tbe vaccines: immunogenicity, effectiveness and safety · tbe sage meeting, geneva, april 2011...

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) EIA‘s and NT‘s 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


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

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


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)


Löw-Baselli et al., Hum Vaccin. 2009: 5, 551-556

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


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)


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 <10%; ratio of Encepur vs. FSME-Immune app. 1:9


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: • 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)??


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 GP‘s 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 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


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

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


tbe vaccines: immunogenicity, effectiveness and safety · tbe sage meeting, geneva, april 2011...

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