Hans Jürgen Dornbusch

Transcription

1 Epidemiology of Invasive Meningococcal Disease Hans Jürgen Dornbusch Infectious Vaccination Disease Working Working Group Group Severe bacterial infections Pneumococcus Haemophilus influenzae b 3 rd World! Meningococcus Group B Streptococcus 1

2 Invasive Meningococcal Disease Case Report Insidious onset rapid progression 4-8 hours hours hours Irritability Anorexia, Nausea Fever Sore throat, Coryza Myalgia- / Arthralgia Cold hands/feet Purpura Neck Stiffness Photophobia Confusion, Seizures Unconsciousness Sepsis Syndrome, Shock Multi Organ Failure Death Early symptoms, Often misleading rapid growth of Meningococci Hospital admission after 19 hours Intervention frequently late in the course of disease Thompson MJ, et al. Lancet. 2006; 367: Variants: - Transient Bacteremia - Organ infections (Pneumonia) - Meningitis purulenta -Sepsis + Meningitis - fulminant Sepsis Mortality: ( No 4 after Ebola, Avian Influenza & Smallpox) Meningitis 1% Meningitis + Sepsis 5-10% fulminant Sepsis (WFS) > 25% Permanent Sequelae: 10-20% - Amputation, Deafness, Paresis, Organ damage Prehospital Antibiotic Therapy Post-Exposition Chemoprophylaxis Vaccination!? 2

3 Persistence of Men C Ab-Titers following conjugate vaccination (infants / adolescents) Kinetics of Booster Response vs Polysaccharide-Antigens in children after conjugate vaccination in infancy Day 3 Day 7 Day 4-5 Day Pichichero M, Ped Inf Dis J days required! Nasopharyngeal Bacterial Colonisation (Meningococci) Transient Bacteremia (Pneumonia) Distribution to other individuals! Meningitis (40%) Sepsis (25%) Sepsis + Meningitis (30%) NP-Colonisation ( Carriage ) is a Prerequisite for Invasive Meningococcal Disease 3

4 Indirect Vaccine Effects Herd Immunity Susceptibility for Meningococcal Infection Nearly everyone colonized during lifetime Antibodies are protective Incidence in infants 1:10000 (what about the other 9999?) Other mechanisms??? 4

5 First genome-wide association study in patients with IMD 1500 children SNPs Complement Factor H Most significant human gene related to susceptibility inhibits human complement (C3) increased production of factor H increased complement inhibition higher susceptibility for invasive meningococcal disease Bacteria produce factor H binding protein (fhbp) get covered with fh ( protective coat ) human complement is inactivated on bacterial surface 4-5 Mo Risik Factor Age Incidence of Invasive Meningococcal Disease according to age groups, Austria ( ) Austrian National Reference Center for Meningococci 5

6 Poor Immune Response of Infants versus bacterial capsular Polysaccharide Antigens (Meningococci, Pneumococci cocci, Haemophilus influenzae B, GBS) iter Antibody T Maternal passive immunity Physiological Immune Deficiency Mature Immunity months 5 years Neisseria meningitidis Age dependant Carriage Percentage carriage rate Overall Rate = 10.9% Age (years) Outbreak in Stonehouse, Gloucestershire, UK, 1986 Cartwright KA, et al. Epidemiol Infect. 1987;99: Promotors of Carriage Military barracks Dormitory Crowded house Travel Smoking Coughing Kissing Pubs/Clubs Brigham KS, et al. Curr Opin Pediatr. 2009;21:

7 Carriage Rates of Neisseria meningitidis Among First-Year University Students Percentage 19.0 carriage rate Days of first week of first term* First 3 months in catered halls* *Number of students swabbed: Day 1=825; Day 2=669; Day 3=691; Day 4=268; Oct=1872; Nov=542; Dec=653. Neal KR, et al. BMJ. 2000;320: Invasive Meningococcal Disease Variable Incidence 0,3 4 / ,2 14 / ,2 1 / ,5 / > 1000 / / ,6 2,6 / / ,6 / Adapted from Stephens DS. FEMS Microbiol Rev. 2007:31: Public Health Agency of Canada. Canada Communicable Disease Report (CCDR). June 2007;33:1-15; 2. Informe Regional de SIREVA II: datos por país y por grupos de edad sobre las características de los aislamientos de Streptococcus pneumoniae, Haemophilus influenzae y Neisseria meningitidis en procesos invasores, ; 3. Lingappa JR, et al. Emerg Infect Dis. 2003;8: ; 4. Coulson GB, et al; for Group for Enteric, Respiratory and Meningeal Disease Surveillance in South Africa. Emerg Infect Dis. 2007;13: ; 5. Chiou CS, et al. BMC Infect Dis. 2006;6:25; 6. Takahashi H, et al. J Med Microbiol. 2004;53: Incidence of Meningococcal Disease Europe 2011 Incidence*/100,000 persons <0.50 *Confirmed cases of meningococcal disease. Levels of surveillance vary across countries, which may limit direct comparisons of disease incidence. European Centre for Disease Prevention and Control (ECDC). Surveillance of Invasive Bacterial Diseases in Europe, Stockholm, Sweden: ECDC;

8 Invasive Meningococcal Disease Austria 2012 Incidence (overall): 0,71/ Austrian National Reference Center for Meningococci Typing of Meningococci Low variability of polysaccharide capsule 5 serogroups High variability of cell membrane proteins Por A 135 x 375 x variable Fet A clonal complexes High genetic variability 8976 multi locus sequence types (MLST) Maiden; Caugant D. in Handbook of Meningococcal disease Wiley VCH, 2006 Neisseria meningitidis Serogrouping und typing Polysaccharide capsule: 13 different serogroups A, B, C, E29, H, I, K, L,M, W, X, Y, Z Outer Membrane Proteins (OMP): pora, feta pora: 3 variable gene regions (vr1, vr2, vr3) represent serosubtype e.g.: P1.7,16,35 (4cMenB vaccine contains P1.4) feta: 1 variable region (vr1). 6 families (F1,..,F6) e.g.: F1-2 7 house-keeping genes Multi locus sequence typing (MLST) of these genes results in sequence type e.g.: ST-11 Example for complete antigen formula: Serogroup: PorA (vr1):pora (vr2):pora(vr3):feta(vr1):sequence type B:P1.7,16,35:F1-2:ST-11 8

9 Different MenB strains (variable PorA proteins) in UK 2003/4 Class 5 PorA OMV Class 4 PorB LPS PorA Immunodominant in the outer membrane vesicles Highly variable across different strains of meningococcus Immune response in infants/ younger children relatively serosubtype (pora) specific Makes coverage of OMV vaccines limited, only useful if epidemic due to single strain Gray et al, Journal of Medical Microbiology 2006 Incidence of Invasive Meningococcal C Disease in Austria and in the province of Styria Austrian National Reference Center for Meningococci Invasive Meningococcal Disease France Group B: cases / 180 deaths = 9% mortality Group C: 907 cases / 145 deaths = 16% mortality Isabelle Parent du Châtelet, Paris, 7 Nov

10 Invasive Meningococcal Disease cases reported by main Clonal Complexes (MLST) and Serogroups France 2011 National Reference Center, France Neisseria meningitidis 13 Serogroups / capsular antigens A B H I Z C E-29 K W(135) X Y L M 5 Serogroups most important! Rosenstein NE et al. N Engl J Med 2001; 344: Invasive Meningococcal Disease Global Serogroup-Distribution Adapted from Stephens DS. FEMS Microbiol Rev. 2007:31: Public Health Agency of Canada. Canada Communicable Disease Report (CCDR). June 2007;33:1-15; 2. Informe Regional de SIREVA II: datos por país y por grupos de edad sobre las características de los aislamientos de Streptococcus pneumoniae, Haemophilus influenzae y Neisseria meningitidis en procesos invasores, ; 3. Lingappa JR, et al. Emerg Infect Dis. 2003;8: ; 4. Coulson GB, et al; for Group for Enteric, Respiratory and Meningeal Disease Surveillance in South Africa. Emerg Infect Dis. 2007;13: ; 5. Chiou CS, et al. BMC Infect Dis. 2006;6:25; 6. Takahashi H, et al. J Med Microbiol. 2004;53:

11 Meningococcal serogroup dynamics USA Serogroup B Serogroup C Serogroup Y Serogroup W-135 and non groupable 2% 45% 7% 23% 33% 29% 37% 46% 27% 17% 25% 9% CDC. ABCs Report: Emerging Infections Program Network, Neisseria meningitidis, pp1-10/tables 1-10 Jackson LA, et al. MMWR CDC Surveill Summ. 1993;42(2): p.25/3 Meningoccal Y Disease in Europe % Bröker et al, Human Vacc & Immunother 2014 Meningococcal Serogroups causing Invasive Disease Turkey *May include serogroups X, 29E, Z29E, O or non-groupable; Serogroup not identified. Ceyhan M, et al. Poster presented at: 31st Annual Meeting of the European Society for Paediatric Infectious Diseases (ESPID); May 28-June 1, 2013; Milan, Italy. 11

12 England and Wales is experiencing a year on year increase in Meningococcal Serogroup W disease since 2009/10, following rapid expansion of a single endemic hyper virulent ST 11 clone. MenW infections were associated with severe disease, atypical clinical presentations (septic arthritis, severe RTIs) and fatal outcomes. SN Ladhani et al. Clinical Infectious Diseases, 10 Nov 2014 Meningococcal Disease in Europe 2011 according to serogroups 2% 14% 8% 1% B C W-135 n= % Y A Other/NG Austria, Belgium, Czech Republic, Denmark, Estonia, Finland, France, Germany, Greece, Hungary, Iceland, Ireland, Italy, Latvia, Lithuania, Luxembourg, Malta, Netherlands, Norway, Poland, Portugal, Romania, Slovakia, Slovenia, Spain, Sweden, United Kingdom; Cases for which serogroup information was known; NG=non groupable. European Centre for Disease Prevention and Control (ECDC). Surveillance of Invasive Bacterial Diseases in Europe, Stockholm, Sweden: ECDC; Meningococcal Disease in Infants <1 Year of Age Europe 2011 N=605 *Austria, Belgium, Czech Republic, Denmark, Estonia, Finland, France, Germany, Greece, Hungary, Iceland, Ireland, Italy, Latvia, Lithuania, Malta, Netherlands, Norway, Poland, Portugal, Romania, Slovakia, Slovenia, Spain, Sweden, United Kingdom; May include serogroups X, 29E, Z29E, O or non-groupable; Serogroup not identified. European Centre for Disease Prevention and Control (ECDC). Surveillance of Invasive Bacterial Diseases in Europe, Stockholm, Sweden: ECDC;

13 Invasive Meningococcal Disease and Death Rates in Austria ~ 50% of fatal cases due to serotype B Lab confirmed cases with IMD Mortality % Nationales Referenzzentrum für Meningokokken Serogroup Distribution in Austria Austrian National Reference Center for Meningococci Invasive Meningococcal Disease in Austria Serogroup Distribution in Austria according to Age Groups ( ) Source: National Reference Center for Meningococci (AGES) Only laboratory confirmed cases with MenB, C, W, Y invasive disease shown 13

14 Moving Targets for Meningococcal Vaccines 14