Menactra is a trademark of Aventis Pasteur Inc. Menomune ®, Tripedia ® and Typhim Vi ® are registered trademarks of Aventis Pasteur. C-1 MENACTRA ™ Meningococcal

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 - 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


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


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 - 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 - 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 - 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 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 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









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


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










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%


8%8%


Reported Cases of Meningococcal Disease, Reported Cases of Meningococcal Disease, U.S., 1967-2002U.S., 1967-2002

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1,3231,323

3,5253,525

CDC CDC MMWRMMWR Oct. 1997, Apr 2004. Oct. 1997, Apr 2004.


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.

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FemaleFemale


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

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0-2 2-5 6-11 12-17 18-23 24-54 >55

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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..

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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.


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

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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

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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.










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%


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.


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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TimeTime

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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.


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.










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


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)

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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)


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


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.


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


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.


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.


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










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










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


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



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.


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


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



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



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


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


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


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


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


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


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


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 %

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MTA02: 4-Fold Rises in SBA Titer by MTA02: 4-Fold Rises in SBA Titer by Serogroup in AdolescentsSerogroup in Adolescents

MenactraMenactra

Menomune Menomune


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


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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


Group:Group: Menactra, Day 0Menactra, Day 0

Menomune, Day 0Menomune, Day 0

Menactra, Day 28Menactra, 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

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SBA Antibody Titers for Meningococcal Serogroup CSBA Antibody Titers for Meningococcal Serogroup C

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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

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SBA Antibody Titers for Meningococcal Serogroup YSBA Antibody Titers for Meningococcal Serogroup Y

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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

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SBA Antibody Titers for Meningococcal Serogroup W-135SBA Antibody Titers for Meningococcal Serogroup W-135

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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


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

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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



P < 0.001P < 0.001P = 0.12

P = 0.12

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600600

800800

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SerogroupSerogroup

SB

A G

MT

SB

A G

MT




Age-matched NaïveAge-matched Naïve

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800800

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MT

AA CC YY W-135W-135

SerogroupSerogroup



MTA19: RCD Curves for SBA Antibody Titers for MTA19: RCD Curves for SBA Antibody Titers for Meningococcal Serogroup AMeningococcal Serogroup A

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PW Menomune at Day 0PW Menomune at Day 0PW Menactra at Day 0PW Menactra at Day 0

Naïve at Day 0Naïve at Day 0


MTA19: RCD Curves for SBA Antibody Titers for MTA19: RCD Curves for SBA Antibody Titers for Meningococcal Serogroup CMeningococcal Serogroup C

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MTA19: RCD Curves for SBA Antibody Titers for MTA19: RCD Curves for SBA Antibody Titers for Meningococcal Serogroup YMeningococcal Serogroup Y

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MTA19: RCD Curves for SBA Antibody Titers for MTA19: RCD Curves for SBA Antibody Titers for Meningococcal Serogroup W-135Meningococcal Serogroup W-135




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


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




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




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




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


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



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



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

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V2 + 8d

V2 + 28d

Menactra after MenomuneMenomune

ThreeYears

0

500

1000

1500

2000

2500

Menomune


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











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


Hypothesis: short-term immune response not Hypothesis: short-term immune response not inferior to Menomuneinferior to Menomune


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%

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-2-2 -1-1 00 11 22 33 44 55 66 77 88 99 1010

4.14.1




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)



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45004500

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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




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




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)


*Adjusted for baseline titers using ANCOVA.*Adjusted for baseline titers using ANCOVA.


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

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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

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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

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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

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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)


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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



AA CC YY W-135W-13500

10001000

20002000

30003000

40004000

50005000

60006000

70007000

80008000

90009000

Menactra Lot 1Menactra Lot 2Menactra Lot 3


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)


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




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.


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


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

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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:



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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:



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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

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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








MTA12: Concomitant Menactra and Td in MTA12: Concomitant Menactra and Td in adolescentsadolescents



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


Hypothesis: concomitant administration is not Hypothesis: concomitant administration is not inferior to sequential administrationinferior to sequential administration


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




-30-30 -25-25 -20-20 -15-15 -10-10 -5-5 00 55 1010

0.480.48




-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)


2020 2525


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


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)


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


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%)


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


-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









MTA12: Concomitant Menactra and Td in MTA12: Concomitant Menactra and Td in adolescentsadolescents



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


Hypothesis: concomitant administration is not Hypothesis: concomitant administration is not inferior to sequential administrationinferior to sequential administration


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


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 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


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)



-30-30 -25-25 -20-20 -15-15 -10-10 -5-5 00 55 1010

-4.49-4.49




-1.17-1.17

-9.25-9.25

-1.40-1.40

1515


2020 2525


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


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)


-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


-9-9

Typhim Vi + PlaceboTyphim Vi + Placebovs.vs.



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









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


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



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


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








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


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








MTA04: Solicited Systemic Reactions MTA04: Solicited Systemic Reactions in Adolescentsin Adolescents

MenactraMenactra(N = 2265)(N = 2265)

%%


%%

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


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


MTA04: Systemic Reaction Profile MTA04: Systemic Reaction Profile in Adolescentsin Adolescents


%%


%%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


MTA04: Severe Solicited Systemic Reactions MTA04: Severe Solicited Systemic Reactions in Adolescents in Adolescents


%%


%%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



DiarrheaDiarrhea 0.3*0.3* 00



FeverFever 00 0.10.1

SeizuresSeizures 00 00


MTA02: Solicited Systemic Reactions MTA02: Solicited Systemic Reactions in Adolescentsin Adolescents


%%


%%


57.257.2 51.951.9


3.93.9 4.14.1



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




MTA02: Systemic Reaction Profile MTA02: Systemic Reaction Profile in Adolescentsin Adolescents


%%


%%

HeadacheHeadache 44.944.9 39.539.5




Fever Fever 3.43.4 2.52.5

Vomiting Vomiting 2.32.3 2.02.0


MTA02: Severe Solicited Systemic Reactions MTA02: Severe Solicited Systemic Reactions in Adolescents in Adolescents


%%


%%

RashRash 1.61.6 1.61.6




DiarrheaDiarrhea 00 0.20.2


FeverFever 0.20.2 00


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








MTA09: Solicited Systemic Reactions MTA09: Solicited Systemic Reactions in Adultsin Adults


%%


%%


61.961.9 60.360.3


3.83.8 2.62.6



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




MTA09: Systemic Reaction ProfileMTA09: Systemic Reaction Profilein Adultsin Adults


%%






Diarrhea Diarrhea 16.016.0 14.014.0

Anorexia Anorexia 11.811.8 9.99.9

Chills Chills 9.79.7 5.65.6



Rash Rash 1.41.4 0.80.8

Seizures Seizures 00 00


MTA09: Severe Solicited Systemic Reactions MTA09: Severe Solicited Systemic Reactions in Adultsin Adults


%%


%%RashRash 1.41.4 0.80.8




ChillsChills 0.6*0.6* 00

Anorexia Anorexia 0.40.4 0.40.4




FeverFever 00 00

Seizures Seizures 00 00


MTA14: Solicited Systemic Reactions MTA14: Solicited Systemic Reactions in Adultsin Adults


%%


%%


53.453.4 49.249.2


2.22.2 5.55.5


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



0.250.25



MTA14: Systemic Reaction ProfileMTA14: Systemic Reaction Profilein Adultsin Adults


%%











RashRash 1.01.0 2.42.4

SeizureSeizure 00 00


MTA14: Severe Solicited Systemic Reactions MTA14: Severe Solicited Systemic Reactions in Adultsin Adults


%%


%%RashRash 1.01.0 2.42.4


MalaiseMalaise 0.30.3 1.8*1.8*


ChillsChills 00 0.40.4



ArthralgiaArthralgia 00 0.40.4

VomitingVomiting 00 00

FeverFever 00 00

SeizureSeizure 00 00


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








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


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








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


MTA04/MTA02/MTA12: Adolescents MTA04/MTA02/MTA12: Adolescents Induration, Swelling, RednessInduration, Swelling, Redness

MenomuneMenomune MenactraMenactra TdTd PlaceboPlacebo


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


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


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









MTA09/MTA14/MTA11: Adults MTA09/MTA14/MTA11: Adults Pain at Injection SitePain at Injection Site

MenomuneMenomune MenactraMenactra Typhim ViTyphim Vi PlaceboPlacebo


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


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


MTA09/MTA14/MTA11: Adults MTA09/MTA14/MTA11: Adults Induration, Swelling, RednessInduration, Swelling, Redness

MenomuneMenomune MenactraMenactra Typhim ViTyphim Vi PlaceboPlacebo


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


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


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



42.342.3

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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

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


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


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


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








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









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


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


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


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


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

Documents

Menactra is a trademark of Aventis Pasteur Inc. Menomune ®, Tripedia ® and Typhim Vi ® are registered trademarks of Aventis Pasteur. C-1 MENACTRA ™ Meningococcal