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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
TBE SAGE meeting, Geneva, April 2011

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)

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 97-100% (both vaccines, nearly 100% after vacc#3.
Limited prospective studies on long term Ab-persistence
Various test systems (commercial and in-house) EIAs and NTs used for determination of AB-formation

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
Lw-Baselli et al, Hum Vacc.5:7,1-6,2009

Refs: 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

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

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

Study design
347 subjects, 18-67 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)
Lw-Baselli et al., Hum Vaccin. 2009: 5, 551-556

Lw-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 NTs than after vacc.#3!) after 3 years with one booster vaccination
Interchangeability of Western vaccines for primary series documented

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) EIAs, HI-tests; only one study used NTs for determination of AB-formation (Leonova&Pavlenko,2009)

Efficacy and effectiveness

TBE in Austria and Czech Republic 1979-2006
0
100
200
300
400
500
600
700
800
900
1000
1100
79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 00 01 02 03 04 05 060
10
20
30
40
50
60
70
80
90
100
F.X. Heinz
No. of TBE cases Percent vaccinated
Czech Republic (Nat. Ref. Center of Epidemiol., Prague) Austria Vaccination coverage in Austria (at least 1 vaccination)
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

Incidence/100,000
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
B. worst case
Age group Unvaccinated Regularly vaccinated
Incidence/100,000 FE 95% CI 0-15 y
16-49 y 50-59 y
60+ y
Incidence/100,000 Age group Unvaccinated Regularly vaccinated
Incidence/100,000 FE 95% CI 0-15 y
50-59 y 60+ y
16-49 y
Total
Total
1.435 4.964 6.444 6.790
5.922
0.043 0.009 0.059 0.075
0.039
97.0 99.8 99.1 98.9
99.3
86.81-99.02 99.52-99.90 97.25-99.57 97.88-99.32
98.92-99.56
1.435 4.964 6.444 6.790 5.922
0.057 0.039 0.118 0.113 0.079
96.0 99.2 98.2 98.3 98.7
84.24-98.67 98.29-99.59 95.29-99.14 96.99-98.97 97.98-99.09
FE ~ 99% Heinz FX et al.:Field effectiveness of vaccination against tick-borne encephalitis. Vaccine. 2007 Oct 23;25(43):7559-67.

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)

Vaccination breakthroughs (Western vaccines)
Stiasny et al, 2009: 25 VBT from Austria 2002-2008; 8 fully vaccinated; no apparent
risk parameters
Andersson et al,2010: 27 VBT from Sweden 2000-2008; 21 fully vaccinated, no risk
parameters identified
Summary from both papers: VBTs show anamnestic response, indicating that immunological
priming and memory was insufficient or not fast enough to prevent disease
VBTs disease course not significantly mitigated VBTs do not occur more often with longer interval to last
immunization Unknown: inapparent VBTs (no neurological signs)??

SAFETY

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

Cochrane review (Demicheli et al, 2009)
Pooled data of 8.184 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 life-threatening (with either vaccine)
Newer studies not included in analysis TBE SAGE meeting, Geneva, April 2011

Western vaccines: Postmarketing surveillance

Safety field study (Austrian Green Cross): (Weinzettel et al, WieKliWo, 2007) (descriptive; 25.905 vaccinations; records by GPs and Pediatricians)
~ 15% Encepur. ~ 85% FSME-
Immun
Total side effects recorded: 107/25.905 (0,413%)
1. 2. 3. 4. 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

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 R

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