# Presentation: 307884

## MENACTRATM

**Meningococcal (Groups A, C, Y and W-135) Polysaccharide Diphtheria Toxoid Conjugate Vaccine**

**Vaccines and Related Biological Products**
**Advisory Committee**

**September 22, 2004**

## Menactra - Agenda

**Introduction****	****Luc Kuykens, MD, MPH****	****VP Regulatory Affairs**
**Epidemiology****	****Greg Gilmet, MD, MPH****	****Director Scientific & Medical Affairs**** **
**Immunogenicity****	****Michael Decker, MD, MPH****	****VP Scientific & Medical Affairs**
**Safety****	****Gary Chikami, MD****	****Senior Director Regulatory Affairs**
**Conclusions****	****Luc Kuykens, MD, MPH****	****VP Regulatory Affairs**

## Public Health Need for Improved Meningococcal Vaccine

**Persistence of bactericidal antibodies**
**Ability to prime and boost**
**Absence of hyporesponsiveness seen with current polysaccharide vaccines**
**Reduction in carriage**
**Herd immunity**

## Vaccine Formulation

_**Menactra**_**	**_**Menomune**__**®**__** (single dose)**_
**4 μg each A,C,Y,W-135 PS****	****50 μg each A,C,Y,W-135 PS **
**48 μg of diphtheria toxoid****	****       ****	****	**
**No adjuvant****	****No adjuvant****	****	**
**No preservative****	****No preservative**
**Liquid formulation****	****Lyophilized formulation**
**Administered IM****	****Administered SC**

## Menactra - Content

**Polysaccharides manufactured under the existing license for Menomune**
**Diphtheria toxoid manufactured under existing license for Tripedia****®**

## Menactra - Clinical Experience

**	****	****Persons Receiving****Population** **	**** Clinical Trials** **	****Menactra**
**Adults****	****3****	****3,911**
**Adolescents****	****3****	****3,731**
**Children****	****3****	****2,649**
**TOTAL****	****9****	****10,291**

## Menactra - Clinical Experience

**	****	****Persons Receiving****Population** **	**** Clinical Trials** **	****Menactra**
**Adults****	****3****	****3,911**
**Adolescents****	****3****	****3,731**
**TOTAL****	****6****	****7,642**
**Children****	****3****	****2,649**

## Menactra Clinical Development Program

**Active comparison to standard of care**
**Demonstration of non-inferiority for both immunogenicity and safety**
**Concomitant administration with Td and Typhim Vi**

## Menactra Key Findings

**Menactra met every pre-specified criteria for non-inferiority**
**Immunogenicity**
**Safety**
**Menactra demonstrated characteristics of conjugate vaccine**
**Persistence**
**Prime and boost**
**Overcomes hyporesponsiveness**

## Menactra - Agenda

**Introduction****	****Luc Kuykens, MD, MPH****	****VP Regulatory Affairs**
**Epidemiology****	****Greg Gilmet, MD, MPH****	****Director Scientific & Medical Affairs**** **
**Immunogenicity****	****Michael Decker, MD, MPH****	****VP Scientific & Medical Affairs**
**Safety****	****Gary Chikami, MD****	****Senior Director Regulatory Affairs**
**Conclusions****	****Luc Kuykens, MD, MPH****	****VP Regulatory Affairs**

## Presentation Outline

**Clinical Challenge of Meningococcal Disease**
**Current U.S. Epidemiology**
**Current UK and European Epidemiology**
**Benefits of Conjugate Vaccines**
**UK Experience with C Conjugate Meningococcal Vaccines**
**Epidemiology Summary**

## The Challenge of Invasive Meningococcal Disease

**Most common cause of bacterial meningitis **
**Unique ability to cause outbreaks and epidemics**
**Serogroups shift over time and geography**
**Strikes healthy individuals**
**High mortality rate (10-15%)**
**60% symptomatic < 24 hrs prior to hospitalization**
**Difficult to diagnose, high emotional impact**

## Presentation Outline

**Clinical Challenge of Meningococcal Disease**
**Current U.S. Epidemiology**
**Current UK and European Epidemiology**
**Benefits of Conjugate Vaccines**
**UK Experience with C Conjugate Meningococcal Vaccines**
**Epidemiology Summary**

## Changing Meningococcal Serogroup Distribution in the U.S.*

***ABCs data **

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

**Number of ****Reported Cases**

**Year**

**0**

**500**

**1000**

**1500**

**2000**

**2500**

**3000**

**3500**

**4000**

**1967**

**1971**

**1975**

**1979**

**1983**

**1987**

**1991**

**1995**

**1999**

**1,323**

**3,525**

**CDC *****MMWR***** Oct. 1997, Apr 2004. **

## Age- and Gender-Specific Rates of Meningococcal Disease in the U.S.

**Rosenstein NE, et al. *****J Infect***** *****Dis.***** 1999;180:1894-901.**

**Age (years)**

**Incidence per ****100,000 Population**

**Male**

**0**

**1**

**2**

**3**

**4**

**5**

**6**

**5-9**

**10-14**

**15-19**

**20-24**

**25-29**

**30-34**

**35-39**

**40-44**

**45-49**

**50-54**

**55-59**

**60-64**

**65-69**

**70-74**

**75-79**

**80-84**

**≥ ****85**

**0-4**

**Female**

## Most Cases in U.S. Adolescents and Young Adults Are Potentially Vaccine-Preventable*

***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.**
**CDC. *****MMWR Morb Mortal Wkly Rep.***** 2000;49(RR-7):13.**

**48%**

**48%**

**65%**

**71%**

**70%**

**79%**

**87%**

**Potentially Vaccine-Preventable**

**0**

**25**

**50**

**75**

**100**

**125**

**150**

**175**

**200**

**225**

**250**

**0-2**

**2-5**

**6-11**

**12-17**

**18-23**

**24-54**

**>55**

**Age Group**

**Number of Cases**

**B**

**C**

**Y**

**W-135**

## Distribution of Meningococcal Fatalities by Age Group, U.S. 1997 – 2001 

**CDC. *****Natl. Vital Stats. Rep*****.**

**Number of Deaths**

**139**

**146**

**135**

**266**

**90**

**93**

**102**

**48**

**56**

**57**

**48**

**0**

**50**

**100**

**150**

**200**

**250**

**300**

**<1**

**1-4**

**5-14**

**15-24**

**25-34**

**35-44**

**45-54**

**55-64**

**65-74**

**75-84**

**>85**

## Meningococcal Disease in Adolescents and Young Adults: Increased Lethality; More Vaccine-Preventable

**	****	****	****	****Events****	****Events****	****Variable****	****<15 yrs****	****15-24 yrs****	****P-Value**
**Death****	****4.6%****	****22.5%****	****.001**
**Vaccine-****Preventable****	****	****Disease*****	****68.1%****	****82.8%****	****.04**

***Defined as serogroups A, C, Y, W-135.**

## Impact of Polysaccharide Immunization on Hospitalizations (U.S. Army 1964-1998)

***Bars indicate hospitalization frequencies; line indicates rates. DeFraites RF. *****MSMR.***** 2000;6:2.**

**Year**

**Number of****Hospitalizations **

**Monovalent****(Group C)**

**Bivalent****(A,C)**

**Quadrivalent (A,C,Y,W-135)**

**0**

**50**

**100**

**150**

**200**

**250**

**300**

**350**

**400**

**450**

**500**

**1964**

**1968**

**1972**

**1976**

**1980**

**1984**

**1988**

**1992**

**1996**

**0**

**5**

**10**

**15**

**20**

**25**

**30**

**35**

**Hospitalization Rates ****(per 100,000 person - years)**

## Rates of Meningococcal Disease in College Students, U.S., 9/1/98 - 6/30/99

**	****	****	****	****Rates/****Groups****	****# Cases****	****Population****	****100,000**
**All 18-23 year olds****	****304****	****22,070,535****	****1.4**
**College Students****	****90****	****14,897,268****	****0.6**
**Undergraduates****	****87****	****12,771,228****	****0.7**
**Freshmen Students****	****40****	****2,285,001****	****1.9**
**Dormitory Residents****	****45****	****2,085,618****	****2.3**
**Freshmen Living****	****in Dormitories****	****27****	****591,587****	****5.1**

- 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). *MMWR*. 2000;49(RR-7);1-20.
- Updated in: Bruce MG et al [CDC]. Risk Factors for Meningococcal Disease in College Students. *JAMA*. 2001;286:688-693.

## Presentation Outline

**Clinical Challenge of Meningococcal Disease**
**Current U.S. Epidemiology**
**Current UK and European Epidemiology**
**Benefits of Conjugate Vaccines**
**UK Experience with C Conjugate Meningococcal Vaccines**
**Epidemiology Summary**

## European and U.S. Meningococcal Serogroup Distribution 

**Europe**

- European and U.S. Meningococcal Serogroup Distribution

**B = 63%**

**C = 32%**

**Y = 1%**

**U.S.**

**1998-2002**

**1997-2003**

**C = 24%**

**W135 + Other =****14%**

**B = 34%**

**Y = 28%**

**W-135 + Other = 4%**

**European Union Invasive Bacterial Infections Surveillance Network. 2002.**

## Carriage Rates of N. meningitidisCollege Freshmen, Nottingham University, UK, 1997

**Neal KR, et al. *****BMJ.***** 2000;320:846-49.**

**0**

**5**

**10**

**15**

**20**

**25**

**30**

**35**

**Day 1**

**Day 2**

**Day 3**

**Day 4**

**Month 1**

**Month 2**

**Time**

**Carriage Rate (%)**

## Presentation Outline

**Clinical Challenge of Meningococcal Disease**
**Current U.S. Epidemiology**
**Current UK and European Epidemiology**
**Benefits of Conjugate Vaccines**
**UK Experience with C Conjugate Meningococcal Vaccines**
**Epidemiology Summary**

## Conjugate vs. Polysaccharide Vaccines

**T-cell-dependent ****immune response****	****No****	****Yes**
**	****Immune memory****	****No****	****Yes**
**	****Persistence of protection****	****No****	****Yes**
**	****Booster effect****	****No****	****Yes**
**	****Reduction of carriage****	****No****	****Yes**
**	****Herd immunity****	****No****	****Yes**
**	****Lack of hyporesponsiveness****	****No****	****Yes**

**Granoff, DM et al. In: Plotkin SA, ed. *****Vaccines*****. 4th ed. Philadelphia: W.B. Saunders Co;2004.**

## Conjugate vs. Polysaccharide Vaccines

**T-cell-dependent ****immune response****	****No****	****Yes**
**	****Immune memory****	****No****	****Yes**
**	****Persistence of protection****	****No****	****Yes**
**	****Booster effect****	****No****	****Yes**
**	****Reduction of carriage****	****No****	****Yes**
**	****Herd immunity****	****No****	****Yes**
**	****Lack of hyporesponsiveness****	****No****	****Yes**

**Granoff, DM et al. In: Plotkin SA, ed. *****Vaccines*****. 4th ed. Philadelphia: W.B. Saunders Co;2004.**

## Presentation Outline

**Clinical Challenge of Meningococcal Disease**
**Current U.S. Epidemiology**
**Current UK and European Epidemiology**
**Benefits of Conjugate Vaccines**
**UK Experience with C Conjugate Meningococcal Vaccines**
**Epidemiology Summary**

## Meningococcal Serogroup C-conjugate Vaccine

**Licensed in the United Kingdom in 1999–2000**
**Initially introduced in 15- to 17-year-olds, as they displayed highest mortality rates**
**Younger age groups sequentially added**
**C-conjugate subsequently introduced in Spain, Ireland, Belgium, Netherlands, Canada, ****and Australia**

## Laboratory Confirmed Cases of Serogroup C Meningococcal Disease, England and WalesCumulative Cases Ages 15 to 17

**Week Number (total from mid-year)**

**Number of Cases**

**Immunization with serogroup C**
**conjugate vaccine in 15- to 17-year-olds**
**began on Nov 1, 1999**

**100**

**150**

**50**

**1**

**5**

**10**

**15**

**20**

**25**

**30**

**35**

**40**

**45**

**50**

**0**

**Health Protection Agency Website. Available at: www.hpa.org.uk/infections/topics_az/meningo/graph_meni-groupC.htm.**

**Before**

**After**

**During**

## Reductions in C-Disease in UK After Nationwide Immunization with Conjugate Vaccine

**Miller E, et al. *****Vaccine.***** 2002;20:S58.**

**	****Age Group****	****Cases****	****Cases****	****Reduction****	****(years)****	****1998/1999****	****2000/2001 ****	****(%)**
**	****< 1****	****81****	****14****	****83**
**	****1 - 2****	****119****	****25****	****81**
**	****3 - 4****	****67****	****14****	****80**
**	****5 - 9****	****75****	****27****	****64**
**	****10 - 14****	****74****	****8****	****89**
**	****15 - 17****	****121****	****15****	****88**
**	****Total****	****537****	****103****	****81**

## Group C: Carriage of Meningococci in 15 to 17 Year-old School Children in the UK

**decrease,*****P***** = 0.001**

- Group C: Carriage of Meningococci in 15 to 17 Year-old School Children in the UK

**% with Meningococci**

**Capsular****	****1999****	****2000****	****Ratio****Group****	****(N = 14,064)****	****(N = 16,583)****	****2000:1999**
**B****	****4.11****	****4.14****	****1.01**
**C****	****0.45****	****0.15****	****0.34**
**Y****	****0.97****	****1.05****	****1.09**
**W-135****	****1.12****	****1.42****	****1.27**
**Not groupable****	****10.05****	****11.22****	****1.12****or other groups**

**Maiden MCJ, et al. *****Lancet*****. 2002;359:1829-30.**

## Herd Immunity: Serogroup C Attack Rates in Unvaccinated Children Before and After UK Program

**Ramsay ME, et al. *****BMJ*****. 2003;326:365.**

**	****July 1998–June****	****July 2001–June****	****1999 Attack****	****2002 Attack****	****% Reduction****Cohort****	****Rate/100,000****	****Rate/100,000****	****in Unvaccinated**
**Infants****	****7.49****	****1.56****	****79**
**Toddlers****	****6.82****	****2.05****	****70**
**Preschool****	****3.94****	****1.20****	****70**
**Grades 1 – 6 ****	****1.94****	****1.00****	****48**
**Grades 7 – 10****	****5.54****	****1.11****	****80**
**Older adolescents ****	****5.28****	****1.79****	****66**

## Meningococcal Polysaccharide Vaccine, A,C,Y, W-135 Combined (Menomune)

**Licensed since 1982 – ages 2 and above**
**Indicated for travelers, occupational exposure, college students in dormitories, immune compromised persons and military recruits**
**85% to 87% effective in multiple outbreak studies***
**Excellent safety profile**
**More than 20 million doses have been administered in U.S.**

***Menomume package insert.**

## Expected Attributes of Menactra Vaccine in the U.S.

**Persistence of protective antibody**
**Ability to prime and boost**
**Booster dose not associated with hyporesponsiveness**
**Reduction in carriage**
**Herd immunity**
**Replicate the UK experience in the U.S.**

## N. meningitidis: The Next Focus for Bacterial Meningitis Prevention in the U.S.

**2004 and beyond**

**Mid 1990s to****early 2000s**

**1980 to mid 1990s**

***H influenzae***** type b (Hib) disease virtually eliminated**

**Pneumococcal disease drastically reduced**

**Meningococcal disease now most frequent cause of bacterial meningitis in children, adolescents,****and young adults**

## Presentation Outline

**Clinical Challenge of Meningococcal Disease**
**Current U.S. Epidemiology**
**Current UK and European Epidemiology**
**Benefits of Conjugate Vaccines**
**UK Experience with C Conjugate Meningococcal Vaccines**
**Epidemiology Summary**

## Meningococcal Disease Epidemiology Summary

**Serious and challenging public health problem**
**Adolescents and young adults at high risk **
**C conjugate vaccine largely eradicated serogroup C disease in UK **
**Menactra has potential to prevent up to 70% of disease in U.S. adolescents if used as part of universal immunization program targeting persons aged 11 to 18**

## Menactra - Agenda

**Introduction****	****Luc Kuykens, MD, MPH****	****VP Regulatory Affairs**
**Epidemiology****	****Greg Gilmet, MD, MPH****	****Director Scientific & Medical Affairs**** **
**Immunogenicity****	****Michael Decker, MD, MPH****	****VP Scientific & Medical Affairs**
**Safety****	****Gary Chikami, MD****	****Senior Director Regulatory Affairs**
**Conclusions****	****Luc Kuykens, MD, MPH****	****VP Regulatory Affairs**

## Presentation Outline

**Basis for Licensure: Non-inferiority**
**Measuring Immunogenicity**
**Overview of the Clinical Trials**
**Comparative Trials in Adolescents**
**Comparative Trials in Adults**
**Trials of Concomitant Administration**

## Basis for Licensure:Non-Inferiority of Menactra vs. Menomune

**"Non-inferiority" - statistical approach commonly used when standard of care exists (ie, Menomune) **
**“****Non-inferiority threshold”**
**Set at agreed margin (delta) compared to the standard**
**Chosen to exclude clinically important differences within a practical sample size**
**If non-inferior, the new intervention is considered an acceptable alternative**
**The evaluation of Menactra involved demonstrating its non-inferiority to Menomune **

## Measuring Immunogenicity

**Antibody Measurements**
**Common clinical assays measure antibody quantity**
**Examples: ELISA, RIA, etc.**
**Functional assays measure antibody performance**
**Less common, often more difficult to perform**
**Examples: Serum bactericidal antibody (SBA), CHO cell assay, etc.**

## Evidence for the Importance of Bactericidal Antibodies in Meningococcal Disease

**Gotschlich et al, Fort Dix study: serogroup C disease occurred only in individuals lacking bactericidal antibodies****1**
**SBA titers ******** 1:4 correlated strongly with protection **
**Serum bactericidal activity could be absorbed with the group-specific capsular polysaccharide**

| Number of Recruits | Bactericidal Titer at Baseline | Number of Cases | Attack Rate/1000 (8 weeks) | Percent Protective Effect |
| --- | --- | --- | --- | --- |
| 12,073 (82%)* |  1:4 | 3 | 0.3 | 98.4% |
| 2,668 (18%)* | < 1:4 | 51 | 19.1 |  |

**1****Goldschneider I, Gotschlich EC, and Artenstein MS. *****J. Exp Med.***** 1969;129:1307-1326.**

***Based on bactericidal titer determinations of 540 non-case controls**

## Measuring Immunogenicity Regulatory Perspective – Correlate of Protection

**1999 VRBPAC Conclusions:**
**Immunological data can be used to predict efficacy of meningococcal vaccines for populations for whom the current polysaccharide vaccine ****is licensed**
**Bactericidal activity may be used as a measure of functional antibody and, therefore, presumed protective activity**
**Total antibody measured by ELISA techniques cannot be used as a serologic correlate for functional bactericidal antibody**

## Measuring Immunogenicity

**We will present SBA results**
**Standard approach for meningococcal assays**
**Directly relevant to protection from infection**
**Basis for licensure of Menomune**
**Assay conforms to WHO and CDC standards**
**Aventis Pasteur participated in the interlaboratory collaborative study – assay is fully validated**
**Assay uses baby rabbit complement**
**Difficulties with human complement**
**Consistency**
**Availability**
**Standardization**

## Measuring Immunogenicity

**Immunological End-Points**
**4-Fold Rise**
**% of those whose post-immunization titers are at least 4 times their pre-immunization titers**
**Basis for Menomune licensure**
**Primary (non-inferiority) outcome measure in all Menactra core clinical trials **
**Geometric Mean Titers**
**Normalized average of the post-immunization titers**
**Co-primary outcome measure in some of the core clinical trials; descriptive in others **

## Measuring Immunogenicity (2)

**Immunological End-Points**
**Seroconversion Rates**
**% of those initially seronegative (less than 1:8) who have a 4-fold or greater rise**
**Descriptive only **
**Reverse Cumulative Distribution Curves**
**Graphical presentation of the antibody distribution of the entire studied population**
**Descriptive only **

## Overview of Menactra Clinical Trials (Ages 11 to 55)

**Trial****Number****	****Type of Study****	****Study Groups****	****Ages (yrs)****	****Menactra****	****Menomune**

**MTA02****	****Safety &****	****Menactra vs.****	**** 11 to 18 ****	**** 440****	****441****	****Immunogenicity****	****Menomune****	**

**MTA19****	****3 yr. Follow Up****	****Menactra vs.****	****13 to 21****	****241****	****-**
**	****Menactra ****	****Menomune****	****Revaccination****	****vs. naïve**

**MTA04****	****Safety****	****Menactra vs.****	****11 to 18 ****	****2,270****	****972 ****	****Comparison****	****Menomune ****	**

**MTA09****	****Safety &****	****Menactra vs. ****	****18 to 55 ****	****1,384****	****1,170 ****	****Immunogenicity****	****Menomune****	**

**MTA14****	****Safety &****	****Menactra vs. ****	****18 to 55 ****	****1,582****	****458 ****	****Lot Consistency ****	****Menomune****	**

## Overview of Menactra Clinical Trials (Ages 11 to 55)

**Trial****Number****	****Type of Study****	****Study Groups****	****Ages (yrs)****	****Menactra****	****Menomune**

**Total For All Trials Combined (ages 11 to 55)****	****	****7,642****	****       3,041**

**MTA12****	****Safety &****	****Menactra + Td ****	****11 to 17****	****509****	****None ****	****Immunogenicity****	****  vs.****	****	****	****	****of Concomitant****	****Menactra 1 mo****	****	****512****	****	****Administration****	****after Td****	****	****Total 1,021****	**

**MTA11****	****Safety &****	****Menactra + ****	****18 to 55 ****	****469****	****None ****	****Immunogenicity ****	****Typhim Vi ****	****of Concomitant****	****  vs.****	****	****476****	****	****Administration****	****Menactra 1 mo****	****	****	****	****	****after Typhim Vi****	****	****Total 945**

## Distribution of Clinical Trial Study Populations By Gender and Race/Ethnicity

**Gender**
**   ****Male****	****51.4****	****36.3****	****43.6**
**   ****Female****	****48.6****	****63.7****	****56.4**
**Race/Ethnicity**
**   ****White, non-Hispanic****	****90.5****	****82.5****	****86.2**
**   ****Black, non-Hispanic****	****4.9****	****6.9****	****6.0**
**   ****Hispanic****	****2.5****	****6.7****	****4.7**
**   ****Asian****	****0.9****	****2.5****	****1.8**
**   ****Other****	****1.2****	****1.4****	****1.3**

## Measuring Immunogenicity 

**Results to be Presented**
**MTA02: Comparative trial in adolescents**
**MTA19: Three-year follow-up trial in adolescents**
**MTA09: Comparative trial in adults**
**MTA14: Lot-consistency trial in adults**
**MTA12: Concomitant Menactra and Td in ****	****adolescents **
**MTA11: Concomitant Menactra and Typhim Vi ****	****	****in adults**

## MTA02: Clinical Trial in Adolescents

**Multi-center, randomized, comparative clinical trial in US adolescents**
**Participants: 881 healthy 11 to 18 year-olds**
**440 given one i.m. dose of Menactra protein conjugate**
**441 given one s.c. dose of Menomune polysaccharide**
**Evaluated safety and immunogenicity**
**Hypothesis: short-term immune response not inferior to Menomune**

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

| Menactra | 392 of 423       92.7% | 388 of 423       91.7% | 346 of 423       81.8% | 409 of 423      96.7% |
| --- | --- | --- | --- | --- |
| Menomune | 391 of 423       92.4% | 375 of 423       88.7% | 339 of 423       80.1% | 403 of 423         95.3 % |

**0**

**20**

**40**

**60**

**80**

**100**

**Percentage**

**A**

**C**

**Y**

**W-135**

## MTA02: Non-inferiority Testing of 4-Fold Rises95% CI of Difference (Menomune - Menactra)

- MTA02: Non-inferiority Testing of 4-Fold Rises95% CI of Difference (Menomune - Menactra)

**Serogroup A**

**Within Limit**

**Outside Limit**

**-8**

**-7**

**-6**

**-5**

**-4**

**-3**

**-2**

**-1**

**0**

**1**

**2**

**3**

**4**

**5**

**6**

**7**

**8**

**9**

**10**

**-0.24**

**Serogroup C**

**Serogroup Y**

**Serogroup W-135**

**-3.07**

**-1.65**

**-1.42**

**11**

**12**

**13**

**14**

**15**

**All non-inferiority criteria met**

## MTA02: Geometric Mean Titers at Day 28 by Serogroup in Adolescents  

**0**

**1000**

**2000**

**3000**

**4000**

**5000**

**6000**

**A**

**C**

**Y**

**W-135**

- MTA02: Geometric Mean Titers at Day 28 by Serogroup in Adolescents

| Menactra | 5483 | 1924 | 1322 | 1407 |
| --- | --- | --- | --- | --- |
| Menomune | 3246 | 1639 | 1228 | 1545 |

## MTA02: RCD Curves of Day 0 and Day 28 SBA Titers in Adolescents – Serogroup A

**SBA Antibody Titers for Meningococcal Serogroup A**

**Participants (%)**

**0**

**20**

**40**

**60**

**80**

**100**

## MTA02: RCD Curves of Day 0 and Day 28 SBA Titers in Adolescents – Serogroup C

**SBA Antibody Titers for Meningococcal Serogroup C**

**4**

**16**

**64**

**1024**

**4096**

**16,384**

**65,536**

**256**

**262,144**

**8**

**32**

**128**

**0**

**20**

**40**

**60**

**80**

**100**

**Participants (%)**

## MTA02: RCD Curves of Day 0 and Day 28 SBA Titers in Adolescents – Serogroup Y

**SBA Antibody Titers for Meningococcal Serogroup Y**

**0**

**20**

**40**

**60**

**80**

**100**

**Participants (%)**

## MTA02: RCD Curves of Day 0 and Day 28 SBA Titers in Adolescents – Serogroup W-135

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

**0**

**20**

**40**

**60**

**80**

**100**

**Participants (%)**

## Measuring Immunogenicity

**Results to be Presented**
**MTA02: Comparative trial in adolescents**
**MTA19: Three-year follow-up trial in adolescents**
**MTA09: Comparative trial in adults**
**MTA14: Lot-consistency trial in adults**
**MTA12: Concomitant Menactra and Td in ****	****adolescents **
**MTA11: Concomitant Menactra and Typhim Vi ****	****	****in adults**

## MTA19: Menactra Booster in Adolescents

**Three-year follow up and reimmunization of a subset of participants from trial MTA02**
**Participants: 241 healthy 14 to 21 year-olds**
**76 participants with prior Menactra immunization**
**77 participants with prior Menomune immunization**
**88 age-matched naïve participants**
**Intervention: one dose of Menactra**
**Objectives: **
**Evaluate persistence of antibody over 3-year interval**
**Evaluate ability of Menactra to prime and to boost**
**Evaluate response of Menomune recipients to Menactra**

## MTA19: SBA GMTs of a Subset of ParticipantsDuration of Response at 3 Years Post Vaccination

- MTA19: SBA GMTs of a Subset of ParticipantsDuration of Response at 3 Years Post Vaccination

**0**

**200**

**400**

**600**

**800**

**1000**

**1200**

**A**

**C**

**Y**

**W-135**

**Serogroup**

**SBA GMT**

**0**

**1000**

**2000**

**3000**

**4000**

**5000**

**6000**

**A**

**C**

**Y**

**W**

**-**

**135**

**Menactra**

**Menomune**

**SBA GMT**

## MTA19: SBA GMTs of a Subset of ParticipantsDuration of Response at 3 Years Post Vaccination

***P***** < 0.001**

***P***** < 0.001**

***P***** = 0.12**

***P***** = 0.12**

**0**

**200**

**400**

**600**

**800**

**1000**

**1200**

**A**

**C**

**Y**

**W-135**

**Serogroup**

**SBA GMT**

## MTA19: SBA GMTs of a Subset of ParticipantsDuration of Response at 3 Years Post Vaccination

**Age-matched Naïve**

**0**

**200**

**400**

**600**

**800**

**1000**

**1200**

**SBA GMT**

**A**

**C**

**Y**

**W-135**

**Serogroup**

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

**Participants (%)**

**100**

**SBA Antibody Titers for Meningococcal Serogroup A**

**0**

**20**

**40**

**60**

**80**

**4**

**16**

**64**

**1024**

**4096**

**16,384**

**65,536**

**256**

**262,144**

**Group:**

**PW Menomune at Day 0**

**PW Menactra at Day 0**

**Naïve at Day 0**

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

**Participants (%)**

**100**

**SBA Antibody Titers for Meningococcal Serogroup C**

**0**

**20**

**40**

**60**

**80**

**4**

**16**

**64**

**1024**

**4096**

**16,384**

**65,536**

**256**

**262,144**

**Group:**

**PW Menomune at Day 0**

**PW Menactra at Day 0**

**Naïve at Day 0**

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

**Participants (%)**

**100**

**SBA Antibody Titers for Meningococcal Serogroup Y**

**0**

**20**

**40**

**60**

**80**

**4**

**16**

**64**

**1024**

**4096**

**16,384**

**65,536**

**256**

**262,144**

**Group:**

**PW Menomune at Day 0**

**PW Menactra at Day 0**

**Naïve at Day 0**

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

**100**

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

**0**

**20**

**40**

**60**

**80**

**4**

**16**

**64**

**1024**

**4096**

**16,384**

**65,536**

**256**

**262,144**

**Group:**

**PW Menomune at Day 0**

**PW Menactra at Day 0**

**Naïve at Day 0**

## MTA19: Geometric Mean Titers Before and After 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**

## MTA19: Geometric Mean Titers Before and After Menactra, Menactra-Primed vs. Naïve – Serogroup Y 

**Menactra**

**0**

**2000**

**4000**

**6000**

**8000**

**10000**

**12000**

**14000**

**Pre-boost**

**Post-boost 8**

**Post-boost 28**

**Menactra**

**Naïve Control**

## MTA19: Geometric Mean Titers Before and After Menactra, Menactra-Primed vs. Naïve – Serogroup W-135 

**Menactra**

**0**

**2000**

**4000**

**6000**

**8000**

**10000**

**12000**

**Pre-boost**

**Post-boost 8**

**Post-boost 28**

**Menactra**

**Naïve Control**

## MTA19: Geometric Mean Titers Before and After Menactra, Menactra-Primed vs. Naïve – Serogroup A 

**Menactra**

**0**

**2000**

**4000**

**6000**

**8000**

**10000**

**12000**

**14000**

**Pre-boost**

**Post-boost 8**

**Post-boost 28**

**Menactra**

**Naïve Control**

## MTA19: SBA Primary Immunization with Menomune and Reimmunization with Menactra – C 

- MTA19: SBA Primary Immunization with Menomune and Reimmunization with Menactra – C

**Pre-V1**

**V1 + 28d**

**0**

**500**

**1000**

**1500**

**2000**

**2500**

**3000**

**Pre-V2**

**V2 + 8d**

**V2 + 28d**

**Menomune**

- Three
- Years

**Menactra after Menomune**

## MTA19: SBA Primary Immunization with Menomune and Reimmunization with Menactra – A 

- MTA19: SBA Primary Immunization with Menomune and Reimmunization with Menactra – A

**Menomune**

**0**

**500**

**1000**

**1500**

**2000**

**2500**

**3000**

**3500**

**4000**

**4500**

**5000**

**Pre-V1**

**V1 + 28d**

- Three
- Years

**Pre-V2**

**V2 + 8d**

**V2 + 28d**

**Menactra after Menomune**

## MTA19: SBA Primary Immunization with Menomune and Reimmunization with Menactra – Y 

- MTA19: SBA Primary Immunization with Menomune and Reimmunization with Menactra – Y

**0**

**500**

**1000**

**1500**

**2000**

**2500**

**3000**

**3500**

**Pre-V1**

**V1 + 28d**

**Pre-V2**

**V2 + 8d**

**V2 + 28d**

- Three
- Years

**Menomune**

**Menactra after Menomune**

**Notes:**
104; 1162; 364; 2910; 2353

## MTA19: SBA Primary Immunization with Menomune and Reimmunization with Menactra – W-135

**0**

**500**

**1000**

**1500**

**2000**

**2500**

**Pre-V1**

**V1 + 28d**

**Pre-V2**

**V2 + 8d**

**V2 + 28d**

**Menactra after Menomune**

- Three
- Years

**Menomune**

## MTA19: Summary and Conclusions

**Superior persistence of antibody **
**At 3 years, Menactra SBA GMTs are higher than seen following Menomune or in naïve controls **
**Ability of Menactra to prime and to boost**
**Rapid, high anamnestic response, far exceeding response of naïve controls, demonstrates priming, memory, and boosting**
**Response of Menomune recipients to Menactra**
**Prior Menomune recipients given Menactra demonstrate a rapid increase in bactericidal antibody, to levels exceeding those that would be expected if reimmunized with Menomune**
**Conclusion: Menactra demonstrates the important immunologic characteristics expected of a ****conjugate vaccine**

## Measuring Immunogenicity 

**Results to be Presented**
**MTA02: Comparative trial in adolescents**
**MTA19: Three-year follow-up trial in adolescents**
**MTA09: Comparative trial in adults**
**MTA14: Lot-consistency trial in adults**
**MTA12: Concomitant Menactra and Td in ****	****adolescents **
**MTA11: Concomitant Menactra and Typhim Vi ****	****	****in adults**

## MTA09: Clinical Trial in Adults

**Multi-center, randomized, comparative clinical trial in adults**
**Participants: 2,554 healthy 18 to 55 year-olds**
**1,384 given one i.m. dose of Menactra protein conjugate**
**1,170 given one s.c. dose of Menomune polysaccharide**
**Evaluated safety and immunogenicity**
**Hypothesis: short-term immune response not inferior to Menomune**

## MTA09: 4-Fold Rises in SBA Titer by Serogroup in Adults

| Menactra | 1030 of 1280    80.5% | 1133 of 1280    88.5% | 941 of 1280     73.5% | 1144 of 1280    89.4% |
| --- | --- | --- | --- | --- |
| Menomune | 929 of 1098      84.6% | 985 of 1098     89.7% | 872 of 1098     79.4% | 1036 of 1098    94.4% |

**0**

**20**

**40**

**60**

**80**

**100**

**A**

**C**

**Y**

**W-135**

**Percentage**

**Menactra**

**Menomune **

## MTA09: Non-inferiority Testing of 4-Fold Rises 95% CI of Difference (Menomune – Menactra)

**Within Limit**

**Outside Limit**

**-2**

**-1**

**0**

**1**

**2**

**3**

**4**

**5**

**6**

**7**

**8**

**9**

**10**

**4.1**

**Serogroup C**

**Serogroup Y**

**Serogroup W-135**

**1.2**

**5.9**

**5.0**

**11**

**12**

**13**

**14**

**15**

- MTA09: Non-inferiority Testing of 4-Fold Rises 95% CI of Difference (Menomune – Menactra)

**All non-inferiority criteria met**

## MTA09: Geometric Mean Titers at Day 28 by Serogroup in Adults

**0**

**500**

**1000**

**1500**

**2000**

**2500**

**3000**

**3500**

**4000**

**4500**

**Geometric****Mean Titer**

**A**

**C**

**Y**

**W-135**

| Menactra | 3897 | 3231 | 1750 | 1271 |
| --- | --- | --- | --- | --- |
| Menomune | 4114 | 3469 | 2449 | 1871 |

## MTA09: Non-Inferiority Testing of the Ratio of GMTs* 95% CI of the Ratio (Menomune/Menactra) 

**Serogroup A**

**Within Limit**

**Outside Limit**

**0.50**

**0.75**

**1.00**

**1.25**

**1.50**

**1.75**

**2.00**

**2.25**

**2.50**

**1.07**

**Serogroup C**

**Serogroup Y**

**Serogroup W-135**

**1.10**

**1.50**

**1.39**

- MTA09: Non-Inferiority Testing of the Ratio of GMTs* 95% CI of the Ratio (Menomune/Menactra)

**All non-inferiority criteria met**

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

## MTA09: RCD Curves of Day 0 and Day 28 SBA Titers in Adults – Serogroup C

**Participants (%)**

**SBA Antibody Titers for Meningococcal Serogroup C**

**4**

**16**

**64**

**1024**

**4096**

**16,384**

**65,536**

**256**

**262,144**

**0**

**20**

**40**

**60**

**80**

**100**

**8**

**32**

**128**

## MTA09: RCD Curves of Day 0 and Day 28 SBA Titers in Adults – Serogroup A

**SBA Antibody Titers for Meningococcal Serogroup A**

**0**

**20**

**40**

**60**

**80**

**100**

**4**

**16**

**64**

**1024**

**4096**

**16,384**

**65,536**

**256**

**262,144**

**8**

**32**

**128**

## MTA09: RCD Curves of Day 0 and Day 28 SBA Titers in Adults – Serogroup Y

**0**

**20**

**40**

**60**

**80**

**100**

**4**

**16**

**64**

**1024**

**4096**

**16,384**

**65,536**

**256**

**262,144**

**8**

**32**

**128**

**SBA Antibody Titers for Meningococcal Serogroup Y**

## MTA09: RCD Curves of Day 0 and Day 28 SBA Titers in Adults – Serogroup W-135

**0**

**20**

**40**

**60**

**80**

**100**

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

**4**

**16**

**64**

**1024**

**4096**

**16,384**

**65,536**

**256**

**262,144**

**8**

**32**

**128**

## Measuring Immunogenicity 

**Results to be Presented**
**MTA02: Comparative trial in adolescents**
**MTA19: Three-year follow-up trial in adolescents**
**MTA09: Comparative trial in adults**
**MTA14: Lot-consistency trial in adults**
**MTA12: Concomitant Menactra and Td in ****	****adolescents **
**MTA11: Concomitant Menactra and Typhim Vi ****	****in adults**

## MTA14: Lot-Consistency Trial in Adults

**Multi-center, randomized, lot-consistency and comparative clinical trial in US adults**
**Participants: 2,040 healthy 18 to 55 year-olds**
**1582 given one i.m. dose of Menactra protein conjugate (divided evenly among 3 vaccine lots)**
**458 given one s.c. dose of Menomune polysaccharide**
**Evaluated immunogenicity (lot consistency) and safety (in 26 to 55 year-olds)**
**Hypothesis: equivalence of three Menactra lots (maximum ratio, 1.5)**

## MTA14: Geometric Mean Titers at Day 28 by Serogroup in Adults

| Menactra Lot 1 | 8169 | 3868 | 2898 | 2031 |
| --- | --- | --- | --- | --- |
| Menactra Lot 2 | 8215 | 4155 | 2472 | 2573 |
| Menactra Lot 3 | 6679 | 3217 | 3805 | 2457 |

**0**

**1000**

**2000**

**3000**

**4000**

**5000**

**6000**

**7000**

**8000**

**9000**

**Menactra Lot 1**

**Menactra Lot 2**

**Menactra Lot 3**

## 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) 

- 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)

**Within Limit**

**Outside Limit**

**1.5**

**1.75**

**2.00**

**1.01**

**Serogroup A**

**Lot 1/2**

**Lot 1/3**

**Lot 2/3**

**Serogroup C**

**Serogroup Y**

**Serogroup W-135**

**Outside Limit**

**.66**

**.50**

**.25**

**1.23**

**Lot 1/2**

**Lot 1/3**

**Lot 2/3**

**Lot 1/2**

**Lot 1/3**

**Lot 2/3**

**Lot 1/2**

**Lot 1/3**

**Lot 2/3**

**1.22**

**0.89**

**1.22**

**1.37**

**0.79**

**1.02**

**0.73**

**1.09**

**0.67**

**0.81**

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

## MTA14: RCD Curves of Day 0 and Day 28 SBA Titers in Adults – Serogroup A

**SBA Antibody Titers for Meningococcal Serogroup A**

**Group:**

**Participants (%)**

**0**

**20**

**40**

**60**

**80**

**100**

**4**

**16**

**64**

**1024**

**4096**

**16,384**

**65,536**

**256**

**262,144**

## MTA14: RCD Curves of Day 0 and Day 28 SBA Titers in Adults – Serogroup C

**Group:**

**Participants (%)**

**0**

**20**

**40**

**60**

**80**

**100**

**4**

**16**

**64**

**1024**

**4096**

**16,384**

**65,536**

**256**

**262,144**

**SBA Antibody Titers for Meningococcal Serogroup C**

## MTA14: RCD Curves of Day 0 and Day 28 SBA Titers in Adults – Serogroup Y

**Group:**

**Participants (%)**

**0**

**20**

**40**

**60**

**80**

**100**

**4**

**16**

**64**

**1024**

**4096**

**16,384**

**65,536**

**256**

**262,144**

**SBA Antibody Titers for Meningococcal Serogroup Y**

## MTA14: RCD Curves of Day 0 and Day 28SBA Titers in Adults – Serogroup W-135

**Participants (%)**

**0**

**20**

**40**

**60**

**80**

**100**

**4**

**16**

**64**

**1024**

**4096**

**16,384**

**65,536**

**256**

**262,144**

**Group:**

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

## MTA14: Summary of Results for the Consistency Lots By Serogroup

| Serogroup | Lot | GMT | % 4-Fold | %  128 |
| --- | --- | --- | --- | --- |
| A | 1 | 8169 | 85 | 100 |
|  | 2 | 8215 | 85 | 100 |
|  | 3 | 6679 | 82 | 100 |
| C | 1 | 3868 | 86 | 97 |
|  | 2 | 4155 | 89 | 99 |
|  | 3 | 3217 | 83 | 97 |
| Y | 1 | 2898 | 75 | 99 |
|  | 2 | 2472 | 72 | 98 |
|  | 3 | 3805 | 81 | 98 |
| W-135 | 1 | 2031 | 86 | 97 |
|  | 2 | 2573 | 88 | 96 |
|  | 3 | 2457 | 92 | 98 |

## Measuring Immunogenicity 

**Results to be Presented**
**MTA02: Comparative trial in adolescents**
**MTA19: Three-year follow-up trial in adolescents**
**MTA09: Comparative trial in adults**
**MTA14: Lot-consistency trial in adults**
**MTA12: Concomitant Menactra and Td in ****	****adolescents**** **
**MTA11: Concomitant Menactra and Typhim Vi ****	****in adults**

## MTA12: Concomitant Menactra and Td Clinical Trial in Adolescents

**Multi-center, randomized, comparative clinical trial in US adolescents**
**Participants: 1,021 healthy 11 to 17 year-olds**
**509 given Menactra + Td followed 28 days later ****by placebo**
**512 given Td + placebo followed 28 days later ****by Menactra**
**Evaluated safety and immunogenicity**
**Hypothesis: concomitant administration is not inferior to sequential administration**

## MTA12: 4-Fold Rise in SBA Titer by Serogroup

**0**

**20**

**40**

**60**

**80**

**100**

**A**

**C**

**Y**

**W-135**

**Menactra + Td **

**Menactra 28 days after Td**

| Menactra + Td | 419 of 465
(90.1%) | 424 of 465
(91.2%) | 399 of 465
(85.8%) | 448 of 465
(96.3%) |
| --- | --- | --- | --- | --- |
| Menactra 28 days after Td | 433 of 478
(90.6%) | 394 of 478
(82.4%) | 311 of 478
(65.1%) | 419 of 478
(87.7%) |

**Percentage**

## MTA12: Non-inferiority Testing of 4-Fold Rises95% CI of the Difference (Sequential - Simultaneous)

**Within Limit**

**Outside Limit**

**-30**

**-25**

**-20**

**-15**

**-10**

**-5**

**0**

**5**

**10**

**0.48**

**Serogroup C**

**Serogroup Y**

**Serogroup W-135**

**-8.76**

**-20.74**

**-8.69**

**15**

- MTA12: Non-inferiority Testing of 4-Fold Rises95% CI of the Difference (Sequential - Simultaneous)

**All non-inferiority criteria met**

**20**

**25**

## MTA12: Geometric Mean Titers Level Comparison 28 Days Post Menactra Vaccination

**1**

**10**

**100**

**1000**

**10000**

**100000**

**Menactra + Td**

**Geometric Mean Titer****(log scale)**

**A**

**C**

**Y**

**W-135**

| Menactra + Td | 11,313 | 5059 | 3391 | 4195 |
| --- | --- | --- | --- | --- |
| Menactra 28 days after Td | 10,391 | 2136 | 1331 | 1339 |

## MTA12: Geometric Mean Titers 28 Days Post Menactra Vaccination

| MTA02 | 5483 | 1924 | 1322 | 1407 |
| --- | --- | --- | --- | --- |
| Menactra + Td | 11,313 | 5059 | 3391 | 4195 |
| Menactra 28 days after Td | 10,391 | 2136 | 1331 | 1339 |

**1**

**10**

**100**

**1000**

**10000**

**100000**

**A**

**C**

**Y**

**W-135**

**Menactra + Td**

**Menactra 28 days after Td**

**Geometric Mean Titer****(log scale)**

## MTA12: Percent Tetanus Antibody Response

| 2-Fold (Pre-titer > 2.7 IU/mL) | 18/49
(36.7%) | 17/45
(37.8%) |
| --- | --- | --- |
| 4-Fold (Pre-titer  2.7 IU/mL) | 391/413
(94.7%) | 408/426
(95.8%) |
| Total Responders | 409/462
(88.5%) | 425/471
(90.2%) |

**Menactra + Td**

**Td + Placebo**

**2-Fold Responders**

**4-Fold Responders**

**Total Responders**

**Percentage**

**0**

**20**

**40**

**60**

**80**

**100**

## MTA12: Percent Diphtheria Antibody Response

**Menactra + Td**

**Td + Placebo**

**0**

**20**

**40**

**60**

**80**

**100**

**Percentage**

**2-Fold Responders**

**4-Fold Responders**

**Total Responders**

| 2-Fold (Pre-titer > 2.56 IU/mL) | 8/8
(100.0%) | 7/13
(53.9%) |
| --- | --- | --- |
| 4-Fold (Pre-titer  2.56 IU/mL) | 454/456
(99.6%) | 439/458
(95.9%) |
| Total Responders | 462/464
(99.6%) | 446/471
(94.7%) |

## MTA12: Non-Inferiority Testing of Response Rates 95% CI of the Difference (Sequential - Simultaneous)

**Tetanus**

**Within Limit**

**Outside Limit**

**-8**

**-7**

**-6**

**-5**

**-4**

**-3**

**-2**

**-1**

**0**

**1**

**2**

**3**

**4**

**5**

**6**

**7**

**8**

**9**

**10**

**1.71**

**Diphtheria**

**-4.88**

**11**

**12**

**13**

**14**

**15**

**All non-inferiority criteria met**

## Measuring Immunogenicity 

**Results to be Presented**
**MTA02: Comparative trial in adolescents**
**MTA19: Three-year follow-up trial in adolescents**
**MTA09: Comparative trial in adults**
**MTA14: Lot-consistency trial in adults**
**MTA12: Concomitant Menactra and Td in ****	****adolescents**** **
**MTA11: Concomitant Menactra and Typhim Vi ****	****in adults**

## MTA11: Concomitant Typhim Vi and Menactra Clinical Trial in Adults

**Multi-center, randomized, comparative clinical trial in US adults**
**Participants: 945 healthy 18 to 55 year-olds**
**469 given Typhim Vi + Menactra followed 28 days later by placebo**
**476 given Typhim Vi + placebo followed 28 days later by Menactra**
**Evaluated safety and immunogenicity**
**Hypothesis: concomitant administration is not inferior to sequential administration**

## MTA11: Geometric Mean Titers at Day 28 after Menactra in Adults

**0**

**2000**

**4000**

**6000**

**8000**

**A**

**C**

**Y**

**W-135**

**Menactra + Typhim Vi**

**Menactra 28 days****after Typhim Vi**

**Geometric****Mean Titer**

| Menactra + Typhim Vi | 5138 | 3061 | 1821 | 1002 |
| --- | --- | --- | --- | --- |
| Menactra 28 days after Typhim Vi | 5110 | 3145 | 1742 | 929 |

## MTA11: 4-Fold Rises in SBA Titer by Serogroup in Adults

**0**

**20**

**40**

**60**

**80**

**100**

**A**

**C**

**Y**

**W-135**

**Menactra + Typhim Vi**

**Menactra 28 days after Typhim Vi**

| Menactra + Typhim Vi | 333 of 418
(79.7%) | 374 of 418
(89.5%) | 311 of 418
(74.4%) | 356 of 418
(85.2%) |
| --- | --- | --- | --- | --- |
| Menactra 28 days afterTyphim Vi | 315 of 419
(75.2%) | 370 of 419
(88.3%) | 273 of 419
(65.2%) | 351 of 419
(83.8%) |

**Percentage**

## MTA11: Non-Inferiority Testing of 4-Fold Rises95% CI of the Difference (Sequential - Simultaneous)

**Serogroup A**

**Within Limit**

**Outside Limit**

**-30**

**-25**

**-20**

**-15**

**-10**

**-5**

**0**

**5**

**10**

**-4.49**

**Serogroup C**

**Serogroup Y**

**Serogroup W-135**

**-1.17**

**-9.25**

**-1.40**

**15**

**All non-inferiority criteria met**

**20**

**25**

## MTA11: Proportion of Participants with Typhim Vi Antibody Titer >1.0 μg/mL at 28 Days Post-Vaccination

| Menactra + Typhim Vi | Typhim Vi + Placebo |
| --- | --- |
| 341 of 418
(81.6%) | 328 of 418
(78.5%) |

**0**

**20**

**40**

**60**

**80**

**100**

**Menactra + Typhim Vi**

**Typhim Vi + Placebo**

**Percentage**

## MTA11: Non-Inferiority Testing of the Percentage >1.0 μg/mL 95% CI of the Difference (Sequential – Simultaneous) 

**Within Limit**

**Outside Limit**

**-8**

**-7**

**-6**

**-5**

**-4**

**-3**

**-2**

**-1**

**0**

**1**

**2**

**3**

**4**

**5**

**6**

**7**

**8**

**9**

**10**

**-3.11**

**11**

**12**

**13**

**14**

**15**

**All non-inferiority criteria met**

**-9**

**Typhim Vi + Placebo****vs.****Menactra + Typhim Vi**

## Menactra Immunogenicity: Conclusions

**Menactra is consistently immunogenic in adolescents and adults, satisfying all non-inferiority criteria**
**Menactra SBAs after 3 years are superior to those seen following Menomune or in naïve controls**
**One dose of Menactra primes for memory, as demonstrated by a rapid and very high booster response upon reimmunization**
**Menactra offers a superior reimmunization pathway for prior Menomune recipients**
**Menactra demonstrates the important immunologic characteristics expected of a conjugate vaccine **

## Menactra - Agenda

**Introduction****	****Luc Kuykens, MD, MPH****	****VP Regulatory Affairs**
**Epidemiology****	****Greg Gilmet, MD, MPH****	****Director Scientific & Medical Affairs**** **
**Immunogenicity****	****Michael Decker, MD, MPH****	****VP Scientific & Medical Affairs**
**Safety****	****Gary Chikami, MD****	****Senior Director Regulatory Affairs**
**Conclusions****	****Luc Kuykens, MD, MPH****	****VP Regulatory Affairs**

## Objectives for the Evaluation of the Safety Profile of Menactra

**To compare safety profile of Menactra to ****safety profile of Menomune**
**Demonstrate that rate of severe solicited systemic reactions reported in Menactra and Menomune recipients are comparable **
**To characterize overall safety profile of Menactra**

## Safety Data Collected

**Immediate reactions collected 0 to 30 minutes**
**Solicited systemic and local reactions collected Day 0 through Day 7 **
**Unsolicited adverse events**
**Days 0 to 28**
**Day 29 to month 6**
**Serious adverse events**

## Presentation Outline

**Immediate Reactions**
**Solicited Systemic Reactions**
**Adolescents – MTA04, MTA02 & MTA12**
**Adults – MTA09, MTA14 & MTA11**
**Solicited Local Reactions**
**Adolescents – MTA04, MTA02 & MTA12**
**Adults – MTA09, MTA14 & MTA11**
**Unsolicited Adverse Events and SAEs**
**Conclusions**

## Immediate Reactions

|  | Menactra
(N = 7642) |  | Menomune
(N = 3041) |  |
| --- | --- | --- | --- | --- |
|  | n | % | n | % |
| At least one reaction | 23 | 0.3 | 6 | 0.2 |
| 	Syncope (5 Vasovagal) | 8 | 0.1 | 0 | 0 |
| 	Dizziness | 6 | 0.1 | 1 | 0 |
| 	Sweating | 4 | 0.1 | 1 | 0 |
| 	Nausea | 3 | 0 | 0 | 0 |
| 	Vomiting | 2 | 0 | 0 | 0 |
| 	Injection site reaction | 2 | 0 | 2 | 0.1 |
| 	Injection site edema | 1 | 0 | 1 | 0 |
| 	Injection site inflammation | 1 | 0 | 0 | 0 |
| 	Chills | 1 | 0 | 0 | 0 |
| 	Fever | 1 | 0 | 0 | 0 |
| 	Increased cough | 0 | 0 | 2 | 0.1 |
| 	Laryngismus | 0 | 0 | 1 | 0 |
| 	Pharyngitis | 0 | 0 | 1 | 0 |

## Presentation Outline

**Immediate Reactions**
**Solicited Systemic Reactions**
**Adolescents – MTA04, MTA02 & MTA12**
**Adults – MTA09, MTA14 & MTA11**
**Solicited Local Reactions**
**Adolescents – MTA04, MTA02 & MTA12**
**Adults – MTA09, MTA14 & MTA11**
**Unsolicited Adverse Events and SAEs**
**Conclusions**

## Solicited Systemic Adverse Events: All Trials

**Pre-established list of systemic medical conditions**
**Fever, chills, headache, anorexia, vomiting, diarrhea, fatigue, malaise, arthralgia, seizures, rash **
**Clinical severity documented according to defined rating scale (mild, moderate, severe)**
**Information recorded Day 0 through Day 7**
**Presence of events and intensity recorded daily on the diary**

## Safety Hypothesis: Systemic

**Expected rate in the control group = 1%**

**Menactra is non-inferior to Menomune in the proportion of participants with at least one severe solicited systemic reaction reported during Day 0 through Day 7.**

**Non-inferiority criteria:**
_**MTA04 & MTA09:**_** upper limit****	**_**MTA02 & MTA14:**_** upper limit of ****of the two-sided 95% CI of the****	****the two-sided 95% Cl of the ****ratio *****p*****Menactra**** / *****p*****Menomune**** < 3****	****difference *****p*****Menactra**** – *****p*****Menomune**** < 0.1**

## Presentation Outline

**Immediate Reactions**
**Solicited Systemic Reactions**
**Adolescents – MTA04, MTA02 & MTA12**
**Adults – MTA09, MTA14 & MTA11**
**Solicited Local Reactions**
**Adolescents – MTA04, MTA02 & MTA12**
**Adults – MTA09, MTA14 & MTA11**
**Unsolicited Adverse Events and SAEs**
**Conclusions**

## MTA04: Solicited Systemic Reactions in Adolescents

|  | Menactra
(N = 2265)% | Menomune
(N = 970)% |
| --- | --- | --- |
| Participants with any systemic reaction | 55.1 | 48.7 |
| Participants with any severe systemic reactions | 4.3 | 2.6 |

## MTA04: Non-inferiority Testing of Severe Systemic Reactions, 95% CI of Ratio (Menactra/Menomune)

**1.66**

**3.0**

**3.5**

**0.5**

**1.0**

**1.5**

**2.0**

**2.5**

**0.75**

**1.25**

**1.75**

**2.25**

**2.75**

**3.25**

**3.75**

**Within Limit**

**Outside****Limit**

**Non-inferiority criteria met**

## MTA04: Systemic Reaction Profile in Adolescents

|  | Menactra
(N = 2265)
% | Menomune
(N = 970)
% |
| --- | --- | --- |
| Headache | 35.6 | 29.3 |
| Fatigue | 30.0 | 25.1 |
| Malaise | 21.9 | 16.8 |
| Arthralgia | 17.4 | 10.2 |
| Diarrhea | 12.0 | 10.2 |
| Anorexia | 10.7 | 7.7 |
| Chills | 7.0 | 3.5 |
| Fever | 5.1 | 3.0 |
| Vomiting | 1.9 | 1.4 |
| Rash | 1.6 | 1.4 |
| Seizures | 0 | 0 |

## MTA04: Severe Solicited Systemic Reactions in Adolescents 

|  | Menactra
(N = 2265)
% | Menomune
(N = 970)
% |
| --- | --- | --- |
| Rash | 1.6 | 1.4 |
| Headache | 1.1* | 0.4 |
| Fatigue | 1.1* | 0.2 |
| Malaise | 1.1* | 0.4 |
| Arthralgia | 0.4 | 0.1 |
| Anorexia | 0.3 | 0.2 |
| Diarrhea | 0.3* | 0 |
| Vomiting | 0.3 | 0.3 |
| Chills | 0.2 | 0.1 |
| Fever | 0 | 0.1 |
| Seizures | 0 | 0 |

## MTA02: Solicited Systemic Reactions in Adolescents

|  | Menactra
(N = 439)% | Menomune
(N = 441)% |
| --- | --- | --- |
| Participants with any systemic reaction | 57.2 | 51.9 |
| Participants with any severe systemic reactions | 3.9 | 4.1 |

## MTA02: Non-inferiority Testing of Severe Systemic Reactions, 95% CI of Ratio (Menactra/Menomune)

**0.95**

**3.0**

**3.5**

**0.5**

**1.0**

**1.5**

**2.0**

**2.5**

**0.75**

**1.25**

**1.75**

**2.25**

**2.75**

**3.25**

**3.75**

**Within Limit**

**Outside****Limit**

**Non-inferiority criteria met**

## MTA02: Systemic Reaction Profile in Adolescents

|  | Menactra
(N = 439)
% | Menomune
(N = 441)
% |
| --- | --- | --- |
| Headache | 44.9 | 39.5 |
| Fatigue | 28.2 | 23.6 |
| Anorexia | 12.3 | 12.2 |
| Diarrhea | 10.9 | 14.1 |
| Fever  | 3.4 | 2.5 |
| Vomiting  | 2.3 | 2.0 |

## MTA02: Severe Solicited Systemic Reactions in Adolescents 

|  | Menactra
(N = 439)
% | Menomune
(N = 441)
% |
| --- | --- | --- |
| Rash | 1.6 | 1.6 |
| Headache | 1.6 | 1.8 |
| Fatigue | 1.1 | 0.7 |
| Anorexia | 0.9 | 0.7 |
| Diarrhea | 0 | 0.2 |
| Vomiting | 0.2 | 0.2 |
| Fever | 0.2 | 0 |

## Solicited Systemic Reactions: Adolescents

|  | MTA12 |  | MTA04 | MTA02 |
| --- | --- | --- | --- | --- |
|  | Td
+ Menactra
(N = 505)
% | Td
+ Placebo
(N = 510)
% | (N = 2265)
% | (N = 439)
% |
| Solicited systemic reactions  | 58.6  | 54.1  | 55.1  | 57.2 |
| Severe solicited systemic reactions | 4.8  | 3.7  | 4.3  | 3.9 |

## Presentation Outline

**Immediate Reactions**
**Solicited Systemic Reactions**
**Adolescents – MTA04, MTA02 & MTA12**
**Adults – MTA09, MTA14 & MTA11**
**Solicited Local Reactions**
**Adolescents – MTA04, MTA02 & MTA12**
**Adults – MTA09, MTA14 & MTA11**
**Unsolicited Adverse Events and SAEs**
**Conclusions**

## MTA09: Solicited Systemic Reactions in Adults

|  | Menactra
(N = 1371)% | Menomune
(N = 1159)% |
| --- | --- | --- |
| Participants with any systemic reaction | 61.9 | 60.3 |
| Participants with any severe systemic reactions | 3.8 | 2.6 |

## MTA09: Non-inferiority Testing of Severe Systemic Reactions, 95% CI of Ratio (Menactra/Menomune)

**1.47**

**3.0**

**3.5**

**0.5**

**1.0**

**1.5**

**2.0**

**2.5**

**0.75**

**1.25**

**1.75**

**2.25**

**2.75**

**3.25**

**3.75**

**Within Limit**

**Outside****Limit**

**Non-inferiority criteria met**

## MTA09: Systemic Reaction Profilein Adults

|  | Menactra
(N = 1371)
% | Menomune
(N = 1159)
% |
| --- | --- | --- |
| Headache | 41.4 | 41.8 |
| Fatigue | 34.7 | 32.3 |
| Malaise | 23.6 | 22.3 |
| Arthralgia | 19.8 | 16.0 |
| Diarrhea  | 16.0 | 14.0 |
| Anorexia   | 11.8 | 9.9 |
| Chills  | 9.7 | 5.6 |
| Vomiting | 2.3 | 1.5 |
| Fever | 1.5 | 0.5 |
| Rash  | 1.4 | 0.8 |
| Seizures  | 0 | 0 |

## MTA09: Severe Solicited Systemic Reactions in Adults

|  | Menactra
(N = 1371)
% | Menomune
(N = 1159)
% |
| --- | --- | --- |
| Rash | 1.4 | 0.8 |
| Headache | 1.2 | 0.9 |
| Malaise | 1.1 | 0.9 |
| Fatigue | 0.9 | 0.4 |
| Chills | 0.6* | 0 |
| Anorexia   | 0.4 | 0.4 |
| Diarrhea | 0.4 | 0.3 |
| Arthralgia | 0.3 | 0.1 |
| Vomiting | 0.2 | 0.4 |
| Fever | 0 | 0 |
| Seizures  | 0 | 0 |

## MTA14: Solicited Systemic Reactions in Adults

|  | Menactra
(N = 685)% | Menomune
(N = 455)% |
| --- | --- | --- |
| Participants with any systemic reaction | 53.4 | 49.2 |
| Participants with any severe systemic reactions | 2.2 | 5.5 |

## MTA14: Non-inferiority Testing of Severe Systemic Reactions, 95% CI of Ratio (Menactra/Menomune)

**0.40**

**3.0**

**3.5**

**0.5**

**1.0**

**1.5**

**2.0**

**2.5**

**0.75**

**1.25**

**1.75**

**2.25**

**2.75**

**3.25**

**Within Limit**

**Outside****Limit**

**0.25**

**Non-inferiority criteria met**

## MTA14: Systemic Reaction Profilein Adults

|  | Menactra
(N = 685)
% | Menomune
(N = 455)
% |
| --- | --- | --- |
| Headache | 35.0 | 33.6 |
| Fatigue | 28.0 | 25.1 |
| Malaise | 19.6 | 17.6 |
| Diarrhea | 15.3 | 15.4 |
| Arthralgia | 15.2 | 12.5 |
| Anorexia | 9.3 | 7.7 |
| Chills | 6.6 | 3.3 |
| Vomiting | 1.2 | 1.3 |
| Fever | 0.6 | 0.4 |
| Rash | 1.0 | 2.4 |
| Seizure | 0 | 0 |

## MTA14: Severe Solicited Systemic Reactions in Adults

|  | Menactra
(N = 685)
% | Menomune
(N = 455)
% |
| --- | --- | --- |
| Rash | 1.0 | 2.4 |
| Headache | 0.4 | 1.1 |
| Malaise | 0.3 | 1.8* |
| Fatigue | 0.6 | 1.3 |
| Chills | 0 | 0.4 |
| Anorexia | 0.1 | 0.2 |
| Diarrhea | 0.3 | 0.7 |
| Arthralgia | 0 | 0.4 |
| Vomiting | 0 | 0 |
| Fever | 0 | 0 |
| Seizure | 0 | 0 |

## Solicited Systemic Reactions: Adults

|  | MTA11 |  | MTA09 | MTA14 |
| --- | --- | --- | --- | --- |
|  | Typhim Vi
+ Menactra
(N = 456)
% | Typhim Vi
+ Placebo
(N = 470)
% | (N = 1371)
% | (N = 685)
% |
| Solicited systemic reactions  | 60.5  | 59.6  | 61.9  | 53.4 |
| Severe solicited systemic reactions | 5.3  | 1.5  | 3.8  | 2.2 |

## Presentation Outline

**Immediate Reactions**
**Solicited Systemic Reactions**
**Adolescents – MTA04, MTA02 & MTA12**
**Adults – MTA09, MTA14 & MTA11**
**Solicited Local Reactions**
**Adolescents – MTA04, MTA02 & MTA12**
**Adults – MTA09, MTA14 & MTA11**
**Unsolicited Adverse Events and SAEs**
**Conclusions**

## Solicited Local Reactions

**Pre-established list of vaccine injection ****site reactions**
**Redness, swelling, induration, pain at the ****injection site**
**Clinical severity documented**
**Mild, moderate, or severe**
**Information recorded on pre-printed diary on Day 0 through Day 7 **

## Local Reactions: Intensity Scale

_**Pain at injection site**_**:**
**0 =****	****None**
**1 =****	****Mild: symptom present, but arm movement was not ****	****affected**
**2 =****	****Moderate: discomfort, interferes with or limits arm  ****	****movement**
**3 =****	****Severe: too painful to move arm**
_**Induration, swelling and redness:**_
**0 =****	****None**
**1 =****	****Mild: < 1.0 inch**
**2 =****	****Moderate: 1.0 – 2.0 inches**
**3 =****	****Severe: > 2.0 inches**

## Presentation Outline

**Immediate Reactions**
**Solicited Systemic Reactions**
**Adolescents – MTA04, MTA02 & MTA12**
**Adults – MTA09, MTA14 & MTA11**
**Solicited Local Reactions**
**Adolescents – MTA04, MTA02 & MTA12**
**Adults – MTA09, MTA14 & MTA11**
**Unsolicited Adverse Events and SAEs**
**Conclusions**

## MTA04/MTA02/MTA12: Adolescents Pain at Injection Site

|  | Menomune | Menactra | Td | Placebo |
| --- | --- | --- | --- | --- |
| Any (range), % | 28.7 – 30.2 | 52.9 – 68.9 | 70.9 – 71.0 | 15.5 – 22.7 |
| Severe (range), % | 0 | 0 – 0.8 | 0.2 | 0  |
| Duration
	Any	(median in days) | 1.0 | 2.0 | 2.0 – 3.0 | 1.0 |
| 	Severe Portion 	(median in days) | 0 | 1.0 | 1.0 | 0 |

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

|  | Menomune | Menactra | Td | Placebo |
| --- | --- | --- | --- | --- |
| Any (range), % | 3.6 – 7.7 | 10.8 – 20.3 | 14.5 – 25.9 | 1.6 – 7.6 |
| Severe (range), % | 0 | 0.2 – 1.4 | 0.2 – 1.6 | 0 – 0.2 |
| Duration
	Any	(median in days) | 1.0 | 1.0 – 2.0 | 1.0 – 2.0 | 1.0 – 2.0 |
| 	Severe Portion 	(median in days) | 0 | 1.0 – 2.0 | 1.0 | 1.0 |

## Adolescent Local Reactions

**72.4**

**57.0**

**73.3**

**58.0**

**74.7**

**0**

**10**

**20**

**30**

**40**

**50**

**60**

**70**

**80**

**90**

**100**

**Local Reactions**

**% of Participants Reporting**

**62.7**

**MTA12: Td Site Given w/Menactra**

**MTA12: Menactra Site Given w/ Td**

**MTA12: Td Given w/Placebo**

**MTA12: Menactra Site Given ****One Month after Td**

**MTA02: Menactra**

**MTA04: Menactra**

## Presentation Outline

**Immediate Reactions**
**Solicited Systemic Reactions**
**Adolescents – MTA04, MTA02 & MTA12**
**Adults – MTA09, MTA14 & MTA11**
**Solicited Local Reactions**
**Adolescents – MTA04, MTA02 & MTA12**
**Adults – MTA09, MTA14 & MTA11**
**Unsolicited Adverse Events and SAEs**
**Conclusions**

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

|  | Menomune | Menactra | Typhim Vi | Placebo |
| --- | --- | --- | --- | --- |
| Any (range), % | 19.8 – 48.1 | 38.5 – 53.9 | 75.2 – 75.7 | 13.6 – 21.9 |
| Severe (range), % | 0 – 0.1 | 0 – 1.8 | 0.4 – 0.6 | 0 – 0.2 |
| Duration
	Any	(median in days) | 1.0 | 2.0 | 2.0 | 2.0 |
| 	Severe Portion 	(median in days) | 0 – 1.0 | 1.5 – 2.0 | 2.5 | 0 – 1.0 |

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

|  | Menomune | Menactra | Typhim Vi | Placebo |
| --- | --- | --- | --- | --- |
| Any (range), % | 4.6 – 16.0 | 10.5 – 17.1 | 14.0 – 21.7 | 2.8 – 6.0 |
| Severe (range), % | 0 – 0.1 | 0.4 – 1.1 | 0 – 0.4 | 0 – 0.2 |
| Duration
	Any	(median in days) | 1.0 – 2.0 | 2.0 | 1.0 | 1.0 |
| 	Severe Portion 	(median in days) | 0 – 1.0 | 1.0 – 3.0 | 1.0 | 0 – 3.0 |

## Adult Local Reactions

**57.6**

**47.2**

**77.4**

**51.3**

**77.4**

**0**

**10**

**20**

**30**

**40**

**50**

**60**

**70**

**80**

**90**

**100**

**Local Reactions**

**MTA11: Typhim Vi Site Given w/Menactra**

**MTA11: Menactra Site Given w/ Typhim Vi**

**MTA11: Typhim Vi Given w/Placebo**

**MTA11: Menactra Site Given ****One Month after Typhim Vi**

**MTA09: Menactra**

**MTA14: Menactra**

**42.3**

**% of Participants Reporting**

## Presentation Outline

**Immediate Reactions**
**Solicited Systemic Reactions**
**Adolescents – MTA04, MTA02 & MTA12**
**Adults – MTA09, MTA14 & MTA11**
**Solicited Local Reactions**
**Adolescents – MTA04, MTA02 & MTA12**
**Adults – MTA09, MTA14 & MTA11**
**Unsolicited Adverse Events and SAEs**
**Conclusions**

## Most Frequent Unsolicited AEs That Occurred in at Least 1% of Participants, Day 0 to Day 28

**	****	****Menactra****	****Menomune****COSTART Body System/****	****(N = 7500)****	**** (N = 3004)****Preferred Term****	****%****	**** %**
**At least one unsolicited AE****	****28.3****	****28.6**
**Body as a whole****	****	****	****Infection****	****2.9****	****4.1****	****Pain****	****2.0****	****1.9****	****Injury accidental****	****1.9****	****1.9****	****Pain back****	****1.8****	****1.4****	****Allergic reaction****	****1.6****	****1.6****	****Headache****	****1.2****	****1.3****	****Pain abdominal****	****0.8****	****1.2**
**Respiratory system****	****	****	****Pharyngitis****	****3.7****	****4.4****	****Rhinitis****	****2.9****	****3.4****	****Cough increasing****	****1.6****	****1.2****	****Sinusitis****	****1.1****	****1.0**
**Urogenital system****	****Dysmenorrhea****	****3.1****	****3.3**
**Digestive System****	****Dyspepsia****	****0.9****	****1.5**

## Unsolicited Adverse Events, Day 29 to Month 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 Trials

**Total participants reporting SAEs**
**Menactra – 77 (1.0%)**
**Menomune – 39 (1.3%)**
**All except one reported as unrelated to****study vaccine**
**17 y/o with distal esophageal ulceration**
- Presented with symptoms 2 days after vaccination
- History of NSAID use for 4 weeks prior to vaccination to treat sport-related injury

## Deaths

**Two deaths reported across the six studies **
**Both in study MTA14**
**Both classified by investigator as unrelated to study vaccine**
**One in Menactra group**
- Motor vehicle accident 109 days after vaccination
**One in Menomune group**
- Drug overdose 79 days after vaccination

## Presentation Outline

**Immediate Reactions**
**Solicited Systemic Reactions**
**Adolescents – MTA04, MTA02 & MTA12**
**Adults – MTA09, MTA14 & MTA11**
**Solicited Local Reactions**
**Adolescents – MTA04, MTA02 & MTA12**
**Adults – MTA09, MTA14 & MTA11**
**Unsolicited Adverse Events and SAEs**
**Conclusions**

## Conclusions – Safety  

**Menactra safe and well tolerated among adolescents and adults**
**Menactra met all agreed non-inferiority criteria **
**Local reactions seen with Menactra as expected for protein conjugate vaccine and comparable to those seen with Td**
**Menactra may be administered either concomitantly or one month after Td or Typhim Vi**

## Menactra - Agenda

**Introduction****	****Luc Kuykens, MD, MPH****	****VP Regulatory Affairs**
**Epidemiology****	****Greg Gilmet, MD, MPH****	****Director Scientific & Medical Affairs**** **
**Immunogenicity****	****Michael Decker, MD, MPH****	****VP Scientific & Medical Affairs**
**Safety****	****Gary Chikami, MD****	****Senior Director Regulatory Affairs**
**Conclusions****	****Luc Kuykens, MD, MPH****	****VP Regulatory Affairs**

## Conclusions – Immunogenicity

**Menactra consistently immunogenic in adolescents and adults**
**Immune responses to the four meningococcal serogroups included in Menactra non-inferior to those induced by Menomune**
**Menactra can be administered concomitantly or one month after Td or Typhim Vi**

## Conclusions – Immunogenicity (2)

**Bactericidal antibody elicited by single dose of Menactra persists for at least three years**
**One dose of Menactra primes for memory **
**Adolescents primed with one dose of Menactra exhibited booster response to second dose **
**Booster dose of Menactra not associated with hyporesponsiveness**

## Conclusions – Safety

**Menactra safe and well-tolerated among adolescents and adults**
**Menactra met all agreed non-inferiority criteria **
**Local reactions as expected for protein-conjugate vaccine and comparable to those seen with Td**
**Menactra may be administered concomitantly or one month after Td or Typhim Vi**

## Risk/Benefit

**Risks**
**Reactogenicity profile consistent with conjugate vaccine**
**Increased rate of local reactions**
**Benefits**
**Highly immunogenic**
**Improved antibody persistence**
**Priming and boosting**
**Overcomes hyporesponsiveness**

## Bactericidal Titers Comparison:  4-Fold Rise (BRC) vs.  1:4 (HuC), Serogroup C

|  | Menomune
Vaccinees | Menactra
Vaccinees |
| --- | --- | --- |
| SBA-BRC 
4-Fold Rise | 73 of 81 
90% | 75 of 84 
89% |
| SBA-HuC 
 1:4 | 70 of 81 
86% | 79 of 84 
94% |

- Bactericidal Titers Comparison:  4-Fold Rise (BRC) vs.  1:4 (HuC), Serogroup C

**11 to 18 year olds (MTA02)**

**Percentage**

**SBA-BRC (4-fold rise)**

**SBA-HuC (******** 1:4)**

**0**

**20**

**40**

**60**

**80**

**100**