Animal use in biologics development, production, and testing

Transcription

1 Animal use in biologics development, production, and testing Implementing Nonanimal Approaches to Human and Veterinary Vaccine Testing: Achieving Scientific and Regulatory Success for Rabies and Beyond October 10, 2018 Jeffrey Brown

2 PETA International Science Consortium 2

3 PETA International Science Consortium See full list of publications at PISCLtd.org.uk/SciPubs 3

4 Outline o Progress and problems 3Rs policies for rabies vaccines (etc.) Tracking animal use and 3Rs policy implementation Peripheral animal use o Progress to come Antibody production Pyrogen testing 4

5 2011 rabies vaccine workshop 5

6 2011 rabies vaccine workshop 6

7 2011 rabies vaccine workshop: NIH test problems o ~200 mice per test o ~50% experience significant unrelieved pain prior to euthanasia o Up to 42% of tests invalid, must be repeated o Up to 400% differences in estimated potency Stokes W, McFarland R, Kulpa-Eddy J, Gatewood D, Levis R, Halder M, Pulle G, Kojima H, Casey W, Gaydamka A, Miller T, Brown K, Lewis C, Capsal JM, Bruckner L, Gairola S, Kamphuis E, Rupprecht CE, Wunderli P, McElhinney L, De Mattia F, Gamoh K, Hill R, Reed D, Doelling V, Johnson N, Allen D, Rinkel L, Jones B. Report on the international workshop on alternative methods for human and veterinary rabies vaccine testing: state of the science and planning the way forward. Biologicals. 2012;40(5):

8 NIH test Bruckner L, Cussler K, Halder M, Barrat J, Castle P, Duchow K, Gatewood DM, Gibert R, Groen J, Knapp B, Levis R, Milne C, Parker S, Stünkel K, Visser N, Volkers P; ECVAM. Three Rs approaches in the quality control of inactivated rabies vaccines. The report and recommendations of ECVAM workshop 48. Altern Lab Anim. 2003; 31(4):

9 NIH test Bruckner L, Cussler K, Halder M, Barrat J, Castle P, Duchow K, Gatewood DM, Gibert R, Groen J, Knapp B, Levis R, Milne C, Parker S, Stünkel K, Visser N, Volkers P; ECVAM. Three Rs approaches in the quality control of inactivated rabies vaccines. The report and recommendations of ECVAM workshop 48. Altern Lab Anim. 2003; 31(4):

10 2011 rabies vaccine workshop: Progress o Implementation strategy to: o Replace NIH test with ELISA and/or SNT EPAA pre-validation study and EDQM international collaborative study o Reduce numbers of mice used to meet NIH test requirements USDA Center for Veterinary Biologics (CVB) Notice 13-10, eliminates upper limit LD50 for a valid challenge o Reduce pain for mice used in NIH test USDA SAM 308 revised, allows anesthesia for mice prior to virus injection USDA CVB Notice 12-12, firms encouraged to use anesthesia prior to virus injection (etc.) Stokes W, McFarlandR, Kulpa-Eddy J, Gatewood D, Levis R, Halder M, Pulle G, Kojima H, Casey W, Gaydamka A, Miller T, Brown K, Lewis C, Capsal JM, Bruckner L, Gairola S, Kamphuis E, Rupprecht CE, Wunderli P, McElhinney L, De Mattia F, Gamoh K, Hill R, Reed D, Doelling V, Johnson N, Allen D, Rinkel L, Jones B. Report on the international workshop on alternative methods for human and veterinary rabies vaccine testing: state of the science and planning the way forward. Biologicals. 2012;40(5):

11 2011 rabies vaccine workshop: Progress o Implementation strategy to: o Replace NIH test with ELISA and/or SNT EPAA pre-validation study and EDQM international collaborative study o Reduce numbers of mice used to meet NIH test requirements USDA Center for Veterinary Biologics (CVB) Notice 13-10, eliminates upper limit LD50 for a valid challenge o Reduce pain for mice used in NIH test USDA SAM 308 revised, allows anesthesia for mice prior to virus injection USDA CVB Notice 12-12, firms encouraged to use anesthesia prior to virus injection (etc.) Stokes W, McFarland R, Kulpa-Eddy J, Gatewood D, Levis R, Halder M, Pulle G, Kojima H, Casey W, Gaydamka A, Miller T, Brown K, Lewis C, Capsal JM, Bruckner L, Gairola S, Kamphuis E, Rupprecht CE, Wunderli P, McElhinney L, De Mattia F, Gamoh K, Hill R, Reed D, Doelling V, Johnson N, Allen D, Rinkel L, Jones B. Report on the international workshop on alternative methods for human and veterinary rabies vaccine testing: state of the science and planning the way forward. Biologicals. 2012;40(5):

12 Problems: counting animals 12

13 Problems: counting animals 13 Laboratory Animal Welfare Act of 1966, P.L

14 Problems: Not just the NIH test o Required to carry out NIH test Virus propagation: birds, mice, hamsters o Required to meet product standard requirements Immunogenicity: target species Purity: mice Safety: mice, rabbits, other species Duration of immunity: target species o Peripheral animals used in experiments Antibody sources Serum sources Pyrogen testing 14

15 Problems: Animal-derived antibodies Stokes W, McFarland R, Kulpa-Eddy J, Gatewood D, Levis R, Halder M, Pulle G, Kojima H, Casey W, Gaydamka A, Miller T, Brown K, Lewis C, Capsal JM, Bruckner L, Gairola S, Kamphuis E, Rupprecht CE, Wunderli P, McElhinney L, De Mattia F, Gamoh K, Hill R, Reed D, Doelling V, Johnson N, Allen D, Rinkel L, Jones B. Report on the international workshop on alternative methods for human and veterinary rabies vaccine testing: state of the science and planning the way forward. Biologicals. 2012;40(5):

16 Problems: Animal-derived antibodies 16 Groff K, Brown J, Clippinger AJ. Modern affinity reagents: recombinant antibodies and aptamers. Biotechnol Adv. 2015;33(8):

17 Problems: Animal-derived antibodies 17 Image: PETA US

18 Progress to come: recombinant antibodies o Phage display 18

19 Progress to come: recombinant antibodies 19 Bradbury A, Plückthun A. Reproducibility: Standardize antibodies used in research. Nature. 2015;518(7537):27-29.

20 Progress to come: recombinant antibodies 20 Bradbury A, Plückthun A. Reproducibility: Standardize antibodies used in research. Nature. 2015;518(7537):27-29.

21 Progress to come: recombinant antibodies 21

22 Progress to come: recombinant antibodies 22

23 Animal use: antibody sources Images: USDA Inspection Reports 23

24 Animal use: antibody sources Images: USDA Inspection Reports 24

25 Animal use: antibody sources Images: USDA Inspection Reports 25

26 Animal use: antibody sources Images: USDA Inspection Reports 26

27 Animal use: antibody sources Images: USDA Inspection Reports 27

28 Animal use: antibody sources Images: PETA India 28

29 Animal use: antibody sources Images: PETA India 29

30 Animal use: antibody sources Images: PETA India 30

31 Progress to come: replacing animal antibodies o Datmab project Phage display, select recombinant human antibodies against diphtheria toxin Assess toxin neutralization of toxin binding antibodies Convert neutralizing antibodies with best binding affinity to IgG Freeze-dry formulation and stability testing Public health stakeholders, further development 31

32 Progress to come: pyrogen testing Images: Cruelty Free International; Timothy Fadek / Corbis / Getty; The Atlantic 32

33 Progress to come: pyrogen testing Zhang S. The Last Days of the Blue-Blood Harvest. The Atlantic. May 9,

34 Progress to come: pyrogen testing Image: Merck 34

35 Summary o Success is difficult to quantify o How to measure impact of animal replacement, reduction, refinement policies? o NIH test replacement is within reach o Improved antibody sources should be prioritised o Antibody production recombinant methods o Research, diagnostic, and therapeutic relevance o Ensuring use of other available replacements o RPT/BET MAT Contact: Jeffrey Brown JeffreyB@PISCLtd.org.uk 35