1 Downloaded from 2 on May 29, 2020 by ... · 7/18/2013 · 11 3Pan American Medical Research...

1

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

on Decem

ber 2, 2020 by guesthttp://cvi.asm

.org/D

ownloaded from

http://cvi.asm.org/

2

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

on Decem


.org/D

ownloaded from

http://cvi.asm.org/

3

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

on Decem


.org/D

ownloaded from

http://cvi.asm.org/

4

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

on Decem


.org/D

ownloaded from

http://cvi.asm.org/

5

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

on Decem


.org/D

ownloaded from

http://cvi.asm.org/

6

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

on Decem


.org/D

ownloaded from

http://cvi.asm.org/

7

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

on Decem


.org/D

ownloaded from

http://cvi.asm.org/

8

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

on Decem


.org/D

ownloaded from

http://cvi.asm.org/

9

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

on Decem


.org/D

ownloaded from

http://cvi.asm.org/

10

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

on Decem


.org/D

ownloaded from

http://cvi.asm.org/

11

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

on Decem


.org/D

ownloaded from

http://cvi.asm.org/

12

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

on Decem


.org/D

ownloaded from

http://cvi.asm.org/

13

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

on Decem


.org/D

ownloaded from

http://cvi.asm.org/

14

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

on Decem


.org/D

ownloaded from

http://cvi.asm.org/

15

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

on Decem


.org/D

ownloaded from

http://cvi.asm.org/

16

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

on Decem


.org/D

ownloaded from

http://cvi.asm.org/

17

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

on Decem


.org/D

ownloaded from

http://cvi.asm.org/

18

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

on Decem


.org/D

ownloaded from

http://cvi.asm.org/

19

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

on Decem


.org/D

ownloaded from

http://cvi.asm.org/

20

References 442

1. Findlow J, Balmer P, Yero D, Niebla O, Pajon R, Borrow R. 2007. Neisseria 443

vaccines 2007. Expert.Rev.Vaccines. 6:485-489. 444

2. Harrison LH, Trotter CL, Ramsay ME. 2009. Global epidemiology of meningococcal 445

disease. Vaccine. 27 (Suppl 2):B51-B63. doi: 10.1016/j.vaccine.2009.04.063. 446

3. Pollard AJ. 2004. Global epidemiology of meningococcal disease and vaccine efficacy. 447

Pediatr.Infect.Dis.J. 23:S274-S279. 448

4. Rouphael NG, Stephens DS. 2012. Neisseria meningitidis: biology, microbiology, and 449

epidemiology. Methods Mol.Biol. 799:1-20. 450

5. Khatami A, Pollard AJ. 2010. The epidemiology of meningococcal disease and the 451

impact of vaccines. Expert.Rev.Vaccines. 9:285-298. doi: 10.1586/erv.10.3. 452

6. Harrison LH, Pass MA, Mendelsohn AB, Egri M, Rosenstein NE, Bustamante A, 453

Razeq J, Roche JC. 2001. Invasive meningococcal disease in adolescents and young 454

adults. JAMA. 286:694-699. 455

7. Harrison LH. 2010. Epidemiological profile of meningococcal disease in the United 456

States. Clin Infect.Dis. 50 (Suppl 2):S37-S44. doi: 10.1086/648963. 457

8. Stephens DS. 2007. Conquering the meningococcus. FEMS Microbiol.Rev. 31:3-14. 458

9. Caugant DA, Maiden MC. 2009. Meningococcal carriage and disease--population 459

biology and evolution. Vaccine. 27 (Suppl 2):B64-B70. doi: 460

10.1016/j.vaccine.2009.04.061. 461

on Decem


.org/D

ownloaded from

http://cvi.asm.org/

21

10. Tan LK, Carlone GM, Borrow R. 2010. Advances in the development of vaccines 462

against Neisseria meningitidis. N.Engl.J.Med. 362:1511-1520. doi: 463

10.1056/NEJMra0906357. 464

11. Efron AM, Sorhouet C, Salcedo C, Abad R, Regueira M, Vázquez JA. 2009. W135 465

invasive meningococcal strains spreading in South America: significant increase in 466

incidence rate in Argentina. J Clin Microbiol. 47:1979-80. doi: 10.1128/JCM.02390-08. 467

12. von Gottberg A, du Plessis M, Cohen C, Prentice E, Schrag S, de Gouveia L, 468

Coulson G, de Jong G, Klugman K; Group for Enteric, Respiratory and Meningeal 469

Disease Surveillance in South Africa. 2008. Emergence of endemic serogroup W135 470

meningococcal disease associated with a high mortality rate in South Africa. Clin Infect 471

Dis. 46:377-86. doi: 10.1086/525260. 472

13. Sáfadi MA, González-Ayala S, Jäkel A, Wieffer H, Moreno C, Vyse A. 2012. The 473

epidemiology of meningococcal disease in Latin America 1945-2010: an unpredictable 474

and changing landscape. Epidemiol Infect. 9:1-12. 475

14. Vyse A, Wolter JM, Chen J, Ng T, Soriano-Gabarro M. 2011. Meningococcal 476

disease in Asia: an under-recognized public health burden. Epidemiol.Infect. 15:1-19. 477

15. Shao PL, Chang LY, Hsieh SM, Chang SC, Pan SC, Lu CY, Hsieh YC, Lee CY, 478

Dobbelaere K, Boutriau D, Tang H, Bock HL, Huang LM. 2009. Safety and 479

immunogenicity of a tetravalent polysaccharide vaccine against meningococcal disease. 480

J.Formos.Med.Assoc. 108:539-547. doi: 10.1016/S0929-6646(09)60371-5. 481

16. Harrison LH. 2006. Prospects for vaccine prevention of meningococcal infection. Clin 482

Microbiol.Rev. 19:142-164. 483

on Decem


.org/D

ownloaded from

http://cvi.asm.org/

22

17. Terranella A, Cohn A, Clark T. 2011. Meningococcal conjugate vaccines: optimizing 484

global impact. Infect.Drug Resist. 4:161-169. doi: 10.2147/IDR.S21545. 485

18. Borrow R, Miller E. 2006. Long-term protection in children with meningococcal C 486

conjugate vaccination: lessons learned. Expert.Rev.Vaccines. 5:851-857. 487

19. Khatami A, Peters A, Robinson H, Williams N, Thompson A, Findlow H, Pollard 488

AJ, Snape MD. 2011. Maintenance of immune response throughout childhood 489

following serogroup C meningococcal conjugate vaccination in early childhood. Clin 490

Vaccine Immunol. 18:2038-2042. doi: 10.1128/CVI.05354-11. 491

20. Maiden MC, Ibarz-Pavon AB, Urwin R, Gray SJ, Andrews NJ, Clarke SC, Walker 492

AM, Evans MR, Kroll JS, Neal KR, Ala'aldeen DA, Crook DW, Cann K, Harrison 493

S, Cunningham R, Baxter D, Kaczmarski E, Maclennan J, Cameron JC, Stuart 494

JM. 2008. Impact of meningococcal serogroup C conjugate vaccines on carriage and 495

herd immunity. J.Infect.Dis. 197:737-743. doi: 10.1086/527401. 496

21. FDA, US Food and Drug Administration. June 14, 2012. Approval Letter - 497

MenHibrix. Available at: 498

http://www.fda.gov/BiologicsBloodVaccines/Vaccines/ApprovedProducts/ucm308573.499

htm (accessed on September 26, 2012). 500

22. Centers for Disease Control and Prevention (CDC). 2011. Recommendation of the 501

Advisory Committee on Immunization Practices (ACIP) for use of quadrivalent 502

meningococcal conjugate vaccine (MenACWY-D) among children aged 9 through 23 503

months at increased risk for invasive meningococcal disease. MMWR 504

Morb.Mortal.Wkly.Rep. 60:1391-1392. 505

on Decem


.org/D

ownloaded from

http://cvi.asm.org/

23

23. FDA, US Food and Drug Administration. Menactra Approval Letter. April 2011. 506

Available at: 507

http://www.fda.gov/BiologicsBloodVaccines/Vaccines/ApprovedProducts/ucm252511.508

htm (accessed on September 26, 2012). 509

24. Sanofi Pasteur Inc. Menactra® (meningococcal [groups A, C, Y and W-135] 510

polysaccharide diphtheria toxoid conjugate vaccine); US prescribing information 511

[online]. Available at: 512

http://www.fda.gov/downloads/biologicsbloodvaccines/vaccines/approvedproducts/ucm513

131170.pdf (accessed on January 14, 2013). 514

25. Sanofi Pasteur press release. Available at: http://www.sanofipasteur.com/sanofi-515

pasteur4/ImageServlet?imageCode=27961&siteCode=SP_CORP4 (accessed on January 516

14, 2013). 517

26. Australian Government. Department of Health and Aging. 2011. Australian Public 518

Assessment Report for Groups A, C, Y and W-135 Meningococcal Polysaccharide 519

Diphtheria Toxoid Conjugate Vaccine. Available at: 520

http://www.tga.gov.au/pdf/auspar/auspar-menactra-110929.pdf (accessed on May 23, 521

2013). 522

27. Cooper B, DeTora L, Stoddard J. 2011. Menveo(R)): a novel quadrivalent 523

meningococcal CRM197 conjugate vaccine against serogroups A, C, W-135 and Y. 524

Expert.Rev.Vaccines. 10:21-33. doi: 10.1586/erv.10.147. 525

28. Deeks ED. 2010. Meningococcal quadrivalent (serogroups A, C, w135, and y) 526

conjugate vaccine (Menveo): in adolescents and adults. BioDrugs. 24:287-297. doi: 527

10.2165/11204790-000000000-00000. 528

on Decem


.org/D

ownloaded from

http://cvi.asm.org/

24

29. European Medicines Agency Committee for Medicinal Products for Human Use 529

(CHMP). 2012. Menveo, meningococcal group A, C, W135 and Y conjugate vaccine. 530

Available at: 531

http://www.ema.europa.eu/docs/en_GB/document_library/Summary_of_opinion/human532

/001095/WC500124220.pdf (accessed on September 26, 2012). 533

30. Lee B. 2012. Meningococcal Vaccines. Available at: 534

http://orion.pleksus.com.tr/puader/v2/files/file/pdf/sunum_2012/PUADER_Congress_535

Meningococcal_Vaccines_LEE_FINAL.pdf) (accessed on January 14, 2013). 536

31. Australian Government. Department of Health and Aging. 2010. Australian Public 537

Assessment Report for Meningococcal Conjugated Vaccine. Meningococcal Vaccines. 538

Available at: http://www.tga.gov.au/pdf/auspar/auspar-menveo.pdf (accessed on May 539

23, 2013). 540

32. European Medicines Agency Committee for Medicinal Products for Human Use 541

(CHMP). 2012. EPAR summary for the public: Nimenrix, Meningococcal group A, C, 542

W-135 and Y conjugate vaccine. 543

Available at: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-544

_Summary_for_the_public/human/002226/WC500127665.pdf (accessed on September 545

26, 2012). 546

33. Berry DS, Lynn F, Lee CH, Frasch CE, Bash MC. 2002. Effect of O acetylation of 547

Neisseria meningitidis serogroup A capsular polysaccharide on development of 548

functional immune responses. Infect.Immun. 70:3707-3713. 549

on Decem


.org/D

ownloaded from

http://cvi.asm.org/

25

34. Andrews N, Borrow R, Miller E. 2003. Validation of serological correlate of 550

protection for meningococcal C conjugate vaccine by using efficacy estimates from 551

postlicensure surveillance in England. Clin Diagn.Lab Immunol. 10:780-786. 552

35. Borrow R, Balmer P, Miller E. 2005. Meningococcal surrogates of protection--serum 553

bactericidal antibody activity. Vaccine. 23:2222-2227. 554

36. Centers for Disease Control and Prevention (CDC). 2006. Inadvertent 555

misadministration of meningococcal conjugate vaccine-United States, June-August 556

2005. MMWR Morb Mortal Wkly Rep. 55:1016-1017. 557

37. Jennings HJ, Bhattacharjee AK, Bundle DR, Kenny CP, Martin A, Smith IC. 1977. 558

Structures of the capsular polysaccharides of Neisseria meningitidis as determined by 559

13C-nuclear magnetic resonance spectroscopy. J Infect.Dis. 136 (Suppl 1):S78-S83. 560

38. Lemercinier X, Jones C. 1996. Full 1H NMR assignment and detailed O-acetylation 561

patterns of capsular polysaccharides from Neisseria meningitidis used in vaccine 562

production. Carbohydr.Res. 296:83-96. 563

39. Dbaibo G, Van der Wielen M, Reda M, Medlej F, Tabet C, Boutriau D, Sumbul A, 564

Anis S, Miller JM. 2012. The tetravalent meningococcal serogroups A, C, W-135, and 565

Y tetanus toxoid conjugate vaccine is immunogenic with a clinically acceptable safety 566

profile in subjects previously vaccinated with a tetravalent polysaccharide vaccine. Int.J 567

Infect.Dis. 16:e608-e615. doi: 10.1016/j.ijid.2012.04.006. 568

40. Ostergaard L, Lebacq E, Poolman J, Maechler G, Boutriau D. 2009. 569

Immunogenicity, reactogenicity and persistence of meningococcal A, C, W-135 and Y-570

tetanus toxoid candidate conjugate (MenACWY-TT) vaccine formulations in 571

adolescents aged 15-25 years. Vaccine. 27:161-168. doi: 10.1016/j.vaccine.2008.08.075. 572

on Decem


.org/D

ownloaded from

http://cvi.asm.org/

26

41. Dbaibo G, Macalalad N, Aplasca-De Los Reyes MR, Dimaano E, Bianco V, Baine 573

Y, Miller J. 2012. The immunogenicity and safety of an investigational meningococcal 574

serogroups A, C, W-135, Y tetanus toxoid conjugate vaccine (ACWY-TT) compared 575

with a licensed meningococcal tetravalent polysaccharide vaccine: a randomized, 576

controlled non-inferiority study. Hum.Vaccin.Immunother. 8:873-880. doi: 577

10.4161/hv.20211. 578

42. Lechevin I, Le Bras V, Lestrate PR, Wauters D. 2012. Identification of key 579

parameters that impact the sensitivity of the MenC-rSBA assay to natural antibodies. 580

IPNC; XVIIIth International Pathogenic Neisseria Conference (IPNC) 2012 (abstract). 581

43. Campbell JD, Edelman R, King JC, Jr., Papa T, Ryall R, Rennels MB. 2002. 582

Safety, reactogenicity, and immunogenicity of a tetravalent meningococcal 583

polysaccharide-diphtheria toxoid conjugate vaccine given to healthy adults. J Infect.Dis. 584

186:1848-1851. 585

44. Kshirsagar N, Mur N, Thatte U, Gogtay N, Viviani S, Preziosi MP, Elie C, Findlow 586

H, Carlone G, Borrow R, Parulekar V, Plikaytis B, Kulkarni P, Imbault N, 587

LaForce FM. 2007. Safety, immunogenicity, and antibody persistence of a new 588

meningococcal group A conjugate vaccine in healthy Indian adults. Vaccine. 25 (Suppl 589

1):A101-A107. 590

45. Goldschneider I, Gotschlich EC, Artenstein MS. 1969. Human immunity to the 591

meningococcus. II. Development of natural immunity. J Exp.Med. 129:1327-1348. 592

46. Ibarz-Pavón AB, Lemos AP, Gorla MC, Regueira M; SIREVA Working Group II, 593

Gabastou JM. 2012. Laboratory-based surveillance of Neisseria meningitidis isolates 594

on Decem


.org/D

ownloaded from

http://cvi.asm.org/

27

from disease cases in Latin American and Caribbean countries, SIREVA II 2006-2010. 595

PLoS One. 7:e44102. doi: 10.1371. 596

47. Baxter R, Baine Y, Ensor K, Bianco V, Friedland LR, Miller JM. 2011. 597

Immunogenicity and safety of an investigational quadrivalent meningococcal ACWY 598

tetanus toxoid conjugate vaccine in healthy adolescents and young adults 10 to 25 years 599

of age. Pediatr.Infect.Dis.J. 30:e41-e48. doi: 10.1097/INF.0b013e3182054ab9. 600

48. Ostergaard L, Silfverdal SA, Berglund J, Flodmark CE, West C, Bianco V, Baine 601

Y, Miller JM. 2012. A tetravalent meningococcal serogroups A, C, W-135, and Y 602

tetanus toxoid conjugate vaccine is immunogenic and well-tolerated when co-603

administered with Twinrix((R)) in subjects aged 11-17 years: an open, randomised, 604

controlled trial. Vaccine. 30:774-783. doi: 10.1016/j.vaccine.2011.11.051. 605

49. Bermal N, Huang LM, Dubey AP, Jain H, Bavdekar A, Lin TY, Bianco V, Baine Y, 606

Miller JM. 2011. Safety and immunogenicity of a tetravalent meningococcal 607

serogroups A, C, W-135 and Y conjugate vaccine in adolescents and adults. 608

Hum.Vaccin. 7:239-247. 609

50. Knuf M, Kieninger-Baum D, Habermehl P, Muttonen P, Maurer H, Vink P, 610

Poolman J, Boutriau D. 2010. A dose-range study assessing immunogenicity and 611

safety of one dose of a new candidate meningococcal serogroups A, C, W-135, Y 612

tetanus toxoid conjugate (MenACWY-TT) vaccine administered in the second year of 613

life and in young children. Vaccine. 28:744-753. doi: 10.1016/j.vaccine.2009.10.064. 614

51. Memish ZA, Dbaibo G, Montellano M, Verghese VP, Jain H, Dubey AP, Bianco V, 615

Van der Wielen M, Gatchalian S, Miller JM. 2011. Immunogenicity of a single dose 616

of tetravalent meningococcal serogroups A, C, W-135, and Y conjugate vaccine 617

on Decem


.org/D

ownloaded from

http://cvi.asm.org/

28

administered to 2- to 10-year-olds is noninferior to a licensed-ACWY polysaccharide 618

vaccine with an acceptable safety profile. Pediatr.Infect.Dis.J. 30:e56-e62. doi: 619

10.1097/INF.0b013e31820e6e02. 620

52. Black S, Klein NP, Shah J, Bedell L, Karsten A, Dull PM. 2010. Immunogenicity and 621

tolerability of a quadrivalent meningococcal glycoconjugate vaccine in children 2-10 622

years of age. Vaccine. 28:657-663. doi: 10.1016/j.vaccine.2009.10.104. 623

53. Keyserling H, Papa T, Koranyi K, Ryall R, Bassily E, Bybel MJ, Sullivan K, 624

Gilmet G, Reinhardt A. 2005. Safety, immunogenicity, and immune memory of a 625

novel meningococcal (groups A, C, Y, and W-135) polysaccharide diphtheria toxoid 626

conjugate vaccine (MCV-4) in healthy adolescents. Arch.Pediatr.Adolesc.Med. 627

159:907-913. 628

54. Wassilak SG, Roper MH, Murphy TV, Orenstein WA. 2004. Tetanus toxoid, p 766. 629

In: Plotkin SA and Orenstein WA (eds). Vaccines, 4th edition. Philadelphia: WB 630

Saunders Company. 631

632

on Decem


.org/D

ownloaded from

http://cvi.asm.org/

29

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



Error bars represent 95% confidence intervals. 650

651

on Decem


.org/D

ownloaded from

http://cvi.asm.org/

30

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



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

on Decem


.org/D

ownloaded from

http://cvi.asm.org/

31

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



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

675

on Decem


.org/D

ownloaded from

http://cvi.asm.org/

32

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



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

693

on Decem


.org/D

ownloaded from

http://cvi.asm.org/

33

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)

on Decem


.org/D

ownloaded from

http://cvi.asm.org/

34

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



on Decem


.org/D

ownloaded from

http://cvi.asm.org/

35


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

on Decem


.org/D

ownloaded from

http://cvi.asm.org/

on Decem


.org/D

ownloaded from

http://cvi.asm.org/

1 Downloaded from 2 on May 29, 2020 by ... · 7/18/2013 · 11 3Pan American Medical Research...

Documents

Transcript of 1 Downloaded from 2 on May 29, 2020 by ... · 7/18/2013 · 11 3Pan American Medical Research...