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Meningococcal polysaccharide A O-acetylation level does not impact the 1
immunogenicity of the quadrivalent meningococcal tetanus toxoid 2
conjugate vaccine (MenACWY-TT): results from a randomized, controlled 3
Phase III study in healthy adults aged 18–25 years. 4
Socorro Lupisan1#, Kriengsak Limkittikul2, Nestor Sosa3, Pornthep Chanthavanich2, 5
Véronique Bianco4, Yaela Baine5, Marie Van der Wielen4, Jacqueline M. Miller5 6
1Research Institute for Tropical Medicine, Department of Health Compound, Filinvest Corporate city, 7
Muntinlupa City, Philippines 1781 8
2Department of Tropical Paediatrics, Faculty of Tropical Medicine, Mahidol University, 420/6 Ratchawithi 9
Road, Ratchathewi, Bangkok, Thailand 10400 10
3Pan American Medical Research Center (PAMRI), Consultorios Medicos Paitilla 210-212, Calle 53 11
urbanizacion Marbella, Panama 12
4GlaxoSmithKline Vaccines, Wavre, Belgium 13
5GlaxoSmithKline Vaccines, King of Prussia, United States 14
#Correspondence: [email protected] 15
Running title: ACWY-TT conjugate vaccine in 18–25 year old adults 16
17
Copyright © 2013, American Society for Microbiology. All Rights Reserved.Clin. Vaccine Immunol. doi:10.1128/CVI.00162-13 CVI Accepts, published online ahead of print on 24 July 2013
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Abstract 18
The study compared the immunogenicity of two lots of the meningococcal ACWY-tetanus 19
toxoid conjugate vaccine (MenACWY-TT) differing in serogroup A polysaccharide (PS) O-20
acetylation levels, and evaluated immunogenicity and safety compared to a licensed ACWY 21
polysaccharide vaccine (Men-PS). 22
In this phase III, partially-blinded, controlled study, 1170 healthy subjects aged 18–25 23
years were randomized (1:1:1) to receive one dose of MenACWY-TT Lot A (ACWY-A; 68% 24
O-acetylation), Lot B (ACWY-B; 92% O-acetylation) or Men-PS (82% O-acetylation). 25
Immunogenicity was evaluated in terms of serum bactericidal activity using rabbit 26
complement (rSBA). Solicited symptoms, unsolicited adverse events (AEs) and serious AEs 27
(SAEs) were recorded. 28
Immunogenicity, in terms of rSBA geometric mean titers, was comparable for both lots of 29
MenACWY-TT. Vaccine response rates across serogroups were 79.1–97.0% in both ACWY 30
groups, and 73.7–94.1% in the Men-PS group. All subjects achieved rSBA titers ≥1:8 for all 31
serogroups. All subjects in both ACWY groups and 99.5–100% in the Men-PS group 32
achieved rSBA titers ≥1:128. Pain was the most common solicited local symptom, reported 33
more frequently in the ACWY (53.9–54.7%) than in the Men-PS (36.8%) groups. The most 34
common solicited general symptoms were fatigue and headache, reported by 28.6–30.3% and 35
26.9–31.0% of subjects, respectively. Two subjects reported SAEs; one was considered 36
related to vaccination (blighted ovum; ACWY-B group). 37
The level of serogroup A PS O-acetylation did not impact vaccine immunogenicity. 38
MenACWY-TT (Lot A) was non-inferior to Men-PS in terms of vaccine response and was 39
well tolerated. 40
This study is registered at www.clinicaltrials.gov NCT01154088. 41
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Introduction 42
Neisseria meningitidis is a major cause of serious invasive bacterial infections, such as 43
meningitis and meningococcemia. These diseases are associated with high morbidity and 44
mortality and remain a major public health problem globally (1-3). Annually, there are an 45
estimated 1.2 million cases of meningococcal infections and approximately 135,000 deaths 46
worldwide. Today, the overall mortality rate of invasive meningococcal disease (IMD) is 10–47
15% (4). The incidence of IMD is highest in infants, and a second peak is observed in 48
adolescents and young adults (4,5). Case-fatality rates are also highest in infants and young 49
children, although case fatality rates up to 25% have been recorded in adolescents and young 50
adults aged 15–24 years (6). 51
Among 13 serogroups of N. meningitidis identified based on the biochemical composition 52
of the capsular polysaccharide (PS), only six, A, B, C, W-135, Y and more recently X, 53
account for almost all IMD cases (2,4,7,8). Global serogroup distribution is widely variable. 54
Serogroups A and C are responsible for the majority of cases; however, the prevalence of 55
serogroups Y and W-135 has increased over recent years (2,9,10). In particular, serogroup W-56
135 has recently emerged as a cause of epidemic disease in South Africa and South America 57
(11,12). In Latin America, outbreaks due to serogroup C have been reported since the 1970s 58
in several countries, whereas serogroups W-135 and Y have only recently emerged in some 59
countries (4,13). In Asia, serogroup A caused large outbreaks in several countries in the last 60
century; however, more recently, local outbreaks due to serogroups C, W-135 and Y have 61
been also reported (4,14). Thailand experienced a few cases of IMD due to serogroups A, C, 62
and W-135 between 1994 and 1999, whereas in the Philippines, two large outbreaks due to 63
serogroup A occurred between 1989 and 2005 (14). 64
Prevention of meningococcal disease through vaccination with multivalent vaccines 65
providing broad serogroup coverage is needed, considering the high incidence and mortality 66
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rates in children and young adults, the diverse worldwide distribution of meningococcal 67
serogroups, and the increasing rate of global travel. 68
Plain PS vaccines against serogroups A, C, W-135 and Y have been available since the 69
1970s. The quadrivalent ACWY PS vaccine, Men-PS (Mencevax™, GlaxoSmithKline, 70
Rixensart, Belgium), is indicated for active immunization of adults and children aged ≥ two 71
years and is broadly used worldwide (15). However, meningococcal PSs are poorly 72
immunogenic in infants and toddlers, do not elicit a persistent antibody response, do not 73
reduce mucosal carriage, and do not confer herd protection (16,17). The immunogenicity of 74
PS vaccines can be improved by conjugation of the capsular PS to a carrier protein, as 75
demonstrated by monovalent meningococcal serogroup C conjugate vaccines (18-20). Four 76
multivalent meningococcal conjugate vaccines are currently available, a Haemophilus 77
influenzae type b (Hib) and meningococcal serogroups C and Y tetanus toxoid (TT) conjugate 78
vaccine, HibMenCY-TT (MenHibrix™, GlaxoSmithKline, Rixensart, Belgium), licensed in 79
the United States for vaccination of infants in a four-dose series from six weeks through 18 80
months of age (21), and three quadrivalent vaccines against serogroups A, C, W-135 and Y: a 81
diphtheria toxoid (DT) conjugate vaccine, MenACWY-DT (Menactra™, Sanofi Pasteur, Inc., 82
Swiftwater, PA), licensed in the US, Canada, Gulf Cooperation States in the Middle East, 83
Australia and the Philippines for the use in individuals nine months through 55 years of age 84
(22-26); a mutant diphtheria toxoid (CRM197) conjugate vaccine, MenACWY-CRM 85
(Menveo™, Novartis Vaccines, Bellaria-Rosia, Italy), licensed in the US, Canada, Argentina, 86
Pakistan, Saudi Arabia, Australia, the Philippines and European Union for active 87
immunization of children (≥ two years of age), adolescents and adults (27-31); and a TT 88
conjugate vaccine, MenACWY-TT (Nimenrix™, GlaxoSmithKline, Rixensart, Belgium), 89
approved in 2012 by the European Medicines Agency for the active immunization of 90
individuals from 12 months of age (32). 91
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O-acetylation of meningococcal serogroup A PS may be important for its immunogenicity 92
(33). This study was conducted to compare the immunogenicity of two lots of MenACWY-93
TT differing in the percentage of O-acetylation of meningococcal serogroup A PS and to 94
evaluate the immunogenicity and safety of MenACWY-TT as compared to Men-PS in 18–25 95
years old adults from Panama, the Philippines and Thailand. 96
Materials and Methods 97
Study design 98
This was a phase III, partially blinded, randomized, controlled study conducted at three 99
centers in Panama, the Philippines and Thailand between August and December 2010. 100
Subjects were randomized (1:1:1) to receive a single dose of MenACWY-TT Lot A (ACWY-101
A group: 68% O-acetylation of meningococcal serogroup A PS), MenACWY-TT Lot B 102
(ACWY-B group: 92% O-acetylation of meningococcal serogroup A PS) or Men-PS (Men-PS 103
group: 82% O-acetylation of meningococcal serogroup A PS). Treatment allocation was 104
performed using a central randomization call-in system on the internet. The study was 105
observer-blinded with respect to MenACWY-TT lots, but open with respect to MenACWY-106
TT or Men-PS, due to the different routes of injection (intramuscular for MenACWY-TT 107
versus subcutaneous for Men-PS). 108
Written informed consent was obtained from subjects before the performance of any study-109
specific procedures. The protocol and associated documents were reviewed and approved by 110
local Independent Ethics Committee or Institutional Review Boards. This study was 111
conducted in accordance with Good Clinical Practice and all applicable regulatory 112
requirements, including the Declaration of Helsinki. This study is registered at 113
www.clinicaltrials.gov (NCT01154088). 114
Study objectives 115
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The co-primary objectives were (1) to compare the immunogenicity of MenACWY-TT 116
vaccine lots in terms of serum bactericidal activity using baby rabbit complement (rSBA) 117
(using an in-house assay) and (2) to demonstrate the non-inferiority of the vaccine response 118
(VR) induced by MenACWY-TT (Lot A) compared to Men-PS. 119
The secondary objectives included the evaluation of the non-inferiority of MenACWY-TT 120
Lot A to Men-PS in terms of rSBA (using the Health Protection Agency [HPA] assay), and 121
evaluation of immunogenicity and safety of MenACWY-TT and Men-PS. 122
Study subjects 123
Healthy adults aged 18–25 years at the time of vaccination who provided written informed 124
consent and who complied with the requirements of the protocol (completion of the diary 125
cards, return for the follow-up visits) were eligible for the study. 126
Subjects were excluded if they had previous administration or planned administration 127
during the study period of any investigational or non-registered product within 30 days prior 128
to the study, immunoglobulins or any blood products within three months preceding the 129
study, or a vaccine not foreseen by the study protocol (with the exception of any licensed 130
inactivated influenza vaccine, including H1N1 vaccine). Subjects who were 131
immunosuppressed for any reason or were previously vaccinated with a meningococcal 132
conjugate vaccine at any time, with a meningococcal PS vaccine within five years prior to the 133
study, or with a TT-containing vaccine within the last month were also excluded. Subjects 134
with history of meningococcal disease, neurologic disorders, including Guillain-Barré 135
Syndrome, bleeding disorders, allergic disease likely to be exacerbated by any component of 136
the study vaccine, chronic alcohol consumption and/or drug abuse were ineligible. Moreover, 137
subjects were ineligible if they had major congenital defects, a serious chronic illness or acute 138
disease at the time of enrollment. Females of child-bearing potential were required to practice 139
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adequate contraception for 30 days prior to vaccination, have a negative pregnancy test prior 140
to enrollment, and to practice adequate contraception throughout the study period. 141
Study vaccines 142
The MenACWY-TT vaccine was developed and manufactured by GlaxoSmithKline, 143
Rixensart, Belgium. One 0.5 mL dose of the MenACWY-TT vaccine contained 5 µg capsular 144
PS from each meningococcal serogroup (A, C, W-135, and Y) conjugated to TT 145
(approximately 44 µg of TT in each dose); the level of meningococcal serogroup A PS O-146
acetylation was 68% for Lot A, and 92% for Lot B. A 0.5 mL dose of the Men-PS vaccine 147
(Mencevax™, GlaxoSmithKline, Rixensart, Belgium) contained 50 µg capsular PS from each 148
meningococcal serogroup (A, C, W-135, and Y); the level of meningococcal serogroup A PS 149
O-acetylation was 82%. Each vaccine was administered as a single injection: MenACWY-TT 150
was administered intramuscularly into the non-dominant deltoid, and Men-PS was 151
administered subcutaneously into non-dominant upper arm. 152
Immunogenicity assessment 153
For the assessment of the vaccine immunogenicity, blood samples were collected from all 154
subjects prior to and one month after vaccination. Functional anti-meningococcal serogroup 155
A, C, W-135 and Y activity was determined by an rSBA assay with an antibody titer cut-off 156
of 1:8. This cut-off is considered indicative of seroprotection for serogroup C, and has been 157
extended to the other serogroups (34-36). Assays were performed at GlaxoSmithKline (for the 158
primary endpoints) and at HPA (UK) laboratories (for the secondary endpoints). Percentages 159
of subjects achieving rSBA titers ≥1:8 and ≥1:128 and geometric mean antibody titers 160
(GMTs) were determined for serogroups A, C, W-135 and Y using both rSBA assays. 161
Safety and reactogenicity assessment 162
Local (pain, redness, swelling) and general (fever, headache, fatigue, and gastrointestinal 163
symptoms including nausea, vomiting, diarrhea and/or abdominal pain) solicited symptoms 164
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were recorded up to four days after vaccination. The intensity of each symptom was graded 165
on a scale of 0 to 3. Symptoms of grade 3 intensity were defined as injection site redness or 166
swelling with a diameter >50 mm, fever with axillary/oral temperature >39.5°C, and all other 167
adverse events (AEs) that prevented normal, everyday activities. All solicited local (injection 168
site) reactions were considered causally related to vaccination. Causality of all other AEs was 169
assessed by the investigator. 170
All AEs, serious adverse events (SAEs), and the new onset of chronic illnesses (NOCIs) 171
occurring within one month (minimum 30 days) following vaccine administration were 172
recorded. 173
Statistical analysis 174
With 1050 evaluable subjects (350 per group), the global power to meet both co-primary 175
objectives was 92.8%. Assuming that up to 10% of enrolled subjects might have been 176
excluded from the according-to-protocol (ATP) cohort for immunogenicity, 1170 subjects 177
(390 per group) were planned to be enrolled. 178
The analysis of safety was performed on the total vaccinated cohort (TVC), which included 179
all vaccinated subjects. The analysis of immunogenicity was performed on the ATP cohort for 180
immunogenicity, comprising all subjects meeting all eligibility criteria, complying with the 181
procedures defined in the protocol and for whom immunogenicity results were available for 182
antibodies against at least one study vaccine antigen. 183
For each treatment group and for each antibody at pre- and post-vaccination time points, 184
rSBA GMTs were calculated with their 95% confidence intervals (CIs). rSBA GMTs were 185
calculated by taking the anti-log of the mean of the log titer transformations. Antibody titers 186
below the cut-off of the assay were given an arbitrary value of half the cut-off for the purpose 187
of GMT calculation. The proportion and 95% CIs of subjects with rSBA titers above pre-188
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specified cut-offs, and the proportion and 95% CIs of subjects with an rSBA VR were also 189
calculated. 190
The first primary objective of the clinical comparability of MenACWY-TT Lot A to Lot B 191
with respect to rSBA GMTs (as measured at GlaxoSmithKline laboratory) for serogroups A, 192
C, W-135, and Y was evaluated through computation of the 95% CIs of the rSBA GMT ratios 193
(ACWY-B over ACWY-A) using an analysis of covariance (ANCOVA) model on the log10 194
transformation of the titers including the vaccine group as fixed effect, and using the pre-195
vaccination log10 transformation of the titers and the country as covariates. The non-inferiority 196
of Lot B versus Lot A was demonstrated if the upper limit of the two-sided 95% CIs on the 197
rSBA GMT ratios was below a limit of two. 198
The second primary objective of the non-inferiority of the rSBA VR (as measured at 199
GlaxoSmithKline laboratory) induced by MenACWY-TT Lot A compared to Men-PS was 200
demonstrated for each serogroup if the lower limit of the two-sided standardized asymptotic 201
95% CI for the group difference (MenACWY-TT Lot A minus Men-PS) in the percentage of 202
subjects with VR was ≥-10%. VR was defined as a post-vaccination rSBA titer of at least 1:32 203
in initially seronegative subjects (rSBA titer <1:8) and a four-fold increase in rSBA titer in 204
initially seropositive subjects (rSBA titer ≥1:8). 205
Non-inferiority of MenACWY-TT Lot A compared to Men-PS with respect to rSBA 206
GMTs tested by HPA was evaluated through computation of the 95% CIs of the rSBA GMT 207
ratios (Men-PS over ACWY-A) using an ANCOVA model on the log10 transformation of the 208
titers including the vaccine group as fixed effect, and using the pre-vaccination log10 209
transformation of the titers and the country as covariates. The non-inferiority of ACWY-A 210
versus Men-PS was demonstrated if the upper limit of the 95% CI for the GMT ratio was 211
lower than two. 212
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In the exploratory analysis, the two groups were considered to be statistically significantly 213
different in terms of percentage of subjects with titers above the specified cut-offs, if the 95% 214
CI for the difference in rates between the two vaccine groups did not contain the value 0. Two 215
groups were considered to be statistically significantly different in terms of antibody titers, if 216
the 95% CI for the GMT ratio between the two groups did not contain the value 1. 217
Exploratory analyses were not adjusted for multiplicity; therefore the results should be 218
interpreted cautiously. 219
The percentage of subjects reporting each solicited local and general symptom (any grade, 220
grade 3, and in addition for general symptoms, related, and grade 3 related symptoms), each 221
unsolicited AE (grade 3, related, and grade 3 related), SAEs, and NOCI(s) were tabulated 222
with exact 95% CI. SAEs and withdrawal due to AE(s) were described in detail. 223
All statistical analyses were performed using SAS® software version 9.2 (SAS Institute 224
Inc., Cary, NC, US) and Proc StatXact 7.0. 225
Results 226
Study subjects 227
Out of the 1172 subjects enrolled, 1170 were vaccinated. Subjects were equally distributed 228
between the three study centers (130 subjects per center per treatment group). 1153 subjects 229
completed the study; all 17 withdrawn subjects were lost to follow-up after receipt of the 230
study vaccine (Figure 1). The demographic characteristics were comparable between the 231
study groups with respect to mean age and racial distribution. There were more females than 232
males enrolled in the ACWY-B group as compared with the other groups (Table 1). Almost 233
all subjects recruited from Thailand and the Philippines were South-East Asian, whereas the 234
majority of subjects from Panama were of Hispanic and mixed racial backgrounds. There was 235
no major difference in the age of subjects recruited from the different countries. More females 236
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than males were recruited from Panama (52.6%) and Thailand (59.0%), whereas the reverse 237
was true in the Philippines (49.0%) (Supplementary Table 1). 238
1.1. Immunogenicity (assay performed at GlaxoSmithKline) 239
The primary criterion to demonstrate the non-inferiority of the immunogenicity of 240
MenACWY-TT Lot A (68% O-acetylation of serogroup A PS) versus Lot B (92% O-241
acetylation of serogroup A PS) at one month after vaccination was reached, as the upper limit 242
of the 95% CIs of the rSBA GMT ratios (ACWY-B over ACWY-A) was below the limit of 243
two for all serogroups. Exploratory analyses suggested that the post-vaccination rSBA GMTs 244
for serogroup Y were statistically significantly higher in the ACWY-A compared to the 245
ACWY-B group (Table 2). 246
The primary criterion to demonstrate the non-inferiority of MenACWY-TT (Lot A) versus 247
Men-PS in terms of VR was reached, as for each serogroup separately, the lower limit of the 248
95% CI for the group difference (ACWY-A minus Men-PS) was greater than the pre-defined 249
limit of -10%. Exploratory analyses suggested that rSBA VR rates for serogroups W-135 and 250
Y were statistically significantly higher in the ACWY-A group than in the Men-PS group 251
(Table 3). 252
At one month after vaccination, VR rates for each of the four serogroups ranged from 253
79.1% to 97.0% in the MenACWY-TT groups and from 73.7% to 94.1% in the Men-PS 254
group (Table 4). The percentage of subjects with rSBA titers ≥1:8 for the four serogroups 255
increased to 100% in all three groups. All subjects in the MenACWY-TT groups and 99.5–256
100% of subjects in the Men-PS group achieved rSBA titers ≥1:128 (Table 4). 257
In all groups, rSBA GMTs for each serogroup were at least eight-fold higher at one month 258
post-vaccination compared to pre-vaccination. At one month post-vaccination, exploratory 259
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analyses suggested that the rSBA GMTs for serogroups A, W-135, and Y were statistically 260
significantly higher in the MenACWY-TT groups than in the Men-PS group (Table 4). 261
The percentage of subjects with pre-vaccination rSBA titers (≥1:8) for serogroup C 262
appeared lower in Panama (41.2–47.8%) than in Thailand (61.1–67.7%) or the Philippines 263
(69.6–77.4%). There were no major between-country differences in terms of percentage of 264
subjects with pre- or post-vaccination rSBA titers ≥1:8 or ≥1:128 for the other serogroups 265
(Supplementary Table 2). 266
1.2. Immunogenicity (assay performed at the Health Protection Agency) 267
At one month after vaccination, the non-inferiority of ACWY-A versus Men-PS in terms 268
of rSBA GMTs as measured by the HPA assay was demonstrated, since the upper limit of the 269
95% CIs of the rSBA GMT ratios (Men-PS over ACWY-A) was below the limit of two for all 270
serogroups. In both vaccine groups, the rSBA GMTs for each serogroup were over 200-fold 271
higher at one month post-vaccination compared to pre-vaccination. Exploratory analyses 272
suggested that the rSBA GMTs for serogroups A, W-135 and Y were statistically significantly 273
higher in the ACWY-A group compared to the Men-PS group (Supplementary Table 3). 274
The VR rates for each of the four serogroups ranged from 97.8% to 98.9% in the ACWY-275
A group and from 95.3% to 98.1% in the Men-PS group (Supplementary Table 4). 276
Exploratory analyses suggested that for serogroups W-135 and Y, rSBA VR rates were 277
statistically significantly higher in the ACWY-A group than in the Men-PS group. One month 278
post-vaccination, the percentage of subjects with rSBA titers ≥1:8 for the four serogroups 279
reached 98.9–100% in the ACWY-A group and 96.8–99.7% in the Men-PS group. The 280
proportion of subjects with rSBA titers ≥1:128 was 98.4–100% in the ACWY-A group and 281
96.2–98.4% in the Men-PS group. Exploratory analyses suggested that the percentages of 282
subjects with rSBA titers ≥1:8 for serogroups C and Y and rSBA titers ≥1:128 for serogroups 283
A, W-135, and Y were statistically significantly higher in the ACWY-A group compared to 284
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the Men-PS group. At one month post-vaccination, exploratory analyses suggested that the 285
rSBA GMTs for serogroups A, W-135, and Y were statistically significantly higher in the 286
ACWY-A group than in the Men-PS group (Supplementary Table 4). 287
Similar to the results obtained with the GlaxoSmithKline rSBA assay, aside from a trend 288
for lower pre-vaccination seropositivity rates for serogroup C in Panama, there were no major 289
differences in pre- or post-vaccination seropositivity rates observed between the countries 290
(data not shown). 291
Safety/reactogenicity 292
The most commonly reported solicited local symptom was pain at the injection site, 293
reported by 53.9% of subjects in the ACWY-A, 54.7% of subjects in the ACWY-B, and 294
36.8% of subjects in the Men-PS groups. The percentage of patients reporting pain tended to 295
be higher in both MenACWY-TT groups than in the Men-PS group, as indicated by the non-296
overlapping 95% CIs (Figure 2). Overall, solicited local symptoms seemed reported more 297
frequently in the MenACWY-TT groups than in the Men-PS group. The most common 298
solicited general symptoms were fatigue and headache, with an incidence of 28.6–30.3% and 299
26.9–31.0%, respectively (Figure 2). The incidence of fever (≥37.5°C) ranged from 6.0% to 300
7.3% across the groups; fever above 39.5°C was not reported. The proportions of subjects 301
reporting general symptoms were comparable between all three groups (Figure 2). Grade 3 302
solicited local and general symptoms were reported in ≤2.1% of subjects. 303
In all groups, the incidence of grade 3 unsolicited AEs ranged from 1.8–3.6%; the most 304
commonly reported were upper respiratory tract infection (0.3–1.0%), headache (0.3–0.5%) 305
and dysmenorrhea (0.0–0.8%). Grade 3 unsolicited symptoms causally related to vaccination 306
were reported by four subjects: one in the ACWY-A group (rash), one in the ACWY-B group 307
(blighted ovum, also reported as an SAE, see below) and two in the Men-PS group (one 308
reported migraine and one reported dermatitis atopic). 309
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Two subjects reported SAEs, one in the ACWY-B group (blighted ovum) and one in the 310
Men-PS group (acute appendicitis). The blighted ovum was considered by the investigators to 311
be potentially related to the study vaccination. This event was resolved when the subject had a 312
dilation and curettage. The appendicitis was considered as not related to the study vaccine. 313
The episode completely resolved after the subject was hospitalized and underwent 314
appendectomy. No subjects reported NOCIs and no fatal SAEs were reported during the 315
study. 316
Discussion 317
It has been shown that the removal of the O-acetyl groups reduced the immunogenicity of 318
the meningococcal serogroup A capsular PS in mice (33). The meningococcal serogroup A 319
capsular PS is 70–90% O-acetylated at carbon 3 and O-acetylation is susceptible to alkaline 320
hydrolysis (33,37,38). Potential differences in O-acetylation levels between different lots may 321
occur if O-acetyl groups are partially removed in the process of PS conjugation. This study 322
was conducted to ensure that a lower O-acetylation level (68%) of the meningococcal 323
serogroup A PS in MenACWY-TT vaccine Lot A did not unduly impact the immunogenicity 324
of the vaccine compared to the MenACWY-TT Lot B with a higher level of serogroup A PS 325
O-acetylation (92%) and to a licensed PS vaccine with 82% serogroup A PS O-acetylation. 326
The primary criterion for non-inferiority of MenACWY-TT Lot A versus Lot B was met. 327
A comparable immunogenicity of the two lots of MenACWY-TT differing in the levels of 328
meningococcal serogroup A capsular PS O-acetylation (68% and 92% of O-acetylation) was 329
demonstrated in terms of rSBA GMTs for all serogroups. Our results indicate that the lower 330
O-acetylation level of the meningococcal serogroup A capsular PS in MenACWY-TT did not 331
result in a reduced VR. The primary criteria for non-inferiority of Men-ACWY-TT (Lot A) 332
versus a licensed Men-PS vaccine in terms of VR to meningococcal serogroups A, C, W-135 333
and Y were met. 334
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At one month post-vaccination, high VR rates for all four serogroups were observed in all 335
groups. Moreover, when the GlaxoSmithKline rSBA assays were used, all subjects had rSBA 336
titers ≥1:8 and at least 99.5% had rSBA titers ≥1:128 with a high fold increase in rSBA 337
GMTs. These observations are consistent with results of previous studies evaluating the 338
immune response to MenACWY-TT in adolescents and young adults (39,40). 339
The results of the immunogenicity analyses performed at the HPA laboratories were in line 340
with those obtained with rSBA assays performed at GlaxoSmithKline. The MenACWY-TT 341
lot with the lowest O-acetylation level of the meningococcal serogroup A PS was shown to be 342
non-inferior to Men-PS in terms of rSBA GMTs. Furthermore, high VR rates and percentages 343
of subjects with rSBA titers ≥1:8 and ≥1:128 were observed in both groups. Exploratory 344
analyses showed that the rSBA GMTs evaluated by both GlaxoSmithKline and HPA assays 345
for meningococcal serogroups A, W-135, and Y were higher in subjects vaccinated with 346
MenACWY-TT compared with those who received the Men-PS vaccine. These results are 347
consistent with those previously obtained in adults aged 18–55 years (41). Exploratory 348
analysis done on the results obtained with HPA assay showed that the percentages of subjects 349
with rSBA titers ≥1:8 for serogroups C and Y, and with rSBA titers ≥1:128 for serogroups A, 350
W-135, and Y were statistically significantly higher in subjects vaccinated with the 351
MenACWY-TT lot with the lowest O-acetylation level of the meningococcal serogroup A PS 352
than in those who received the Men-PS vaccine. 353
In this study, the majority of subjects were seropositive for rSBA against all four 354
serogroups at pre-vaccination, as shown with the GlaxoSmithKline assay, although with the 355
HPA assay, approximately 1/3 as many subjects were seropositive for any serogroup at pre-356
vaccination. Different technical parameters used in the GlaxoSmithKline assay render the 357
assay more sensitive to naturally acquired antibodies (42). Thus, inter-laboratory differences 358
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may explain the lower reported rSBA titers measured by the HPA assay as compared to the 359
GlaxoSmithKline in-house assay. 360
High pre-vaccination rSBA titers have also been reported in other studies with 361
meningococcal conjugate vaccines conducted in adults (41,43,44) and are consistent with the 362
knowledge that the immunity to meningococcal strains increases with age (45). It is likely that 363
circulating meningococcal strains causing asymptomatic nasopharyngeal carriage and 364
acquisition of functional antibodies due to natural immunity may contribute to these high 365
observed seropositivity rates. Therefore, VR was chosen as a primary endpoint of this study, 366
as it measures the ability of subjects to respond to the vaccine regardless of their serostatus at 367
pre-vaccination. Interestingly, the percentage of subjects with pre-vaccination serogroup C 368
rSBA titers ≥1:8 appeared lower for Panama compared to Thailand or the Philippines. It is 369
possible that this could result from different levels of asymptomatic carriage of serogroup C 370
in these countries. However, as the carriage data from these countries are scarce, and 371
moreover, the prevalence of serogroup C in other parts of the South America (e.g. Brazil) is 372
high, these possible differences in pre-vaccination rSBA titers should be interpreted with 373
caution (13,46). 374
All vaccines administered in this study were well-tolerated. The safety profile of 375
MenACWY-TT was comparable to that observed in previous studies conducted in adolescents 376
and young adults (47,48). However, a lower incidence of pain at the injection site was 377
observed in two other studies, one conducted in adolescents from India, Taiwan and the 378
Philippines (26.2%) (49), and the other, in adults from Lebanon and the Philippines (19.4%) 379
(41). It is possible that the lower incidence of pain observed in these two latter studies, 380
reflects cultural differences in reporting symptoms. Pain at the injection site tended to be more 381
frequently reported in participants who received the MenACWY-TT vaccine than the Men-PS 382
vaccine. This observation is consistent with previous studies showing that the injection site 383
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reactions are more frequent in individuals vaccinated with MenACWY-TT compared to Men-384
PS (40,41,50,51), and in those vaccinated with other quadrivalent meningococcal conjugate 385
vaccines compared to plain PS vaccines (52,53). It is likely that the increased reactogenicity 386
following vaccination with the MenACWY-TT vaccine is due to the TT component (54). 387
Grade 3 unsolicited symptoms as well as unsolicited symptoms considered related to 388
vaccination were infrequent, and only two SAEs were reported. 389
Potential limitations of the study include the partial blinding due to the different routes of 390
administration for MenACWY-TT (intramuscular) and the meningococcal PS control vaccine 391
(subcutaneous). This could have theoretically impacted the evaluation of safety objectives, 392
although it is most likely that any bias would have occurred in favor of the control group. The 393
immunogenicity evaluations are very unlikely to have been impacted by the level of study 394
blinding since laboratory personnel remained blinded to treatment group throughout the 395
conduct of the study. Multiplicity adjustments were not made for the numerous exploratory 396
statistical analyses, and therefore the results of the exploratory comparisons should be 397
interpreted cautiously. 398
In conclusion, this study showed that the level of meningococcal serogroup A PS O-399
acetylation did not affect the immunogenicity of the vaccine, and the vaccine lot of 400
MenACWY-TT with the lower level of O-acetylation was non-inferior to the lot with the 401
higher level of O-acetylation. A single dose of MenACWY-TT was non-inferior to a single 402
dose of Men-PS in terms of the VR. 403
NIMENRIX, MENCEVAX and MENHIBRIX are trademarks of the GlaxoSmithKline group of 404
companies. MENACTRA is a trademark of Sanofi Pasteur. MENVEO is a trademark of Novartis 405
Vaccines. 406
Acknowledgements 407
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GlaxoSmithKline Biologicals SA was the funding source and was involved in all stages of 408
the study conduct and analysis. GlaxoSmithKline Biologicals SA also funded all costs 409
associated with the development and the publishing of the present manuscript. 410
The authors are indebted to the study subjects, clinicians, nurses, and laboratory 411
technicians at the study site, as well as to clinical investigators for their contribution to this 412
study. We would also like to thank the following employees of GlaxoSmithKline Vaccines for 413
their valuable contributions: Salvacion Gatchalian, Maria Mercedes Castrejon and Yongyuth 414
Wangroongsarb for their assistance in coordination of the study; Emmanuel Aris and Anne 415
Sumbul for their input into the statistical analysis; and Koen Maleux for conducting 416
laboratory assays. Finally, we thank Urszula Miecielica, PhD (XPE Pharma & Science) and 417
Wouter Houthoofd, PhD and Virginie Durbecq, PhD (XPE Pharma & Science, on behalf of 418
GlaxoSmithKline Vaccines) for providing medical writing services and editorial support in 419
preparing this manuscript. 420
The institutes of Dr Pornthep Chanthavanich (Mahidol University) and Dr Nestor Sosa 421
(Medical and Research Center) received grants from the GlaxoSmithKline group of 422
companies. Dr Pornthep Chanthavanich received support for meetings, travel or 423
accommodation expenses from the GlaxoSmithKline group of companies. Dr Nestor Sosa is 424
board membership of the Latin American HIV advisory board (MSD) and received payment 425
for lecture from Novartis and Pfizer. The institution of Dr Nestor Sosa received grants from 426
Bristol Myers Squibb and Tibotec (antiretroviral clinical trial) and from Pfizer (pneumonia 427
clinical trial). Veronique Bianco, Dr Yaela Baine, Dr Marie Van der Wielen and Dr 428
Jacqueline Miller are employees of GlaxoSmithKline Vaccines. Dr Marie Van der Wielen 429
declares stock ownership in the GlaxoSmithKline group of companies. Dr Yaela Baine and Dr 430
Jacqueline Miller declare restricted share in the GlaxoSmithKline group of companies. Dr 431
Socorro Lupisan and Dr Kriengsak Limkittikul declare that they have no competing interests. 432
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Dr S. Lupisan, Dr K. Limkittikul, Dr N. Sosa, and Dr P. Chanthavanich were 433
investigators involved in the supervision of the study, administrative, logistic and technical 434
supports, the recruitment and the medical evaluation of subjects, the evaluation of any 435
reported AEs/ SAEs for severity and causality, the collection and interpretation of the data, 436
and the drafting and approval of the manuscript. Dr Y. Baine, Dr JM. Miller, Dr M. Van der 437
Wielen (clinical development scientists) and V. Bianco (biostatistician) are employed by 438
GlaxoSmithKline Vaccines and were involved in all stages of the study (study design, data 439
analyses and interpretations, drafting and approval of the manuscript). 440
441
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632
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Figure legends 633
Figure 1. Subject flow chart showing number of subjects enrolled, completed and reasons for 634
exclusion from the ATP cohort for immunogenicity. 635
Footnote: *One subject had the randomization code broken at the investigator site (to know which vaccine was 636
administered), as the subject experienced a serious adverse event (blighted ovum) assessed by the 637
investigators as possibly related to the study vaccine. 638
ACWY-A=subjects vaccinated with MenACWY-TT Lot A 639
ACWY-B=subjects vaccinated with MenACWY-TT Lot B 640
Men-PS=subjects vaccinated with Men-PS 641
ATP=according-to-protocol 642
N=number of subjects 643
644
Figure 2. Percentage of subjects who reported local and general solicited symptoms within 645
the four-day post-vaccination period (Total vaccinated cohort). 646
Footnote: ACWY-A=subjects vaccinated with MenACWY-TT Lot A 647
ACWY-B=subjects vaccinated with MenACWY-TT Lot B 648
Men-PS=subjects vaccinated with Men-PS 649
Error bars represent 95% confidence intervals. 650
651
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Table 1. Summary of demographic characteristics (Total vaccinated cohort). 652
Characteristics ACWY-A ACWY-B Men-PS
N 390 390 390
Age Mean (SD) 20.8 (2.14) 20.9 (2.10) 20.6 (1.94)
Sex Female, n (%) 197 (50.5) 225 (57.7) 204 (52.3)
Male, n (%) 193 (49.5) 165 (42.3) 186 (47.7)
Race Asian – South-East Asian heritage, n (%)
Asian – East Asian heritage, n (%)
Asian – Central/South Asian heritage, n (%)
Asian – Japanese heritage, n (%)
258 (66.2)
2 (0.5)
0 (0.0)
0 (0.0)
259 (66.4)
1 (0.3)
1 (0.3)
0 (0.0)
257 (65.9)
2 (0.5)
0 (0.0)
1 (0.3)
African heritage/African American, n (%)
White – Caucasian/European heritage, n (%)
White – Arabic/North African heritage, n (%)
16 (4.1)
13 (3.3)
1 (0.3)
13 (3.3)
14 (3.6)
0 (0.0)
17 (4.4)
13 (3.3)
0 (0.0)
Other*, n (%) 100 (25.6) 102 (26.2) 100 (25.6)
653 Footnote: ACWY-A=subjects vaccinated with MenACWY-TT Lot A 654
ACWY-B=subjects vaccinated with MenACWY-TT Lot B 655
Men-PS=subjects vaccinated with Men-PS 656
N=number of subjects 657
n (%)=number (percentage) of subjects in a given category 658
SD=standard deviation 659
Other*=Hispanic, Indigenous, Kuna (Indigenous), Latin, Mixed and Panamanian Lebanese 660
661
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Table 2. Adjusted GMT ratios between ACWY-B and ACWY-A groups for rSBA-MenA, 662
rSBA-MenC, rSBA-MenW-135, rSBA-MenY titers one month after vaccination, 663
GlaxoSmithKline rSBA assay (ATP cohort for immunogenicity). 664
Antibody ACWY-B ACWY-A Adjusted GMT ratio
(ACWY-B/ACWY-A)
N Adjusted
GMT
N Adjusted
GMT
Value (95%CI)
rSBA-MenA 298 5195.3 302 4997.0 1.04 (0.92, 1.17)
rSBA-MenC 342 6874.5 346 5988.0 1.15 (0.96, 1.37)
rSBA-MenW-135 327 9202.5 338 10115.0 0.91 (0.80, 1.04)
rSBA-MenY 353 10339.0 358 11757.9$ 0.88 (0.78, 0.99)
665
Footnote: ACWY-A=subjects vaccinated with MenACWY-TT Lot A 666
ACWY-B=subjects vaccinated with MenACWY-TT Lot B 667
N=number of subjects with both pre- and post-vaccination available results 668
Adjusted GMT=geometric mean antibody titer adjusted for country, baseline titer 669
95% CI=95% confidence interval for the adjusted GMT ratio (ANCOVA model: adjustment for 670
country and baseline titer - pooled variance) 671
Bold: the upper limit of 95% CI is below non-inferiority limit of two. 672
$Statistically significantly higher value in the ACWY-A group compared to the ACWY-B group 673
(exploratory analysis). 674
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Table 3. Difference between the ACWY-A and Men-PS groups in the percentage of subjects 676
with vaccine response to rSBA antibodies one month after vaccination, GlaxoSmithKline 677
rSBA assay (ATP cohort for immunogenicity). 678
Antibody ACWY-A Men-PS Difference in vaccine response rate
(ACWY-A minus Men-PS)
N % N % % (95% CI)
rSBA-MenA 302 79.1 293 73.7 5.42 (-1.41, 12.25)
rSBA-MenC 346 93.6 353 94.1 -0.41 (-4.11, 3.25)
rSBA-MenW-135 338 97.0$ 337 90.2 6.83 (3.28, 10.78)
rSBA-MenY 358 93.3$ 357 86.3 7.02 (2.63, 11.58)
679
Footnote: ACWY-A=subjects vaccinated with MenACWY-TT Lot A 680
Men-PS=subjects vaccinated with Men-PS 681
N=number of subjects with available results 682
%=percentage of subjects with a vaccine response 683
95% CI=standardized asymptotic 95% confidence interval 684
Vaccine response was defined as: 685
For initially seronegative subjects (rSBA titer <1:8): post-vaccination titer ≥1:32 686
For initially seropositive subjects (rSBA titer ≥1:8): post-vaccination titer ≥four-fold pre-687
vaccination antibody titer 688
Bold: the lower limit of 95% CI for the group difference between ACWY-A and Men-PS is above the 689
non-inferiority limit of -10%. 690
$Statistically significantly higher value in the ACWY-A group compared to the Men-PS group 691
(exploratory analysis). 692
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Table 4. Percentage of subjects with rSBA titers ≥ the cut-off values of 1:8 and 1:128 and GMTs (prior to and one month after vaccination), and 694
vaccine response, GlaxoSmithKline rSBA assay (ATP cohort for immunogenicity). 695
Group Timepoint GSK rSBA titers Vaccine response
N % ≥1:8 (95% CI) % ≥1:128 (95% CI) GMT (95% CI)* N£ % (95% CI)
rSBA-MenA
ACWY-A Pre 320 92.5 (89.0, 95.1) 85.0 (80.6, 88.7) 348.4 (293.0, 414.2)
Post 359 100 (99.0, 100) 100 (99.0, 100) 4846.0$ (4459.8, 5265.7) 302 79.1 (74.1, 83.6)
ACWY-B Pre 328 95.7 (92.9, 97.6) 89.0 (85.1, 92.2) 401.4 (347.2, 464.1)
Post 343 100 (98.9, 100) 100 (98.9, 100) 5064.6$ (4657.5, 5507.2) 298 79.9 (74.9, 84.3)
Men-PS Pre 310 95.2 (92.1, 97.3) 88.7 (84.6, 92.0) 424.4 (362.9, 496.5)
Post 356 100 (99.0, 100) 100 (99.0, 100) 3421.0 (3134.7, 3733.4) 293 73.7 (68.3, 78.7)
rSBA-MenC
ACWY-A Pre 351 60.1 (54.8, 65.3) 37.9 (32.8, 43.2) 36.3 (29.3, 45.0)
Post 374 100 (99.0, 100) 100 (99.0, 100) 6025.4 (5269.0, 6890.2) 346 93.6 (90.5, 96.0)
ACWY-B Pre 350 60.9 (55.5, 66.0) 42.9 (37.6, 48.2) 44.7 (35.6, 56.2)
Post 370 100 (99.0, 100) 100 (99.0, 100) 7070.7 (6225.3, 8030.9) 342 95.6 (92.9, 97.5)
Men-PS Pre 361 62.0 (56.8, 67.1) 44.0 (38.9, 49.3) 46.9 (37.2, 59.0)
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Post 372 100 (99.0, 100) 99.5 (98.1, 99.9) 5953.1 (5188.2, 6830.7) 353 94.1 (91.0, 96.3)
rSBA-MenW-135
ACWY-A Pre 343 86.3 (82.2, 89.8) 71.1 (66.0, 75.9) 185.9 (153.1, 225.6)
Post 375 100 (99.0, 100) 100 (99.0, 100) 9836.7$ (8939.2, 10824.3) 338 97.0$ (94.6, 98.6)
ACWY-B Pre 333 85.9 (81.7, 89.4) 72.1 (66.9, 76.8) 191.2 (155.9, 234.4)
Post 370 100 (99.0, 100) 100 (99.0, 100) 8855.5$ (8021.8, 9775.9) 327 95.4$ (92.5, 97.4)
Men-PS Pre 345 86.4 (82.3, 89.8) 70.7 (65.6, 75.5) 205.5 (167.6, 252.0)
Post 372 100 (99.0, 100) 99.7 (98.5, 100) 4675.1 (4145.9, 5272.0) 337 90.2 (86.5, 93.2)
rSBA-MenY
ACWY-A Pre 363 92.3 (89.0, 94.8) 84.6 (80.4, 88.1) 387.5 (324.9, 462.2)
Post 375 100 (99.0, 100) 100 (99.0, 100) 11632.5$ (10675.1, 12675.8) 358 93.3$ (90.2, 95.7)
ACWY-B Pre 359 94.2 (91.2, 96.3) 85.8 (81.7, 89.2) 426.8 (362.2, 502.8)
Post 371 100 (99.0, 100) 100 (99.0, 100) 10386.7$ (9557.5, 11287.9) 353 91.8$ (88.4, 94.4)
Men-PS Pre 364 92.3 (89.1, 94.8) 86.0 (82.0, 89.4) 412.6 (346.8, 490.8)
Post 373 100 (99.0, 100) 100 (99.0, 100) 6315.9 (5787.9, 6892.1) 357 86.3 (82.3, 89.7) 696
Footnote: ACWY-A=subjects vaccinated with MenACWY-TT Lot A 697
ACWY-B=subjects vaccinated with MenACWY-TT Lot B 698
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Men-PS=subjects vaccinated with Men-PS 699
N=number of subjects with available results 700
N£=number of subjects with both pre- and post-vaccination results available 701
GSK=GlaxoSmithKline 702
%=percentage of subjects with titer within the specified range 703
95% CI=95% confidence interval 704
GMT=geometric mean antibody titer 705
*Note: GMTs in this table have not been adjusted for baseline titer or country and per the study report. 706
Pre=pre-vaccination at month 0 707
Post=post-vaccination at month 1 708
Vaccine response was defined as: 709
For initially seronegative subjects (rSBA titer <1:8): post-vaccination titer ≥1:32 710
For initially seropositive subjects (rSBA titer ≥1:8): post-vaccination titer ≥four-fold pre-vaccination antibody titer 711
$Statistically significantly higher value in the ACWY-A or ACWY-B group compared to the Men-PS group (exploratory analysis). 712 713
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