
of 1:128 and 1:8, respectively. An hSBA titre P1:4 was demonstrated to correlate with protection in humans who developed natural immunity to serogroup C [9]. A rSBA titre of P1:8 was shown to correlate with protection in populations vaccines with monovalent serogroup C vaccines [7,11]. It is common practice to extend these thresholds to the other vaccine serogroups. The primary objective was to assess the percentage of subjects with rSBA antibody titres P1:8 for each of the four serogroups. Evaluation of antibody persistence using hSBA was a secondary objective. Serious adverse events (SAEs) considered by the investigator to be related to study procedures or GlaxoSmithKline concomitant medication were captured retrospectively at the year 2 study visit. An exploratory evaluation of the differences at each time point was performed for the percentage of subjects with rSBA-MenC antibody titres P1:8 and P1:128 and hSBA-MenC antibody titres P1:4 and P1:8 with standardised asymptotic 95% CIs and the ratio of the rSBA-MenC and hSBA-MenC GMTs with 95% CIs between the MenACWY-TT and MenC-CRM groups. A statistically significant difference was indicated if the value ‘1’ was excluded from the 95% CI on the GMT ratios or if the value ‘0’ was excluded from the 95% CI on differences between groups. Note that potential differences should be interpreted with caution considering that there was no adjustment for multiplicity for these comparisons. Statistical analyses were performed using SASÒ software version 9.2 (SAS Institute Inc., Cary, NC, United States) and ProcStatXact 8.1. Results The year 2 follow-up study took place between 25 August and 16 December 2009. There were 295 subjects who returned at year 2 (253 in the MenACWY-TT group and 42 in the MenC-CRM group). Of these, 218 subjects contributed to the According-to-protocol persistence cohort (Fig. 1). The median time since the primary
Primary vaccination at 12-23 months of age N=1000 Subjects randomised (3:3:1:1)
MenACWY-TT+MMRV N=375
MenACWY-TT→MMRV N=374
MMRV→MenC-CRM N=126
MenC-CRM→MMRV N=125
Year 2 Blood sample N=295 MenACWY-TT group N=253 (120 F, 133 M) age 40.7 (1.87) months*
MenC-CRM group N=42 (20 F, 22 M) age 41.1 (1.74) months*
65 eliminated: not eligible (2); eliminated during primary study (2); non-compliance with blood sampling schedule (59); sample not taken or quantity not sufficient (2) N=188
12 eliminated: non-compliance with blood sampling schedule (12) N=30
Year 2 ATP persistence cohort N=218 Fig. 1. Subject flow. ⁄Mean age (standard deviation); F = female, M = male. N = number of subjects in each group/cohort. Primary vaccination study: MenACWYTT + MMRV = subjects vaccinated with MenACWY-TT co-administered with MMRV; MenACWY-TT ? MMRV = subjects vaccinated with MenACWY-TT and 42 days later with MMRV; MMRV ? MenC-CRM = subjects vaccinated with MMRV and 42 days later with MenC-CRM197; MenC-CRM ? MMRV = subjects vaccinated with MenC-CRM197 and 42 days later with MMRV. Persistence study: MenACWY-TT = subjects previously primed with MenACWY-TT (with or without MMRV), i.e., pooled MenACWY-TT + MMRV and MenACWY-TT ? MMRV groups. MenC-CRM197 = subjects previously primed with MenC-CRM197 (given 42 days before or after MMRV), i.e., pooled MMRV ? MenC-CRM and MenC-CRM ? MMRV groups.
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Table 1 rSBA and hSBA antibody persistence 42 days and 2 years after vaccination with MenACWY-TT or MenC-CRM197 at 12–23 months of age (According-to-protocol cohort for persistence at Year 2). Serogroup
MenACWY-TT
rSBA
N
% P1:8 [95% CI]
% P1:128 [95% CI]
GMT [95% CI]
N
% P1:8 % [95% CI]
% P1:128 [95% CI]
GMT [95% CI]
186 181 184 186 186 188 185 188
100 [98.0; 100] 97.8 [94.4; 99.4] 100 [98.0; 100] 88.2 [82.6; 92.4] 100 [98.0; 100] 98.9 [96.2; 99.9] 100 [98.0; 100] 97.9 [94.6; 99.4]
100 [98.0; 100] 91.7 [86.7; 95.3] 94.0 [89.6; 97.0] 48.4 [41.0; 55.8] 100 [98.0; 100] 91.0 [85.9; 94.6] 100 [98.0; 100] 81.9 [75.7; 87.1]
1924 [1698; 2181] 420 [356; 496] 447 [397; 503] 98 [78; 124] 2241 [1999; 2512] 397 [342; 461] 2550 [2213; 2937] 397 [324; 486]
14 28 30 29 16 29 16 30
50.0 82.1 93.3 69.0 50.0 58.6 75.0 80.0
28.6 57.1 60.0 48.3 18.8 41.4 56.3 66.7
[8.4; 58.1] [37.2; 75.5] [40.6; 77.3] [29.4; 67.5] [4.0; 45.6] [23.5; 61.1] [29.9; 80.2] [47.2; 82.7]
22 [7; 66] 91 [46; 178] 146 [84; 255] 54 [26; 112] 22 [7; 65] 42 [19; 96] 88 [30; 262] 151 [69; 331]
N
% P1:4 [95% CI]
% P1:8 [95% CI]
GMT [95% CI]
N
% P1:4 % [95% CI]
% P1:8 [95% CI]
GMT [95% CI]
179 183 179 175 176 180 169 154
83.2 25.1 98.3 88.0 81.8 92.8 79.3 87.0
81.0 23.0 98.3 86.9 81.3 91.1 79.3 87.0
23.2 [18.7; 28.7] 3.8 [3.2; 4.5] 170.2 [143.4; 202.0] 50.2 [38.7; 65.1] 42.1 [32.4; 54.7] 77.7 [61.8; 97.6] 29.5 [22.8; 38.1] 58.1 [44.5; 75.8]
23 23 23 19 23 23 23 22
0.0 [0.0; 14.8] 8.7 [1.1; 28.0] 82.6 [61.2; 95.0] 57.9 [33.5; 79.7] 4.3 [0.1; 21.9] 0.0 [0.0; 14.8] 4.3 [0.1; 21.9] 22.7 [7.8; 45.4]
0.0 [0.0; 14.8] 0.0 [0.0; 14.8] 82.6 [61.2; 95.0] 52.6 [28.9; 75.6] 4.3 [0.1; 21.9] 0.0 [0.0; 14.8] 4.3 [0.1; 21.9] 22.7 [7.8; 45.4]
2.0 [2.0; 2.0] 2.2 [1.9; 2.4] 45.9 [21.0; 100.1] 10.4 [4.7; 22.8] 2.3 [1.8; 2.9] 2.0 [2.0; 2.0] 2.5 [1.6; 4.1] 5.0 [2.2; 11.1]
A C W Y
M1 Y2 M1 Y2 M1 Y2 M1 Y2
hSBA A C W Y
M1 Y2 M1 Y2 M1 Y2 M1 Y2
[76.9; [19.0; [95.2; [82.2; [75.3; [88.0; [72.4; [80.7;
MenC-CRM197
88.4] 32.1] 99.7] 92.4] 87.2] 96.1] 85.1] 91.9]
[74.5; [17.1; [95.2; [80.9; [74.7; [86.0; [72.4; [80.7;
86.5] 29.7] 99.7] 91.5] 86.7] 94.8] 85.1] 91.9]
[23.0; [63.1; [77.9; [49.2; [24.7; [38.9; [47.6; [61.4;
77.0] 93.9] 99.2] 84.7] 75.3] 76.5] 92.7] 92.3]
M1 = 42 days after vaccination; Y2 = 2 years after vaccination; N = number of subjects with available results. Note that in the case of insufficient sera, not all assays were able to be performed; 95% CI = 95% confidence interval.
vaccination dose was 26 months. Subjects in the two pooled treatment groups were similar in terms of age and gender (Fig. 1). rSBA antibodies Two years after primary vaccination, 97.8–98.9% of subjects in the MenACWY-TT group had persisting rSBA antibody titres P1:8 for serogroups A, W and Y, and 88.2% for serogroup C (Table 1).
For each serogroup, rSBA GMTs decreased by year 2 but remained higher than pre-vaccination levels (Table 1 and Fig. 2). The percentage of subjects in the MenC-CRM group with serogroup C rSBA titres P1:8 was 69.0% (Table 1). The rSBA-MenC GMT decreased by year 2 but remained higher than prevaccination levels (Table 1 and Fig. 2). The exploratory group comparison indicated that antibody persistence for serogroup C was significantly higher in the
Fig. 2. Reverse cumulative curves for rSBA titres at pre- and post-vaccination and at year 2 (M24) (ATP cohort for persistence at year 2).
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Fig. 3. Reverse cumulative curves for hSBA titres at pre- and post-vaccination and at year 2 (M24) (ATP cohort for persistence at year 2).
MenACWY-TT group than in the MenC-CRM group as measured by the percentage of subjects with rSBA titres P1:8. No statistically significant differences between groups were observed for the percentage with rSBA-MenC titres P1:128 or for the rSBA-MenC GMT at year 2 (exploratory analysis). After primary vaccination the percentage of MenC-CRM197 recipients with rSBA titres P1:8 was 50.0% for serogroups A and W, and 75.0% for serogroup Y. At year 2, the percentages had increased to 82.1% for serogroup A, 58.6% for W and 80.0% for Y. hSBA antibodies Two years after primary vaccination, the percentage of subjects in the MenACWY-TT group with persisting hSBA antibody titres P1:8 was 86.9% for serogroup C, 91.1% for W and 87.0% for Y, while only 23.0% retained hSBA antibody for serogroup A (Table 1). For serogroups A and C, hSBA GMTs decreased by year 2 but remained higher than pre-vaccination levels (Table 1 and Fig. 3). The percentage of subjects in the MenC-CRM group with hSBAMenC titres P1:8 was 52.6%. The hSBA-MenC GMT reduced by year 2 but remained higher than pre-vaccination levels (Table 1 and Fig. 3). The exploratory group comparison indicated that antibody persistence for serogroup C was statistically significantly higher in the MenACWY-TT group than in the MenC-CRM group in terms of the percentage of subjects with hSBA titres P1:8 and the hSBAMenC GMT. In contrast to measurements using rSBA, few subjects in the MenC-CRM group had antibody titres P1:8 against the other serogroups using hSBA: 0.0% for serogroups A and W, and 22.7% for serogroup Y.
Safety No vaccine-related SAEs were reported from the end of the primary vaccination study until the year 2 persistence visit. Discussion This study of antibody persistence in toddlers showed that antibodies as measured by rSBA persisted in the majority of subjects vaccinated with MenACWY-TT until 2 years after vaccination. Exploratory analyses conducted after the primary vaccination dose indicated that the post-vaccination rSBA-MenC GMT was statistically significantly higher in MenACWY-TT recipients than in MenC-CRM197 recipients [6]. In-line with these results, we observed a higher percentage of subjects with rSBA-MenC titres P1:8 in the MenACWY-TT group compared to the MenC-CRM group at year 2 (exploratory analysis). The results of our study using the GSK rSBA are consistent with other studies of MenACWY-TT persistence in adolescents and children where the same assay was employed [12–14]. Good antibody persistence up until 3 years after vaccination of adolescents with MenACWY-TT has been demonstrated, while in toddlers, persisting antibody levels have been observed to be similar or higher than after vaccination with licensed MenC-CRM197 [13–17]. In MenACWY-TT-primed children, hSBA antibodies for serogroups C, W and Y persisted until year 2, whereas hSBA for serogroup A declined rapidly (23.0% P 1:8 at year 2). Similar rapid decay of hSBA-MenA antibodies has been observed using other quadrivalent vaccines tested for hSBA by different laboratories: five years after vaccination of infants with three doses of
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MenACWY-CRM197 (Menveo™ Novartis) the percentage with hSBAMenA P1:8 was no higher than 4% [18]. Two years after vaccination of adolescents with MenACWY-CRM197 or MenACWY-DT, the percentage with hSBA-MenA P1:8 had decreased from 75% to 36%, and from 67% to 25%, respectively [19]. Persistence of hSBA for the other serogroups after MenACWYTT vaccination appeared comparable to other quadrivalent vaccines: 2–3 years after vaccination of 2–3 year olds with a single dose of MenACWY-DT (Menactra™ Sanofi Pasteur), 14.6% of children had hSBA P1:4 [20]; five years after 3 MenACWYCRM197 doses by 12 months of age, hSBA P1:8 for serogroups C, W and Y was observed in 27–45%, 81–84% and 42–57%, respectively [18]. In the present study we observed that rSBA antibody GMTs for serogroups A, W and Y increased at year 2 in the control group who had not received vaccination with these serogroups. The percentage of subjects with rSBA titres P1:8 for serogroups A, W and Y increased to as high as 82.1% (serogroup A) by year 2. The observed increases in rSBA probably reflects the development of natural immunity during childhood [9,21]. Natural immunity develops through production of IgM, and rabbit complement is thought to be activated by IgM as well as IgG [22,23]. By contrast, hSBA titres remained very low for serogroups A and W in MenC-CRM197 recipients, while the percentage of children with hSBA-MenY titres P1:8 increased to 22.7%. The increase in hSBA-MenY titres over time may reflect natural exposure to serogroup Y, which in Finland, along with other Scandinavian countries, causes a substantial proportion of invasive meningococcal disease [24]. Thus, the GSK rSBA and GSK hSBA assays detect natural immunity differently, with the GSK rSBA assay having a greater sensitivity than the GSK hSBA assay. It is unclear whether natural immunity as measured by GSK rSBA represents true seroprotection in contrast to the vaccine-induced immunity measured with this assay. hSBA GMTs (but not rSBA GMTs) for serogroup W and Y were also observed to increase between month 1 and year 2 in the MenACWY-TT group. Similar observations have been made by other authors after vaccination of infants with Menveo™ [25], and after vaccination of toddlers with Menactra™ [26], possibly as a result of avidity maturation, a slower antibody response, or a boosting effect due to natural exposure. Follow-up of our study cohort is planned until year 10 post-vaccination. At year 4, children were invited to receive a booster dose of the same meningococcal vaccine they had received at 12– 23 months of age (results published elsewhere). We used GSK’s rSBA until year 2 and samples collected after year 2 will be tested at a different laboratory. Thus, the present results will not be directly comparable with future persistence studies. Conclusions In conclusion, 2 years after a single dose of MenACWY-TT administered to toddlers, antibodies measured by both rSBA and hSBA assays persisted for all serogroups A, C, W and Y, with indication of higher antibody persistence for serogroup C after vaccination with MenACWY-TT than with MenC-CRM197. Sources of support GlaxoSmithKline Biologicals SA was the funding source and was involved in all stages of the study conduct and analysis. GlaxoSmithKline Biologicals SA also funded all costs associated with the development and the publishing of the present manuscript. The corresponding author had full access to the data and was responsible for submission of the publication.
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Authors’ contributions Pr Vesikari and Dr. Forsten were investigators involved in the supervision of the study, administrative, logistic and technical supports, the recruitment and the medical evaluation of subjects, the evaluation of any reported SAEs for causality, the collection and interpretation of the data, and the drafting and approval of the manuscript. Dr. J.M. Miller, Dr. M. Van der Wielen (clinical development scientists) and V. Bianco (biostatistician) are employed by GlaxoSmithKline Vaccines and were involved in all stages of the study (study design, data analyses and interpretations, drafting and approval of the manuscript). Acknowledgments The authors thank the families and children who participated in the study as well as the participating investigators and nurses without whom this study would not have been possible. We are also grateful to teams in GlaxoSmithKline Vaccines for their contribution to this study, including Markku Pulkkinen, Taneli Puumalainen and Sindia Troletti for their assistance in coordination of the study, Emmanuel Aris for input into statistical analysis, Mark Franco and Leentje Moerman for protocol writing and Pascal R Lestrate for conducting laboratory assays. We also thank Drs. Joanne Wolter (on behalf of GlaxoSmithKline Vaccines) and Virginie Durbecq (XPE Pharma & Science, on behalf of GlaxoSmithKline Vaccines) for providing writing and editorial support in preparing this manuscript. References [1] A.C. Cohn, J.R. MacNeil, L.H. Harrison, C. Hatcher, J. Theodore, M. Schmidt, et al., Changes in Neisseria meningitidis disease epidemiology in the United States, 1998–2007: implications for prevention of meningococcal disease, Clin. Infect. Dis. 50 (2010) 184–191. [2] L.H. Harrison, C.L. Trotter, M.E. Ramsay, Global epidemiology of meningococcal disease, Vaccine 27 (Suppl. 2) (2009) B51–B63. [3] S.A. Halperin, J.A. Bettinger, B. Greenwood, L.H. Harrison, J. Jelfs, S.N. Ladhani, et al., The changing and dynamic epidemiology of meningococcal disease, Vaccine 30 (Suppl. 2) (2012) B26–B36. [4] E. Miller, D. Salisbury, M. Ramsay, Planning, registration, and implementation of an immunisation campaign against meningococcal serogroup C disease in the UK: a success story, Vaccine 20 (Suppl. 1) (2001) S58–S67. [5] C. Auckland, S. Gray, R. Borrow, N. Andrews, D. Goldblatt, M. Ramsay, et al., Clinical and immunologic risk factors for meningococcal C conjugate vaccine failure in the United Kingdom, J. Infect. Dis. 194 (2006) 1745–1752. [6] T. Vesikari, A. Karvonen, V. Bianco, M. Van der Wielen, J. Miller, Tetravalent meningococcal serogroups A, C, W-135 and Y conjugate vaccine is well tolerated and immunogenic when co-administered with measles-mumpsrubella-varicella vaccine during the second year of life: an open, randomized controlled trial, Vaccine 29 (2011) 4274–4284. [7] N. Andrews, R. Borrow, E. Miller, Validation of serological correlate of protection for meningococcal C conjugate vaccine by using efficacy estimates from postlicensure surveillance in England, Clin. Diagn. Lab. Immunol. 10 (2003) 780–786. [8] R. Borrow, N. Andrews, D. Goldblatt, E. Miller, Serological basis for use of meningococcal serogroup C conjugate vaccines in the United Kingdom: reevaluation of correlates of protection, Infect. Immun. 69 (2001) 1568–1573. [9] I. Goldschneider, E.C. Gotschlich, M.S. Artenstein, Human immunity to the meningococcus. I. The role of humoral antibodies, J. Exp. Med. 129 (1969) 1307–1326. [10] S.E. Maslanka, L.L. Gheesling, D.E. Libutti, K.B. Donaldson, H.S. Harakeh, J.K. Dykes, et al., Standardization and a multilaboratory comparison of Neisseria meningitidis serogroup A and C serum bactericidal assays. The Multilaboratory Study Group, Clin. Diagn. Lab. Immunol. 4 (1997) 156–167. [11] R. Borrow, P. Balmer, E. Miller, Meningococcal surrogates of protection – serum bactericidal antibody activity, Vaccine 23 (2005) 2222–2227. [12] L. Ostergaard, M. Van der Wielen, V. Bianco, J.M. Miller, Persistence of antibodies for 42 months following vaccination of adolescents with a meningococcal serogroups A, C, W-135, and Y tetanus toxoid conjugate vaccine (MenACWY-TT), Int. J. Infect. Dis. (2012). [13] T. Vesikari, A. Forstén, D. Boutriau, V. Bianco, M. Van der Wielen, J.M. Miller, A randomized study to assess the immunogenicity, antibody persistence and safety of a tetravalent meningococcal serogroups A, C, W-135 and Y tetanus toxoid conjugate vaccine in children aged 2–10 y, Hum. Vaccin. Immunother. 8 (2012).
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