OS16 - 1.1.b Frenkel Lecture - A. Dekker

1. Open Session of the EuFMD - Cascais –Portugal 26-28 October 2016 FMD vaccine quality assurance why does it maGer Frenkel Lecture A. Dekker

2. Bernd Haas 14 March 1958 – 4 October 2015

3. Why was Bernd important for VQA •  He started in Tübingen with Dr. Ahl and was among others responsible for vaccine quality control •  Studied relaVon between Ab and protecVon

4. Some papers and presentaVons by Bernd For more detail see poster outside

5. Bernd worked on many important issues •  Vaccine Quality –  RelaVon Ab and protecVon (neutralisaVon and ELISA) –  MAb speciﬁc for 12S and 146S for quality control –  Heterologous protecVon •  DiagnosVc tests –  Use of LPB ELISA for import export serology –  RT-PCR development and validaVon for FMD –  DIVA tesVng validaVon and development of new techniques –  European diagnosVc bank –  Non invasive sampling •  Biosecurity standards for the EuFMD commission

6. Bernd worked on many important issues •  Vaccine Quality –  Rela.on Ab and protec.on (neutralisa.on and ELISA) –  MAb speciﬁc for 12S and 146 for quality control –  Heterologous protec.on •  DiagnosVc tests –  Use of LPB ELISA for import export serology –  RT-PCR development and validaVon for FMD –  DIVA tesVng validaVon and development of new techniques –  European diagnosVc bank –  Non invasive sampling •  Biosecurity standards for the EuFMD commission

7. FMD vaccine quality •  Why is quality so extremely important –  History on control with vaccinaVon –  Good quality vaccine longer duraVon of immunity –  Economics of vaccine quality •  How is vaccine quality affected –  Adjuvant and other addiVons –  Amount of anVgen –  Ageing effect •  How can a consumer assess vaccine quality –  History of efficacy tesVng –  RelaVon anVbody response and protecVon –  StandardisaVon of serology

8. FMD vaccine quality •  Why is quality so extremely important –  History on control with vaccina.on –  Good quality vaccine longer dura.on of immunity –  Economics of vaccine quality •  How is vaccine quality affected –  Adjuvant and other addiVons –  Amount of anVgen –  Ageing effect •  How can a consumer assess vaccine quality –  History of efficacy tesVng –  RelaVon anVbody response and protecVon –  StandardisaVon of serology

9. Number of FMD cases in the Netherlands 1 10 100 1000 10000 100000 1909 1914 1919 1924 1929 1934 1939 1944 1949 1954 1959 1964 1969 1974 1979 1984 1989 1994 1999 2004 Year Numberofcases Start mass vaccination cattle End vaccination campaign History of FMD control with vaccinaVon South-America Naranjo, J. and O. Cosivi (2013). "EliminaVon of foot-and-mouth disease in South America: lessons and challenges." Philosophical TransacVons of the Royal Society B: Biological Sciences 368(1623) Lombard, M., P. P. Pastoret and A. M. Moulin (2007). "A brief history of vaccines and vaccinaVon." Revue scienVﬁque et technique oﬃce internaVonal des epizooVes 26(1): 29-48.

10. Good quality vaccine longer DOI (reducVon of vaccinaVon costs)

11. Economics •  Direct costs of disease •  ProducVon losses •  Vaccine applicaVon costs •  Costs of the vaccine •  Control costs •  More evaluaVons are necessary Source: MSD emergence focus on. http://www.emergence-msd-animal- health.com/NewsletterArticle.aspx?NL=5&Article=2

12. FMD vaccine quality •  Why is quality so extremely important –  History on control with vaccinaVon –  Good quality vaccine longer duraVon of immunity –  Economics of vaccine quality •  How is vaccine quality affected –  Adjuvant and other addi.ons –  Amount of an.gen –  Ageing effect •  How can a consumer assess vaccine quality –  History of efficacy tesVng –  RelaVon anVbody response and protecVon –  StandardisaVon of serology

13. Barei, S., G. F. Panina, Z. Orfei, L. Nardelli and S. Castelli (1979). "Comparison of the potency for caGle of trivalent FMD vaccines adjuvanted by aluminum hydroxide-saponin or oil emulsion." Zentralbl Veterinarmed B 26(6): 454-60. Adjuvant diﬀerences •  Aluminum hydroxide saponin –  Works perfectly in ruminants •  Oil emulsion adjuvant –  Works both in ruminants and pigs –  Not all oil emulsions are the same •  Comparison of aluminium hydroxide saponin and oil adjuvant indicates superiority of oil adjuvant in ruminants –  Using the same anVgen concentraVon we observed the same potency in Aluminium hydroxide saponin adjuvanted vaccines compared to oil emulsion vaccines •  local reacVons with oil emulsion vaccines are more severe especially in sheep

14. Amount of anVgen •  Old studies by Frenkel, 10 Vmes more anVgen 0.45 – 0.5 log10 higher anVbody level •  Pay and Hingley, 1987, 10 Vmes more anVgen 0.4 log10 higher anVbody level •  Potency tests in pigs with diﬀerent Ag doses, 10 Vmes more anVgen 0.5 log10 higher anVbody level (unpublished data)

15. Type of FMD anVgen VP1 VP1 VP1 VP1 VP2 VP3 Intact 146S Good immune response Dissociated 12S Poor immune response

16. ProtecVon of 12S and 146S in guinea pigs •  Doel and Chong 1982 •  Potency tests in guinea pigs •  400 Vmes more 12S needed for protecVon than 146S •  Very limited data in caGle •  Huge gap: Rela.on between 12S induced an.body response and protec.on

17. Immunogenicity of 12S in pigs •  12S produced by heaVng at 56°C for 1 hour •  VaccinaVon of pigs with the same anVgen heated and non- treated •  FormulaVon in double oil emulsion Approximately 1 log10 lower antibody response.

18. Stability of anVgen is poor •  Most 146S anVgen (O Manisa) disintegrates in oil emulsion vaccines within 3 months when using thiomersal as addiVve •  Stability of Aluminum hydroxide vaccines has not been tested yet •  Similar results in caGle vaccinaVon stability studies Harmsen et al. 2015, vaccines including thiomersal

19. Stability can be improved by addiVon of sugar and BSA M.M. Harmsen et al. 2015. Stabilizing eﬀects of excipients on dissociaVon of intact (146S) foot-and-mouth disease virions into 12S parVcles during storage as oil-emulsion vaccine, Vaccine, 33(21):2477-2484 DOE vaccine

20. CaGle studies and stability •  Frenkel vaccine •  2, 6 and 10 weeks post vac •  1.5 year old •  0.2 year old •  0 – 1 log10 difference •  Titres sVll at protecVve level Frenkel, S. (1964). "ModificaVons de la méthode de culture du virus aphteux selon Frenkel, valeur des vaccins selon les données du laboratoire." BulleVn Office InternaVonal des EpizooVes 61: 9-10

21. CaGle protecVon studies and stability •  Reports of no protecVon against SAT1 strains 6 month amer formulaVon using ISA 206B (which could be pH related) (2013, F.R.M. Peta, thesis) •  T = 0 è 5/5 protected •  T = 6 è 0/5 protected LPBE .tre (log10)

22. FMD vaccine quality •  Why is quality so extremely important –  History on control with vaccinaVon –  Good quality vaccine longer duraVon of immunity –  Economics of vaccine quality •  How is vaccine quality affected –  Adjuvant and other addiVons –  Amount of anVgen –  Ageing effect •  How can a consumer assess vaccine quality –  History of efficacy tes.ng –  Rela.on an.body response and protec.on –  Standardisa.on of serology

23. How can customers test the vaccine quality •  History of eﬃcacy tesVng –  Potency tests •  3 groups of 5 caGle with full, 1/4 and 1/16 dose (at least 3 PD50/dose ≈ 75% protecVon) •  PGP test 16 caGle determining the level of protecVon (at least 75%) à Based on these protecVon test the relaVon between anVbody and protecVon was determinedß –  Small decrease in An.body response huge decrease in protec.on

24. Historically many studies analysing relaVon Ab response and protecVon •  Loeﬄer and Frosch, 1897 –  Passive anVbodies can protect against infecVon •  Van Bekkum et al. 1969 –  566 caGle –  2 weeks post vaccinaVon type C (n=424) –  9-49 months post vaccinaVon 3 serotypes (n=142) •  Pay and Hingley, 1987 –  360 vaccinated and challenged caGle –  3 weeks post vaccinaVon –  3 serotypes •  South-America (several publicaVons, hundreds of caGle) –  Using Liquid phase blocking ELISA

25. VNT titre Protection 0.9 1.2 1.5 1.8 2.1 2.4 2.7 3.0 3.3 3.6 3.9 0.00.20.40.60.81.0 Example: results Pay and Hingley •  RelaVon between Ab and protecVon 3 weeks post- vaccinaVon •  Same slope for all 3 serotypes (observed in many studies) •  Serology can be used for vaccine release •  Diﬀerent cut-oﬀ for each strain Type A24 Type OBFS Type C1 fractionprotected

26. Conclusions from literature •  AnVbody response is a good predictor for protecVon against challenge in both caGle and pigs •  Immunity does not depend on anVbodies alone •  For different vaccines different relaVons are found •  For different routes of vaccinaVon different relaVons are found •  Differences between laboratories can be standardised by inclusion of a standard serum •  Vaccine inducing highest .tre is best choice

27. RelaVon anVbody and protecVon of O Manisa vaccine Titre 10 log Fractionprotected 0.0 0.5 1.0 1.5 2.0 2.5 3.0 0.00.20.40.60.81.0 Example to show the dramaVc eﬀect when the anVbody response is low.

30. Can we use the informaVon in the ﬁeld Jamal et al. 2013. Clear differences between locally produced and internationally acquired FMDV vaccine

31. Yes we can! VNT titre equal to 50% protection for O Manisa is approximately 1.5 in our laboratory NB! Titres decrease after 4 – 5 weeks. Cut-off is determined at 3 -4 weeks

32. Conclusions from literature on relaVon Ab and protecVon •  Small differences (0.5 log10) can have huge consequences in protecVon (in steep part of the curve) •  ProtecVve Vtres determined 3 – 4 weeks amer vaccinaVon, should not be applied to other vaccinaVon sampling intervals without cauVon •  NB! ProtecVon against idl challenge will sufficiently reduce transmission, but in the field lower levels might be sufficient (Van Bekkum et al. 1969)

33. StandardisaVon of serology •  FAO phase XIV study (1996) •  19 laboratories using the same ingredients in the same ELISA •  4 anVbody posiVve reference sera •  Diﬀerence between highest and lowest result varied between 0.8 and 1.0 log10 •  StandardisaVon with a ref serum reduced variaVon to 0.4 to 0.7 log10

34. Potency test results O Manisa 3 laboratories Ukkel, 10 potency tests Pirbright, 2 potency tests Lelystad, 7 potency test StandardisaVon reduced diﬀerences

35. Potency test results O Manisa 3 laboratories Ukkel, 10 potency tests Pirbright, 2 potency tests Lelystad, 7 potency test StandardisaVon reduced diﬀerences

36. Conclusion standardisaVon •  StandardisaVon will reduce variaVon •  VariaVon will sVll exist •  Results will give an indicaVon, but should not be interpreted too absolute

37. Overall conclusion •  Huge diﬀerences between vaccines from diﬀerent producers •  Using poor quality vaccine costs money •  Also good quality vaccines can degrade –  Cold-chain important (especially at airport of arrival) •  Vaccine quality should be monitored –  At Vme of acquisiVon –  At Vme of applicaVon

38. Current gaps in knowledge •  Insuﬃcient data on relaVon anVbody response and protecVon in African and Asian FMD strains –  What precision is needed •  No sera available for standardisaVon of serology Who should do the tesVng •  NaVonal laboratories –  Making them proﬁcient in serology, builds capacity in the country •  InternaVonal reference laboratories –  No experVse on relaVon anVbody response and protecVon with African and Asian strains

OS16 - 1.1.b Frenkel Lecture - A. Dekker

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