Menactrais a trademark of Aventis Pasteur Inc. Menomune ® , Tripedia ® and Typhim Vi ® are registered trademarks of Aventis Pasteur. C-1 MENACTRA MENACTRA ™ ™ Meningococcal (Groups A, C, Y Meningococcal (Groups A, C, Y and W-135) Polysaccharide and W-135) Polysaccharide Diphtheria Toxoid Conjugate Diphtheria Toxoid Conjugate Vaccine Vaccine Vaccines and Related Biological Products Vaccines and Related Biological Products Advisory Committee Advisory Committee September 22, September 22, 2004 2004
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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 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
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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.
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
*Defined as serogroups A, C, Y, W-135.*Defined as serogroups A, C, Y, W-135.
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Impact of Polysaccharide Immunization on Impact of Polysaccharide Immunization on Hospitalizations (U.S. Army 1964-1998)Hospitalizations (U.S. Army 1964-1998)
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.
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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
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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.
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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.
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1010
1515
2020
2525
3030
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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 (
%)
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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
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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
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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
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of
Ca
ses
Nu
mb
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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
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.
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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
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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
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.
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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
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.
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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.
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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
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 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
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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
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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.
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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
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
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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
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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
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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
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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
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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
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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
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Distribution of Clinical Trial Study Populations Distribution of Clinical Trial Study Populations By Gender and Race/EthnicityBy Gender and Race/Ethnicity
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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
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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
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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
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Pe
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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
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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
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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
SBA Antibody Titers for Meningococcal Serogroup ASBA Antibody Titers for Meningococcal Serogroup A
Pa
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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
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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
SBA Antibody Titers for Meningococcal Serogroup YSBA Antibody Titers for Meningococcal Serogroup Y
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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
SBA Antibody Titers for Meningococcal Serogroup W-135SBA Antibody Titers for Meningococcal Serogroup W-135
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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
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
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
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
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
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
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
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
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
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
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
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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
All non-inferiority criteria metAll non-inferiority criteria met
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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
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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
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
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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
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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
All non-inferiority criteria metAll non-inferiority criteria met
2020 2525
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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
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
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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
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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 Events and SAEsUnsolicited Adverse Events and SAEs ConclusionsConclusions
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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,
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
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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.
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
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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
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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)
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
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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)
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
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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)
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
Unsolicited Adverse Events and SAEsUnsolicited Adverse Events and SAEs ConclusionsConclusions
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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
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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
Unsolicited Adverse Events and SAEsUnsolicited Adverse Events and SAEs ConclusionsConclusions
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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
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
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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
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Unsolicited Adverse Events and SAEsUnsolicited Adverse Events and SAEs ConclusionsConclusions
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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
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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
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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
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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
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Risk/BenefitRisk/Benefit
RisksRisks
Reactogenicity profile consistent with conjugate Reactogenicity profile consistent with conjugate vaccinevaccine– Increased rate of local reactionsIncreased rate of local reactions