TBE vaccines: immunogenicity, effectiveness and safety

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1 TBE vaccines: immunogenicity, effectiveness and safety Prof. H.Kollaritsch, MD., DTM., Associate professor for Specific Prophylaxis and Tropical Medicine, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna

2 Vaccines Two Western vaccines (EMA approved) FSME-Immun (adults/children) Encepur (adults/children) Two Russian vaccines (approved by Russian NRA) TBE vaccine Chumakow, Moscow (children >3yrs and adults) EnceVir (adults/children) All vaccines: PCEC produced, killed whole virus (different strains), adjuvanted (Alumn), no preservatives; HSA: FSME-Immun and Moscow-vaccine Similar, but not identical application schedules (2+1 as standard basic immunization, regular boosters)

3 Antibody induction and persistence: a) Western vaccines 16 controlled studies for Encepur and 10 for FSME-Immun, several uncontrolled studies All age classes included, separate studies for children > 1year for both vaccines seroconversion after 2 vaccinations % (both vaccines, nearly 100% after vacc#3. Limited prospective studies on long term Ab-persistence Various test systems (commercial and in-house) EIA s and NT s used for determination of AB-formation

4 Study on long-term-antibody persistence after TBE- vaccination Open study Inclusion of 427 subjects with complete basic course (and boosters) of immunization 3 to 21 years ago (TBE-Immune ). Two age strata (below and above age of 50) After first blood draw 1 booster vaccination (Encepur ) 21 days later antibody testing Recall for testing in 2 year regular intervals; exclusion of subjects with NT below 1:10 Status: 8 years postbooster results; ongoing Löw-Baselli et al, Hum Vacc.5:7,1-6,2009

5 Ref s: Rendi-Wagner et al, Vaccine 2004a, 2004b, Rendi-Wagner et al, Vaccine 2007, Rendi-Wagner et al, IJMM, 2008, Paulke-Korinek et al, Vaccine 2009, Paulke-Korinek et al. 2011, manuscript in preparation

6 Decrease of TBE-antibodies Antibody decline depends on number of vaccinations ~ 15% decrease per year ~1% decrease per year

7 Conclusion Antibody decline depends on number of vaccinations received: Decline is more rapid after basic immunization only. after 4 and more TBE vaccinations seroprotection exceeds the recommended booster intervals and antibody levels will remain stable for many years in most vaccinees, loss of seroprotection is around 1% of study population per year small proportion (~3%) of low responders requires shorter booster intervals Age is the most important predictive parameter for lower titers and earlier loss of antibodies

8 Löw-Baselli et al., Hum Vaccin. 2009: 5, Study design 347 subjects, years Prevaccinated subjects (conventional schedule), 3 vaccinations (2+1 basic immunization) only either complete series of FSME-Immune or 2 basic immunizations Encepur plus 1 booster FSME-Immune) Antibody decline for 3 years tracked, then One booster after 3 years (FSME-Immune)

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10 Löw-Baselli et al., Good data for 3 years after the FIRST booster (vaccination #3 in conventional schedule) Age is directly associated with probability to loose antibodies earlier and to develop lower NT-titers Annual decline rate 0,58 per year after 3rd vaccination (supports data on fast AB-decline after basic immunization only) Solid and exceptionally strong booster response (markedly higher NT s than after vacc.#3!) after 3 years with one booster vaccination Interchangeability of Western vaccines for primary series documented

11 Antibody induction and persistence: b) Russian vaccines 6 controlled studies for Moscow-vaccine and 4 for EnceVir, several uncontrolled studies with old formulation, none registered in clinicaltrials.gov Children > 3 years and adults seroconversion after 2 vaccinations 78-97%% (EnceVir) and 84%-100% (Moscow-vaccine), nearly 100% after vacc#3. No prospective studies on long term Ab-persistence, 1-2 years follow up: 88% and 84% pos. in NT Various test systems (commercial and in-house) EIA s, HI-tests; only one study used NT s for determination of AB-formation (Leonova&Pavlenko,2009)

12 Efficacy and effectiveness

13 TBE in Austria and Czech Republic No. of TBE cases Percent vaccinated Steady decrease of TBE cases with increasing vaccination coverage (at least 1 vaccination) over a period of >25yrs; epidemiologically controlled by TBE cases in a region with vaccination coverage <10%; ratio of Encepur vs. FSME-Immune app. 1: Czech Republic (Nat. Ref. Center of Epidemiol., Prague) Austria Vaccination coverage in Austria (at least 1 vaccination) F.X. Heinz

14 Field effectiveness (FE) of TBE vaccination in different age groups within the regular vaccination schedule (Austria 2000 to 2006; ratio Encepur/FSME-Immune: ~1:9)) A. best case Age group 0-15 y y y 60+ y Unvaccinated Incidence/100, Regularly vaccinated Incidence/100,000 FE 95% CI Total B. worst case Age group 0-15 y y y 60+ y Total Unvaccinated Incidence/100, Regularly vaccinated Incidence/100,000 FE 95% CI FE ~ 99% Heinz FX et al.:field effectiveness of vaccination against tick-borne encephalitis. Vaccine Oct 23;25(43):

15 Clinical efficacy of Russian vaccines Sverdlovsk-region; comparison of TBE morbidity in vaccinated and nonvacc.population; 80% Moscow-vaccine, 6% EnceVir, 12% FSME-Immun, 2% Encepur (Romanenko et al, 2007)

16 Vaccination breakthroughs (Western vaccines) Stiasny et al, 2009: 25 VBT from Austria ; 8 fully vaccinated; no apparent risk parameters Andersson et al,2010: 27 VBT from Sweden ; 21 fully vaccinated, no risk parameters identified Summary from both papers: VBT s show anamnestic response, indicating that immunological priming and memory was insufficient or not fast enough to prevent disease VBT s disease course not significantly mitigated VBT s do not occur more often with longer interval to last immunization Unknown: inapparent VBT s (no neurological signs)??

17 SAFETY

18 WESTERN VACCINES 16 controlled studies for Encepur and 10 for FSME-Immun, several uncontrolled studies One idependent safety field study One Cochrane evaluation available Postmarketing surveillance available All age classes included, separate studies for children > 1year for both vaccines

19 Cochrane review (Demicheli et al, 2009) Pooled data of subjects (6586 adults, 1598 children) 9 studies with Western vaccines (all ages, 2 with old formulations), controlled randomized and blinded trials versus placebo or comparator-vaccine (6586 adults, 1375 children) 1 study with Russian vaccine versus FSME-Immune (age 7-17, 223 subjects) Cochrane summary: Side effects were common, but none were severe or lifethreatening (with either vaccine) Newer studies not included in analysis

20 Western vaccines: Postmarketing surveillance

21 Safety field study (Austrian Green Cross): (Weinzettel et al, WieKliWo, 2007) (descriptive; vaccinations; records by GP s and Pediatricians) ~ 15% Encepur. ~ 85% FSME- Immun nn Absolute numbers of recorded side effects related to number of vaccination Side effects and vaccines Percent fever reactions and intensity Fever reaction 69,4 24,49 6,12 Total side effects recorded: 107/ (0,413%)

22 Safety: Russian vaccines Tarasevich State Institute for Standardization and Control of Medical Biological Products reports low reactogenicity (data not published) Safety study (325 children, both vaccines, local and systemic parameters; Pavlova et al, 2003): no striking evidence for side effects Several other publications (in Russian only) state (without details) good tolerability of both vaccines No published data in international journals One study compares FSME-Immune (old formulation) with the Moscow-vaccine

23 Pavlova et al, 1999: Safety by fever reaction: Moscow vaccine versus FSME-Immun (old formulation)

24 Pavlova et al, 1999: Safety by fever reaction: Moscow vaccine versus FSME-Immun (old formulation) Summary: Total fever incidence with Moscow-vaccine: 21,2% of subjects, 7,8% moderate or severe fever reaction Incidence of fever was 4x higher than with FSME-Immune (old formulation) moderate or severe reations were seen with Moscow vaccine only No differentiation between first and consecutive vaccination Small number of participants, unblinded study