1. Meningococcal Disease: Optimizing Protection in Adolescents
Amanda Cohn, MD
National Center for Immunization and Respiratory DIseases
March 31, 2011
National Center for Immunization & Respiratory Diseases
Meningitis and Vaccine Preventable Diseases Branch

2. Presentation Goals
Understand updates to adolescent meningococcal vaccine recommendations
Provide context and rationale behind new recommendations
Low burden of devastating disease
Assumptions about long-term protection changing

3. Meningococcal Disease
Niesseria meningitidis: gram negative bacilli: Serogroups B, C, and Y in U.S.
Three syndromes: meningitis, bacteremia, pneumonia
High morbidity and mortality
Most disease occurs in previously healthy persons

4. Meningococcal Disease Incidence, United States
MPSV4 licensed
College Recs
MCV4 Recs
NNDSS data, ABCs data projected to U.S. population

5. Why recommend meningococcal conjugate vaccines in the first place?
Conjugate vaccines expected to provide long-term protection even though circulating antibody declines
Induce t-cell response, immunologic memory, and herd immunity
Recent conjugate vaccine successes
PCV7, Hib vaccination programs in the United States
MenC conjugate vaccines in the United Kingdom
Entire population <19 years vaccinated in large scale campaign,
Wiped out serogroup C disease caused by a clonal strain
Long term reductions in disease

6. Adolescent Meningococcal Vaccination Program
ACIP Recommendation, Oct 2007:
11-12 year-olds at their pre-adolescence vaccination visit
13-18 year-olds who have not been previously vaccinated
Two licensed MCV4 vaccines: 2-55 year-olds
Menactra®: Serogroups A, C, W, Y conjugated to diphtheria toxoid
Menveo®: Serogroups A,C,W,Y conjugated to Crm-197
The current adolescent vaccination recommendation states that year olds should be vaccinated at their pre-adolescence vaccination visit year olds who have not been previously vaccinated should be vaccinated at the earliest opportunity. There are currently two licensed quadrivalent meningococcal conjugate vaccines for year-olds, Menactra and Menveo.

7. Rates of Meningococcal Disease (C and Y) by Age, 1999-2008
Period of risk
This slide shows serogroup C and Y disease by single year of life. You can see the peak of disease rates between ages year. Serogroup C rates cause a greater portion of this peak compared to serogroup Y, but both serogroups follow this peak.
*Active Bacterial Core surveillance (ABCs), estimated to the US population

8. Rates of Serogroup C,Y,W-135 Meningococcal Disease*
Year
Rate per 100,000 (95% confidence intervals)
11-19 year-olds
≥20 year-olds
2004 and 2005
(0.15, 0.35)
(0.13, 0.20)
2006 and 2007
(0.18, 0.40)
(0.18, 0.26)
2008 and 2009
(0.08, 0.24)
( )
We are starting to see a direct impact of vaccination on meningococcal disease rates. This slide shows rates of serogroup C, Y and W disease in year-olds compared to persons 20 and older. As you can see, we see declines among year olds in that are not seen in persons 20 and older.
*Active Bacterial Core surveillance, estimated to the U.S. population

9. Average Annual Number of Cases of C,Y,W-135 Meningococcal Disease
Age Group
Percent Change
11-14 yrs 46 12
-74%
15-18 yrs
106 77
-27%
19-22 yrs 62 52
-16%
Total (11-22 yrs)
214
141
-34%
However, it appears this decline is primarily among younger adolescents. This slide shows the average annual number of cases of meningococcal disease pre and post routine meningococcal vaccination. We see a 74% decline in disease among year-olds, and since vaccination we see approximately 12 cases annually, but we are still seeing 77 cases among adolescents ages years, a 27% decline. We do not see differences in vaccine coverage by age among year olds. There was a 16% decline in persons college ages (19-22 years), but there was likely impact of polysaccharide vaccine during Importantly, during we are still seeing an average of 141 cases of preventable meningococcal disease among adolescents annually.
*Active Bacterial Core surveillance, estimated to the US population

10. Meningococcal Disease Among Persons Previously Vaccinated
Reports of over 30 cases of meningococcal disease among persons who received MCV4
Case-fatality ratio of vaccinated cases high (20%)
Increasing number of vaccinated cases occurring 2-5 years after vaccination

11. Preliminary Results: Vaccine Effectiveness of Menactra®
I am now going to present preliminary results of an evaluation of Menactra vaccine effectiveness

12. Demographics Eligible Cases (n=207) Enrolled Cases (n=120) Controls
Mean Age:
17.9 years (11-24)
18.3 years (11-23)
18.2 years (10-24)
Male:
59%
62%
52%
Race:
White
71%
78%
89%
Black
18%
15% 4%
Other 3% 8%
Unknown 6% 1%
Case fatality ratio
13%
10%
Analysis results based on paperwork received by March 23, 2010; excludes cases and controls vaccinated with MPSV4 only
PRELIMINARY RESULTS, SUBJECT TO CHANGE.

13. Preliminary VE, Menactra Effectiveness, (0-5 years after vaccination)
All Enrolled Cases Controlling for:
VE (95% CI)
All Serogroups
74% (35-90%)
Serogroup C
???
Serogroup Y
Analysis results based on paperwork received by March 23, 2010.
Controls for smoking status and underlying condition status
PRELIMINARY RESULTS, SUBJECT TO CHANGE.

14. Preliminary Menactra VE Estimates, Duration of Protection*
Cases*
VE (95% CI)
All cases (n=120)
Cases with no underlying illness (n=105)
Vaccinated <1 year
99% (0,100%)
99% (0, 100%)
Vaccinated 1 to 2 years
80% (-3,96%)
89% (5, 99%)
Vaccinated 2 to 5 years
46% (-66, 83%)
56% (-48, 87%)
Analysis results based on paperwork received by March 23, 2010.
Controls for smoking status and underlying condition status
PRELIMINARY RESULTS, SUBJECT TO CHANGE.

15. What’s going on? Immunologic memory not enough
Boost response takes 5-7 days after exposure, incubation period of N. meningitidis is 1-4 days.
Need circulating antibody at time of exposure
Circulating antibody wanes after conjugate vaccine
Approximately 50-60% of persons vaccinated had titers above level required for licensure 5 years after vaccination
Unlikely getting the additional benefits of herd immunity with the current U.S. program
Coverage increasing slowly, only now over 60%
Adolescent immunity at population level lower than 60%
In summary low disease incidence and low vaccination coverage have contributed to limited power, and there are wide confidence intervals around point estimates. However, the trend in point estimates is consistent with serologic data, and Estimates in persons without underlying conditions does not change conclusion of waning immunity

16. SBA-BR pre- and post-booster: Menactra, serogroup C
This slide shows not only do 100%of persons respond to a booster, but the geometric mean titer,s, which were 1924 after the first dose of menactra, were more than 2 fold higher, at 23,613 after a booster dose.
n= 108, 207, 107
n= 55,
*Data courtesy of sanofi pasteur, 5 year follow-up of (11-18 year-olds at dose 1)

17. Illustration of Antibody Titers Over Time*
*Not real SBA data

18. Illustration of Antibody Titers Over Time*
Exposure
*Not real SBA data

19. Illustration of Antibody Titers Over Time*
Exposure
Disease
*Not real SBA data

20. What do you do to ensure adolescents are protected through the period of risk?
Move single dose of MCV to age years
Add a booster dose at age 16 years to year old dose

21. MMWR, January 28, 2011

22. But what about…..? College Students who are 19-21 years?
Guidance that for colleges requiring vaccination, there should have documentation of a dose in the last 5 years for students entering college
Focus on adolescents getting primary or booster dose prior to age years, regardless of plans for college
Persons age years may benefit, vaccination not recommended after age 21 years
Interval between doses?
The booster dose can be administered anytime after the 16th birthday to ensure that the booster is provided. The minimum interval between doses is 8 weeks.

23. Future Meningococcal Vaccination Strategies
Infant vaccination
Serogroup B vaccines

24. Estimated Annual Number of Cases of Meningococcal Disease, United States: Age 0 - 21 years
Serogroup B- Blue
Serogroups A,C,Y,W-135- Yellow
ABCs cases from and projected to the U.S. population

25. Update to Tdap Recommendations
ACIP recommends that pertussis vaccination, when indicated, should not be delayed and that Tdap should be administered regardless of interval since the last tetanus or diphtheria toxoid-containing vaccine. ACIP concluded that while longer intervals between Td and Tdap vaccination could decrease the occurrence of local reactions, the benefits of protection against pertussis outweigh the potential risk for adverse events.

26. Acknowledgements
Health departments participating in the MCVE evaluation
ACIP Meningococcal Working Group
Jessica MacNeil
Tom Clark
Nancy Messonnier

27. Thank you!

28. Incidence of Meningococcal Disease by Year and Serogroup, All Ages,1999-2008
This slide shows the incidence of meningococcal disease by year and serogroup among all ages. Rates of all serogroups have declined since 1999, and we are currently at historic low rates of disease.
*Active Bacterial Core Surveillance, estimated to the US population

29. ACIP Recommendation: Two-dose Primary Series
Persons with persistent complement component deficiencies (e.g., C5--C9, properidin, factor H, or factor D) or asplenia should receive a 2-dose primary series administered 2 months apart and then receive a booster dose every 5 years.
Adolescents aged 11 through 18 years with HIV infection should be routinely vaccinated with a 2-dose primary series. Other persons with HIV who are vaccinated should receive a 2-dose primary series administered 2 months apart.
The proposed language is as follows: Persons with persistent complement component deficiency (C3, properidin, factor D, and late component ), and asplenia who have not been previously vaccinated should receive a two dose primary series of MenACWY (0, 2 months)
Persons with Human Immunodeficiency Virus (HIV) who elect to be vaccinated with MenACWY and alladolescents ages years with HIV should receive a two dose primary series (0, 2 months)

30. Summary: Serogroup C Antibody Persistence Studies
Age at vaccination N
Years post vaccine
Measure
Proportion over measure
years*
273, 185 2
hSBA≥ 1:8
Menveo %
Menactra 58%
11-18 years**
52, 48 3
hSBA≥ 1:4
Menactra 35%
MPSV %
11-18 years***
71, 72
brSBA≥ 1:128
Menactra 75%
MPSV %
2-10 years***
108, 207 5
Menactra 55%
MPSV %
16, 10
Menactra 56%
This slide summarizes multiple small studies which consistently show decreasing antibody persistence over time. The first column is the age group studied, the second column are the vaccines compared, and the third column are the numbers studied in each group. The last two columns show the number of years post-vaccination, and the proportion of persons in each group with an SBA above the threshhold used for licensure. Two years after vaccination, only 62% of menveo recipients and 58% of menactra recipients had a human SBA >=1:8. In one study, 3 years post vaccination only 35% of menactra recipients had a human SBA of >=1:4 and in another 75% of menactra recipients had a brSBA of >=1:128. Moving to 5 years, in one study of children vaccinated at ages 2-10 years 5 years previously, only 55% of persons vaccinated with menactra had titers above 1:128, and among persons vaccinated at ages years, 56% of persons vaccinated with Menactra had SBAs >=1:128. At 5 years persons vaccinated with menactra were the same as those vaccinated with polysaccharide vaccine. Each of these studies has a small sample size, but we see consistent results demonstrating waning functional antibodies across studies.
*Gill et al, Human Vaccines, Nov **Vu et al, JID, March 2006, ***ACIP meeting, June 2009