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

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

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

Meningococcal Disease Incidence, United States MPSV4 licensed College Recs MCV4 Recs 1921-1996 NNDSS data, 1997-2008 ABCs data projected to U.S. population

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

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 11-12 year olds should be vaccinated at their pre-adolescence vaccination visit. 13-18 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 11-18 year-olds, Menactra and Menveo.

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 16-21 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

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 0.23 (0.15, 0.35) 0.16 (0.13, 0.20) 2006 and 2007 0.27 (0.18, 0.40) 0.22 (0.18, 0.26) 2008 and 2009 0.14 (0.08, 0.24) 0.21 (0.18-0.26) 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 11-19 year-olds compared to persons 20 and older. As you can see, we see declines among 11-19 year olds in 2008-9 that are not seen in persons 20 and older. *Active Bacterial Core surveillance, estimated to the U.S. population

Average Annual Number of Cases of C,Y,W-135 Meningococcal Disease Age Group 2000-2004 2005-2009 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 11-14 year-olds, and since vaccination we see approximately 12 cases annually, but we are still seeing 77 cases among adolescents ages 15-18 years, a 27% decline. We do not see differences in vaccine coverage by age among 13-17 year olds. There was a 16% decline in persons college ages (19-22 years), but there was likely impact of polysaccharide vaccine during 2000-2004. Importantly, during 2005-2009 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

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

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

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.

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.

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.

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

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, 56 *Data courtesy of sanofi pasteur, 5 year follow-up of (11-18 year-olds at dose 1)

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

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

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

What do you do to ensure adolescents are protected through the period of risk? Move single dose of MCV to age 14-15 years Add a booster dose at age 16 years to 11-12 year old dose

MMWR, January 28, 2011

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 19-21 years, regardless of plans for college Persons age 19-21 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.

Future Meningococcal Vaccination Strategies Infant vaccination Serogroup B vaccines

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 1996-2005 and projected to the U.S. population

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.

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

Thank you!

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

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 11-18 years with HIV should receive a two dose primary series (0, 2 months)

Summary: Serogroup C Antibody Persistence Studies Age at vaccination N Years post vaccine Measure Proportion over measure 11- 18 years* 273, 185 2 hSBA≥ 1:8 Menveo 62% Menactra 58% 11-18 years** 52, 48 3 hSBA≥ 1:4 Menactra 35% MPSV4 35% 11-18 years*** 71, 72 brSBA≥ 1:128 Menactra 75% MPSV4 60% 2-10 years*** 108, 207 5 Menactra 55% MPSV4 42% 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 11-18 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 2010. **Vu et al, JID, March 2006, ***ACIP meeting, June 2009