Meningococcal Conjugate Vaccine Failures in the United States National Immunization Conference April 2, 2009 Jessica MacNeil, Amanda Cohn, and Elaine Miller for the Active Bacterial Core Surveillance (ABCs) Team and MeningNet Surveillance Partners

Meningococcal Disease Caused by the bacterium Neisseria meningitidis Typically presents as meningitis or bacteremia Case-fatality rate is 10-15%, and as many as 20% of survivors have permanent sequelae

Underlying Immune Defects as Risk Factors Deficiencies in terminal complement pathway Asplenia Diseases associated with immunosuppression (e.g. HIV) Diseases associated with transient complement deficiencies (e.g. Lupus, nephrotic syndrome)

Cross-Sectional View of the Cell Membrane Capsular polysaccharide (serogroup) Outer-membrane proteins (serotype/ subserotype)

Quadrivalent Meningococcal Conjugate Vaccine: MCV4 Protects against serogroups A, C, Y, W135 Licensed for use in 2-55 year olds ACIP recommendations: Routine use in 11-18 year olds Persons at increased risk of disease

Estimated Annual Number of Cases of Meningococcal Disease, United States: Age 0-21 years ABCs cases from 1998-2007 projected to the US population

NIS-Teen Coverage: MCV4 2006-2007 MMWR August 31,2007; 56 (34):885-888 MMWR October 10, 2008; 57 (40):1100-1103

MCV4 Post-licensure Evaluation Case-Control Study Enrollment started in January 2006 Enrollment has been slow Difficult to enroll adolescents Incidence of disease continues to be very low Screening Method Surveillance for breakthrough cases

Objectives To determine the number of cases of meningococcal disease in vaccinated persons since licensure of MCV4 To describe the epidemiology of breakthrough cases

Case Definition Isolation of Neisseria meningitidis (serogroup A, C, Y, or W-135), or detection of N. meningitidis DNA using a standardized polymerase chain reaction (PCR) In a clinical specimen taken from a normally sterile site ≥10 days after vaccination with MCV4

Identification of Cases January 2005-December 2008 Active Bacterial Core Surveillance (ABCs) and MeningNet sites participating in the MCV4 effectiveness case-control study VAERS reports

Surveillance for Breakthrough Cases ABCs: Active surveillance Laboratory based surveillance for cases of culture confirmed N. meningitidis MeningNet: Enhanced surveillance Surveillance for culture confirmed or PCR positive N. meningitidis VAERS: Passive surveillance Reports of any adverse event following vaccination

ABCs and MeningNet Sites

Meningococcal Disease in Vaccinated Persons 13 confirmed cases* 8 identified by ABCs or MeningNet sites only 1 identified by VAERS only 4 identified through both sources No common lot of vaccine Cases identified in 6 of 20 participating sites *Cases identified through December 31, 2008

Descriptive Epidemiology 6 (46%) cases were male 7 (54%) cases were attending college 2 (15%) cases were military recruits Median age at vaccination was 18.3 years (range 12.6-19.8) Median age at time of disease 19.6 years (range 15.2-21.6 years)

Laboratory Confirmation 12 (92%) cases culture confirmed, 1 PCR+ with clinically compatible illness 8 (62%) serogroup C and 5 (38%) serogroup Y MLST patterns consistent with circulating strains

Clinical Description 12 (92%) cases were hospitalized Median hospitalization time was 3 days (range 0-46 days) 3 fatal cases; 23% case fatality Meningitis was reported in 6 (46%) cases and bacteremia in 7 (54%) cases

Underlying Medical Conditions Case Description 1 Pulmonary embolism and deep vein thrombosis 2 Diabetes and mitrovalve prolapse 3 Irritable bowel syndrome, eczema 4 Current smoker 5 History of pyelonephritis 6 None reported 7 Seasonal allergies 8 9 Prior history of bacterial meningitis, recurrent infections 10 11 12 13 Aplastic anemia and receiving cyclosporines

Time from Vaccination to Disease Onset, n=13* 10-365 days 6 (46%) 366-730 days 3 (23%) 730-1,095 days 4 (31%) *Cases identified through December 31, 2008

Cases by Month of Disease and Year of Vaccination, n=13* *Cases identified through December 31, 2008

Summary of Breakthrough Cases Breakthrough cases occurring as vaccination coverage increases Most cases among college students and military Several may have contributory underlying conditions

What Does This Mean? Breakthrough cases expected Response to MCV4 in pre-licensure studies 81% serogroup Y 91% serogroup C Immunogenicity at 28 days

Why Would a Breakthrough Case Occur? Host Non-response to vaccine Duration of protection Immune deficiencies Environment Organism

Next Steps MCV4 effectiveness case-control study is ongoing Increasing sites under surveillance for cases of breakthrough disease Vaccine effectiveness using observed data Identification of risk factors and immune profiles

Acknowledgements CDC (MVPDB) Amanda Cohn Nancy Messonnier Tom Clark Brian Plikaytis Elizabeth Zell CDC (ISO) Elaine Miller ABCs Sites: California Colorado Connecticut Georgia Maryland Minnesota New Mexico New York Oregon Tennessee MeningNet Sites: Maine Massachusetts Michigan New Hampshire New York City Pennsylvania South Carolina Texas West Virginia Wisconsin

Thank you!