Menactra is a trademark of Aventis Pasteur Inc. Menomune ®, Tripedia ® and Typhim Vi ® are...
-
Upload
juliet-may-johnston -
Category
Documents
-
view
227 -
download
8
Transcript of Menactra is a trademark of Aventis Pasteur Inc. Menomune ®, Tripedia ® and Typhim Vi ® are...
Menactra is a trademark of Aventis Pasteur Inc. Menomune®, Tripedia® and Typhim Vi® are registered trademarks of Aventis Pasteur. C-1
MENACTRAMENACTRA™™
Meningococcal (Groups A, C, Y and Meningococcal (Groups A, C, Y and W-135) Polysaccharide Diphtheria W-135) Polysaccharide Diphtheria
Toxoid Conjugate VaccineToxoid Conjugate Vaccine
Vaccines and Related Biological ProductsVaccines and Related Biological ProductsAdvisory CommitteeAdvisory Committee
September 22, 2004September 22, 2004
Menactra is a trademark of Aventis Pasteur Inc. Menomune®, Tripedia® and Typhim Vi® are registered trademarks of Aventis Pasteur. C-2
Menactra - AgendaMenactra - Agenda
IntroductionIntroduction Luc Kuykens, MD, MPHLuc Kuykens, MD, MPHVP Regulatory AffairsVP Regulatory Affairs
EpidemiologyEpidemiology Greg Gilmet, MD, MPHGreg Gilmet, MD, MPHDirector Scientific & Medical AffairsDirector Scientific & Medical Affairs
ImmunogenicityImmunogenicity Michael Decker, MD, MPHMichael Decker, MD, MPHVP Scientific & Medical AffairsVP Scientific & Medical Affairs
SafetySafety Gary Chikami, MDGary Chikami, MDSenior Director Regulatory AffairsSenior Director Regulatory Affairs
ConclusionsConclusions Luc Kuykens, MD, MPHLuc Kuykens, MD, MPHVP Regulatory AffairsVP Regulatory Affairs
Menactra is a trademark of Aventis Pasteur Inc. Menomune®, Tripedia® and Typhim Vi® are registered trademarks of Aventis Pasteur. C-3
Public Health Need for Improved Public Health Need for Improved Meningococcal VaccineMeningococcal Vaccine
Persistence of bactericidal antibodiesPersistence of bactericidal antibodies
Ability to prime and boostAbility to prime and boost
Absence of hyporesponsiveness seen with Absence of hyporesponsiveness seen with current polysaccharide vaccinescurrent polysaccharide vaccines
Reduction in carriageReduction in carriage
Herd immunityHerd immunity
Menactra is a trademark of Aventis Pasteur Inc. Menomune®, Tripedia® and Typhim Vi® are registered trademarks of Aventis Pasteur. C-4
Vaccine FormulationVaccine Formulation
MenactraMenactra MenomuneMenomune®® (single dose) (single dose)
4 µg each A,C,Y,W-135 PS4 µg each A,C,Y,W-135 PS 50 μg each A,C,Y,W-135 PS 50 μg each A,C,Y,W-135 PS
48 μg of diphtheria toxoid48 μg of diphtheria toxoid
No adjuvantNo adjuvant No adjuvantNo adjuvant
No preservativeNo preservative No preservativeNo preservative
Liquid formulationLiquid formulation Lyophilized formulationLyophilized formulation
Administered IMAdministered IM Administered SCAdministered SC
Menactra is a trademark of Aventis Pasteur Inc. Menomune®, Tripedia® and Typhim Vi® are registered trademarks of Aventis Pasteur. C-5
Menactra - ContentMenactra - Content
Polysaccharides manufactured under the Polysaccharides manufactured under the existing license for Menomuneexisting license for Menomune
Diphtheria toxoid manufactured under existing Diphtheria toxoid manufactured under existing license for Tripedialicense for Tripedia®®
Menactra is a trademark of Aventis Pasteur Inc. Menomune®, Tripedia® and Typhim Vi® are registered trademarks of Aventis Pasteur. C-6
Menactra - Clinical ExperienceMenactra - Clinical Experience
Persons ReceivingPersons ReceivingPopulationPopulation Clinical Trials Clinical Trials MenactraMenactra
AdultsAdults 33 3,9113,911
AdolescentsAdolescents 33 3,7313,731
ChildrenChildren 33 2,6492,649
TOTALTOTAL 99 10,29110,291
Menactra is a trademark of Aventis Pasteur Inc. Menomune®, Tripedia® and Typhim Vi® are registered trademarks of Aventis Pasteur. C-7
Menactra - Clinical ExperienceMenactra - Clinical Experience
Persons ReceivingPersons ReceivingPopulationPopulation Clinical Trials Clinical Trials MenactraMenactra
AdultsAdults 33 3,9113,911
AdolescentsAdolescents 33 3,7313,731
TOTALTOTAL 66 7,6427,642
ChildrenChildren 33 2,6492,649
Menactra is a trademark of Aventis Pasteur Inc. Menomune®, Tripedia® and Typhim Vi® are registered trademarks of Aventis Pasteur. C-8
Menactra Clinical Development ProgramMenactra Clinical Development Program
Active comparison to standard of careActive comparison to standard of care
Demonstration of non-inferiority for both Demonstration of non-inferiority for both immunogenicity and safetyimmunogenicity and safety
Concomitant administration with Td and Concomitant administration with Td and Typhim ViTyphim Vi
Menactra is a trademark of Aventis Pasteur Inc. Menomune®, Tripedia® and Typhim Vi® are registered trademarks of Aventis Pasteur. C-9
Menactra Key FindingsMenactra Key Findings
Menactra met every pre-specified criteria for Menactra met every pre-specified criteria for non-inferioritynon-inferiority– ImmunogenicityImmunogenicity
– SafetySafety
Menactra demonstrated characteristics of Menactra demonstrated characteristics of conjugate vaccineconjugate vaccine– PersistencePersistence
– Prime and boostPrime and boost
– Overcomes hyporesponsivenessOvercomes hyporesponsiveness
Menactra is a trademark of Aventis Pasteur Inc. Menomune®, Tripedia® and Typhim Vi® are registered trademarks of Aventis Pasteur. C-10
Menactra - AgendaMenactra - Agenda
IntroductionIntroduction Luc Kuykens, MD, MPHLuc Kuykens, MD, MPHVP Regulatory AffairsVP Regulatory Affairs
EpidemiologyEpidemiology Greg Gilmet, MD, MPHGreg Gilmet, MD, MPHDirector Scientific & Medical AffairsDirector Scientific & Medical Affairs
ImmunogenicityImmunogenicity Michael Decker, MD, MPHMichael Decker, MD, MPHVP Scientific & Medical AffairsVP Scientific & Medical Affairs
SafetySafety Gary Chikami, MDGary Chikami, MDSenior Director Regulatory AffairsSenior Director Regulatory Affairs
ConclusionsConclusions Luc Kuykens, MD, MPHLuc Kuykens, MD, MPHVP Regulatory AffairsVP Regulatory Affairs
Menactra is a trademark of Aventis Pasteur Inc. Menomune®, Tripedia® and Typhim Vi® are registered trademarks of Aventis Pasteur. C-11
Presentation OutlinePresentation Outline
Clinical Challenge of Meningococcal DiseaseClinical Challenge of Meningococcal Disease
Current U.S. EpidemiologyCurrent U.S. Epidemiology
Current UK and European EpidemiologyCurrent UK and European Epidemiology
Benefits of Conjugate VaccinesBenefits of Conjugate Vaccines
UK Experience with C Conjugate UK Experience with C Conjugate Meningococcal VaccinesMeningococcal Vaccines
Epidemiology SummaryEpidemiology Summary
Menactra is a trademark of Aventis Pasteur Inc. Menomune®, Tripedia® and Typhim Vi® are registered trademarks of Aventis Pasteur. C-12
The Challenge of Invasive Meningococcal The Challenge of Invasive Meningococcal DiseaseDisease
Most common cause of bacterial meningitis Most common cause of bacterial meningitis
Unique ability to cause outbreaks and epidemicsUnique ability to cause outbreaks and epidemics
Serogroups shift over time and geographySerogroups shift over time and geography
Strikes healthy individualsStrikes healthy individuals
High mortality rate (10-15%)High mortality rate (10-15%)
60% symptomatic < 24 hrs prior to hospitalization60% symptomatic < 24 hrs prior to hospitalization
Difficult to diagnose, high emotional impactDifficult to diagnose, high emotional impact
Menactra is a trademark of Aventis Pasteur Inc. Menomune®, Tripedia® and Typhim Vi® are registered trademarks of Aventis Pasteur. C-13
Presentation OutlinePresentation Outline
Clinical Challenge of Meningococcal DiseaseClinical Challenge of Meningococcal Disease
Current U.S. EpidemiologyCurrent U.S. Epidemiology
Current UK and European EpidemiologyCurrent UK and European Epidemiology
Benefits of Conjugate VaccinesBenefits of Conjugate Vaccines
UK Experience with C Conjugate UK Experience with C Conjugate Meningococcal VaccinesMeningococcal Vaccines
Epidemiology SummaryEpidemiology Summary
Menactra is a trademark of Aventis Pasteur Inc. Menomune®, Tripedia® and Typhim Vi® are registered trademarks of Aventis Pasteur. C-14
Changing Meningococcal Serogroup Changing Meningococcal Serogroup Distribution in the U.S.*Distribution in the U.S.*
*ABCs data *ABCs data
1997 - 2003 1997 - 2003 1990 - 19921990 - 1992
C = 24%C = 24%
W135 + W135 + Other =Other =
14%14%
B = 34%B = 34% Y = 28%Y = 28%
Y = 9%Y = 9%
C = 40%C = 40%
B = 43%B = 43%
W135 + W135 + Other =Other =
8%8%
Menactra is a trademark of Aventis Pasteur Inc. Menomune®, Tripedia® and Typhim Vi® are registered trademarks of Aventis Pasteur. C-15
Reported Cases of Meningococcal Disease, Reported Cases of Meningococcal Disease, U.S., 1967-2002U.S., 1967-2002
Nu
mb
er
of
Nu
mb
er
of
Re
po
rted
Ca
ses
Re
po
rted
Ca
ses
YearYear
00
500500
10001000
15001500
20002000
25002500
30003000
35003500
40004000
19671967 19711971 19751975 19791979 19831983 19871987 19911991 19951995 19991999
1,3231,323
3,5253,525
CDC CDC MMWRMMWR Oct. 1997, Apr 2004. Oct. 1997, Apr 2004.
Menactra is a trademark of Aventis Pasteur Inc. Menomune®, Tripedia® and Typhim Vi® are registered trademarks of Aventis Pasteur. C-16
Age- and Gender-Specific Rates of Age- and Gender-Specific Rates of Meningococcal Disease in the U.S.Meningococcal Disease in the U.S.
Rosenstein NE, et al. Rosenstein NE, et al. J InfectJ Infect Dis.Dis. 1999;180:1894-901. 1999;180:1894-901.
Age (years)Age (years)
Inci
den
ce p
er
Inci
den
ce p
er
100,
000
Po
pu
lati
on
100,
000
Po
pu
lati
on
MaleMale
00
11
22
33
44
55
66
5-95-9 10-1410-14 15-1915-19 20-2420-24 25-2925-29 30-3430-34 35-3935-39 40-4440-44 45-4945-49 50-5450-54 55-5955-59 60-6460-64 65-6965-69 70-7470-74 75-7975-79 80-8480-84 ≥ ≥ 85850-40-4
FemaleFemale
Menactra is a trademark of Aventis Pasteur Inc. Menomune®, Tripedia® and Typhim Vi® are registered trademarks of Aventis Pasteur. C-17
Most Cases in U.S. Adolescents and Young Most Cases in U.S. Adolescents and Young Adults Are Potentially Vaccine-Preventable*Adults Are Potentially Vaccine-Preventable*
*Serogroup distribution by age group, United States, 1994–1998; potentially vaccine preventable was calculated *Serogroup distribution by age group, United States, 1994–1998; potentially vaccine preventable was calculated assuming 100% efficacy using an A/C/Y/W-135 quadrivalent vaccine.assuming 100% efficacy using an A/C/Y/W-135 quadrivalent vaccine.CDC. CDC. MMWR Morb Mortal Wkly Rep.MMWR Morb Mortal Wkly Rep. 2000;49(RR-7):13. 2000;49(RR-7):13.
48%48% 48%48% 65%65% 71%71% 70%70% 79%79% 87%87%
Potentially Vaccine-PreventablePotentially Vaccine-Preventable
0255075
100125150175200225250
0-2 2-5 6-11 12-17 18-23 24-54 >55
Age Group
Nu
mb
er
of
Ca
ses
BCYW-135
Menactra is a trademark of Aventis Pasteur Inc. Menomune®, Tripedia® and Typhim Vi® are registered trademarks of Aventis Pasteur. C-18
Distribution of Meningococcal Fatalities by Distribution of Meningococcal Fatalities by Age Group, U.S. 1997 – 2001 Age Group, U.S. 1997 – 2001
CDC. CDC. Natl. Vital Stats. RepNatl. Vital Stats. Rep..
Nu
mb
er
of
De
ath
sN
um
be
r o
f D
eat
hs
139139 146146135135
266266
9090 9393 102102
4848 5656 5757 4848
00
5050
100100
150150
200200
250250
300300
<1<1 1-41-4 5-145-14 15-2415-24 25-3425-34 35-4435-44 45-5445-54 55-6455-64 65-7465-74 75-8475-84 >85>85
Menactra is a trademark of Aventis Pasteur Inc. Menomune®, Tripedia® and Typhim Vi® are registered trademarks of Aventis Pasteur. C-19
Harrison LH, et al. Invasive Meningococcal Disease in Adolescents and Young Adults. Harrison LH, et al. Invasive Meningococcal Disease in Adolescents and Young Adults. JAMA.JAMA. 2001;286:694-699. 2001;286:694-699.
Meningococcal Disease in Adolescents and Young Meningococcal Disease in Adolescents and Young Adults: Increased Lethality; More Vaccine-PreventableAdults: Increased Lethality; More Vaccine-Preventable
EventsEvents EventsEventsVariableVariable <15 yrs<15 yrs 15-24 yrs15-24 yrs P-ValueP-Value
DeathDeath 4.6%4.6% 22.5%22.5% .001.001
Vaccine-Vaccine-PreventablePreventableDisease*Disease* 68.1%68.1% 82.8%82.8% .04.04
*Defined as serogroups A, C, Y, W-135.*Defined as serogroups A, C, Y, W-135.
Menactra is a trademark of Aventis Pasteur Inc. Menomune®, Tripedia® and Typhim Vi® are registered trademarks of Aventis Pasteur. C-20
Impact of Polysaccharide Immunization on Impact of Polysaccharide Immunization on Hospitalizations (U.S. Army 1964-1998)Hospitalizations (U.S. Army 1964-1998)
*Bars indicate hospitalization frequencies; line indicates rates. DeFraites RF. *Bars indicate hospitalization frequencies; line indicates rates. DeFraites RF. MSMR.MSMR. 2000;6:2. 2000;6:2.
YearYear
Nu
mb
er o
fH
os
pit
aliz
ati
on
s
MonovalentMonovalent(Group C)(Group C)
BivalentBivalent(A,C)(A,C)
Quadrivalent Quadrivalent (A,C,Y,W-135)(A,C,Y,W-135)
005050
100100150150
200200250250
300300350350
400400450450
500500
19641964 19681968 19721972 19761976 19801980 19841984 19881988 19921992 1996199600
55
1010
1515
2020
2525
3030
3535
Ho
sp
ita
liza
tio
n R
ates
H
os
pit
aliz
ati
on
Rat
es
(pe
r 10
0,00
0 p
erso
n -
yea
rs)
(pe
r 10
0,00
0 p
erso
n -
yea
rs)
Menactra is a trademark of Aventis Pasteur Inc. Menomune®, Tripedia® and Typhim Vi® are registered trademarks of Aventis Pasteur. C-21
Rates of Meningococcal Disease in College Rates of Meningococcal Disease in College Students, U.S., 9/1/98 - 6/30/99Students, U.S., 9/1/98 - 6/30/99
Rates/Rates/GroupsGroups # Cases# Cases PopulationPopulation 100,000100,000
All 18-23 year oldsAll 18-23 year olds 304304 22,070,53522,070,535 1.41.4
College StudentsCollege Students 9090 14,897,26814,897,268 0.60.6
UndergraduatesUndergraduates 8787 12,771,22812,771,228 0.70.7
Freshmen StudentsFreshmen Students 4040 2,285,0012,285,001 1.91.9
Dormitory ResidentsDormitory Residents 4545 2,085,6182,085,618 2.32.3
Freshmen LivingFreshmen Livingin Dormitoriesin Dormitories 2727 591,587591,587 5.15.1
Centers for Disease Control and Prevention. Prevention and control of meningococcal disease and Centers for Disease Control and Prevention. Prevention and control of meningococcal disease and Meningococcal disease and college students: Recommendations of the Advisory Committee on Immunization Practices (ACIP). Meningococcal disease and college students: Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWRMMWR. 2000;49(RR-7);1-20.. 2000;49(RR-7);1-20.Updated in: Bruce MG et al [CDC]. Risk Factors for Meningococcal Disease in College Students. Updated in: Bruce MG et al [CDC]. Risk Factors for Meningococcal Disease in College Students. JAMAJAMA. 2001;286:688-693.. 2001;286:688-693.
Menactra is a trademark of Aventis Pasteur Inc. Menomune®, Tripedia® and Typhim Vi® are registered trademarks of Aventis Pasteur. C-22
Presentation OutlinePresentation Outline
Clinical Challenge of Meningococcal DiseaseClinical Challenge of Meningococcal Disease
Current U.S. EpidemiologyCurrent U.S. Epidemiology
Current UK and European EpidemiologyCurrent UK and European Epidemiology
Benefits of Conjugate VaccinesBenefits of Conjugate Vaccines
UK Experience with C Conjugate UK Experience with C Conjugate Meningococcal VaccinesMeningococcal Vaccines
Epidemiology SummaryEpidemiology Summary
Menactra is a trademark of Aventis Pasteur Inc. Menomune®, Tripedia® and Typhim Vi® are registered trademarks of Aventis Pasteur. C-23
EuropeEurope
European and U.S. Meningococcal European and U.S. Meningococcal Serogroup Distribution Serogroup Distribution
B = 63%B = 63%
C = 32%C = 32%
Y = 1%Y = 1%
U.S.U.S.
1998-20021998-2002 1997-20031997-2003
C = 24%C = 24%
W135 + W135 + Other =Other =
14%14%
B = 34%B = 34% Y = 28%Y = 28%
W-135 + W-135 + Other = 4%Other = 4%
European Union Invasive Bacterial Infections Surveillance Network. 2002.European Union Invasive Bacterial Infections Surveillance Network. 2002.
Menactra is a trademark of Aventis Pasteur Inc. Menomune®, Tripedia® and Typhim Vi® are registered trademarks of Aventis Pasteur. C-24
Carriage Rates of Carriage Rates of N. meningitidisN. meningitidisCollege Freshmen, Nottingham University, UK, 1997College Freshmen, Nottingham University, UK, 1997
Neal KR, et al. Neal KR, et al. BMJ.BMJ. 2000;320:846-49. 2000;320:846-49.
00
55
1010
1515
2020
2525
3030
3535
Day 1Day 1 Day 2Day 2 Day 3Day 3 Day 4Day 4 Month 1Month 1 Month 2Month 2
TimeTime
Ca
rria
ge
Ra
te (
%)
Ca
rria
ge
Ra
te (
%)
Menactra is a trademark of Aventis Pasteur Inc. Menomune®, Tripedia® and Typhim Vi® are registered trademarks of Aventis Pasteur. C-25
Presentation OutlinePresentation Outline
Clinical Challenge of Meningococcal DiseaseClinical Challenge of Meningococcal Disease
Current U.S. EpidemiologyCurrent U.S. Epidemiology
Current UK and European EpidemiologyCurrent UK and European Epidemiology
Benefits of Conjugate VaccinesBenefits of Conjugate Vaccines
UK Experience with C Conjugate UK Experience with C Conjugate Meningococcal VaccinesMeningococcal Vaccines
Epidemiology SummaryEpidemiology Summary
Menactra is a trademark of Aventis Pasteur Inc. Menomune®, Tripedia® and Typhim Vi® are registered trademarks of Aventis Pasteur. C-26
PropertyProperty Polysaccharide Polysaccharide ConjugateConjugate
T-cell-dependent T-cell-dependent immune responseimmune response NoNo YesYes
Immune memoryImmune memory NoNo YesYes
Persistence of protectionPersistence of protection NoNo YesYes
Booster effectBooster effect NoNo YesYes
Reduction of carriageReduction of carriage NoNo YesYes
Herd immunityHerd immunity NoNo YesYes
Lack of hyporesponsivenessLack of hyporesponsiveness NoNo YesYes
Conjugate vs. Polysaccharide VaccinesConjugate vs. Polysaccharide Vaccines
Granoff, DM et al. In: Plotkin SA, ed. Granoff, DM et al. In: Plotkin SA, ed. VaccinesVaccines. 4th ed. Philadelphia: W.B. Saunders Co;2004.. 4th ed. Philadelphia: W.B. Saunders Co;2004.
Menactra is a trademark of Aventis Pasteur Inc. Menomune®, Tripedia® and Typhim Vi® are registered trademarks of Aventis Pasteur. C-27
PropertyProperty Polysaccharide Polysaccharide ConjugateConjugate
T-cell-dependent T-cell-dependent immune responseimmune response NoNo YesYes
Immune memoryImmune memory NoNo YesYes
Persistence of protectionPersistence of protection NoNo YesYes
Booster effectBooster effect NoNo YesYes
Reduction of carriageReduction of carriage NoNo YesYes
Herd immunityHerd immunity NoNo YesYes
Lack of hyporesponsivenessLack of hyporesponsiveness NoNo YesYes
Conjugate vs. Polysaccharide VaccinesConjugate vs. Polysaccharide Vaccines
Granoff, DM et al. In: Plotkin SA, ed. Granoff, DM et al. In: Plotkin SA, ed. VaccinesVaccines. 4th ed. Philadelphia: W.B. Saunders Co;2004.. 4th ed. Philadelphia: W.B. Saunders Co;2004.
Menactra is a trademark of Aventis Pasteur Inc. Menomune®, Tripedia® and Typhim Vi® are registered trademarks of Aventis Pasteur. C-28
Presentation OutlinePresentation Outline
Clinical Challenge of Meningococcal DiseaseClinical Challenge of Meningococcal Disease
Current U.S. EpidemiologyCurrent U.S. Epidemiology
Current UK and European EpidemiologyCurrent UK and European Epidemiology
Benefits of Conjugate VaccinesBenefits of Conjugate Vaccines
UK Experience with C Conjugate UK Experience with C Conjugate Meningococcal VaccinesMeningococcal Vaccines
Epidemiology SummaryEpidemiology Summary
Menactra is a trademark of Aventis Pasteur Inc. Menomune®, Tripedia® and Typhim Vi® are registered trademarks of Aventis Pasteur. C-29
Meningococcal Serogroup C-conjugate Meningococcal Serogroup C-conjugate VaccineVaccine
Licensed in the United Kingdom in 1999–2000Licensed in the United Kingdom in 1999–2000
Initially introduced in 15- to 17-year-olds, as Initially introduced in 15- to 17-year-olds, as they displayed highest mortality ratesthey displayed highest mortality rates
Younger age groups sequentially addedYounger age groups sequentially added
C-conjugate subsequently introduced in C-conjugate subsequently introduced in Spain, Ireland, Belgium, Netherlands, Canada, Spain, Ireland, Belgium, Netherlands, Canada, and Australiaand Australia
Menactra is a trademark of Aventis Pasteur Inc. Menomune®, Tripedia® and Typhim Vi® are registered trademarks of Aventis Pasteur. C-30
Laboratory Confirmed Cases of Serogroup C Meningococcal Laboratory Confirmed Cases of Serogroup C Meningococcal Disease, England and WalesDisease, England and WalesCumulative Cases Ages 15 to 17Cumulative Cases Ages 15 to 17
Week Number (total from mid-year)Week Number (total from mid-year)
Nu
mb
er
of
Ca
ses
Nu
mb
er
of
Ca
ses
Immunization with serogroup CImmunization with serogroup Cconjugate vaccine in 15- to 17-year-oldsconjugate vaccine in 15- to 17-year-oldsbegan on Nov 1, 1999began on Nov 1, 1999
Cumulative cases 1998/1999Cumulative cases 1998/1999
100100
150150
5050
11 55 1010 1515 2020 2525 3030 3535 4040 4545 505000
Health Protection Agency Website. Available at: www.hpa.org.uk/infections/topics_az/meningo/graph_meni-groupC.htm.Health Protection Agency Website. Available at: www.hpa.org.uk/infections/topics_az/meningo/graph_meni-groupC.htm.
BeforeBefore
AfterAfter
DuringDuring
Cumulative cases 1999/2000Cumulative cases 1999/2000Cumulative cases 2000/2001 (to week 16/2001)Cumulative cases 2000/2001 (to week 16/2001)
Menactra is a trademark of Aventis Pasteur Inc. Menomune®, Tripedia® and Typhim Vi® are registered trademarks of Aventis Pasteur. C-31
Reductions in C-Disease in UK After Nationwide Reductions in C-Disease in UK After Nationwide Immunization with Conjugate VaccineImmunization with Conjugate Vaccine
Miller E, et al. Miller E, et al. Vaccine.Vaccine. 2002;20:S58. 2002;20:S58.
Age GroupAge Group CasesCases CasesCases ReductionReduction(years)(years) 1998/19991998/1999 2000/2001 2000/2001 (%)(%)
< 1< 1 8181 1414 8383
1 - 21 - 2 119119 2525 8181
3 - 43 - 4 6767 1414 8080
5 - 95 - 9 7575 2727 6464
10 - 1410 - 14 7474 88 8989
15 - 1715 - 17 121121 1515 8888
TotalTotal 537537 103103 8181
Menactra is a trademark of Aventis Pasteur Inc. Menomune®, Tripedia® and Typhim Vi® are registered trademarks of Aventis Pasteur. C-32
66%66%decrease,decrease,PP = 0.001 = 0.001
Group C: Carriage of Meningococci in 15 to 17 Group C: Carriage of Meningococci in 15 to 17 Year-old School Children in the UKYear-old School Children in the UK
% with Meningococci% with Meningococci
CapsularCapsular 19991999 20002000 RatioRatioGroupGroup (N = 14,064)(N = 14,064) (N = 16,583)(N = 16,583) 2000:19992000:1999
BB 4.114.11 4.144.14 1.011.01
CC 0.450.45 0.150.15 0.340.34
YY 0.970.97 1.051.05 1.091.09
W-135W-135 1.121.12 1.421.42 1.271.27
Not groupableNot groupable 10.0510.05 11.2211.22 1.121.12or other groupsor other groups
Maiden MCJ, et al. Maiden MCJ, et al. LancetLancet. 2002;359:1829-30.. 2002;359:1829-30.
Menactra is a trademark of Aventis Pasteur Inc. Menomune®, Tripedia® and Typhim Vi® are registered trademarks of Aventis Pasteur. C-33
Herd Immunity: Serogroup C Attack Rates in Herd Immunity: Serogroup C Attack Rates in Unvaccinated Children Before and After UK ProgramUnvaccinated Children Before and After UK Program
Ramsay ME, et al. Ramsay ME, et al. BMJBMJ. 2003;326:365.. 2003;326:365.
July 1998–JuneJuly 1998–June July 2001–JuneJuly 2001–June1999 Attack1999 Attack 2002 Attack2002 Attack % Reduction% Reduction
CohortCohort Rate/100,000Rate/100,000 Rate/100,000Rate/100,000 in Unvaccinatedin Unvaccinated
InfantsInfants 7.497.49 1.561.56 7979
ToddlersToddlers 6.826.82 2.052.05 7070
PreschoolPreschool 3.943.94 1.201.20 7070
Grades 1 – 6 Grades 1 – 6 1.941.94 1.001.00 4848
Grades 7 – 10Grades 7 – 10 5.545.54 1.111.11 8080
Older adolescents Older adolescents 5.285.28 1.791.79 6666
Menactra is a trademark of Aventis Pasteur Inc. Menomune®, Tripedia® and Typhim Vi® are registered trademarks of Aventis Pasteur. C-34
Meningococcal Polysaccharide Vaccine, Meningococcal Polysaccharide Vaccine, A,C,Y, W-135 Combined (Menomune)A,C,Y, W-135 Combined (Menomune)
Licensed since 1982 – ages 2 and aboveLicensed since 1982 – ages 2 and above
Indicated for travelers, occupational exposure, Indicated for travelers, occupational exposure, college students in dormitories, immune college students in dormitories, immune compromised persons and military recruitscompromised persons and military recruits
85% to 87% effective in multiple outbreak studies*85% to 87% effective in multiple outbreak studies*
Excellent safety profileExcellent safety profile
More than 20 million doses have been administered More than 20 million doses have been administered in U.S.in U.S.
*Menomume package insert.*Menomume package insert.
Menactra is a trademark of Aventis Pasteur Inc. Menomune®, Tripedia® and Typhim Vi® are registered trademarks of Aventis Pasteur. C-35
Expected Attributes of Menactra Vaccine in Expected Attributes of Menactra Vaccine in the U.S.the U.S.
Persistence of protective antibodyPersistence of protective antibody
Ability to prime and boostAbility to prime and boost
Booster dose not associated with Booster dose not associated with hyporesponsivenesshyporesponsiveness
Reduction in carriageReduction in carriage
Herd immunityHerd immunity
Replicate the UK experience in the U.S.Replicate the UK experience in the U.S.
Menactra is a trademark of Aventis Pasteur Inc. Menomune®, Tripedia® and Typhim Vi® are registered trademarks of Aventis Pasteur. C-36
N.N. meningitidis: meningitidis: The Next Focus for Bacterial The Next Focus for Bacterial Meningitis Prevention in the U.S.Meningitis Prevention in the U.S.
2004 and beyondMid 1990s toearly 2000s
1980 to mid 1990s
H influenzaeH influenzae type b type b (Hib) disease virtually (Hib) disease virtually
eliminatedeliminated
Pneumococcal Pneumococcal disease drastically disease drastically
reducedreduced
Meningococcal Meningococcal disease now most disease now most frequent cause of frequent cause of
bacterial meningitis in bacterial meningitis in children, adolescents,children, adolescents,
and young adultsand young adults
Menactra is a trademark of Aventis Pasteur Inc. Menomune®, Tripedia® and Typhim Vi® are registered trademarks of Aventis Pasteur. C-37
Presentation OutlinePresentation Outline
Clinical Challenge of Meningococcal DiseaseClinical Challenge of Meningococcal Disease
Current U.S. EpidemiologyCurrent U.S. Epidemiology
Current UK and European EpidemiologyCurrent UK and European Epidemiology
Benefits of Conjugate VaccinesBenefits of Conjugate Vaccines
UK Experience with C Conjugate UK Experience with C Conjugate Meningococcal VaccinesMeningococcal Vaccines
Epidemiology SummaryEpidemiology Summary
Menactra is a trademark of Aventis Pasteur Inc. Menomune®, Tripedia® and Typhim Vi® are registered trademarks of Aventis Pasteur. C-38
Meningococcal Disease Epidemiology SummaryMeningococcal Disease Epidemiology Summary
Serious and challenging public health problemSerious and challenging public health problem
Adolescents and young adults at high risk Adolescents and young adults at high risk
C conjugate vaccine largely eradicated C conjugate vaccine largely eradicated serogroup C disease in UK serogroup C disease in UK
Menactra has potential to prevent up to 70% of Menactra has potential to prevent up to 70% of disease in U.S. adolescents if used as part of disease in U.S. adolescents if used as part of universal immunization program targeting universal immunization program targeting persons aged 11 to 18persons aged 11 to 18
Menactra is a trademark of Aventis Pasteur Inc. Menomune®, Tripedia® and Typhim Vi® are registered trademarks of Aventis Pasteur. C-39
Menactra - AgendaMenactra - Agenda
IntroductionIntroduction Luc Kuykens, MD, MPHLuc Kuykens, MD, MPHVP Regulatory AffairsVP Regulatory Affairs
EpidemiologyEpidemiology Greg Gilmet, MD, MPHGreg Gilmet, MD, MPHDirector Scientific & Medical AffairsDirector Scientific & Medical Affairs
ImmunogenicityImmunogenicity Michael Decker, MD, MPHMichael Decker, MD, MPHVP Scientific & Medical AffairsVP Scientific & Medical Affairs
SafetySafety Gary Chikami, MDGary Chikami, MDSenior Director Regulatory AffairsSenior Director Regulatory Affairs
ConclusionsConclusions Luc Kuykens, MD, MPHLuc Kuykens, MD, MPHVP Regulatory AffairsVP Regulatory Affairs
Menactra is a trademark of Aventis Pasteur Inc. Menomune®, Tripedia® and Typhim Vi® are registered trademarks of Aventis Pasteur. C-40
Presentation OutlinePresentation Outline
Basis for Licensure: Non-inferiorityBasis for Licensure: Non-inferiority
Measuring ImmunogenicityMeasuring Immunogenicity
Overview of the Clinical TrialsOverview of the Clinical Trials
Comparative Trials in AdolescentsComparative Trials in Adolescents
Comparative Trials in AdultsComparative Trials in Adults
Trials of Concomitant AdministrationTrials of Concomitant Administration
Menactra is a trademark of Aventis Pasteur Inc. Menomune®, Tripedia® and Typhim Vi® are registered trademarks of Aventis Pasteur. C-41
Basis for Licensure:Basis for Licensure:Non-Inferiority of Menactra vs. MenomuneNon-Inferiority of Menactra vs. Menomune
"Non-inferiority" - statistical approach commonly used "Non-inferiority" - statistical approach commonly used when standard of care exists (ie, Menomune) when standard of care exists (ie, Menomune)
““Non-inferiority threshold”Non-inferiority threshold”– Set at agreed margin (delta) compared to the standardSet at agreed margin (delta) compared to the standard
– Chosen to exclude clinically important differences within a Chosen to exclude clinically important differences within a practical sample sizepractical sample size
If non-inferior, the new intervention is considered an If non-inferior, the new intervention is considered an acceptable alternativeacceptable alternative
The evaluation of Menactra involved demonstrating its The evaluation of Menactra involved demonstrating its non-inferiority to Menomune non-inferiority to Menomune
Menactra is a trademark of Aventis Pasteur Inc. Menomune®, Tripedia® and Typhim Vi® are registered trademarks of Aventis Pasteur. C-42
Measuring ImmunogenicityMeasuring Immunogenicity
Antibody MeasurementsAntibody Measurements
Common clinical assays measure antibody Common clinical assays measure antibody quantityquantity– Examples: ELISA, RIA, etc.Examples: ELISA, RIA, etc.
Functional assays measure antibody Functional assays measure antibody performanceperformance– Less common, often more difficult to performLess common, often more difficult to perform
– Examples: Serum bactericidal antibody (SBA), Examples: Serum bactericidal antibody (SBA), CHO cell assay, etc.CHO cell assay, etc.
Menactra is a trademark of Aventis Pasteur Inc. Menomune®, Tripedia® and Typhim Vi® are registered trademarks of Aventis Pasteur. C-43
Evidence for the Importance of Bactericidal Evidence for the Importance of Bactericidal Antibodies in Meningococcal DiseaseAntibodies in Meningococcal Disease
Gotschlich et al, Fort Dix study: serogroup C disease Gotschlich et al, Fort Dix study: serogroup C disease occurred only in individuals lacking bactericidal antibodiesoccurred only in individuals lacking bactericidal antibodies11
SBA titers SBA titers 1:4 correlated strongly with protection 1:4 correlated strongly with protection
Serum bactericidal activity could be absorbed with the Serum bactericidal activity could be absorbed with the group-specific capsular polysaccharidegroup-specific capsular polysaccharide
Number of Number of RecruitsRecruits
Bactericidal Titer Bactericidal Titer at Baselineat Baseline Number of CasesNumber of Cases Attack Rate/1000 Attack Rate/1000
(8 weeks)(8 weeks)Percent Percent
Protective EffectProtective Effect
12,073 (82%)*12,073 (82%)* 1:41:4 33 0.30.398.4%98.4%
2,668 (18%)*2,668 (18%)* < 1:4< 1:4 5151 19.119.1
11Goldschneider I, Gotschlich EC, and Artenstein MS. Goldschneider I, Gotschlich EC, and Artenstein MS. J. Exp Med.J. Exp Med. 1969;129:1307-1326. 1969;129:1307-1326.
*Based on bactericidal titer determinations of 540 non-case controls*Based on bactericidal titer determinations of 540 non-case controls
Menactra is a trademark of Aventis Pasteur Inc. Menomune®, Tripedia® and Typhim Vi® are registered trademarks of Aventis Pasteur. C-44
Measuring Immunogenicity Measuring Immunogenicity Regulatory Perspective – Correlate of ProtectionRegulatory Perspective – Correlate of Protection
1999 VRBPAC Conclusions:1999 VRBPAC Conclusions:
– Immunological data can be used to predict efficacy Immunological data can be used to predict efficacy of meningococcal vaccines for populations for of meningococcal vaccines for populations for whom the current polysaccharide vaccine whom the current polysaccharide vaccine is licensedis licensed
– Bactericidal activity may be used as a measure of Bactericidal activity may be used as a measure of functional antibody and, therefore, presumed functional antibody and, therefore, presumed protective activityprotective activity
– Total antibody measured by ELISA techniques Total antibody measured by ELISA techniques cannot be used as a serologic correlate for cannot be used as a serologic correlate for functional bactericidal antibodyfunctional bactericidal antibody
Menactra is a trademark of Aventis Pasteur Inc. Menomune®, Tripedia® and Typhim Vi® are registered trademarks of Aventis Pasteur. C-45
Measuring ImmunogenicityMeasuring Immunogenicity
We will present SBA resultsWe will present SBA results– Standard approach for meningococcal assaysStandard approach for meningococcal assays
– Directly relevant to protection from infectionDirectly relevant to protection from infection
– Basis for licensure of MenomuneBasis for licensure of Menomune
Assay conforms to WHO and CDC standardsAssay conforms to WHO and CDC standards– Aventis Pasteur participated in the interlaboratory collaborative Aventis Pasteur participated in the interlaboratory collaborative
study – assay is fully validatedstudy – assay is fully validated
– Assay uses baby rabbit complementAssay uses baby rabbit complement Difficulties with human complementDifficulties with human complement
– ConsistencyConsistency
– AvailabilityAvailability
– StandardizationStandardization
Menactra is a trademark of Aventis Pasteur Inc. Menomune®, Tripedia® and Typhim Vi® are registered trademarks of Aventis Pasteur. C-46
Measuring ImmunogenicityMeasuring Immunogenicity
Immunological End-PointsImmunological End-Points
4-Fold Rise4-Fold Rise– % of those whose post-immunization titers are at least 4 times % of those whose post-immunization titers are at least 4 times
their pre-immunization titerstheir pre-immunization titers
– Basis for Menomune licensureBasis for Menomune licensure
– Primary (non-inferiority) outcome measure in all Menactra core Primary (non-inferiority) outcome measure in all Menactra core clinical trials clinical trials
Geometric Mean TitersGeometric Mean Titers– Normalized average of the post-immunization titersNormalized average of the post-immunization titers
– Co-primary outcome measure in some of the core clinical trials; Co-primary outcome measure in some of the core clinical trials; descriptive in others descriptive in others
Menactra is a trademark of Aventis Pasteur Inc. Menomune®, Tripedia® and Typhim Vi® are registered trademarks of Aventis Pasteur. C-47
Measuring Immunogenicity (2)Measuring Immunogenicity (2)
Immunological End-PointsImmunological End-Points
Seroconversion RatesSeroconversion Rates– % of those initially seronegative (less than 1:8) who % of those initially seronegative (less than 1:8) who
have a 4-fold or greater risehave a 4-fold or greater rise
– Descriptive only Descriptive only
Reverse Cumulative Distribution CurvesReverse Cumulative Distribution Curves– Graphical presentation of the antibody distribution Graphical presentation of the antibody distribution
of the entire studied populationof the entire studied population
– Descriptive only Descriptive only
Menactra is a trademark of Aventis Pasteur Inc. Menomune®, Tripedia® and Typhim Vi® are registered trademarks of Aventis Pasteur. C-48
Overview of Menactra Overview of Menactra Clinical Trials (Ages 11 to 55)Clinical Trials (Ages 11 to 55)
TrialTrialNumberNumber Type of StudyType of Study Study GroupsStudy Groups Ages (yrs)Ages (yrs) MenactraMenactra MenomuneMenomune
MTA02MTA02 Safety &Safety & Menactra vs.Menactra vs. 11 to 18 11 to 18 440 440 441441ImmunogenicityImmunogenicity MenomuneMenomune
MTA19MTA19 3 yr. Follow Up3 yr. Follow Up Menactra vs.Menactra vs. 13 to 2113 to 21 241241 --Menactra Menactra MenomuneMenomuneRevaccinationRevaccination vs. naïvevs. naïve
MTA04MTA04 SafetySafety Menactra vs.Menactra vs. 11 to 18 11 to 18 2,2702,270 972 972 ComparisonComparison Menomune Menomune
MTA09MTA09 Safety &Safety & Menactra vs. Menactra vs. 18 to 55 18 to 55 1,3841,384 1,170 1,170 ImmunogenicityImmunogenicity MenomuneMenomune
MTA14MTA14 Safety &Safety & Menactra vs. Menactra vs. 18 to 55 18 to 55 1,5821,582 458 458 Lot Consistency Lot Consistency MenomuneMenomune
Menactra is a trademark of Aventis Pasteur Inc. Menomune®, Tripedia® and Typhim Vi® are registered trademarks of Aventis Pasteur. C-49
Overview of Menactra Overview of Menactra Clinical Trials (Ages 11 to 55)Clinical Trials (Ages 11 to 55)
TrialTrialNumberNumber Type of StudyType of Study Study GroupsStudy Groups Ages (yrs)Ages (yrs) MenactraMenactra MenomuneMenomune
Total For All Trials Combined (ages 11 to 55)Total For All Trials Combined (ages 11 to 55) 7,6427,642 3,041 3,041
MTA12MTA12 Safety &Safety & Menactra + Td Menactra + Td 11 to 1711 to 17 509509 None None ImmunogenicityImmunogenicity vs. vs.of Concomitantof Concomitant Menactra 1 moMenactra 1 mo 512512AdministrationAdministration after Tdafter Td Total 1,021Total 1,021
MTA11MTA11 Safety &Safety & Menactra + Menactra + 18 to 55 18 to 55 469469 None None Immunogenicity Immunogenicity Typhim Vi Typhim Vi of Concomitantof Concomitant vs. vs. 476476AdministrationAdministration Menactra 1 moMenactra 1 mo
after Typhim Viafter Typhim Vi Total 945Total 945
Menactra is a trademark of Aventis Pasteur Inc. Menomune®, Tripedia® and Typhim Vi® are registered trademarks of Aventis Pasteur. C-50
AdolescentsAdolescents AdultsAdults11 – 1811 – 18 18 – 5518 – 55 TotalTotal
(N = 3731)(N = 3731) (N = 3911)(N = 3911) (N = (N = 7642)7642)
%% %% %%
GenderGender
MaleMale 51.451.4 36.336.3 43.643.6
FemaleFemale 48.648.6 63.763.7 56.456.4
Race/EthnicityRace/Ethnicity
White, non-HispanicWhite, non-Hispanic 90.590.5 82.582.5 86.286.2
Black, non-HispanicBlack, non-Hispanic 4.94.9 6.96.9 6.06.0
HispanicHispanic 2.52.5 6.76.7 4.74.7
AsianAsian 0.90.9 2.52.5 1.81.8
OtherOther 1.21.2 1.41.4 1.31.3
Distribution of Clinical Trial Study Populations Distribution of Clinical Trial Study Populations By Gender and Race/EthnicityBy Gender and Race/Ethnicity
Menactra is a trademark of Aventis Pasteur Inc. Menomune®, Tripedia® and Typhim Vi® are registered trademarks of Aventis Pasteur. C-51
Measuring Immunogenicity Measuring Immunogenicity
Results to be PresentedResults to be Presented
MTA02: Comparative trial in adolescentsMTA02: Comparative trial in adolescents
MTA19: Three-year follow-up trial in adolescentsMTA19: Three-year follow-up trial in adolescents
MTA09: Comparative trial in adultsMTA09: Comparative trial in adults
MTA14: Lot-consistency trial in adultsMTA14: Lot-consistency trial in adults
MTA12: Concomitant Menactra and Td in MTA12: Concomitant Menactra and Td in adolescents adolescents
MTA11: Concomitant Menactra and Typhim Vi MTA11: Concomitant Menactra and Typhim Vi in adultsin adults
Menactra is a trademark of Aventis Pasteur Inc. Menomune®, Tripedia® and Typhim Vi® are registered trademarks of Aventis Pasteur. C-52
MTA02: Clinical Trial in AdolescentsMTA02: Clinical Trial in Adolescents
Multi-center, randomized, comparative clinical Multi-center, randomized, comparative clinical trial in US adolescentstrial in US adolescents
Participants: 881 healthy 11 to 18 year-oldsParticipants: 881 healthy 11 to 18 year-olds– 440 given one i.m. dose of Menactra protein 440 given one i.m. dose of Menactra protein
conjugateconjugate
– 441 given one s.c. dose of Menomune 441 given one s.c. dose of Menomune polysaccharidepolysaccharide
Evaluated safety and immunogenicityEvaluated safety and immunogenicity
Hypothesis: short-term immune response not Hypothesis: short-term immune response not inferior to Menomuneinferior to Menomune
Menactra is a trademark of Aventis Pasteur Inc. Menomune®, Tripedia® and Typhim Vi® are registered trademarks of Aventis Pasteur. C-53
MenactraMenactra 392 of 423 392 of 423 92.7%92.7%
388 of 423 388 of 423 91.7%91.7%
346 of 423 346 of 423 81.8%81.8%
409 of 423 409 of 423 96.7%96.7%
MenomuneMenomune 391 of 423 391 of 423 92.4%92.4%
375 of 423 375 of 423 88.7%88.7%
339 of 423 339 of 423 80.1%80.1%
403 of 423 403 of 423 95.3 %95.3 %
00
2020
4040
6060
8080
100100
Pe
rce
nta
ge
Pe
rce
nta
ge
AA CC YY W-135W-135
MTA02: 4-Fold Rises in SBA Titer by MTA02: 4-Fold Rises in SBA Titer by Serogroup in AdolescentsSerogroup in Adolescents
MenactraMenactra
Menomune Menomune
Menactra is a trademark of Aventis Pasteur Inc. Menomune®, Tripedia® and Typhim Vi® are registered trademarks of Aventis Pasteur. C-54
MTA02: Non-inferiority Testing of 4-Fold RisesMTA02: Non-inferiority Testing of 4-Fold Rises95% CI of Difference (Menomune - Menactra)95% CI of Difference (Menomune - Menactra)
Serogroup ASerogroup A
Within LimitWithin Limit Outside LimitOutside Limit
-8-8 -7-7 -6-6 -5-5 -4-4 -3-3 -2-2 -1-1 00 11 22 33 44 55 66 77 88 99 1010
-0.24-0.24
Serogroup CSerogroup C
Serogroup YSerogroup Y
Serogroup W-135Serogroup W-135
-3.07-3.07
-1.65-1.65
-1.42-1.42
1111 1212 1313 1414 1515
All non-inferiority criteria metAll non-inferiority criteria met
Menactra is a trademark of Aventis Pasteur Inc. Menomune®, Tripedia® and Typhim Vi® are registered trademarks of Aventis Pasteur. C-55
Ge
om
etr
icG
eo
me
tric
Me
an
Tit
er
Me
an
Tit
er
00
10001000
20002000
30003000
40004000
50005000
60006000
AA CC YY W-135W-135
MTA02: Geometric Mean Titers at Day 28 by MTA02: Geometric Mean Titers at Day 28 by Serogroup in Adolescents Serogroup in Adolescents
MenactraMenactra 54835483 19241924 13221322 14071407
MenomuneMenomune 32463246 16391639 12281228 15451545
MenactraMenactra
Menomune Menomune
Menactra is a trademark of Aventis Pasteur Inc. Menomune®, Tripedia® and Typhim Vi® are registered trademarks of Aventis Pasteur. C-56
Group:Group: Menactra, Day 0Menactra, Day 0
Menomune, Day 0Menomune, Day 0
Menactra, Day 28Menactra, Day 28
Menomune, Day 28Menomune, Day 28
MTA02: RCD Curves of Day 0 and Day 28 MTA02: RCD Curves of Day 0 and Day 28 SBA Titers in Adolescents – Serogroup ASBA Titers in Adolescents – Serogroup A
44 1616 6464 10241024 40964096 16,38416,384 65,53665,536256256 262,144262,14488 3232 128128
SBA Antibody Titers for Meningococcal Serogroup ASBA Antibody Titers for Meningococcal Serogroup A
Pa
rtic
ipa
nts
(%
)P
art
icip
an
ts (
%)
00
2020
4040
6060
8080
100100
Menactra is a trademark of Aventis Pasteur Inc. Menomune®, Tripedia® and Typhim Vi® are registered trademarks of Aventis Pasteur. C-57
MTA02: RCD Curves of Day 0 and Day 28 MTA02: RCD Curves of Day 0 and Day 28 SBA Titers in Adolescents – Serogroup CSBA Titers in Adolescents – Serogroup C
SBA Antibody Titers for Meningococcal Serogroup CSBA Antibody Titers for Meningococcal Serogroup C
44 1616 6464 10241024 40964096 16,38416,384 65,53665,536256256 262,144262,14488 3232 128128
Group:Group: Menactra, Day 0Menactra, Day 0
Menomune, Day 0Menomune, Day 0
Menactra, Day 28Menactra, Day 28
Menomune, Day 28Menomune, Day 28
00
2020
4040
6060
8080
100100
Pa
rtic
ipa
nts
(%
)P
art
icip
an
ts (
%)
Menactra is a trademark of Aventis Pasteur Inc. Menomune®, Tripedia® and Typhim Vi® are registered trademarks of Aventis Pasteur. C-58
Group:Group: Menactra, Day 0Menactra, Day 0
Menomune, Day 0Menomune, Day 0
Menactra, Day 28Menactra, Day 28
Menomune, Day 28Menomune, Day 28
MTA02: RCD Curves of Day 0 and Day 28 MTA02: RCD Curves of Day 0 and Day 28 SBA Titers in Adolescents – Serogroup YSBA Titers in Adolescents – Serogroup Y
44 1616 6464 10241024 40964096 16,38416,384 65,53665,536256256 262,144262,14488 3232 128128
SBA Antibody Titers for Meningococcal Serogroup YSBA Antibody Titers for Meningococcal Serogroup Y
00
2020
4040
6060
8080
100100
Pa
rtic
ipa
nts
(%
)P
art
icip
an
ts (
%)
Menactra is a trademark of Aventis Pasteur Inc. Menomune®, Tripedia® and Typhim Vi® are registered trademarks of Aventis Pasteur. C-59
Group:Group: Menactra, Day 0Menactra, Day 0
Menomune, Day 0Menomune, Day 0
Menactra, Day 28Menactra, Day 28
Menomune, Day 28Menomune, Day 28
MTA02: RCD Curves of Day 0 and Day 28 MTA02: RCD Curves of Day 0 and Day 28 SBA Titers in Adolescents – Serogroup W-SBA Titers in Adolescents – Serogroup W-135135
44 1616 6464 10241024 40964096 16,38416,384 65,53665,536256256 262,144262,14488 3232 128128
SBA Antibody Titers for Meningococcal Serogroup W-135SBA Antibody Titers for Meningococcal Serogroup W-135
00
2020
4040
6060
8080
100100
Pa
rtic
ipa
nts
(%
)P
art
icip
an
ts (
%)
Menactra is a trademark of Aventis Pasteur Inc. Menomune®, Tripedia® and Typhim Vi® are registered trademarks of Aventis Pasteur. C-60
Measuring ImmunogenicityMeasuring Immunogenicity
Results to be PresentedResults to be Presented
MTA02: Comparative trial in adolescentsMTA02: Comparative trial in adolescents
MTA19: Three-year follow-up trial in adolescentsMTA19: Three-year follow-up trial in adolescents
MTA09: Comparative trial in adultsMTA09: Comparative trial in adults
MTA14: Lot-consistency trial in adultsMTA14: Lot-consistency trial in adults
MTA12: Concomitant Menactra and Td in MTA12: Concomitant Menactra and Td in adolescents adolescents
MTA11: Concomitant Menactra and Typhim Vi MTA11: Concomitant Menactra and Typhim Vi in adultsin adults
Menactra is a trademark of Aventis Pasteur Inc. Menomune®, Tripedia® and Typhim Vi® are registered trademarks of Aventis Pasteur. C-61
MTA19: Menactra Booster in AdolescentsMTA19: Menactra Booster in Adolescents
Three-year follow up and reimmunization of a subset of Three-year follow up and reimmunization of a subset of participants from trial MTA02participants from trial MTA02
Participants: 241 healthy 14 to 21 year-oldsParticipants: 241 healthy 14 to 21 year-olds– 76 participants with prior Menactra immunization76 participants with prior Menactra immunization
– 77 participants with prior Menomune immunization77 participants with prior Menomune immunization
– 88 age-matched naïve participants88 age-matched naïve participants
Intervention: one dose of MenactraIntervention: one dose of Menactra
Objectives: Objectives: – Evaluate persistence of antibody over 3-year intervalEvaluate persistence of antibody over 3-year interval
– Evaluate ability of Menactra to prime and to boostEvaluate ability of Menactra to prime and to boost
– Evaluate response of Menomune recipients to MenactraEvaluate response of Menomune recipients to Menactra
Menactra is a trademark of Aventis Pasteur Inc. Menomune®, Tripedia® and Typhim Vi® are registered trademarks of Aventis Pasteur. C-62
MTA19: SBA GMTs of a Subset of ParticipantsMTA19: SBA GMTs of a Subset of ParticipantsDuration of Response at 3 Years Post VaccinationDuration of Response at 3 Years Post Vaccination
00
200200
400400
600600
800800
10001000
12001200
AA CC YY W-135W-135
SerogroupSerogroup
SB
A G
MT
SB
A G
MT
MenactraMenactra MenomuneMenomune
1508116212482909Menomune
1586126321055192Menactra
0
1000
2000
3000
4000
5000
6000
A C Y W-135
MenactraMenomune
SB
A G
MT
Menactra is a trademark of Aventis Pasteur Inc. Menomune®, Tripedia® and Typhim Vi® are registered trademarks of Aventis Pasteur. C-63
MTA19: SBA GMTs of a Subset of ParticipantsMTA19: SBA GMTs of a Subset of ParticipantsDuration of Response at 3 Years Post VaccinationDuration of Response at 3 Years Post Vaccination
P < 0.001P < 0.001P = 0.12
P = 0.12
00
200200
400400
600600
800800
10001000
12001200
AA CC YY W-135W-135
SerogroupSerogroup
SB
A G
MT
SB
A G
MT
MenactraMenactra MenomuneMenomune
Menactra is a trademark of Aventis Pasteur Inc. Menomune®, Tripedia® and Typhim Vi® are registered trademarks of Aventis Pasteur. C-64
MTA19: SBA GMTs of a Subset of ParticipantsMTA19: SBA GMTs of a Subset of ParticipantsDuration of Response at 3 Years Post VaccinationDuration of Response at 3 Years Post Vaccination
Age-matched NaïveAge-matched Naïve
00
200200
400400
600600
800800
10001000
12001200
SB
A G
MT
SB
A G
MT
AA CC YY W-135W-135
SerogroupSerogroup
MenactraMenactra MenomuneMenomune
Menactra is a trademark of Aventis Pasteur Inc. Menomune®, Tripedia® and Typhim Vi® are registered trademarks of Aventis Pasteur. C-65
MTA19: RCD Curves for SBA Antibody Titers for MTA19: RCD Curves for SBA Antibody Titers for Meningococcal Serogroup AMeningococcal Serogroup A
Pa
rtic
ipa
nts
(%
)P
art
icip
an
ts (
%)
100100
SBA Antibody Titers for Meningococcal Serogroup ASBA Antibody Titers for Meningococcal Serogroup A
00
2020
4040
6060
8080
44 1616 6464 10241024 40964096 16,38416,384 65,53665,536256256 262,144262,144
Group:Group:
PW Menomune at Day 0PW Menomune at Day 0PW Menactra at Day 0PW Menactra at Day 0
Naïve at Day 0Naïve at Day 0
Menactra is a trademark of Aventis Pasteur Inc. Menomune®, Tripedia® and Typhim Vi® are registered trademarks of Aventis Pasteur. C-66
MTA19: RCD Curves for SBA Antibody Titers for MTA19: RCD Curves for SBA Antibody Titers for Meningococcal Serogroup CMeningococcal Serogroup C
Pa
rtic
ipa
nts
(%
)P
art
icip
an
ts (
%)
100100
SBA Antibody Titers for Meningococcal Serogroup CSBA Antibody Titers for Meningococcal Serogroup C
00
2020
4040
6060
8080
44 1616 6464 10241024 40964096 16,38416,384 65,53665,536256256 262,144262,144
Group:Group:
PW Menomune at Day 0PW Menomune at Day 0PW Menactra at Day 0PW Menactra at Day 0
Naïve at Day 0Naïve at Day 0
Menactra is a trademark of Aventis Pasteur Inc. Menomune®, Tripedia® and Typhim Vi® are registered trademarks of Aventis Pasteur. C-67
MTA19: RCD Curves for SBA Antibody Titers for MTA19: RCD Curves for SBA Antibody Titers for Meningococcal Serogroup YMeningococcal Serogroup Y
Pa
rtic
ipa
nts
(%
)P
art
icip
an
ts (
%)
100100
SBA Antibody Titers for Meningococcal Serogroup YSBA Antibody Titers for Meningococcal Serogroup Y
00
2020
4040
6060
8080
44 1616 6464 10241024 40964096 16,38416,384 65,53665,536256256 262,144262,144
Group:Group:
PW Menomune at Day 0PW Menomune at Day 0PW Menactra at Day 0PW Menactra at Day 0
Naïve at Day 0Naïve at Day 0
Menactra is a trademark of Aventis Pasteur Inc. Menomune®, Tripedia® and Typhim Vi® are registered trademarks of Aventis Pasteur. C-68
Pa
rtic
ipa
nts
(%
)P
art
icip
an
ts (
%)
100100
SBA Antibody Titers for Meningococcal Serogroup W-135SBA Antibody Titers for Meningococcal Serogroup W-135
00
2020
4040
6060
8080
44 1616 6464 10241024 40964096 16,38416,384 65,53665,536256256 262,144262,144
Group:Group:
MTA19: RCD Curves for SBA Antibody Titers for MTA19: RCD Curves for SBA Antibody Titers for Meningococcal Serogroup W-135Meningococcal Serogroup W-135
PW Menomune at Day 0PW Menomune at Day 0PW Menactra at Day 0PW Menactra at Day 0
Naïve at Day 0Naïve at Day 0
Menactra is a trademark of Aventis Pasteur Inc. Menomune®, Tripedia® and Typhim Vi® are registered trademarks of Aventis Pasteur. C-69
MTA19: Geometric Mean Titers Before and After MTA19: Geometric Mean Titers Before and After Menactra, Menactra-Primed vs. Naïve – Serogroup C Menactra, Menactra-Primed vs. Naïve – Serogroup C
Menactra
0
2000
4000
6000
8000
10000
12000
14000
16000
18000
20000
Pre-boost Post-boost 8 Post-boost 28
Menactra Naïve Control
P < 0.001
P < 0.001
Menactra is a trademark of Aventis Pasteur Inc. Menomune®, Tripedia® and Typhim Vi® are registered trademarks of Aventis Pasteur. C-70
MTA19: Geometric Mean Titers Before and After MTA19: Geometric Mean Titers Before and After Menactra, Menactra-Primed vs. Naïve – Serogroup Y Menactra, Menactra-Primed vs. Naïve – Serogroup Y
P = 0.22
P = 0.02
Menactra
0
2000
4000
6000
8000
10000
12000
14000
Pre-boost Post-boost 8 Post-boost 28
Menactra Naïve Control
Menactra is a trademark of Aventis Pasteur Inc. Menomune®, Tripedia® and Typhim Vi® are registered trademarks of Aventis Pasteur. C-71
MTA19: Geometric Mean Titers Before and After Menactra, MTA19: Geometric Mean Titers Before and After Menactra, Menactra-Primed vs. Naïve – Serogroup W-135 Menactra-Primed vs. Naïve – Serogroup W-135
P = 0.02
P = 0.01
Menactra
0
2000
4000
6000
8000
10000
12000
Pre-boost Post-boost 8 Post-boost 28
Menactra Naïve Control
Menactra is a trademark of Aventis Pasteur Inc. Menomune®, Tripedia® and Typhim Vi® are registered trademarks of Aventis Pasteur. C-72
MTA19: Geometric Mean Titers Before and After MTA19: Geometric Mean Titers Before and After Menactra, Menactra-Primed vs. Naïve – Serogroup A Menactra, Menactra-Primed vs. Naïve – Serogroup A
P = 0.03
P = 0.08
Menactra
0
2000
4000
6000
8000
10000
12000
14000
Pre-boost Post-boost 8 Post-boost 28
Menactra Naïve Control
Menactra is a trademark of Aventis Pasteur Inc. Menomune®, Tripedia® and Typhim Vi® are registered trademarks of Aventis Pasteur. C-73
MTA19: SBA Primary Immunization with Menomune MTA19: SBA Primary Immunization with Menomune and Reimmunization with Menactra – C and Reimmunization with Menactra – C
Pre-V1 V1 + 28d0
500
1000
1500
2000
2500
3000
Pre-V2
V2 + 8d
V2 + 28d
Menomune
Menomune
ThreeYears
0
500
1000
1500
2000
2500
3000
Menactra after Menomune
Menactra is a trademark of Aventis Pasteur Inc. Menomune®, Tripedia® and Typhim Vi® are registered trademarks of Aventis Pasteur. C-74
MTA19: SBA Primary Immunization with Menomune MTA19: SBA Primary Immunization with Menomune and Reimmunization with Menactra – A and Reimmunization with Menactra – A
Menomune
Menomune
0
500
1000
1500
2000
2500
3000
3500
4000
4500
5000
Pre-V1 V1 + 28d
ThreeYears
Pre-V2
V2 + 8d
V2 + 28d0
500
1000
1500
2000
2500
3000
3500
4000
4500
5000
Menactra after Menomune
Menactra is a trademark of Aventis Pasteur Inc. Menomune®, Tripedia® and Typhim Vi® are registered trademarks of Aventis Pasteur. C-75
MTA19: SBA Primary Immunization with Menomune MTA19: SBA Primary Immunization with Menomune and Reimmunization with Menactra – Y and Reimmunization with Menactra – Y
0
500
1000
1500
2000
2500
3000
3500
Menomune
Pre-V1 V1 + 28d Pre-V2
V2 + 8d
V2 + 28d0
500
1000
1500
2000
2500
3000
3500
ThreeYears
Menomune
Menactra after Menomune
Menactra is a trademark of Aventis Pasteur Inc. Menomune®, Tripedia® and Typhim Vi® are registered trademarks of Aventis Pasteur. C-76
MTA19: SBA Primary Immunization with Menomune and MTA19: SBA Primary Immunization with Menomune and Reimmunization with Menactra – W-135Reimmunization with Menactra – W-135
0
500
1000
1500
2000
2500
Pre-V1 V1 + 28d Pre-V2
V2 + 8d
V2 + 28d
Menactra after MenomuneMenomune
ThreeYears
0
500
1000
1500
2000
2500
Menomune
Menactra is a trademark of Aventis Pasteur Inc. Menomune®, Tripedia® and Typhim Vi® are registered trademarks of Aventis Pasteur. C-77
MTA19: Summary and ConclusionsMTA19: Summary and Conclusions
Superior persistence of antibody Superior persistence of antibody – At 3 years, Menactra SBA GMTs are higher than seen following Menomune At 3 years, Menactra SBA GMTs are higher than seen following Menomune
or in naïve controls or in naïve controls
Ability of Menactra to prime and to boostAbility of Menactra to prime and to boost– Rapid, high anamnestic response, far exceeding response of naïve controls, Rapid, high anamnestic response, far exceeding response of naïve controls,
demonstrates priming, memory, and boostingdemonstrates priming, memory, and boosting
Response of Menomune recipients to MenactraResponse of Menomune recipients to Menactra– Prior Menomune recipients given Menactra demonstrate a rapid increase in Prior Menomune recipients given Menactra demonstrate a rapid increase in
bactericidal antibody, to levels exceeding those that would be expected if bactericidal antibody, to levels exceeding those that would be expected if reimmunized with Menomunereimmunized with Menomune
Conclusion: Menactra demonstrates the important immunologic Conclusion: Menactra demonstrates the important immunologic characteristics expected of a characteristics expected of a conjugate vaccineconjugate vaccine
Menactra is a trademark of Aventis Pasteur Inc. Menomune®, Tripedia® and Typhim Vi® are registered trademarks of Aventis Pasteur. C-78
Measuring Immunogenicity Measuring Immunogenicity
Results to be PresentedResults to be Presented
MTA02: Comparative trial in adolescentsMTA02: Comparative trial in adolescents
MTA19: Three-year follow-up trial in adolescentsMTA19: Three-year follow-up trial in adolescents
MTA09: Comparative trial in adultsMTA09: Comparative trial in adults
MTA14: Lot-consistency trial in adultsMTA14: Lot-consistency trial in adults
MTA12: Concomitant Menactra and Td in MTA12: Concomitant Menactra and Td in adolescents adolescents
MTA11: Concomitant Menactra and Typhim Vi MTA11: Concomitant Menactra and Typhim Vi in adultsin adults
Menactra is a trademark of Aventis Pasteur Inc. Menomune®, Tripedia® and Typhim Vi® are registered trademarks of Aventis Pasteur. C-79
MTA09: Clinical Trial in AdultsMTA09: Clinical Trial in Adults
Multi-center, randomized, comparative clinical Multi-center, randomized, comparative clinical trial in adultstrial in adults
Participants: 2,554 healthy 18 to 55 year-oldsParticipants: 2,554 healthy 18 to 55 year-olds– 1,384 given one i.m. dose of Menactra protein conjugate1,384 given one i.m. dose of Menactra protein conjugate
– 1,170 given one s.c. dose of Menomune polysaccharide1,170 given one s.c. dose of Menomune polysaccharide
Evaluated safety and immunogenicityEvaluated safety and immunogenicity
Hypothesis: short-term immune response not Hypothesis: short-term immune response not inferior to Menomuneinferior to Menomune
Menactra is a trademark of Aventis Pasteur Inc. Menomune®, Tripedia® and Typhim Vi® are registered trademarks of Aventis Pasteur. C-80
MTA09: 4-Fold Rises in SBA Titer by Serogroup MTA09: 4-Fold Rises in SBA Titer by Serogroup in Adultsin Adults
MenactraMenactra1030 of 1280 1030 of 1280
80.5%80.5%1133 of 1280 1133 of 1280
88.5%88.5%941 of 1280 941 of 1280
73.5%73.5%1144 of 1280 1144 of 1280
89.4%89.4%
MenomuneMenomune929 of 1098 929 of 1098
84.6%84.6%985 of 1098 985 of 1098
89.7%89.7%872 of 1098 872 of 1098
79.4%79.4%1036 of 1098 1036 of 1098
94.4%94.4%
00
2020
4040
6060
8080
100100
AA CC YY W-135W-135
Pe
rce
nta
ge
Pe
rce
nta
ge
MenactraMenactra
Menomune Menomune
Menactra is a trademark of Aventis Pasteur Inc. Menomune®, Tripedia® and Typhim Vi® are registered trademarks of Aventis Pasteur. C-81
Serogroup ASerogroup A
Within LimitWithin Limit Outside LimitOutside Limit
-2-2 -1-1 00 11 22 33 44 55 66 77 88 99 1010
4.14.1
Serogroup CSerogroup C
Serogroup YSerogroup Y
Serogroup W-135Serogroup W-135
1.21.2
5.95.9
5.05.0
1111 1212 1313 1414 1515
MTA09: Non-inferiority Testing of 4-Fold Rises MTA09: Non-inferiority Testing of 4-Fold Rises 95% CI of Difference (Menomune – Menactra)95% CI of Difference (Menomune – Menactra)
All non-inferiority criteria metAll non-inferiority criteria met
Menactra is a trademark of Aventis Pasteur Inc. Menomune®, Tripedia® and Typhim Vi® are registered trademarks of Aventis Pasteur. C-82
00
500500
10001000
15001500
20002000
25002500
30003000
35003500
40004000
45004500
Ge
om
etr
icG
eo
me
tric
Me
an
Tit
er
Me
an
Tit
er
AA CC YY W-135W-135
MenactraMenactra 38973897 32313231 17501750 12711271
MenomuneMenomune 41144114 34693469 24492449 18711871
MTA09: Geometric Mean Titers at Day 28 by MTA09: Geometric Mean Titers at Day 28 by Serogroup in AdultsSerogroup in Adults
MenactraMenactra
Menomune Menomune
Menactra is a trademark of Aventis Pasteur Inc. Menomune®, Tripedia® and Typhim Vi® are registered trademarks of Aventis Pasteur. C-83
Serogroup ASerogroup A
Within LimitWithin Limit Outside LimitOutside Limit
0.500.50 0.750.75 1.001.00 1.251.25 1.501.50 1.751.75 2.002.00 2.252.25 2.502.50
1.071.07
Serogroup CSerogroup C
Serogroup YSerogroup Y
Serogroup W-135Serogroup W-135
1.101.10
1.501.50
1.391.39
MTA09: Non-Inferiority Testing of the Ratio of MTA09: Non-Inferiority Testing of the Ratio of GMTs* 95% CI of the Ratio (Menomune/Menactra) GMTs* 95% CI of the Ratio (Menomune/Menactra)
All non-inferiority criteria metAll non-inferiority criteria met
*Adjusted for baseline titers using ANCOVA.*Adjusted for baseline titers using ANCOVA.
Menactra is a trademark of Aventis Pasteur Inc. Menomune®, Tripedia® and Typhim Vi® are registered trademarks of Aventis Pasteur. C-84
MTA09: RCD Curves of Day 0 and Day 28 MTA09: RCD Curves of Day 0 and Day 28 SBA Titers in Adults – Serogroup CSBA Titers in Adults – Serogroup C
Pa
rtic
ipa
nts
(%
)P
art
icip
an
ts (
%)
SBA Antibody Titers for Meningococcal Serogroup CSBA Antibody Titers for Meningococcal Serogroup C
44 1616 6464 10241024 40964096 16,38416,384 65,53665,536256256 262,144262,14400
2020
4040
6060
8080
100100
88 3232 128128
Group:Group: Menactra, Day 0Menactra, Day 0
Menomune, Day 0Menomune, Day 0
Menactra, Day 28Menactra, Day 28
Menomune, Day 28Menomune, Day 28
Menactra is a trademark of Aventis Pasteur Inc. Menomune®, Tripedia® and Typhim Vi® are registered trademarks of Aventis Pasteur. C-85
Pa
rtic
ipa
nts
(%
)P
art
icip
an
ts (
%)
SBA Antibody Titers for Meningococcal Serogroup ASBA Antibody Titers for Meningococcal Serogroup A
Group:Group: Menactra, Day 0Menactra, Day 0
Menomune, Day 0Menomune, Day 0
Menactra, Day 28Menactra, Day 28
Menomune, Day 28Menomune, Day 28
MTA09: RCD Curves of Day 0 and Day 28 MTA09: RCD Curves of Day 0 and Day 28 SBA Titers in Adults – Serogroup ASBA Titers in Adults – Serogroup A
00
2020
4040
6060
8080
100100
44 1616 6464 10241024 40964096 16,38416,384 65,53665,536256256 262,144262,14488 3232 128128
Menactra is a trademark of Aventis Pasteur Inc. Menomune®, Tripedia® and Typhim Vi® are registered trademarks of Aventis Pasteur. C-86
Pa
rtic
ipa
nts
(%
)P
art
icip
an
ts (
%)
Group:Group: Menactra, Day 0Menactra, Day 0
Menomune, Day 0Menomune, Day 0
Menactra, Day 28Menactra, Day 28
Menomune, Day 28Menomune, Day 28
MTA09: RCD Curves of Day 0 and Day 28 MTA09: RCD Curves of Day 0 and Day 28 SBA Titers in Adults – Serogroup YSBA Titers in Adults – Serogroup Y
00
2020
4040
6060
8080
100100
44 1616 6464 10241024 40964096 16,38416,384 65,53665,536256256 262,144262,14488 3232 128128
SBA Antibody Titers for Meningococcal Serogroup YSBA Antibody Titers for Meningococcal Serogroup Y
Menactra is a trademark of Aventis Pasteur Inc. Menomune®, Tripedia® and Typhim Vi® are registered trademarks of Aventis Pasteur. C-87
Pa
rtic
ipa
nts
(%
)P
art
icip
an
ts (
%)
Group:Group: Menactra, Day 0Menactra, Day 0
Menomune, Day 0Menomune, Day 0
Menactra, Day 28Menactra, Day 28
Menomune, Day 28Menomune, Day 28
MTA09: RCD Curves of Day 0 and Day 28 MTA09: RCD Curves of Day 0 and Day 28 SBA Titers in Adults – Serogroup W-135SBA Titers in Adults – Serogroup W-135
00
2020
4040
6060
8080
100100
SBA Antibody Titers for Meningococcal Serogroup W-135SBA Antibody Titers for Meningococcal Serogroup W-135
44 1616 6464 10241024 40964096 16,38416,384 65,53665,536256256 262,144262,14488 3232 128128
Menactra is a trademark of Aventis Pasteur Inc. Menomune®, Tripedia® and Typhim Vi® are registered trademarks of Aventis Pasteur. C-88
Measuring Immunogenicity Measuring Immunogenicity
Results to be PresentedResults to be Presented
MTA02: Comparative trial in adolescentsMTA02: Comparative trial in adolescents
MTA19: Three-year follow-up trial in adolescentsMTA19: Three-year follow-up trial in adolescents
MTA09: Comparative trial in adultsMTA09: Comparative trial in adults
MTA14: Lot-consistency trial in adultsMTA14: Lot-consistency trial in adults
MTA12: Concomitant Menactra and Td in MTA12: Concomitant Menactra and Td in adolescents adolescents
MTA11: Concomitant Menactra and Typhim Vi MTA11: Concomitant Menactra and Typhim Vi in adultsin adults
Menactra is a trademark of Aventis Pasteur Inc. Menomune®, Tripedia® and Typhim Vi® are registered trademarks of Aventis Pasteur. C-89
MTA14: Lot-Consistency Trial in AdultsMTA14: Lot-Consistency Trial in Adults
Multi-center, randomized, lot-consistency and Multi-center, randomized, lot-consistency and comparative clinical trial in US adultscomparative clinical trial in US adults
Participants: 2,040 healthy 18 to 55 year-oldsParticipants: 2,040 healthy 18 to 55 year-olds– 1582 given one i.m. dose of Menactra protein 1582 given one i.m. dose of Menactra protein
conjugate (divided evenly among 3 vaccine lots)conjugate (divided evenly among 3 vaccine lots)
– 458 given one s.c. dose of Menomune 458 given one s.c. dose of Menomune polysaccharidepolysaccharide
Evaluated immunogenicity (lot consistency) Evaluated immunogenicity (lot consistency) and safety (in 26 to 55 year-olds)and safety (in 26 to 55 year-olds)
Hypothesis: equivalence of three Menactra Hypothesis: equivalence of three Menactra lots (maximum ratio, 1.5)lots (maximum ratio, 1.5)
Menactra is a trademark of Aventis Pasteur Inc. Menomune®, Tripedia® and Typhim Vi® are registered trademarks of Aventis Pasteur. C-90
Ge
om
etr
icG
eo
me
tric
Me
an
Tit
er
Me
an
Tit
er
MTA14: Geometric Mean Titers at Day 28 by MTA14: Geometric Mean Titers at Day 28 by Serogroup in AdultsSerogroup in Adults
Menactra Lot 1Menactra Lot 1 81698169 38683868 28982898 20312031
Menactra Lot 2Menactra Lot 2 82158215 41554155 24722472 25732573
Menactra Lot 3Menactra Lot 3 66796679 32173217 38053805 24572457
AA CC YY W-135W-13500
10001000
20002000
30003000
40004000
50005000
60006000
70007000
80008000
90009000
Menactra Lot 1Menactra Lot 2Menactra Lot 3
Menactra is a trademark of Aventis Pasteur Inc. Menomune®, Tripedia® and Typhim Vi® are registered trademarks of Aventis Pasteur. C-91
MTA14: Equivalence Testing of the Ratio of GMTs*MTA14: Equivalence Testing of the Ratio of GMTs*90% CI of the Ratio (Lot 1/Lot 2, Lot 1/Lot 3, Lot 2/Lot 3) 90% CI of the Ratio (Lot 1/Lot 2, Lot 1/Lot 3, Lot 2/Lot 3)
Within LimitWithin Limit Outside LimitOutside Limit
1.51.5 1.751.75 2.002.00
1.011.01Serogroup ASerogroup ALot 1/2Lot 1/2
Lot 1/3Lot 1/3
Lot 2/3Lot 2/3
Serogroup CSerogroup C
Serogroup YSerogroup Y
Serogroup W-135Serogroup W-135
Outside LimitOutside Limit
.66.66.50.50.25.25
1.231.23
Lot 1/2Lot 1/2
Lot 1/3Lot 1/3
Lot 2/3Lot 2/3
Lot 1/2Lot 1/2
Lot 1/3Lot 1/3
Lot 2/3Lot 2/3
Lot 1/2Lot 1/2
Lot 1/3Lot 1/3
Lot 2/3Lot 2/3
1.221.22
0.890.89
1.221.22
1.371.37
0.790.79
1.021.02
0.730.73
1.091.09
0.670.67
0.810.81
*Adjusted for baseline titers using ANCOVA.*Adjusted for baseline titers using ANCOVA.
Menactra is a trademark of Aventis Pasteur Inc. Menomune®, Tripedia® and Typhim Vi® are registered trademarks of Aventis Pasteur. C-92
MTA14: RCD Curves of Day 0 and Day 28 MTA14: RCD Curves of Day 0 and Day 28 SBA Titers in Adults – Serogroup ASBA Titers in Adults – Serogroup A
SBA Antibody Titers for Meningococcal Serogroup ASBA Antibody Titers for Meningococcal Serogroup A
Group:Group:
Menactra Lot 2 Group at Day 28Menactra Lot 2 Group at Day 28Menactra Lot 2 Group at Day 0Menactra Lot 2 Group at Day 0Menactra Lot 1 Group at Day 28Menactra Lot 1 Group at Day 28Menactra Lot 1 Group at Day 0Menactra Lot 1 Group at Day 0
Menactra Lot 3 Group at Day 28Menactra Lot 3 Group at Day 28Menactra Lot 3 Group at Day 0Menactra Lot 3 Group at Day 0
Pa
rtic
ipa
nts
(%
)P
art
icip
an
ts (
%)
00
2020
4040
6060
8080
100100
44 1616 6464 10241024 40964096 16,38416,384 65,53665,536256256 262,144262,144
Menactra is a trademark of Aventis Pasteur Inc. Menomune®, Tripedia® and Typhim Vi® are registered trademarks of Aventis Pasteur. C-93
MTA14: RCD Curves of Day 0 and Day 28 MTA14: RCD Curves of Day 0 and Day 28 SBA Titers in Adults – Serogroup CSBA Titers in Adults – Serogroup C
Group:Group:
Menactra Lot 2 Group at Day 28Menactra Lot 2 Group at Day 28Menactra Lot 2 Group at Day 0Menactra Lot 2 Group at Day 0Menactra Lot 1 Group at Day 28Menactra Lot 1 Group at Day 28Menactra Lot 1 Group at Day 0Menactra Lot 1 Group at Day 0
Menactra Lot 3 Group at Day 28Menactra Lot 3 Group at Day 28Menactra Lot 3 Group at Day 0Menactra Lot 3 Group at Day 0
Pa
rtic
ipa
nts
(%
)P
art
icip
an
ts (
%)
00
2020
4040
6060
8080
100100
44 1616 6464 10241024 40964096 16,38416,384 65,53665,536256256 262,144262,144
SBA Antibody Titers for Meningococcal Serogroup CSBA Antibody Titers for Meningococcal Serogroup C
Menactra is a trademark of Aventis Pasteur Inc. Menomune®, Tripedia® and Typhim Vi® are registered trademarks of Aventis Pasteur. C-94
MTA14: RCD Curves of Day 0 and Day 28 MTA14: RCD Curves of Day 0 and Day 28 SBA Titers in Adults – Serogroup YSBA Titers in Adults – Serogroup Y
Group:Group:
Menactra Lot 2 Group at Day 28Menactra Lot 2 Group at Day 28Menactra Lot 2 Group at Day 0Menactra Lot 2 Group at Day 0Menactra Lot 1 Group at Day 28Menactra Lot 1 Group at Day 28Menactra Lot 1 Group at Day 0Menactra Lot 1 Group at Day 0
Menactra Lot 3 Group at Day 28Menactra Lot 3 Group at Day 28Menactra Lot 3 Group at Day 0Menactra Lot 3 Group at Day 0
Pa
rtic
ipa
nts
(%
)P
art
icip
an
ts (
%)
00
2020
4040
6060
8080
100100
44 1616 6464 10241024 40964096 16,38416,384 65,53665,536256256 262,144262,144
SBA Antibody Titers for Meningococcal Serogroup YSBA Antibody Titers for Meningococcal Serogroup Y
Menactra is a trademark of Aventis Pasteur Inc. Menomune®, Tripedia® and Typhim Vi® are registered trademarks of Aventis Pasteur. C-95
MTA14: RCD Curves of Day 0 and Day 28MTA14: RCD Curves of Day 0 and Day 28SBA Titers in Adults – Serogroup W-135SBA Titers in Adults – Serogroup W-135
Pa
rtic
ipa
nts
(%
)P
art
icip
an
ts (
%)
00
2020
4040
6060
8080
100100
44 1616 6464 10241024 40964096 16,38416,384 65,53665,536256256 262,144262,144
Group:Group:
Menactra Lot 2 Group at Day 28Menactra Lot 2 Group at Day 28Menactra Lot 2 Group at Day 0Menactra Lot 2 Group at Day 0Menactra Lot 1 Group at Day 28Menactra Lot 1 Group at Day 28Menactra Lot 1 Group at Day 0Menactra Lot 1 Group at Day 0
Menactra Lot 3 Group at Day 28Menactra Lot 3 Group at Day 28Menactra Lot 3 Group at Day 0Menactra Lot 3 Group at Day 0
SBA Antibody Titers for Meningococcal Serogroup W-135SBA Antibody Titers for Meningococcal Serogroup W-135
Menactra is a trademark of Aventis Pasteur Inc. Menomune®, Tripedia® and Typhim Vi® are registered trademarks of Aventis Pasteur. C-96
MTA14: Summary of Results for the MTA14: Summary of Results for the Consistency Lots By SerogroupConsistency Lots By Serogroup
SerogroupSerogroup LotLot GMTGMT % 4-Fold% 4-Fold % % 128 128
AA 11 81698169 8585 100100
22 82158215 8585 100100
33 66796679 8282 100100
CC 11 38683868 8686 9797
22 41554155 8989 9999
33 32173217 8383 9797
YY 11 28982898 7575 9999
22 24722472 7272 9898
33 38053805 8181 9898
W-135W-135 11 20312031 8686 9797
22 25732573 8888 9696
33 24572457 9292 9898
Menactra is a trademark of Aventis Pasteur Inc. Menomune®, Tripedia® and Typhim Vi® are registered trademarks of Aventis Pasteur. C-97
Measuring Immunogenicity Measuring Immunogenicity
Results to be PresentedResults to be Presented
MTA02: Comparative trial in adolescentsMTA02: Comparative trial in adolescents
MTA19: Three-year follow-up trial in adolescentsMTA19: Three-year follow-up trial in adolescents
MTA09: Comparative trial in adultsMTA09: Comparative trial in adults
MTA14: Lot-consistency trial in adultsMTA14: Lot-consistency trial in adults
MTA12: Concomitant Menactra and Td in MTA12: Concomitant Menactra and Td in adolescentsadolescents
MTA11: Concomitant Menactra and Typhim Vi MTA11: Concomitant Menactra and Typhim Vi in adultsin adults
Menactra is a trademark of Aventis Pasteur Inc. Menomune®, Tripedia® and Typhim Vi® are registered trademarks of Aventis Pasteur. C-98
MTA12: Concomitant Menactra and Td MTA12: Concomitant Menactra and Td Clinical Trial in AdolescentsClinical Trial in Adolescents
Multi-center, randomized, comparative clinical trial Multi-center, randomized, comparative clinical trial in US adolescentsin US adolescents
Participants: 1,021 healthy 11 to 17 year-oldsParticipants: 1,021 healthy 11 to 17 year-olds– 509 given Menactra + Td followed 28 days later 509 given Menactra + Td followed 28 days later
by placeboby placebo
– 512 given Td + placebo followed 28 days later 512 given Td + placebo followed 28 days later by Menactraby Menactra
Evaluated safety and immunogenicityEvaluated safety and immunogenicity
Hypothesis: concomitant administration is not Hypothesis: concomitant administration is not inferior to sequential administrationinferior to sequential administration
Menactra is a trademark of Aventis Pasteur Inc. Menomune®, Tripedia® and Typhim Vi® are registered trademarks of Aventis Pasteur. C-99
MTA12: 4-Fold Rise in SBA Titer MTA12: 4-Fold Rise in SBA Titer by Serogroupby Serogroup
00
2020
4040
6060
8080
100100
AA CC YY W-135W-135
Menactra + Td Menactra + Td
Menactra 28 days after TdMenactra 28 days after Td
Menactra + Menactra + TdTd
419 of 465419 of 465(90.1%)(90.1%)
424 of 465424 of 465(91.2%)(91.2%)
399 of 465399 of 465(85.8%)(85.8%)
448 of 465448 of 465(96.3%)(96.3%)
Menactra Menactra 28 days 28 days after Tdafter Td
433 of 478433 of 478(90.6%)(90.6%)
394 of 478394 of 478(82.4%)(82.4%)
311 of 478311 of 478(65.1%)(65.1%)
419 of 478419 of 478(87.7%)(87.7%)
Pe
rce
nta
ge
Pe
rce
nta
ge
Menactra is a trademark of Aventis Pasteur Inc. Menomune®, Tripedia® and Typhim Vi® are registered trademarks of Aventis Pasteur. C-100
Serogroup ASerogroup A
Within LimitWithin Limit Outside LimitOutside Limit
-30-30 -25-25 -20-20 -15-15 -10-10 -5-5 00 55 1010
0.480.48
Serogroup CSerogroup C
Serogroup YSerogroup Y
Serogroup W-135Serogroup W-135
-8.76-8.76
-20.74-20.74
-8.69-8.69
1515
MTA12: Non-inferiority Testing of 4-Fold RisesMTA12: Non-inferiority Testing of 4-Fold Rises95% CI of the Difference (Sequential - Simultaneous)95% CI of the Difference (Sequential - Simultaneous)
All non-inferiority criteria metAll non-inferiority criteria met
2020 2525
Menactra is a trademark of Aventis Pasteur Inc. Menomune®, Tripedia® and Typhim Vi® are registered trademarks of Aventis Pasteur. C-101
MTA12: Geometric Mean Titers Level MTA12: Geometric Mean Titers Level Comparison 28 Days Post Menactra VaccinationComparison 28 Days Post Menactra Vaccination
1
10
100
1000
10000
100000
Menactra + TdMenactra + Td Menactra 28 days after TdMenactra 28 days after Td
Ge
om
etr
ic M
ean
Tit
er
Ge
om
etr
ic M
ean
Tit
er
(lo
g s
cal
e)
(lo
g s
cal
e)
A C Y W-135
Menactra + TdMenactra + Td 11,31311,313 50595059 33913391 41954195
Menactra 28 days Menactra 28 days after Tdafter Td 10,39110,391 21362136 13311331 13391339
Menactra is a trademark of Aventis Pasteur Inc. Menomune®, Tripedia® and Typhim Vi® are registered trademarks of Aventis Pasteur. C-102
MTA12: Geometric Mean Titers 28 Days Post MTA12: Geometric Mean Titers 28 Days Post Menactra VaccinationMenactra Vaccination
MTA02MTA02 54835483 19241924 13221322 14071407
Menactra + TdMenactra + Td 11,31311,313 50595059 33913391 41954195
Menactra 28 days Menactra 28 days after Tdafter Td 10,39110,391 21362136 13311331 13391339
1
10
100
1000
10000
100000
A C Y W-135
Menactra / MTA02Menactra / MTA02 Menactra + TdMenactra + Td Menactra 28 days after TdMenactra 28 days after Td
Ge
om
etr
ic M
ean
Tit
er
Ge
om
etr
ic M
ean
Tit
er
(lo
g s
cal
e)
(lo
g s
cal
e)
Menactra is a trademark of Aventis Pasteur Inc. Menomune®, Tripedia® and Typhim Vi® are registered trademarks of Aventis Pasteur. C-103
MTA12: Percent Tetanus Antibody ResponseMTA12: Percent Tetanus Antibody Response
2-Fold (Pre-titer 2-Fold (Pre-titer >> 2.7 IU/mL 2.7 IU/mL))
18/4918/49(36.7%)(36.7%)
17/4517/45(37.8%)(37.8%)
4-Fold (Pre-titer 4-Fold (Pre-titer 2.7 IU/mL 2.7 IU/mL))
391/413391/413(94.7%)(94.7%)
408/426408/426(95.8%)(95.8%)
Total RespondersTotal Responders 409/462409/462(88.5%)(88.5%)
425/471425/471(90.2%)(90.2%)
Menactra + Td Td + Placebo
2-Fold Responders2-Fold Responders 4-Fold Responders4-Fold Responders Total RespondersTotal RespondersP
erc
en
tag
eP
erc
en
tag
e
0
2020
4040
6060
8080
100100
Menactra is a trademark of Aventis Pasteur Inc. Menomune®, Tripedia® and Typhim Vi® are registered trademarks of Aventis Pasteur. C-104
MTA12: Percent Diphtheria Antibody ResponseMTA12: Percent Diphtheria Antibody Response
Menactra + Td Td + Placebo0
2020
4040
6060
8080
100100
Pe
rce
nta
ge
Pe
rce
nta
ge
2-Fold Responders2-Fold Responders 4-Fold Responders4-Fold Responders Total RespondersTotal Responders
2-Fold (Pre-titer 2-Fold (Pre-titer >> 2.56 2.56 IU/mL IU/mL))
8/8(100.0%)
7/13(53.9%)
4-Fold (Pre-titer 4-Fold (Pre-titer 2.56 IU/mL2.56 IU/mL))
454/456(99.6%)
439/458(95.9%)
Total RespondersTotal Responders462/464(99.6%)
446/471(94.7%)
Menactra is a trademark of Aventis Pasteur Inc. Menomune®, Tripedia® and Typhim Vi® are registered trademarks of Aventis Pasteur. C-105
MTA12: Non-Inferiority Testing of Response Rates MTA12: Non-Inferiority Testing of Response Rates 95% CI of the Difference (Sequential - Simultaneous)95% CI of the Difference (Sequential - Simultaneous)
TetanusTetanus
Within LimitWithin Limit Outside LimitOutside Limit
-8-8 -7-7 -6-6 -5-5 -4-4 -3-3 -2-2 -1-1 00 11 22 33 44 55 66 77 88 99 1010
1.711.71
DiphtheriaDiphtheria-4.88-4.88
1111 1212 1313 1414 1515
All non-inferiority criteria metAll non-inferiority criteria met
Menactra is a trademark of Aventis Pasteur Inc. Menomune®, Tripedia® and Typhim Vi® are registered trademarks of Aventis Pasteur. C-106
Measuring Immunogenicity Measuring Immunogenicity
Results to be PresentedResults to be Presented
MTA02: Comparative trial in adolescentsMTA02: Comparative trial in adolescents
MTA19: Three-year follow-up trial in adolescentsMTA19: Three-year follow-up trial in adolescents
MTA09: Comparative trial in adultsMTA09: Comparative trial in adults
MTA14: Lot-consistency trial in adultsMTA14: Lot-consistency trial in adults
MTA12: Concomitant Menactra and Td in MTA12: Concomitant Menactra and Td in adolescentsadolescents
MTA11: Concomitant Menactra and Typhim Vi MTA11: Concomitant Menactra and Typhim Vi in adultsin adults
Menactra is a trademark of Aventis Pasteur Inc. Menomune®, Tripedia® and Typhim Vi® are registered trademarks of Aventis Pasteur. C-107
MTA11: Concomitant Typhim Vi and Menactra MTA11: Concomitant Typhim Vi and Menactra Clinical Trial in AdultsClinical Trial in Adults
Multi-center, randomized, comparative clinical trial Multi-center, randomized, comparative clinical trial in US adultsin US adults
Participants: 945 healthy 18 to 55 year-oldsParticipants: 945 healthy 18 to 55 year-olds– 469 given Typhim Vi + Menactra followed 28 days later by 469 given Typhim Vi + Menactra followed 28 days later by
placeboplacebo
– 476 given Typhim Vi + placebo followed 28 days later by 476 given Typhim Vi + placebo followed 28 days later by MenactraMenactra
Evaluated safety and immunogenicityEvaluated safety and immunogenicity
Hypothesis: concomitant administration is not Hypothesis: concomitant administration is not inferior to sequential administrationinferior to sequential administration
Menactra is a trademark of Aventis Pasteur Inc. Menomune®, Tripedia® and Typhim Vi® are registered trademarks of Aventis Pasteur. C-108
00
20002000
40004000
60006000
80008000
AA CC YY W-135W-135
Menactra + Typhim ViMenactra + Typhim Vi
Menactra 28 daysMenactra 28 daysafter Typhim Viafter Typhim Vi
Ge
om
etr
icG
eo
me
tric
Me
an
Tit
er
Me
an
Tit
er
Menactra + Menactra + Typhim ViTyphim Vi 51385138 30613061 18211821 10021002
Menactra 28 Menactra 28 days after days after Typhim ViTyphim Vi
51105110 31453145 17421742 929929
MTA11: Geometric Mean Titers at Day 28 MTA11: Geometric Mean Titers at Day 28 after Menactra in Adultsafter Menactra in Adults
Menactra is a trademark of Aventis Pasteur Inc. Menomune®, Tripedia® and Typhim Vi® are registered trademarks of Aventis Pasteur. C-109
MTA11: 4-Fold Rises in SBA Titer by MTA11: 4-Fold Rises in SBA Titer by Serogroup in AdultsSerogroup in Adults
00
2020
4040
6060
8080
100100
AA CC YY W-135W-135
Menactra + Typhim ViMenactra + Typhim Vi
Menactra 28 days after Typhim ViMenactra 28 days after Typhim Vi
Menactra + Menactra + Typhim ViTyphim Vi
333 of 418333 of 418(79.7%)(79.7%)
374 of 418374 of 418(89.5%)(89.5%)
311 of 418311 of 418(74.4%)(74.4%)
356 of 418356 of 418(85.2%)(85.2%)
Menactra 28 Menactra 28 days afterdays afterTyphim ViTyphim Vi
315 of 419315 of 419(75.2%)(75.2%)
370 of 419370 of 419(88.3%)(88.3%)
273 of 419273 of 419(65.2%)(65.2%)
351 of 419351 of 419(83.8%)(83.8%)
Pe
rce
nta
ge
Pe
rce
nta
ge
Menactra is a trademark of Aventis Pasteur Inc. Menomune®, Tripedia® and Typhim Vi® are registered trademarks of Aventis Pasteur. C-110
MTA11: Non-Inferiority Testing of 4-Fold RisesMTA11: Non-Inferiority Testing of 4-Fold Rises95% CI of the Difference (Sequential - Simultaneous)95% CI of the Difference (Sequential - Simultaneous)
Serogroup ASerogroup A
Within LimitWithin Limit Outside LimitOutside Limit
-30-30 -25-25 -20-20 -15-15 -10-10 -5-5 00 55 1010
-4.49-4.49
Serogroup CSerogroup C
Serogroup YSerogroup Y
Serogroup W-135Serogroup W-135
-1.17-1.17
-9.25-9.25
-1.40-1.40
1515
All non-inferiority criteria metAll non-inferiority criteria met
2020 2525
Menactra is a trademark of Aventis Pasteur Inc. Menomune®, Tripedia® and Typhim Vi® are registered trademarks of Aventis Pasteur. C-111
MTA11: Proportion of Participants with Typhim Vi MTA11: Proportion of Participants with Typhim Vi Antibody Titer >1.0 Antibody Titer >1.0 µµg/mL at 28 Days Post-Vaccinationg/mL at 28 Days Post-Vaccination
Menactra + Menactra + Typhim ViTyphim Vi
Typhim Vi + Typhim Vi + PlaceboPlacebo
341 of 418341 of 418(81.6%)(81.6%)
328 of 418328 of 418(78.5%)(78.5%)
0
20
40
60
80
100
Menactra + Typhim ViMenactra + Typhim Vi Typhim Vi + PlaceboTyphim Vi + Placebo
Pe
rce
nta
ge
Pe
rce
nta
ge
Menactra is a trademark of Aventis Pasteur Inc. Menomune®, Tripedia® and Typhim Vi® are registered trademarks of Aventis Pasteur. C-112
MTA11: Non-Inferiority Testing of the Percentage >1.0 µg/mL MTA11: Non-Inferiority Testing of the Percentage >1.0 µg/mL 95% CI of the 95% CI of the Difference (Sequential – Simultaneous) Difference (Sequential – Simultaneous)
Within LimitWithin Limit Outside LimitOutside Limit
-8-8 -7-7 -6-6 -5-5 -4-4 -3-3 -2-2 -1-1 00 11 22 33 44 55 66 77 88 99 1010
-3.11-3.11
1111 1212 1313 1414 1515
All non-inferiority criteria metAll non-inferiority criteria met
-9-9
Typhim Vi + PlaceboTyphim Vi + Placebovs.vs.
Menactra + Typhim ViMenactra + Typhim Vi
Menactra is a trademark of Aventis Pasteur Inc. Menomune®, Tripedia® and Typhim Vi® are registered trademarks of Aventis Pasteur. C-113
Menactra Immunogenicity: ConclusionsMenactra Immunogenicity: Conclusions
Menactra is consistently immunogenic in adolescents and Menactra is consistently immunogenic in adolescents and adults, satisfying all non-inferiority criteriaadults, satisfying all non-inferiority criteria
Menactra SBAs after 3 years are superior to those seen Menactra SBAs after 3 years are superior to those seen following Menomune or in naïve controlsfollowing Menomune or in naïve controls
One dose of Menactra primes for memory, as demonstrated One dose of Menactra primes for memory, as demonstrated by a rapid and very high booster response upon by a rapid and very high booster response upon reimmunizationreimmunization
Menactra offers a superior reimmunization pathway for prior Menactra offers a superior reimmunization pathway for prior Menomune recipientsMenomune recipients
Menactra demonstrates the important immunologic Menactra demonstrates the important immunologic characteristics expected of a conjugate vaccine characteristics expected of a conjugate vaccine
Menactra is a trademark of Aventis Pasteur Inc. Menomune®, Tripedia® and Typhim Vi® are registered trademarks of Aventis Pasteur. C-114
Menactra - AgendaMenactra - Agenda
IntroductionIntroduction Luc Kuykens, MD, MPHLuc Kuykens, MD, MPHVP Regulatory AffairsVP Regulatory Affairs
EpidemiologyEpidemiology Greg Gilmet, MD, MPHGreg Gilmet, MD, MPHDirector Scientific & Medical AffairsDirector Scientific & Medical Affairs
ImmunogenicityImmunogenicity Michael Decker, MD, MPHMichael Decker, MD, MPHVP Scientific & Medical AffairsVP Scientific & Medical Affairs
SafetySafety Gary Chikami, MDGary Chikami, MDSenior Director Regulatory AffairsSenior Director Regulatory Affairs
ConclusionsConclusions Luc Kuykens, MD, MPHLuc Kuykens, MD, MPHVP Regulatory AffairsVP Regulatory Affairs
Menactra is a trademark of Aventis Pasteur Inc. Menomune®, Tripedia® and Typhim Vi® are registered trademarks of Aventis Pasteur. C-115
Objectives for the Evaluation of the Safety Objectives for the Evaluation of the Safety Profile of MenactraProfile of Menactra
To compare safety profile of Menactra to To compare safety profile of Menactra to safety profile of Menomunesafety profile of Menomune– Demonstrate that rate of severe solicited systemic Demonstrate that rate of severe solicited systemic
reactions reported in Menactra and Menomune reactions reported in Menactra and Menomune recipients are comparable recipients are comparable
To characterize overall safety profile of MenactraTo characterize overall safety profile of Menactra
Menactra is a trademark of Aventis Pasteur Inc. Menomune®, Tripedia® and Typhim Vi® are registered trademarks of Aventis Pasteur. C-116
Safety Data CollectedSafety Data Collected
Immediate reactions collected 0 to 30 minutesImmediate reactions collected 0 to 30 minutes
Solicited systemic and local reactions collected Solicited systemic and local reactions collected Day 0 through Day 7 Day 0 through Day 7
Unsolicited adverse eventsUnsolicited adverse events
– Days 0 to 28Days 0 to 28
– Day 29 to month 6Day 29 to month 6
Serious adverse eventsSerious adverse events
Menactra is a trademark of Aventis Pasteur Inc. Menomune®, Tripedia® and Typhim Vi® are registered trademarks of Aventis Pasteur. C-117
Presentation OutlinePresentation Outline
Immediate ReactionsImmediate Reactions Solicited Systemic ReactionsSolicited Systemic Reactions
Adolescents – MTA04, MTA02 & MTA12Adolescents – MTA04, MTA02 & MTA12 Adults – MTA09, MTA14 & MTA11Adults – MTA09, MTA14 & MTA11
Solicited Local ReactionsSolicited Local Reactions Adolescents – MTA04, MTA02 & MTA12Adolescents – MTA04, MTA02 & MTA12 Adults – MTA09, MTA14 & MTA11Adults – MTA09, MTA14 & MTA11
Unsolicited Adverse Events and SAEsUnsolicited Adverse Events and SAEs ConclusionsConclusions
Menactra is a trademark of Aventis Pasteur Inc. Menomune®, Tripedia® and Typhim Vi® are registered trademarks of Aventis Pasteur. C-118
Immediate ReactionsImmediate ReactionsMenactraMenactra(N = 7642)(N = 7642)
MenomuneMenomune(N = 3041)(N = 3041)
nn %% nn %%
At least one reaction 2323 0.30.3 66 0.20.2Syncope (5 Vasovagal)Syncope (5 Vasovagal) 88 0.10.1 00 00
DizzinessDizziness 66 0.10.1 11 00
SweatingSweating 44 0.10.1 11 00
NauseaNausea 33 00 00 00
VomitingVomiting 22 00 00 00
Injection site reactionInjection site reaction 22 00 22 0.10.1
Injection site edemaInjection site edema 11 00 11 00
Injection site inflammationInjection site inflammation 11 00 00 00
ChillsChills 11 00 00 00
FeverFever 11 00 00 00
Increased coughIncreased cough 00 00 22 0.10.1
LaryngismusLaryngismus 00 00 11 00
PharyngitisPharyngitis 00 00 11 00
Menactra is a trademark of Aventis Pasteur Inc. Menomune®, Tripedia® and Typhim Vi® are registered trademarks of Aventis Pasteur. C-119
Presentation OutlinePresentation Outline
Immediate ReactionsImmediate Reactions Solicited Systemic ReactionsSolicited Systemic Reactions
Adolescents – MTA04, MTA02 & MTA12Adolescents – MTA04, MTA02 & MTA12 Adults – MTA09, MTA14 & MTA11Adults – MTA09, MTA14 & MTA11
Solicited Local ReactionsSolicited Local Reactions Adolescents – MTA04, MTA02 & MTA12Adolescents – MTA04, MTA02 & MTA12 Adults – MTA09, MTA14 & MTA11Adults – MTA09, MTA14 & MTA11
Unsolicited Adverse Events and SAEsUnsolicited Adverse Events and SAEs ConclusionsConclusions
Menactra is a trademark of Aventis Pasteur Inc. Menomune®, Tripedia® and Typhim Vi® are registered trademarks of Aventis Pasteur. C-120
Solicited Systemic Adverse Events: All TrialsSolicited Systemic Adverse Events: All Trials
Pre-established list of systemic medical Pre-established list of systemic medical conditionsconditions– Fever, chills, headache, anorexia, vomiting, diarrhea, Fever, chills, headache, anorexia, vomiting, diarrhea,
fatigue, malaise, arthralgia, seizures, rash fatigue, malaise, arthralgia, seizures, rash
Clinical severity documented according to defined Clinical severity documented according to defined rating scale (mild, moderate, severe)rating scale (mild, moderate, severe)
Information recorded Day 0 through Day 7Information recorded Day 0 through Day 7
Presence of events and intensity recorded daily on Presence of events and intensity recorded daily on the diarythe diary
Menactra is a trademark of Aventis Pasteur Inc. Menomune®, Tripedia® and Typhim Vi® are registered trademarks of Aventis Pasteur. C-121
Safety Hypothesis: SystemicSafety Hypothesis: Systemic
Expected rate in the control group = 1%Expected rate in the control group = 1%
Menactra is non-inferior to Menomune in the proportion of Menactra is non-inferior to Menomune in the proportion of participants with at least one severe solicited systemic participants with at least one severe solicited systemic reaction reported during Day 0 through Day 7.reaction reported during Day 0 through Day 7.
Non-inferiority criteria:Non-inferiority criteria:
MTA04 & MTA09:MTA04 & MTA09: upper limit upper limit MTA02 & MTA14:MTA02 & MTA14: upper limit of upper limit of of the two-sided 95% CI of theof the two-sided 95% CI of the the two-sided 95% Cl of the the two-sided 95% Cl of the ratio ratio ppMenactraMenactra / / ppMenomuneMenomune < 3 < 3 difference difference ppMenactraMenactra – – ppMenomuneMenomune < 0.1 < 0.1
Menactra is a trademark of Aventis Pasteur Inc. Menomune®, Tripedia® and Typhim Vi® are registered trademarks of Aventis Pasteur. C-122
Presentation OutlinePresentation Outline
Immediate ReactionsImmediate Reactions Solicited Systemic ReactionsSolicited Systemic Reactions
Adolescents – MTA04, MTA02 & MTA12Adolescents – MTA04, MTA02 & MTA12 Adults – MTA09, MTA14 & MTA11Adults – MTA09, MTA14 & MTA11
Solicited Local ReactionsSolicited Local Reactions Adolescents – MTA04, MTA02 & MTA12Adolescents – MTA04, MTA02 & MTA12 Adults – MTA09, MTA14 & MTA11Adults – MTA09, MTA14 & MTA11
Unsolicited Adverse Events and SAEsUnsolicited Adverse Events and SAEs ConclusionsConclusions
Menactra is a trademark of Aventis Pasteur Inc. Menomune®, Tripedia® and Typhim Vi® are registered trademarks of Aventis Pasteur. C-123
MTA04: Solicited Systemic Reactions MTA04: Solicited Systemic Reactions in Adolescentsin Adolescents
MenactraMenactra(N = 2265)(N = 2265)
%%
MenomuneMenomune(N = 970)(N = 970)
%%
Participants with Participants with any systemic any systemic reactionreaction
55.155.1 48.748.7
Participants with Participants with any severe any severe systemic reactionssystemic reactions
4.34.3 2.62.6
Menactra is a trademark of Aventis Pasteur Inc. Menomune®, Tripedia® and Typhim Vi® are registered trademarks of Aventis Pasteur. C-124
MTA04: Non-inferiority Testing of Severe Systemic MTA04: Non-inferiority Testing of Severe Systemic Reactions, 95% CI of Ratio (Menactra/Menomune)Reactions, 95% CI of Ratio (Menactra/Menomune)
1.661.66
3.03.0 3.53.50.50.5 1.01.0 1.51.5 2.02.0 2.52.50.750.75 1.251.25 1.751.75 2.252.25 2.752.75 3.253.25 3.753.75
Within LimitWithin Limit OutsideOutsideLimitLimit
Non-inferiority criteria metNon-inferiority criteria met
Menactra is a trademark of Aventis Pasteur Inc. Menomune®, Tripedia® and Typhim Vi® are registered trademarks of Aventis Pasteur. C-125
MTA04: Systemic Reaction Profile MTA04: Systemic Reaction Profile in Adolescentsin Adolescents
MenactraMenactra(N = 2265)(N = 2265)
%%
MenomuneMenomune(N = 970)(N = 970)
%%HeadacheHeadache 35.635.6 29.329.3
FatigueFatigue 30.030.0 25.125.1
MalaiseMalaise 21.921.9 16.816.8
ArthralgiaArthralgia 17.417.4 10.210.2
DiarrheaDiarrhea 12.012.0 10.210.2
AnorexiaAnorexia 10.710.7 7.77.7
ChillsChills 7.07.0 3.53.5
FeverFever 5.15.1 3.03.0
VomitingVomiting 1.91.9 1.41.4
RashRash 1.61.6 1.41.4
SeizuresSeizures 00 00
Menactra is a trademark of Aventis Pasteur Inc. Menomune®, Tripedia® and Typhim Vi® are registered trademarks of Aventis Pasteur. C-126
MTA04: Severe Solicited Systemic Reactions MTA04: Severe Solicited Systemic Reactions in Adolescents in Adolescents
MenactraMenactra(N = 2265)(N = 2265)
%%
MenomuneMenomune(N = 970)(N = 970)
%%RashRash 1.61.6 1.41.4
HeadacheHeadache 1.1*1.1* 0.40.4
FatigueFatigue 1.1*1.1* 0.20.2
MalaiseMalaise 1.1*1.1* 0.40.4
ArthralgiaArthralgia 0.40.4 0.10.1
AnorexiaAnorexia 0.30.3 0.20.2
DiarrheaDiarrhea 0.3*0.3* 00
VomitingVomiting 0.30.3 0.30.3
ChillsChills 0.20.2 0.10.1
FeverFever 00 0.10.1
SeizuresSeizures 00 00
Menactra is a trademark of Aventis Pasteur Inc. Menomune®, Tripedia® and Typhim Vi® are registered trademarks of Aventis Pasteur. C-127
MTA02: Solicited Systemic Reactions MTA02: Solicited Systemic Reactions in Adolescentsin Adolescents
MenactraMenactra(N = 439)(N = 439)
%%
MenomuneMenomune(N = 441)(N = 441)
%%
Participants with Participants with any systemic any systemic reactionreaction
57.257.2 51.951.9
Participants with Participants with any severe any severe systemic reactionssystemic reactions
3.93.9 4.14.1
Menactra is a trademark of Aventis Pasteur Inc. Menomune®, Tripedia® and Typhim Vi® are registered trademarks of Aventis Pasteur. C-128
MTA02: Non-inferiority Testing of Severe Systemic MTA02: Non-inferiority Testing of Severe Systemic Reactions, 95% CI of Ratio (Menactra/Menomune)Reactions, 95% CI of Ratio (Menactra/Menomune)
0.950.95
3.03.0 3.53.50.50.5 1.01.0 1.51.5 2.02.0 2.52.50.750.75 1.251.25 1.751.75 2.252.25 2.752.75 3.253.25 3.753.75
Within LimitWithin Limit OutsideOutsideLimitLimit
Non-inferiority criteria metNon-inferiority criteria met
Menactra is a trademark of Aventis Pasteur Inc. Menomune®, Tripedia® and Typhim Vi® are registered trademarks of Aventis Pasteur. C-129
MTA02: Systemic Reaction Profile MTA02: Systemic Reaction Profile in Adolescentsin Adolescents
MenactraMenactra(N = 439)(N = 439)
%%
MenomuneMenomune(N = 441)(N = 441)
%%
HeadacheHeadache 44.944.9 39.539.5
FatigueFatigue 28.228.2 23.623.6
AnorexiaAnorexia 12.312.3 12.212.2
DiarrheaDiarrhea 10.910.9 14.114.1
Fever Fever 3.43.4 2.52.5
Vomiting Vomiting 2.32.3 2.02.0
Menactra is a trademark of Aventis Pasteur Inc. Menomune®, Tripedia® and Typhim Vi® are registered trademarks of Aventis Pasteur. C-130
MTA02: Severe Solicited Systemic Reactions MTA02: Severe Solicited Systemic Reactions in Adolescents in Adolescents
MenactraMenactra(N = 439)(N = 439)
%%
MenomuneMenomune(N = 441)(N = 441)
%%
RashRash 1.61.6 1.61.6
HeadacheHeadache 1.61.6 1.81.8
FatigueFatigue 1.11.1 0.70.7
AnorexiaAnorexia 0.90.9 0.70.7
DiarrheaDiarrhea 00 0.20.2
VomitingVomiting 0.20.2 0.20.2
FeverFever 0.20.2 00
Menactra is a trademark of Aventis Pasteur Inc. Menomune®, Tripedia® and Typhim Vi® are registered trademarks of Aventis Pasteur. C-131
Solicited Systemic Reactions: AdolescentsSolicited Systemic Reactions: Adolescents
MTA12MTA12 MTA04MTA04 MTA02MTA02TdTd
+ Menactra+ Menactra(N = 505)(N = 505)
%%
TdTd+ Placebo+ Placebo(N = 510)(N = 510)
%%(N = 2265)(N = 2265)
%%(N = 439)(N = 439)
%%
Solicited Solicited systemic systemic reactions reactions
58.6 58.6 54.1 54.1 55.1 55.1 57.257.2
Severe Severe solicited solicited systemic systemic reactionsreactions
4.8 4.8 3.7 3.7 4.3 4.3 3.93.9
Menactra is a trademark of Aventis Pasteur Inc. Menomune®, Tripedia® and Typhim Vi® are registered trademarks of Aventis Pasteur. C-132
Presentation OutlinePresentation Outline
Immediate ReactionsImmediate Reactions Solicited Systemic ReactionsSolicited Systemic Reactions
Adolescents – MTA04, MTA02 & MTA12Adolescents – MTA04, MTA02 & MTA12 Adults – MTA09, MTA14 & MTA11Adults – MTA09, MTA14 & MTA11
Solicited Local ReactionsSolicited Local Reactions Adolescents – MTA04, MTA02 & MTA12Adolescents – MTA04, MTA02 & MTA12 Adults – MTA09, MTA14 & MTA11Adults – MTA09, MTA14 & MTA11
Unsolicited Adverse Events and SAEsUnsolicited Adverse Events and SAEs ConclusionsConclusions
Menactra is a trademark of Aventis Pasteur Inc. Menomune®, Tripedia® and Typhim Vi® are registered trademarks of Aventis Pasteur. C-133
MTA09: Solicited Systemic Reactions MTA09: Solicited Systemic Reactions in Adultsin Adults
MenactraMenactra(N = 1371)(N = 1371)
%%
MenomuneMenomune(N = 1159)(N = 1159)
%%
Participants with Participants with any systemic any systemic reactionreaction
61.961.9 60.360.3
Participants with Participants with any severe any severe systemic reactionssystemic reactions
3.83.8 2.62.6
Menactra is a trademark of Aventis Pasteur Inc. Menomune®, Tripedia® and Typhim Vi® are registered trademarks of Aventis Pasteur. C-134
MTA09: Non-inferiority Testing of Severe Systemic MTA09: Non-inferiority Testing of Severe Systemic Reactions, 95% CI of Ratio (Menactra/Menomune)Reactions, 95% CI of Ratio (Menactra/Menomune)
1.471.47
3.03.0 3.53.50.50.5 1.01.0 1.51.5 2.02.0 2.52.50.750.75 1.251.25 1.751.75 2.252.25 2.752.75 3.253.25 3.753.75
Within LimitWithin Limit OutsideOutsideLimitLimit
Non-inferiority criteria metNon-inferiority criteria met
Menactra is a trademark of Aventis Pasteur Inc. Menomune®, Tripedia® and Typhim Vi® are registered trademarks of Aventis Pasteur. C-135
MTA09: Systemic Reaction ProfileMTA09: Systemic Reaction Profilein Adultsin Adults
MenactraMenactra(N = 1371)(N = 1371)
%%
MenomuneMenomune(N = 1159)(N = 1159)
%%HeadacheHeadache 41.441.4 41.841.8
FatigueFatigue 34.734.7 32.332.3
MalaiseMalaise 23.623.6 22.322.3
ArthralgiaArthralgia 19.819.8 16.016.0
Diarrhea Diarrhea 16.016.0 14.014.0
Anorexia Anorexia 11.811.8 9.99.9
Chills Chills 9.79.7 5.65.6
VomitingVomiting 2.32.3 1.51.5
FeverFever 1.51.5 0.50.5
Rash Rash 1.41.4 0.80.8
Seizures Seizures 00 00
Menactra is a trademark of Aventis Pasteur Inc. Menomune®, Tripedia® and Typhim Vi® are registered trademarks of Aventis Pasteur. C-136
MTA09: Severe Solicited Systemic Reactions MTA09: Severe Solicited Systemic Reactions in Adultsin Adults
MenactraMenactra(N = 1371)(N = 1371)
%%
MenomuneMenomune(N = 1159)(N = 1159)
%%RashRash 1.41.4 0.80.8
HeadacheHeadache 1.21.2 0.90.9
MalaiseMalaise 1.11.1 0.90.9
FatigueFatigue 0.90.9 0.40.4
ChillsChills 0.6*0.6* 00
Anorexia Anorexia 0.40.4 0.40.4
DiarrheaDiarrhea 0.40.4 0.30.3
ArthralgiaArthralgia 0.30.3 0.10.1
VomitingVomiting 0.20.2 0.40.4
FeverFever 00 00
Seizures Seizures 00 00
Menactra is a trademark of Aventis Pasteur Inc. Menomune®, Tripedia® and Typhim Vi® are registered trademarks of Aventis Pasteur. C-137
MTA14: Solicited Systemic Reactions MTA14: Solicited Systemic Reactions in Adultsin Adults
MenactraMenactra(N = 685)(N = 685)
%%
MenomuneMenomune(N = 455)(N = 455)
%%
Participants with Participants with any systemic any systemic reactionreaction
53.453.4 49.249.2
Participants with Participants with any severe any severe systemic reactionssystemic reactions
2.22.2 5.55.5
Menactra is a trademark of Aventis Pasteur Inc. Menomune®, Tripedia® and Typhim Vi® are registered trademarks of Aventis Pasteur. C-138
0.400.40
3.03.0 3.53.50.50.5 1.01.0 1.51.5 2.02.0 2.52.50.750.75 1.251.25 1.751.75 2.252.25 2.752.75 3.253.25
Within LimitWithin Limit OutsideOutsideLimitLimit
MTA14: Non-inferiority Testing of Severe Systemic MTA14: Non-inferiority Testing of Severe Systemic Reactions, 95% CI of Ratio (Menactra/Menomune)Reactions, 95% CI of Ratio (Menactra/Menomune)
0.250.25
Non-inferiority criteria metNon-inferiority criteria met
Menactra is a trademark of Aventis Pasteur Inc. Menomune®, Tripedia® and Typhim Vi® are registered trademarks of Aventis Pasteur. C-139
MTA14: Systemic Reaction ProfileMTA14: Systemic Reaction Profilein Adultsin Adults
MenactraMenactra(N = 685)(N = 685)
%%
MenomuneMenomune(N = 455)(N = 455)
%%HeadacheHeadache 35.035.0 33.633.6
FatigueFatigue 28.028.0 25.125.1
MalaiseMalaise 19.619.6 17.617.6
DiarrheaDiarrhea 15.315.3 15.415.4
ArthralgiaArthralgia 15.215.2 12.512.5
AnorexiaAnorexia 9.39.3 7.77.7
ChillsChills 6.66.6 3.33.3
VomitingVomiting 1.21.2 1.31.3
FeverFever 0.60.6 0.40.4
RashRash 1.01.0 2.42.4
SeizureSeizure 00 00
Menactra is a trademark of Aventis Pasteur Inc. Menomune®, Tripedia® and Typhim Vi® are registered trademarks of Aventis Pasteur. C-140
MTA14: Severe Solicited Systemic Reactions MTA14: Severe Solicited Systemic Reactions in Adultsin Adults
MenactraMenactra(N = 685)(N = 685)
%%
MenomuneMenomune(N = 455)(N = 455)
%%RashRash 1.01.0 2.42.4
HeadacheHeadache 0.40.4 1.11.1
MalaiseMalaise 0.30.3 1.8*1.8*
FatigueFatigue 0.60.6 1.31.3
ChillsChills 00 0.40.4
AnorexiaAnorexia 0.10.1 0.20.2
DiarrheaDiarrhea 0.30.3 0.70.7
ArthralgiaArthralgia 00 0.40.4
VomitingVomiting 00 00
FeverFever 00 00
SeizureSeizure 00 00
Menactra is a trademark of Aventis Pasteur Inc. Menomune®, Tripedia® and Typhim Vi® are registered trademarks of Aventis Pasteur. C-141
Solicited Systemic Reactions: AdultsSolicited Systemic Reactions: Adults
MTA11MTA11 MTA09MTA09 MTA14MTA14Typhim ViTyphim Vi+ Menactra+ Menactra(N = 456)(N = 456)
%%
Typhim ViTyphim Vi+ Placebo+ Placebo(N = 470)(N = 470)
%%(N = 1371)(N = 1371)
%%(N = 685)(N = 685)
%%
Solicited Solicited systemic systemic reactions reactions
60.5 60.5 59.6 59.6 61.9 61.9 53.453.4
Severe Severe solicited solicited systemic systemic reactionsreactions
5.3 5.3 1.5 1.5 3.8 3.8 2.22.2
Menactra is a trademark of Aventis Pasteur Inc. Menomune®, Tripedia® and Typhim Vi® are registered trademarks of Aventis Pasteur. C-142
Presentation OutlinePresentation Outline
Immediate ReactionsImmediate Reactions Solicited Systemic ReactionsSolicited Systemic Reactions
Adolescents – MTA04, MTA02 & MTA12Adolescents – MTA04, MTA02 & MTA12 Adults – MTA09, MTA14 & MTA11Adults – MTA09, MTA14 & MTA11
Solicited Local ReactionsSolicited Local Reactions Adolescents – MTA04, MTA02 & MTA12Adolescents – MTA04, MTA02 & MTA12 Adults – MTA09, MTA14 & MTA11Adults – MTA09, MTA14 & MTA11
Unsolicited Adverse Events and SAEsUnsolicited Adverse Events and SAEs ConclusionsConclusions
Menactra is a trademark of Aventis Pasteur Inc. Menomune®, Tripedia® and Typhim Vi® are registered trademarks of Aventis Pasteur. C-143
Solicited Local ReactionsSolicited Local Reactions
Pre-established list of vaccine injection Pre-established list of vaccine injection site reactionssite reactions– Redness, swelling, induration, pain at the Redness, swelling, induration, pain at the
injection siteinjection site
Clinical severity documentedClinical severity documented– Mild, moderate, or severeMild, moderate, or severe
Information recorded on pre-printed diary on Information recorded on pre-printed diary on Day 0 through Day 7 Day 0 through Day 7
Menactra is a trademark of Aventis Pasteur Inc. Menomune®, Tripedia® and Typhim Vi® are registered trademarks of Aventis Pasteur. C-144
Local Reactions: Intensity ScaleLocal Reactions: Intensity Scale
Pain at injection sitePain at injection site:: 0 =0 = NoneNone
1 =1 = Mild: symptom present, but arm movement was not Mild: symptom present, but arm movement was not affectedaffected
2 =2 = Moderate: discomfort, interferes with or limits arm Moderate: discomfort, interferes with or limits arm movementmovement
3 =3 = Severe: too painful to move armSevere: too painful to move arm
Induration, swelling and redness:Induration, swelling and redness: 0 =0 = NoneNone
1 =1 = Mild: < 1.0 inchMild: < 1.0 inch
2 =2 = Moderate: 1.0 – 2.0 inchesModerate: 1.0 – 2.0 inches
3 =3 = Severe: > 2.0 inchesSevere: > 2.0 inches
Menactra is a trademark of Aventis Pasteur Inc. Menomune®, Tripedia® and Typhim Vi® are registered trademarks of Aventis Pasteur. C-145
Presentation OutlinePresentation Outline
Immediate ReactionsImmediate Reactions Solicited Systemic ReactionsSolicited Systemic Reactions
Adolescents – MTA04, MTA02 & MTA12Adolescents – MTA04, MTA02 & MTA12 Adults – MTA09, MTA14 & MTA11Adults – MTA09, MTA14 & MTA11
Solicited Local ReactionsSolicited Local Reactions Adolescents – MTA04, MTA02 & MTA12Adolescents – MTA04, MTA02 & MTA12 Adults – MTA09, MTA14 & MTA11Adults – MTA09, MTA14 & MTA11
Unsolicited Adverse Events and SAEsUnsolicited Adverse Events and SAEs ConclusionsConclusions
Menactra is a trademark of Aventis Pasteur Inc. Menomune®, Tripedia® and Typhim Vi® are registered trademarks of Aventis Pasteur. C-146
MTA04/MTA02/MTA12: Adolescents MTA04/MTA02/MTA12: Adolescents Pain at Injection SitePain at Injection Site
MenomuneMenomune MenactraMenactra TdTd PlaceboPlacebo
Any (range), %Any (range), % 28.7 – 30.228.7 – 30.2 52.9 – 68.952.9 – 68.9 70.9 – 71.070.9 – 71.0 15.5 – 22.715.5 – 22.7
Severe (range), %Severe (range), % 00 0 – 0.80 – 0.8 0.20.2 0 0
DurationDuration
AnyAny(median in days)(median in days)
1.01.0 2.02.0 2.0 – 3.02.0 – 3.0 1.01.0
Severe Portion Severe Portion (median in days)(median in days) 00 1.01.0 1.01.0 00
Menactra is a trademark of Aventis Pasteur Inc. Menomune®, Tripedia® and Typhim Vi® are registered trademarks of Aventis Pasteur. C-147
MTA04/MTA02/MTA12: Adolescents MTA04/MTA02/MTA12: Adolescents Induration, Swelling, RednessInduration, Swelling, Redness
MenomuneMenomune MenactraMenactra TdTd PlaceboPlacebo
Any (range), %Any (range), % 3.6 – 7.73.6 – 7.7 10.8 – 20.310.8 – 20.3 14.5 – 25.914.5 – 25.9 1.6 – 7.61.6 – 7.6
Severe (range), %Severe (range), % 00 0.2 – 1.40.2 – 1.4 0.2 – 1.60.2 – 1.6 0 – 0.20 – 0.2
DurationDuration
AnyAny(median in days)(median in days)
1.01.0 1.0 – 2.01.0 – 2.0 1.0 – 2.01.0 – 2.0 1.0 – 2.01.0 – 2.0
Severe Portion Severe Portion (median in days)(median in days) 00 1.0 – 2.01.0 – 2.0 1.01.0 1.01.0
Menactra is a trademark of Aventis Pasteur Inc. Menomune®, Tripedia® and Typhim Vi® are registered trademarks of Aventis Pasteur. C-148
72.472.4
57.057.0
73.373.3
58.058.0
74.774.7
Adolescent Local ReactionsAdolescent Local Reactions
00
1010
2020
3030
4040
5050
6060
7070
8080
9090
100100
Local ReactionsLocal Reactions
% o
f P
arti
cip
ants
Re
po
rtin
g%
of
Par
tic
ipan
ts R
ep
ort
ing
62.7
MTA12: Td Site Given w/MenactraMTA12: Td Site Given w/Menactra
MTA12: Menactra Site Given w/ TdMTA12: Menactra Site Given w/ Td
MTA12: Td Given w/PlaceboMTA12: Td Given w/Placebo
MTA12: Menactra Site Given MTA12: Menactra Site Given One Month after TdOne Month after Td
MTA02: MenactraMTA02: Menactra
MTA04: MenactraMTA04: Menactra
Menactra is a trademark of Aventis Pasteur Inc. Menomune®, Tripedia® and Typhim Vi® are registered trademarks of Aventis Pasteur. C-149
Presentation OutlinePresentation Outline
Immediate ReactionsImmediate Reactions Solicited Systemic ReactionsSolicited Systemic Reactions
Adolescents – MTA04, MTA02 & MTA12Adolescents – MTA04, MTA02 & MTA12 Adults – MTA09, MTA14 & MTA11Adults – MTA09, MTA14 & MTA11
Solicited Local ReactionsSolicited Local Reactions Adolescents – MTA04, MTA02 & MTA12Adolescents – MTA04, MTA02 & MTA12 Adults – MTA09, MTA14 & MTA11Adults – MTA09, MTA14 & MTA11
Unsolicited Adverse Events and SAEsUnsolicited Adverse Events and SAEs ConclusionsConclusions
Menactra is a trademark of Aventis Pasteur Inc. Menomune®, Tripedia® and Typhim Vi® are registered trademarks of Aventis Pasteur. C-150
MTA09/MTA14/MTA11: Adults MTA09/MTA14/MTA11: Adults Pain at Injection SitePain at Injection Site
MenomuneMenomune MenactraMenactra Typhim ViTyphim Vi PlaceboPlacebo
Any (range), %Any (range), % 19.8 – 48.119.8 – 48.1 38.5 – 53.938.5 – 53.9 75.2 – 75.775.2 – 75.7 13.6 – 21.913.6 – 21.9
Severe (range), %Severe (range), % 0 – 0.10 – 0.1 0 – 1.80 – 1.8 0.4 – 0.60.4 – 0.6 0 – 0.20 – 0.2
DurationDuration
AnyAny(median in days)(median in days)
1.01.0 2.02.0 2.02.0 2.02.0
Severe Portion Severe Portion (median in days)(median in days) 0 – 1.00 – 1.0 1.5 – 2.01.5 – 2.0 2.52.5 0 – 1.00 – 1.0
Menactra is a trademark of Aventis Pasteur Inc. Menomune®, Tripedia® and Typhim Vi® are registered trademarks of Aventis Pasteur. C-151
MTA09/MTA14/MTA11: Adults MTA09/MTA14/MTA11: Adults Induration, Swelling, RednessInduration, Swelling, Redness
MenomuneMenomune MenactraMenactra Typhim ViTyphim Vi PlaceboPlacebo
Any (range), %Any (range), % 4.6 – 16.04.6 – 16.0 10.5 – 17.110.5 – 17.1 14.0 – 21.714.0 – 21.7 2.8 – 6.02.8 – 6.0
Severe (range), %Severe (range), % 0 – 0.10 – 0.1 0.4 – 1.10.4 – 1.1 0 – 0.40 – 0.4 0 – 0.20 – 0.2
DurationDuration
AnyAny(median in days)(median in days)
1.0 – 2.01.0 – 2.0 2.02.0 1.01.0 1.01.0
Severe Portion Severe Portion (median in days)(median in days) 0 – 1.00 – 1.0 1.0 – 3.01.0 – 3.0 1.01.0 0 – 3.00 – 3.0
Menactra is a trademark of Aventis Pasteur Inc. Menomune®, Tripedia® and Typhim Vi® are registered trademarks of Aventis Pasteur. C-152
57.657.6
47.247.2
77.477.4
51.351.3
77.477.4
Adult Local ReactionsAdult Local Reactions
00
1010
2020
3030
4040
5050
6060
7070
8080
9090
100100
Local ReactionsLocal Reactions
MTA11: Typhim Vi Site Given w/MenactraMTA11: Typhim Vi Site Given w/Menactra
MTA11: Menactra Site Given w/ Typhim ViMTA11: Menactra Site Given w/ Typhim Vi
MTA11: Typhim Vi Given w/PlaceboMTA11: Typhim Vi Given w/Placebo
MTA11: Menactra Site Given MTA11: Menactra Site Given One Month after Typhim ViOne Month after Typhim Vi
MTA09: MenactraMTA09: Menactra
MTA14: MenactraMTA14: Menactra
42.342.3
% o
f P
arti
cip
ants
Re
po
rtin
g%
of
Par
tic
ipan
ts R
ep
ort
ing
Menactra is a trademark of Aventis Pasteur Inc. Menomune®, Tripedia® and Typhim Vi® are registered trademarks of Aventis Pasteur. C-153
Presentation OutlinePresentation Outline
Immediate ReactionsImmediate Reactions Solicited Systemic ReactionsSolicited Systemic Reactions
Adolescents – MTA04, MTA02 & MTA12Adolescents – MTA04, MTA02 & MTA12 Adults – MTA09, MTA14 & MTA11Adults – MTA09, MTA14 & MTA11
Solicited Local ReactionsSolicited Local Reactions Adolescents – MTA04, MTA02 & MTA12Adolescents – MTA04, MTA02 & MTA12 Adults – MTA09, MTA14 & MTA11Adults – MTA09, MTA14 & MTA11
Unsolicited Adverse Events and SAEsUnsolicited Adverse Events and SAEs ConclusionsConclusions
Menactra is a trademark of Aventis Pasteur Inc. Menomune®, Tripedia® and Typhim Vi® are registered trademarks of Aventis Pasteur. C-154
Most Frequent Unsolicited AEs That Occurred Most Frequent Unsolicited AEs That Occurred in at Least 1% of Participants, Day 0 to Day 28in at Least 1% of Participants, Day 0 to Day 28
MenactraMenactra MenomuneMenomuneCOSTART Body System/COSTART Body System/ (N = 7500)(N = 7500) (N = 3004) (N = 3004)Preferred TermPreferred Term %% % %
At least one unsolicited AEAt least one unsolicited AE 28.328.3 28.628.6
Body as a wholeBody as a wholeInfectionInfection 2.92.9 4.14.1PainPain 2.02.0 1.91.9
Injury accidentalInjury accidental 1.91.9 1.91.9Pain backPain back 1.81.8 1.41.4
Allergic reactionAllergic reaction 1.61.6 1.61.6HeadacheHeadache 1.21.2 1.31.3Pain abdominalPain abdominal 0.80.8 1.21.2
Respiratory systemRespiratory systemPharyngitisPharyngitis 3.73.7 4.44.4RhinitisRhinitis 2.92.9 3.43.4Cough increasingCough increasing 1.61.6 1.21.2SinusitisSinusitis 1.11.1 1.01.0
Urogenital systemUrogenital systemDysmenorrheaDysmenorrhea 3.13.1 3.33.3
Digestive SystemDigestive SystemDyspepsiaDyspepsia 0.90.9 1.51.5
Menactra is a trademark of Aventis Pasteur Inc. Menomune®, Tripedia® and Typhim Vi® are registered trademarks of Aventis Pasteur. C-155
Unsolicited Adverse Events, Day 29 to Unsolicited Adverse Events, Day 29 to Month 6Month 6
Menactra(N = 5676)
%
Menomune(N = 3041)
%
At least one unsolicited AE 5.8 5.7
Body as a whole 2.2 1.5
Skin and appendages 1.0 0.8
Respiratory system 1.0 1.0
Urogenital system 0.8 0.8
Musculoskeletal system 0.5 0.5
Digestive system 0.4 0.5
Nervous system 0.4 0.5
Hemic and lymphatic system 0.3 0.3
Cardiovascular system 0.2 0.3
Special senses 0.2 0.3
Metabolic and nutritional disorders 0.1 0.1
Endocrine system 0 0.1
Menactra is a trademark of Aventis Pasteur Inc. Menomune®, Tripedia® and Typhim Vi® are registered trademarks of Aventis Pasteur. C-156
SAEs – All TrialsSAEs – All Trials
Total participants reporting SAEsTotal participants reporting SAEs– Menactra – 77 (1.0%)Menactra – 77 (1.0%)
– Menomune – 39 (1.3%)Menomune – 39 (1.3%)
All except one reported as unrelated toAll except one reported as unrelated tostudy vaccinestudy vaccine– 17 y/o with distal esophageal ulceration17 y/o with distal esophageal ulceration
Presented with symptoms 2 days after vaccinationPresented with symptoms 2 days after vaccination
History of NSAID use for 4 weeks prior to vaccination to treat History of NSAID use for 4 weeks prior to vaccination to treat sport-related injurysport-related injury
Menactra is a trademark of Aventis Pasteur Inc. Menomune®, Tripedia® and Typhim Vi® are registered trademarks of Aventis Pasteur. C-157
DeathsDeaths
Two deaths reported across the six studies Two deaths reported across the six studies – Both in study MTA14Both in study MTA14
Both classified by investigator as unrelated to Both classified by investigator as unrelated to study vaccinestudy vaccine– One in Menactra groupOne in Menactra group
Motor vehicle accident 109 days after vaccinationMotor vehicle accident 109 days after vaccination
– One in Menomune groupOne in Menomune group Drug overdose 79 days after vaccinationDrug overdose 79 days after vaccination
Menactra is a trademark of Aventis Pasteur Inc. Menomune®, Tripedia® and Typhim Vi® are registered trademarks of Aventis Pasteur. C-158
Presentation OutlinePresentation Outline
Immediate ReactionsImmediate Reactions Solicited Systemic ReactionsSolicited Systemic Reactions
Adolescents – MTA04, MTA02 & MTA12Adolescents – MTA04, MTA02 & MTA12 Adults – MTA09, MTA14 & MTA11Adults – MTA09, MTA14 & MTA11
Solicited Local ReactionsSolicited Local Reactions Adolescents – MTA04, MTA02 & MTA12Adolescents – MTA04, MTA02 & MTA12 Adults – MTA09, MTA14 & MTA11Adults – MTA09, MTA14 & MTA11
Unsolicited Adverse Events and SAEsUnsolicited Adverse Events and SAEs ConclusionsConclusions
Menactra is a trademark of Aventis Pasteur Inc. Menomune®, Tripedia® and Typhim Vi® are registered trademarks of Aventis Pasteur. C-159
Conclusions – Safety Conclusions – Safety
Menactra safe and well tolerated among adolescents Menactra safe and well tolerated among adolescents and adultsand adults
Menactra met all agreed non-inferiority criteria Menactra met all agreed non-inferiority criteria
Local reactions seen with Menactra as expected for Local reactions seen with Menactra as expected for protein conjugate vaccine and comparable to those protein conjugate vaccine and comparable to those seen with Tdseen with Td
Menactra may be administered either concomitantly or Menactra may be administered either concomitantly or one month after Td or Typhim Vione month after Td or Typhim Vi
Menactra is a trademark of Aventis Pasteur Inc. Menomune®, Tripedia® and Typhim Vi® are registered trademarks of Aventis Pasteur. C-160
Menactra - AgendaMenactra - Agenda
IntroductionIntroduction Luc Kuykens, MD, MPHLuc Kuykens, MD, MPHVP Regulatory AffairsVP Regulatory Affairs
EpidemiologyEpidemiology Greg Gilmet, MD, MPHGreg Gilmet, MD, MPHDirector Scientific & Medical AffairsDirector Scientific & Medical Affairs
ImmunogenicityImmunogenicity Michael Decker, MD, MPHMichael Decker, MD, MPHVP Scientific & Medical AffairsVP Scientific & Medical Affairs
SafetySafety Gary Chikami, MDGary Chikami, MDSenior Director Regulatory AffairsSenior Director Regulatory Affairs
ConclusionsConclusions Luc Kuykens, MD, MPHLuc Kuykens, MD, MPHVP Regulatory AffairsVP Regulatory Affairs
Menactra is a trademark of Aventis Pasteur Inc. Menomune®, Tripedia® and Typhim Vi® are registered trademarks of Aventis Pasteur. C-161
Conclusions – ImmunogenicityConclusions – Immunogenicity
Menactra consistently immunogenic in Menactra consistently immunogenic in adolescents and adultsadolescents and adults
Immune responses to the four meningococcal Immune responses to the four meningococcal serogroups included in Menactra non-inferior serogroups included in Menactra non-inferior to those induced by Menomuneto those induced by Menomune
Menactra can be administered concomitantly Menactra can be administered concomitantly or one month after Td or Typhim Vior one month after Td or Typhim Vi
Menactra is a trademark of Aventis Pasteur Inc. Menomune®, Tripedia® and Typhim Vi® are registered trademarks of Aventis Pasteur. C-162
Conclusions – Immunogenicity (2)Conclusions – Immunogenicity (2)
Bactericidal antibody elicited by single dose of Bactericidal antibody elicited by single dose of Menactra persists for at least three yearsMenactra persists for at least three years
One dose of Menactra primes for memory One dose of Menactra primes for memory
Adolescents primed with one dose of Adolescents primed with one dose of Menactra exhibited booster response to Menactra exhibited booster response to second dose second dose
Booster dose of Menactra not associated with Booster dose of Menactra not associated with hyporesponsivenesshyporesponsiveness
Menactra is a trademark of Aventis Pasteur Inc. Menomune®, Tripedia® and Typhim Vi® are registered trademarks of Aventis Pasteur. C-163
Conclusions – SafetyConclusions – Safety
Menactra safe and well-tolerated among Menactra safe and well-tolerated among adolescents and adultsadolescents and adults
Menactra met all agreed non-inferiority criteria Menactra met all agreed non-inferiority criteria
Local reactions as expected for protein-Local reactions as expected for protein-conjugate vaccine and comparable to those conjugate vaccine and comparable to those seen with Tdseen with Td
Menactra may be administered concomitantly Menactra may be administered concomitantly or one month after Td or Typhim Vior one month after Td or Typhim Vi
Menactra is a trademark of Aventis Pasteur Inc. Menomune®, Tripedia® and Typhim Vi® are registered trademarks of Aventis Pasteur. C-164
Risk/BenefitRisk/Benefit
RisksRisks
Reactogenicity profile consistent with conjugate Reactogenicity profile consistent with conjugate vaccinevaccine– Increased rate of local reactionsIncreased rate of local reactions
BenefitsBenefits
Highly immunogenicHighly immunogenic
Improved antibody persistenceImproved antibody persistence
Priming and boostingPriming and boosting
Overcomes hyporesponsivenessOvercomes hyporesponsiveness
Menactra is a trademark of Aventis Pasteur Inc. Menomune®, Tripedia® and Typhim Vi® are registered trademarks of Aventis Pasteur. C-165
MenomuneMenomuneVaccineesVaccinees
MenactraMenactraVaccineesVaccinees
SBA-BRC SBA-BRC 4-Fold Rise4-Fold Rise
73 of 81 73 of 81 90%90%
75 of 84 75 of 84 89%89%
SBA-HuC SBA-HuC 1:41:4
70 of 81 70 of 81 86%86%
79 of 84 79 of 84 94%94%
Bactericidal Titers Comparison: Bactericidal Titers Comparison: 4-Fold Rise 4-Fold Rise (BRC) vs. (BRC) vs. 1:4 (HuC), Serogroup C 1:4 (HuC), Serogroup C
11 to 18 year olds (MTA02)11 to 18 year olds (MTA02)
Pe
rce
nta
ge
Pe
rce
nta
ge
SBA-BRC (4-fold rise)SBA-BRC (4-fold rise)
SBA-HuC (SBA-HuC ( 1:4) 1:4)
00
2020
4040
6060
8080
100100