Duration of protection by Tick-Borne Encephalitis (TBE) vaccines: Opening a debate

Transcription

1 Duration of protection by Tick-Borne Encephalitis (TBE) vaccines: Opening a debate Robert Steffen Ekkehard Altpeter Epidemiology, Biostatistics and Prevention Institute WHO Collaborating Centre for Travelers Health, Zurich, Switzerland Federal Office of Public Health Bern, Switzerland

2 RS: Conflict of interest declaration I have or had within the past 3 years financial relationships (honorarium or grants for research, support to attend meetings, paid lectures, advisory boards) with: Vaccine producers GlaxoSmithKline (Novartis Vaccines and Diagnostics) Mérieux (Fondation) Pfizer Sanofi Pasteur Takeda Valneva Drug manufacturers (Travelers diarrhea) Dr. Falk Pharma GmbH Host Therabiomics / Clasado Drug manufacturers (Malaria) Biointelect Sixty Degrees Pharmaceuticals 2

3 History of TBE immunization in Switzerland Krech T, Thesis University of Bern 1980 l Vaccine recommendations: l Acceptance TBE vaccine: l Compliance w/ 3y booster: Limited <15% in endemic areas Low to moderate Frustrated GP in Schaffhausen initiated sero-survey 2003 Presented data to Federal Vaccination Commission 2005

4 Serosurvey 1 by A. Kind, MD, Schaffhausen l Self-check: 6 years after last vaccine dose MOC 5.2 MOC = Multiple of Cut-off l Method: IgG prior to TBE boosters, n = 47 l Results - Last dose of vaccine 3 to 11 years prior to test - 46 / 47 with MOC > / 47 with MOC = 0.9: 79 y/o male, last dose 4 years earlier l Conclusions - Primary series: 0, 1, 12 months - Serology IgG 3 years later > if result > 5.0 MOC: no booster dose - Serology IgG 3 to 5 years later Kind A. Wie viele Auffrischimpfungen sind notwendig gegen die Zeckenenzephalitis FSME. Schweizerische Ärztezeitung. 2004; 85: Need for booster every 3 y reduces primary acceptance of TBE vaccine

5 Serosurvey 2 by A. Kind, MD, Schaffhausen l Method: IgG (mostly Enzygnost), various commercial laboratories History of tick bites (number estimate) History of yellow fever immunization l Results - Vaccinated: 313 (294 fully, 19 incomplete) Age data unpublished of 294 (95%) with TBE IgG MOC > 1.0 (= positive ) - Among 18 with last dose > 8 years ago 16 (89%) positive - Unvaccinated controls: 10/184 (5%) positive : tick bites, no YF vaccine l Conclusions - Protection > 3 years after last dose à revision of recommendations Kind A. Erfahrungen mit Titermessungen zur Impfschutzkontrolle bei der Zeckenenzephalitis FSME. Primary Care. 2005; 5: Swiss Federal Office of Public Health, 27 March 2006: After primary series TBE boosters indicated every 10 years Bulletin BAG. 2018; (no volume #):pp

6 Vaccine doses sold in Switzerland, 2002 to ,031, sold vaccine doses , , , , , , ,000 Publication Year

7 Vaccination coverage in 8 y/o: 1 ( 3) doses Switzerland, all 8 (6)% 33 (24)% 33 (26)% 34 (26)% AG 8 (6)% 49 (37)% 42 (35)% 55 (46)% LU 8 (2)% 30 (22)% 32 (24)% 32 (27)% NW NA 43 (36)% 39 (34)% 46 (39)% OW 9 (1)% 44 (32)% 37 (30)% 46 (34)% SG 18 (8)% 32 (23)% 39 (31)% 43 (34)% SCHAFFHAUSEN SH 21 (15)% 62 (45)% 64 (51)% 68 (54)% THURGAU TG 48 (32)% 62 (53)% 56 (46)% 57 (43)% UR 2 (2)% 54 (44)% 47 (39)% 46 (34)% ZURICH ZH 15 (12)% 64 (45)% 64 (50)% 70 (53)% GREEN = 50% with 3 doses NOTE: University of TBE Zurich immunization in CH in general recommended from age 6 years

8 Vaccination coverage in 16 y/o: 1 ( 3) doses Switzerland, all 10 (8)% 26 (19)% 38 (33)% 42 (39)% AG 9 (6)% 36 (28)% 53 (47)% 64 (59)% LU 8 (4)% 32 (25)% 40 (35)% 47 (44)% NW NA 42 (39)% 56 (50)% 51 (50)% OW 8 (4)% 36 (27)% 43 (42)% 55 (52)% SG 18 (14)% 29 (24)% 45 (39)% 60 (53)% SCHAFFHAUSEN SH 26 (22)% 50 (40)% 57 (50)% 64 (59)% THURGAU TG 46 (40)% 64 (58)% 72 (69)% 74 (69)% UR 11 (5)% 56 (41)% 69 (64)% 72 (69)% ZURICH ZH 16 (12)% 40 (25)% 71 (64)% 75 (71)% GREEN = 50% with 3 doses 8

9 TBE case definitions used by the Swiss FOPH (abbreviated) 1984 to 2012: (/ = or) - Clinical: Meningitis (M) / M-encephalitis (ME) / ME-myelitis (MEM) / flu-like illness - Laboratory: IgM significanly elevated / seroconversion / IgG increase x4 / IgG (and IgM) increase significant / Nucl acid + From 2013 (including retrospective analysis from 2000): - EU/ECDC: confirmed and probable cases - CH: possible cases are also retained in order to compare all data from

10 Evolution of TBE in Switzerland, Notification: 1 st laboratories, 2 nd physicians (n = 3 377) Number Hospitalisation in % Total neurological symptoms cases < 6years % Year 10

11 Endemicity (high risk) of TBE in Switzerland,

12 Endemicity Vaccination recommendations, 2017

13 Tick-borne encephalitis in Switzerland, Total cases Known vaccination status Vaccinated 1 dose(s) Vaccinated 3 doses Period n % n % n % 2004 to to to Total

14 Tick-borne encephalitis in Switzerland, : Time since last TBE vaccine dose if 3 doses Time since last dose n % n % 3 years > 3 years Total

15 Tick-borne encephalitis in Switzerland, : Time since last TBE vaccine dose if 3 doses Age 65 years Time since last dose n n % 3 years > 3 years Total

16 Conclusions Part 1 l One GP had impact on Swiss Federal Vaccination Commission l Expansion of booster interval to 10 years - Based on weak data - Was taken in period of low acceptance of TBE vaccine - Resulted in contradiction - Recommendations by Swiss Federal Office of Public Health - Package insert approved by Swissmedic (licensing authority) - Subsequent monitoring of vaccine breakthroughs (older age!) l Booster every 10 years improved acceptance of TBE vaccine l TBE remains frequent in Switzerland: expanding endemicity l No indication that booster q10y associated with more failures l After primary course TBE vaccine offers protection for 10 years 16

17 GSK TBE Vaccine

18 Pfizer TBE Vaccine Conclusion Part 2 Seropersistence of TBEV antibodies demonstrated with both vaccines, but

19 Open questions l Are antibody titers the decisive factor? - Vaccine breakthrough (VBT) with protective level of antibodies (n = 1) Kaiser VBT in fully vaccinated subjects: few % Andersson 2010 (no rate), Heinz 2007 (1%), Kunz 2003 (5%), Swiss data (4%) - VBT patients typically have high IgG antibody and low IgM response, indicative of a memory response often more severe illness (ICU) Stiasny Serology underestimates vaccine effectiveness Korinek th dose 3 y after primary course needed? Konior 2018, Beran 2017, Beskovnik 2016 l Do other factors play the decisive role for protection? - In VBT insufficient T-cell response Garner-Spitzer 2013 Should we just forget to care about serological data? 19

20 Seropersistence vs. field effectiveness SEROPERSISTENCE (%) SEROPERSISTENCE (%) after 3rd dose 1 Vaccinated Vaccinated y 3y 5y 10y y ,4 90, ,4 88, y ,7 88,6 99,8 99,7 96,8 95, Publication 75 in process y ,2 74,5 99,1 98,2 97, y ,5 98,9 98,2 95,2 91,7 after 4th dose (1st booster) 2 FIELD EFFECTIVENESS (Heinz) 3, 4 Regularly yellow bars indicate subjects with irregular vaccination schedules according to the recent SPC 1: Pfizer 5 year seropersistence and boosterability studies after third dose, range of different age strata 2: Pfizer 10 year seropersistence and boosterability studies after 4th dose 3: Heinz : Heinz 2013 Irregularly Konior R et al. Vaccine. 2017; 35: Heinz FX et al. Emerg Infect Dis. 2013; 19:

21 Open questions l Are antibody titers the decisive factor? l Is boostability possibly more important? - Memory response as determining factor for effectiveness? Aerssens Is priming sufficient? Compare to rabies vaccine, WHO/WER 20 April Field effectiveness all age groups higher than expected, Heinz 2009, 2013 l True vaccine failures result from - Host: Individual risk factors? - Virus: High viral load? Virulence factors? TBEV subtype? l Memory: Need of a booster after 3+5 vs. every 10 years? 21

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