Department of Pediatrics, National Taiwan University Hospital, No. 8, Chung-Shan S. Rd., Taipei 10048, TaiwanDepartment of Pediatrics, Mackay Memorial Hospital, No. 92, Sec. 2, Chung-Shan N. Rd., Taipei 10449, TaiwanFar Eastern Memorial Hospital, No. 21, Nan-Ya S. Rd., Sec. 2, Pan-Chiao, Taipei 22060, TaiwanNovartis Vaccines and Diagnostics, Srl., Siena, Italy
r t i c l e i n f o
rticle history:eceived 31 March 2014eceived in revised form 21 June 2014ccepted 17 July 2014vailable online 27 July 2014
Background: MenACWY-CRM (Menveo®, Novartis Vaccines, Siena, Italy) is a quadrivalent meningococcalconjugate vaccine developed to help prevent invasive meningococcal disease caused by Neisseria menin-gitidis serogroups A, C, W, and Y. It is approved within the European Union in persons >2 years of age andin persons from 2 months to 55 years of age in the United States, among other countries. Little is knownabout the immunogenicity and safety of this vaccine in Taiwanese children >2 years and adolescents.This study assessed the immunogenicity and safety of a single injection of MenACWY-CRM vaccine inTaiwanese subjects aged 2–18 years old.Methods: In this phase III, multicentre, open-label study 341 subjects received one dose of MenACWY-CRM. Immunogenicity measures were rates of seroresponse (defined as the proportion of subjects with apostvaccination hSBA ≥1:8 if the prevaccination (baseline) titre was <1:4, or at least a fourfold higher hSBAtitre than baseline if the prevaccination titre was ≥1:4), percentages of subjects with serum bactericidalactivity (hSBA) ≥1:8 for serogroups A, C, W and Y and hSBA geometric mean titres (GMTs). Local andsystemic reactions and all adverse events (AEs) were recorded for 7 days, and medically attended AEs for1 month post-vaccination.Results: Seroresponse rates after MenACWY-CRM vaccination at Day 29 for the serogroups A, C, W, and Y
were 83%, 93%, 50%, and 65%, respectively. At Day 29 the percentages of subjects with hSBA ≥1:8 againstall four serogroups A, C, W and Y were: 83%, 96%, 96% and 82%, respectively. GMTs against all serogroupsrose by ≥7-fold from baseline to Day 29. The vaccine was well tolerated.Conclusions: A single dose of MenACWY-CRM demonstrated a robust immune response, and an acceptablesafety profile in Taiwanese children and adolescents.
significant morbidity and mortality, despite appropriate treatment.Incidence rates are generally highest among infants and childrenyounger than 5 years, and adolescents and young adults aged 16–21years [2–4]. In addition, adolescents and young adults have thehighest rates of meningococcal carriage, which might be due tocontact patterns and social behaviour [5,6].
N. meningitidis can be classified into distinct serogroups accord-ing to their polysaccharide capsule. The most common serogroupsthat cause disease worldwide are groups A, B, C, W, and Y [7].
The incidence and distribution of serogroups generally varies withage and geographical location, and changes over seasons and years[4,7]. In Taiwan, serogroups B and W predominated prior to 2001[8]. However, concurrent with an increase in disease incidence in
which was classified as none, mild (minor light reaction to touch),moderate (cried or protested to touch) and severe (cried wheninjected limb was moved). Rash was categorised as none, urticarial
178 L.-M. Huang et al. / Va
001 and 2002, there was an apparent emergence of serogroups, C and Y [9]. Of 115 confirmed cases reported between 2001 and003, serogroups B, W, Y, C, and A were responsible for 47.8%, 26.1%,4.8%, 5.2%, and 2.6%, respectively; the remaining 3.5% were fromtrains where serogroup information was not available [10].
Immunisation of at-risk populations is an important measure toelp prevent meningococcal disease and the use of a vaccine withotential broad-spectrum coverage could reduce the burden ofisease. MenACWY-CRM, (Menveo®, Novartis Vaccines and Diag-ostics Srl., Siena, Italy) is a quadrivalent meningococcal conjugateaccine indicated to help prevent invasive meningococcal diseaseaused by N. meningitidis serogroups A, C, W, and Y. It is composed ofapsular polysaccharides from serogroups A, C, W, and Y conjugatedo a non-toxic mutant of diphtheria toxin – CRM197. In the Euro-ean Union it has been approved for use in children, adolescentsnd adults from 2 years of age [11]. In the US it has been approvedn infants, children and adults from 2 months to 55 years of age12]. Currently, no meningococcal vaccine is licensed in Taiwan.
MenACWY-CRM has been shown to be immunogenic and wellolerated across all age groups, including children and adoles-ents [13–18]. Before vaccines are introduced into countries it ismportant to test their immunogenicity and safety in populations
ith relevant demographic characteristics. One large multinationalafety study (n = 7744 infants), which included 596 Taiwanesenfants, evaluated the safety of MenACWY-CRM as a four-doseeries of MenACWY-CRM concomitantly administered with routinenfant vaccines starting at 2 months of age [19]. Ideally immun-sation against meningococcal disease would begin in infancy,owever it is also necessary to assess immunogenicity and safety
n other age groups, for example for those who have missed infantaccination and during catch-up immunisation campaigns. Trials inhildren and adolescents aged 2–18 years have mainly been con-ucted in the USA and Canada [13–16], and little is known abouthe immunogenicity and safety of the vaccine in Taiwanese chil-ren and adolescents 2–18 years. Therefore, the aim of the studyas to assess the immunogenicity and safety of a single injection
f MenACWY-CRM vaccine in Taiwanese children and adolescentsged 2–18 years.
. Materials and methods
.1. Study design
This was a phase III, multicentre, open-label study to evaluatehe immunogenicity and safety of a single dose of MenACWY-RM in healthy subjects 2–18 years of age in Taiwan. Institutionaleview Board approval of the protocol was obtained before enrol-ent, and written informed consent was obtained from the parents
r guardians of all subjects enrolled in the study. Written informedssent was also provided by subjects aged 7–18 years. This studyas conducted in accordance with the Declaration of Helsinki, andood Clinical Practice (GCP) with the International Conference onarmonization (ICH) guidelines.
.2. Subjects
Healthy male and female subjects 2–18 years of age were eli-ible for inclusion in this study. Subjects were excluded from thetudy if they had a previous laboratory confirmed N. meningitidisnfection or if they had previously received a meningococcal vac-ine, the latter being a precaution even though no meningococcal
accine is licensed in Taiwan. Other exclusion criteria included hav-ng had a significant acute infection ≤7 days before study entry, orever (≥38 ◦C) ≤3 days before study entry. Subjects with an immu-odeficiency or other serious acute, chronic, or progressive disease
32 (2014) 5177–5184
were also excluded from the study. Eligible children were enrolledin two age strata: ≥2 to ≤10 years and ≥11 to ≤18 years.
2.3. Vaccine
MenACWY-CRM (Lot no. M11006) was prepared by extempora-neous mixing of the lyophilised Men A component with the liquidMenCWY component of the vaccine before intramuscular injectioninto the deltoid area of the non-dominant arm. Subjects receivedone 0.5 mL dose of MenACWY-CRM, which comprised 10 �g of MenA polysaccharide and 5 �g each of Men C, Men W, and Men Ypolysaccharide, conjugated to CRM197.
2.4. Assessment of immunogenicity
Blood samples (10 mL) were taken from subjects before theyreceived the first dose (Day 1) and 28 days post-vaccination (Day29), with a visit window of +14 days. Immunogenicity was assessedin two different age groups: 2–10 years and 11–18 years, and over-all (2–18 years). The immunogenicity was evaluated using serumbactericidal activity using human complement (hSBA) assay formeningococcal serogroups A, C, W, and Y, as previously described[18]. Seroresponse was defined as the proportion of subjects witha postvaccination hSBA ≥1:8 if the prevaccination (baseline) titrewas <1:4, or at least a fourfold higher hSBA titre than baseline if theprevaccination titre was ≥1:4. hSBA for the serogroups A, C, W, andY was performed at the Novartis Vaccines laboratory in Marburg,Germany.
2.5. Assessment of safety
Solicited local and systemic adverse events (AEs) and any otherAEs occurring up to 7 days after the vaccine dose were recorded.Medically attended AEs and SAEs within 29 days of vaccinationwere also recorded. Safety was assessed in three different agegroups: children 2–5 years, children 6–10 years, and adolescents11–18 years because two different sets of local and systemic reac-tions were recorded for subjects 2–5 years and subjects 6–18 years(i.e. 6–10 years and 11–18 years age groups). The subject or sub-ject’s parents/legal guardians were given diary cards to record dailybody temperature (all age groups), any local reactions (subjects 2–5years: tenderness, erythema and induration; subjects 6–18 years:pain, erythema and induration), or any systemic reactions (subjects2–5 years: change in eating habits, sleepiness, irritability, vomiting,diarrhoea and rash; subjects 6–18 years: chills, nausea, malaise,myalgia, arthralgia, headache and rash) that occurred betweenDays 1 and 7.
For all age groups, fever was classified as a body temperatureof ≥38 ◦C (severe ≥40 ◦C), and erythema and induration were cate-gorised as none, 25–<50 mm (mild), 51–<100 mm (moderate) and>100 mm (severe). For subjects 6–18 years, the severity of pain andsystemic AEs, except rash, were categorised as none, mild (transientwith no limitation in normal daily activity), moderate (some limita-tion in normal daily activity) and severe (unable to perform normaldaily activity). For subjects 2–5 years, these AEs were reported aspresent or not present except for tenderness at the injection site,
or other for both age groups.Assessment of the causal relationship of unsolicited AEs to the
vaccination was classified by the investigator as not related, possi-bly related or probably related.
L.-M. Huang et al. / Vaccine 32 (2014) 5177–5184 5179
Table 1Summary of demographic characteristics.
Overall By age group
2–18 yearsN = 341
Child: 2–10 yearsN = 173
Adolescent: 11–18 yearsN = 168
Age: mean ± SD (yrs) 10.1 ± 4.5 6.3 ± 2.6 14.0 ± 2.2Gender: n (%)
The primary endpoint was to assess the immunogenicity of aingle injection of MenACWY-CRM as measured by the percentagef subjects with hSBA seroresponse to N. meningitidis serogroups, C, W and Y at Day 29 in the overall subjects group (2–18 years ofge). Secondary endpoints included the percentage of subjects withSBA seroresponse by age group (2–10 years and 11–18 years);SBA geometric mean titres (GMTs) to serogroups A, C, W and Y atay 1 and Day 29 and postvaccination (Day 29) to prevaccination
Day 1) GMT ratios (GMRs), overall and by age group; and the per-entage of subjects with hSBA titre ≥1:8 to serogroups A, C, W and
at Day 1 and Day 29, overall and by age group.A total of 341 subjects were enrolled in the study (173 sub-
ects in the 2–10 years age group and 168 subjects in the 11–18ears age group). A total of 340 subjects had been planned to benrolled (170 subjects in each age group); this took into account
potential 10% drop-out rate, which would leave approximately53 evaluable subjects in each age group (306 overall). This numberf subjects was considered reasonable to measure immunogenic-ty response, based on the 95% confidence intervals (CI) of thebserved seroresponse, i.e. for the primary endpoint: with 306valuable subjects, the 95% CIs for the following observed serore-ponses were 87–93% for a seroresponse of 90%; 76–85% for aeroresponse of 80%; 65–70% for a seroresponse of 70%; 55–66% for
seroresponse of 60%; and 44–56% for a seroresponse of 50%. Thereas no statistical hypothesis associated with the immunogenic-
ty objectives. All analyses were run descriptively. The primarynd secondary objectives were based on the modified intent-o-treat (MITT) set, i.e. all enrolled subjects who received studyaccination and who provided evaluable serum samples whosessay results were available for at least one serogroup on Day 1nd/or Day 29.
The number and percentage of subjects with hSBA serore-ponse and associated two-sided 95% CIs were computed for eacherogroup (A, C, W and Y) at Day 29, overall and by age group. TheSBA titres at Day 1 and Day 29 were logarithmically transformedbase10) and summarised by serogroup. GMTs and associated two-ided 95% CIs were calculated at each time point by exponentiatinghe corresponding log-transformed means and 95% CIs. The limit ofetection for hSBA was a titre of 4, and the value for titres below thisalue was imputed to 2 for the purpose of analysis. Least squaresstimates of GMTs were calculated from a two-way analysis ofariance (ANOVA) model adjusting for age group and study cen-re. GMTs were reported for each serogroup A, C, W and Y, overallnd by age group.
All subjects who received the study vaccine and provided anyafety data were considered evaluable for the safety analyses.afety and tolerability data were summarised by age group pro-iding the number and percentage of subjects reporting an event.
16.7 ± 2.99 20.8 ± 3.7
3. Results
3.1. Study subjects
There were 341 subjects enrolled into the study and 340 subjectscompleted the study. One subject, in the 11–18 years age group, wasprematurely withdrawn from the study prior to vaccination due towithdrawal of consent. The MITT set for the immunogenicity anal-ysis included 99% (336) of subjects; however, the overall number ofparticipants evaluated for immunogenicity for the four serogroupsvaried from 333 for serogroups C and Y, 334 for serogroup W and335 for serogroup A due to the unavailability of evaluable serumsamples for some serogroups.
The demographic characteristics of the enrolled subjects areshown in Table 1. The mean age of the 2–10 years age group and11–18 years age group was 6.3 and 14.0 years, respectively anda similar number of males and females participated in both agegroups.
3.2. Immunogenicity
Across all age groups, the majority of subjects entered the studywith a baseline hSBA <1:4 to serogroups A, C, and Y, whereas themajority of subjects had a baseline hSBA ≥1:4 against serogroupW (60% overall; 49% in the 2–10 years age group, and 71% in the11–18 years age group) (Table 2). The overall seroresponse ratesafter MenACWY-CRM vaccination at Day 29 for the serogroupsA, C, W, and Y, respectively, were 83%, 93%, 50%, and 65% in theoverall age group; 77%, 92%, 54% and 61% in the 2–10 years agegroup; and 89%, 95%, 46%, and 69% in the 11–18 years age group(Table 2). In subjects with baseline hSBA <1:4, hSBA seroresponseafter MenACWY-CRM vaccination across serogroups was 77–96%in the 2–18 years age group, 72–94% in the 2–10 years age groupand 83–98% in the 11–18 years age group (Table 2).
The hSBA GMTs and the percentages of subjects with hSBA ≥1:8against the four serogroups (A, C, W and Y) overall and by age groupare presented in Fig. 1.
At Day 29 a substantial proportion of subjects vaccinated with asingle dose of MenACWY had hSBA ≥1:8 against serogroups A (83%;77%; 90%), C (96%; 95%; 98%), W (96%; 93%; 99%) and Y (82%; 78%;86%) in the overall and 2–10 years, and 11–18 years age groups,respectively (Fig. 1A).
At Day 29, a rise in hSBA GMTs from baseline (Day 1) was demon-strated against the four serogroups across all age groups (Fig. 1B).The postvaccination (Day 29) to prevaccination (Day 1) ratios inGMTs (i.e. the GMRs) for subjects 2–18 years of age, at Day 29 were
25 (95% CI: 20–31), 57 (48–69), 7 (6–8), and 11 (9–13), respectively,against the serogroups A, C, W, and Y. The GMRs for subjects in the2–10 years age group were 16 (95% CI: 12–21), 44 (35–56), 7 (5–9),and 8 (6–11), respectively, for the serogroups A, C, W, and Y, while
5180 L.-M. Huang et al. / Vaccine 32 (2014) 5177–5184
Table 2Percentage (95% CI) of subjects with seroresponsea at Day 29 after MenACWY-CRM vaccination, by prevaccination status (subjects with a baseline hSBA of <1:4 or ≥1:4) –MITT set.
a Seroresponse was defined as the proportion of subjects with a postvaccination hitre than baseline if the prevaccination titre was ≥1:4.
n the 11–18 years age group the GMRs were 40 (95% CI: 30–53),
5 (59–95), 7 (5–9), and 14 (11–19), respectively.
Table 3 shows a summary of the immunogenicity results in thistudy and two pivotal studies (conducted in the USA and Canada)sed for MenACWY-CRM licensure in countries worldwide, which
Fig. 1. (A) Percentages of subjects (95% CIs) with hSBA ≥1:8 and (B) hSBA GMTs (95%
61 (53–69) 69 (62–76)
1:8 if the prevaccination (baseline) titre was <1:4, or at least a fourfold higher hSBA
evaluated safety and immune responses 1 month following vacci-
nation with one dose of MenACWY-CRM in children 2–10 yearsof age (NCT00616421) [14] and adolescents 11–18 years of age(NCT00450437) [15]. At baseline in the 2–10 year age group,the percentage of subjects with hSBA ≥1:8 were similar for
CIs); at baseline (Day 1) and after MenACWY-CRM vaccination (Day 29) – MITT.
L.-M. Huang et al. / Vaccine 32 (2014) 5177–5184 5181
Table 3Summary of immunogenicity analyses in this study and the pivotal studies used for MenACWY-CRM licensure in countries worldwide in children 2–10 years of age(NCT00616421) and adolescents 11–18 years of age (NCT00450437).
Immunogenicity analysis by serogroup 2–10 years 11–18 years
This study(Taiwan)(n = 167–170)
NCT00616421(USA/Canada)(n = 1136–1161)
This study(Taiwan)(n = 165–166)
NCT00450437(USA)(n = 1024–1483)
% of subjects with hSBA ≥1:8 at baselineMen A 1 2 4 2Men C 11 17 23 20Men W 47 35 70 40Men Y 22 22 26 34
% of subjects with seroresponse post-vaccination (95% CI)Men A 77 (70–83) 74 (71–76) 89 (83–93) 75 (NR)Men C 92 (86–95) 61 (58–64) 95 (90–97) 75 (NR)Men W 54 (46–62) 65 (62–67) 46 (38–54) 75 (NR)Men Y 61 (53–69) 62 (60–65) 69 (62–76) 68 (NR)
% of subjects with seroresponse post-vaccination in subjects seronegative (hSBA <1:4) at baselineMen A 77 (69–83) 74 (72–77) 90 (84–94) 75 (72–77)Men C 94 (88–97) 64 (61–67) 98 (93–100) 79 (76–81)Men W 86 (72–92) 86 (83–88) 96 (86–99) 94 (91–95)Men Y 72 (63–79) 71 (68–74) 83 (75–89) 81 (78–84)
GMTs post-vaccinationMen A 32 (24–43) 30 (27–34) 88 (66–117) 29 (24–35)Men C 117 (93–147) 23 (21–27) 273 (219–342) 59 (48–73)Men W 49 (40–60) 49 (44–54) 104 (85–127) 87 (74–102)Men Y 26 (20–33) 29 (25–32) 56 (43–72) 51 (42–61)
% of subjects with hSBA ≥1:8 post-vaccination (95% CI)Men A 77 (70–83) 75 (72–77) 90 (84–94) 75 (73–78)Men C 95 (90–98) 72 (70–75) 98 (95–100) 84 (82–86)Men W 93 (88–96) 90 (88–92) 99 (96–100) 96 (95–97)Men Y 78 (71–84) 77 (75–80) 86 (79–91) 88 (85–90)
n meanh er hSB
sNwAClhoN
wWssAbtts
3
aos
ny1t
, number of subjects with available results; CI, confidence interval; GMT, geometricSBA ≥1:8 if the prevaccination (baseline) titre was <1:4, or at least a fourfold high
erogroups A and Y, were higher for serogroup W in this study thanCT00616421 and were lower for serogroup C. Seroresponse ratesere similar between this study and NCT00616421 for serogroups
and Y, were lower for serogroup W and were higher for serogroup. Seroresponse rates in subjects seronegative (hSBA <1:4) at base-
ine were similar for all serogroups except serogroup C, which wasigher in this study. For serogroup C GMTs and the percentagef subjects with hSBA ≥1:8 were also higher in this study thanCT00616421.
In the 11–18 years age, at baseline, the percentage of subjectsith hSBA ≥1:8 were similar for all serogroups, except serogroup
which was higher in this study than NCT00616421. Serore-ponse rates were similar between this study and NCT00450437 forerogroup A, were lower for serogroup W and higher for serogroups
and C. Seroresponse rates in subjects seronegative (hSBA <1:4) ataseline were similar for serogroups W and Y and were higher inhis study for serogroups A and C. For serogroup A and C, GMTs andhe percentage of subjects with hSBA ≥1:8 were also higher in thistudy than NCT00450437.
.3. Safety and tolerability
Solicited local or systemic adverse events after vaccination with single dose of MenACWY-CRM were common, reported by 56%f subjects aged 2–5 years, 50% of subjects 6–10 years and 53% ofubjects 11–18 years.
Reported solicited local AEs across the age groups were tender-
ess/pain (38%, 37% and 37%, in the age groups 2–5 years, 6–10ears and 11–18 years, respectively), followed by erythema (10%,7%, and 10%, respectively) and induration (8%, 14%, and 7%, respec-ively) (Table 4).
titre. Seroresponse was defined as the proportion of subjects with a postvaccinationA titre than baseline if the prevaccination titre was ≥1:4.
The most commonly reported solicited systemic AEs were:vomiting (10%), irritability (7%), rash (6%) and fever ≥38 ◦C (6%)in the 2–5 years age group; myalgia (20%), malaise (13%), headache(11%) and nausea (10%) in the 6–10 years age group; and myal-gia (29%), malaise (21%), and headache (17%) in the 11–18 yearsage group (Table 4). The majority of solicited systemic AEs wereof mild or moderate intensity. However, severe intensity reactionswere reported for headache (2%), urticarial rash (2%), malaise (1%),myalgia (1%) and arthralgia (1%) in the 11–18 years age group, andurticarial rash was reported for three subjects (3%) and one subject(1%) in the 6–10 and 2–5 years age groups, respectively.
Overall, 14% of the subjects reported unsolicited AEs before Day7 and 20% of subjects experienced medically attended AEs fromDay 1 to 29. One subject experienced a serious AE (pneumonia onDay 17) judged as not related to the study vaccine. There were noAEs leading to premature withdrawal and there were no deaths.The most commonly reported AEs (i.e. ≥2%) by preferred term (PT)in the 2–10 years age group were: nasopharyngitis (3%), injectionsite induration (2%), injection site pruritis (2%), injection site ery-thema (2%), and upper respiratory tract infection (2%). In the 11–18years age group they were: injection site induration (3%), dizziness(2%), and upper respiratory tract infection (2%). Of the reportedunsolicited AEs, 6% were possibly or probably related to study vac-cination and were most commonly associated with injection siteevents.
4. Discussion
Due to the dynamic and unpredictable nature of N. meningitidisepidemiology, vaccines against more than one serogroup havebeen developed to broaden protection against the disease. This isthe first study to evaluate the immunogenicity of MenACWY-CRM
5182 L.-M. Huang et al. / Vaccine
Table 4Percentage of subjects experiencing local and/or systemic reactions.
Subjects 6–18years
6–18 yearsN = 268
Child: 6–10yearsN = 101
Adolescent:11–18 yearsN = 167
Percentage of subjects 6–18 years experiencing local reactions (severe)Pain 37 (<1) 37 (0) 37 (1)Erythema, any
Percentage of subjects 6–18 years experiencing any other solicited eventUse of anal-
gesics/antipyretics2 2 2
Subjects 2-5 years Child: 2–5 yearsN = 72
Percentage of subjects 2-5 years experiencing local reactions (severe)Tenderness 38 (1)Erythema, any
(>100 mm)10 (1)
Induration, any(>100 mm)
8 (0)
Percentage of subjects 2-5 years experiencing systemic reactionsVomiting 10Irritability 7Rash, any (urticarial) 6 (1)Fever, body
temperature ≥38 ◦C(≥40 ◦C)
6 (0)
Sleepiness 4Change in eating habits 3Diarrhoea 3
Percentage of subjects 2-5 years experiencing any other solicited event
acsfawHT
TYhtatwopsia
logical factors [35].
Use of anal-gesics/antipyretics
6
dministered as a single dose to meningococcal vaccine-naïvehildren and adolescents in Taiwan. One large multinational safetytudy in infants (n = 7744), which included 596 Taiwanese infants,ound that a four-dose series of MenACWY-CRM concomitantlydministered with routine vaccines was clinically acceptableith a similar safety profile to routine vaccines given alone [19].owever, this current study is the first to assess the safety inaiwanese children and adolescents aged 2–18 years.
The available N. meningitidis epidemiological evidence inaiwan suggests that serogroup W is more prevalent than A, C and
serogroups, although all 4 serogroups (as well as serogroup B)ave also been reported [8–10,20,21]. Prior to vaccination, 60% ofhe study subjects had hSBA ≥1:4 to serogroup W, while 32%, 28%nd 4% of subjects had hSBA ≥1:4 to serogroups C, Y and A, respec-ively. The proportion of subjects with hSBA ≥1:4 to serogroup Was high in both age groups, but occurred in a higher proportion
f adolescents (71%) compared with children (49%). Of note, highre-vaccination antibody titres against serogroup W in healthy
ubjects have also been observed in two recent licensure stud-es conducted in Russia (Clinicaltrials.gov identifier NCT01725217)nd Korea (NCT01274897) (unpublished data). For example, in
32 (2014) 5177–5184
the Korean study, 89% of subjects aged 11–59 years had pre-vaccination titres ≥1:4. The cause is unknown, although it couldbe due to early exposure to N. meningitidis serogroup W, or topersistence of N. meningitidis serogroup W in the nasopharyngealtissues i.e. nasopharyngeal carriage [22]. In Taiwan, a retrospec-tive serogroup analysis of isolates from the N. meningitidis 2001outbreak confirmed the predominance of serogroup B in this area,but also noticed a noteworthy increase in serogroup W, which wasresponsible for 26% of meningococcal diseases [10]. It is tempt-ing to speculate that the high rate of seropositive subjects againstserogroup W is to some extent related to an increase in the rates oftransmission and carriage during this period.
Overall seroresponse rates were high for A, C and Y, but werelower for W in both children and adolescents as may be predictedwith high baseline seroprevalence. However, at Day 29 the per-centage of subjects with hSBA ≥1:8 against all serogroups was high(82–96% across serogroups for subjects 2–18 years). Given that anhSBA titre ≥1:4 is considered as a level consistent with protec-tion against meningococcal disease [23], this finding is the mostclinically relevant.
GMTs against all serogroups rose from baseline to Day 29. Insubjects 2–18 years, the GMTs against serogroups A, C and Y rosebetween 11- and 57-fold from baseline; for serogroup W, which hadhigher GMTs at baseline compared with the other serogroups, therewas still a sevenfold rise in GMTs. Although seroresponse rates andhSBA ≥1:8 in the 2–10-year-old and 11–18-year-old were similar,GMTs were slightly higher in the older age group. An increase inGMTs with increasing age in children has previously been noted[14].
We have shown a summary of the immunogenicity resultsin this study and two pivotal studies used for MenACWY-CRMlicensure in countries worldwide, which like this study evalu-ated safety and immune responses 1 month following vaccinationwith one dose of MenACWY-CRM in children 2–10 years ofage (NCT00616421) [14] and adolescents 11–18 years of age(NCT00450437) [15]. However, these studies were conducted inthe USA and Canada and thus the majority were Caucasian (60%of children and 78% of adolescents) and a minority were Asian(5% and 3%). Although in both age groups the seroresponse rateagainst serogroup W at Day 29 was numerically lower in the Taiwanpopulation than the North American population, the Taiwan pop-ulation had a numerically higher baseline titre ≥1:8 against theW serogroup than the North American population (Table 3). Ofnote, seroresponse rates in subjects seronegative at baseline (hSBA<1:4) for serogroup W were the same or similar in both groups(Table 3). This difference in high baseline titre against serogroup Wcould be due to early exposure to N. meningitidis serogroup W ornasopharyngeal carriage in the Taiwan population and not in theNorth American population. In the USA, serogroups B, C, and Y arethe major causes of meningococcal disease, each being responsi-ble for approximately one third of cases [24]. There was a lowerseroresponse rate for serogroup C in 2–10-year-old in the NorthAmerican population (Table 3). In addition, the 11–18-year-old hadhigher seroresponse rates in the Taiwan population for serogroupsA and C, despite having similar baseline titres (Table 3). Dis-parate immune responses between different populations have beennoted for other vaccines [25–30]. The mechanisms are unknown,although they likely involve genetic factors such as polymorphismsin HLA, cytokine and cytokine receptor genes and other immunegenes [31–34]. Overall, the reasons for disparate immune responsesbetween different populations are likely to be complex involvingmultifactorial immunological, genetic, epigenetic and epidemio-
Although we observed numerical differences, it should benoted that this was a purely post hoc comparison of completelydifferent studies, and no statistical analyses were performed;
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L.-M. Huang et al. / Va
herefore clear conclusions that there are differences cannot beade. However, the seroresponse rates in subjects seronegative
t baseline, and GMTs and hSBA titres generated post-vaccinationn the Taiwan population were similar or numerically higher thanhose generated in the North American populations in both ageroups.
The vaccine was generally well tolerated in children (age groups:–5 years and 6–10 years) and adolescents (age group: 11–18ears), which is in-line with other studies in these age groups13–16]. Tenderness/pain was commonly reported (37%/38%),lthough severe reactions were rare (≤2%). The majority of solicitedystemic AEs were of mild or moderate intensity. More severentensity reactions were reported in adolescents compared withhildren 6–10 years, although they were still uncommon (≤2%). Forhildren 2–5 years, the severity of systemic AEs was not reported,xcept for fever and rash, and only one subject reported an urticar-al rash. Overall, no significant safety concerns were raised withhe use of MenACWY-CRM, as has been demonstrated during the
enACWY-CRM clinical trial programme [36], including a recenttudy which included Taiwanese infants [19].
The main limitation of this study was that it was an open-labelrial with a single arm (i.e. no placebo control or comparator), which
ay have influenced the reporting of AEs. No control arm (activer placebo) was included because no meningococcal vaccine isicensed in Taiwan and this vaccine is licensed in the US, the EUnd other countries where it has been found to be immunogenicith an acceptable safety profile [13–16]. For the immunogenic-
ty analysis we did not analyse 2–5-year-old and 6–10-year-oldeparately; however, previous studies have shown robust immuneesponses with a single dose of MenACWY-CRM in both these ageroups [7,13]. In addition, it may be useful for future studies toeport on the persistence of immunogenicity over a longer periodo determine if there is waning of antibodies over time.
In conclusion, over a 29-day period, a single dose of MenACWY-RM demonstrated a robust immune response and acceptableeactogenicity and safety in Taiwanese children and adolescentsged 2–18 years.
ontributors
Chiranjiwi Bhusal and Ashwani Kumar Arora were involved inhe conception and design of the study and the analysis and inter-retation of data. Li-Min Huang, Nan-Chang Chiu and Shu-Jen Yehere the study investigators; they were responsible for conducting
he study and the acquisition, analysis and interpretation of data.ll authors have approved the final article.
cknowledgements
The study was funded by Novartis Vaccines and Diagnostics. Wecknowledge Dr. Amanda Prowse (CHC Europe) and Dr. Debadityaas (Novartis Vaccines) for providing support in the manuscriptreparation, revision and editing.
Conflicts of interest: Li-Min Huang, Nan-Chang Chiu, and Shu-Jeneh have no conflicts of interest. Chiranjiwi Bhusal and Ashwaniumar Arora are permanent employees of Novartis Vaccines andiagnostics, Srl.
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