implementing non-animal approaches to human and veterinary...

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Implementing non-animal approaches to human and veterinary

vaccine testing:Achieving scientific and regulatory

success for rabies and beyond

October 16-17, 2018William H. Natcher Conference Center

National Institutes of HealthBethesda, Maryland

Co-organized by National Toxicology Program Interagency Center for the Evaluation of Alternative Toxicological Methods (NICEATM)

National Toxicology Program Interagency Center for the Evaluation of Alternative Toxicological Methods

Implementing non-animal approaches to human and veterinary vaccine testing: Achieving scientific and regulatory success for rabies and beyond

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National Institutes of Health Natcher Conference Center

Bethesda, Maryland 16-17 October 2018

Day 1 – October 16, 2018 7:30 Registration Poster Set Up

Session 1 Welcome from the Organizers

Moderator: Robin Levis, Food and Drug Administration (FDA)

8:00 Warren Casey, National Toxicology Program Interagency Center for the Evaluation of Alternative Toxicological Methods (NICEATM)

8:15 Richard Hill, International Alliance for Biological Standardization – North America (IABS) Session 2 Setting the Stage for Alternatives to In Vivo Release Testing for Animal and Human Vaccines

Moderator: Richard Hill, IABS

8:30 Human Biologics - North American Regulatory Perspective Robin Levis, FDA

9:00 Animal Biologics - North American Regulatory Perspective Geetha Srinivas, U.S. Department of Agriculture (USDA) – Center for Veterinary Biologics (CVB)

9:30 The “Consistency Approach”: Concept and Progress Since the 2015 Congress Marlies Halder, European Commission Joint Research Center (JRC)

9:50 Rabies and the Innovative Medicines Initiative, Vaccine Lot to Vaccine Lot Comparison by Consistency Testing (IMI Vac2Vac) Catrina Stirling, Zoetis

10:10 Break Poster session available for viewing 10:30 Drivers and Barriers to Replacing the NIH Test for Rabies Vaccine Potency Testing

Marie-Jeanne Schiffelers, Utrecht University 10:50 A Success Story of Alternatives to In Vivo Testing: Pertussis Vaccine Histamine Sensitization Test (HIST)

Waiving and Replacement Juan Arciniega, FDA (retired)

11:10 Substitutions for In Vivo Methods and Potency Test Acceptability: The Fear Factor Dean Smith, Health Canada

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Table of Contents

IABS - Rue de la Vallée, 3 - 1204 Geneva - SwitzerlandTel : +41 22 301 10 36 - Fax : +41 22 301 10 37 - www.iabs.org

Implementing non-animal approaches to human and veterinary vaccine testing :Achieving scientific and regulatory success for rabies and beyond

October 16-17, 2018 - Bethesda, Maryland

Sponsors .............................................................................................................................................................. p.3

About the Conference........................................................................................................................................ p.4

Scientific and Organizing Committee .............................................................................................................. p.4

Scientific Program ...................................................................................................................................... p.5 to 8

Speaker Abstracts .................................................................................................................................... p.9 to 26

Round Table Starter Questions for Session 4 .....................................................................................p.27 to 28

Poster Abstracts .....................................................................................................................................p.29 to 37

Pre-Workshop Webinars ..................................................................................................................................p.38

Bio Sketches ............................................................................................................................................p.39 to 65

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Sponsors




Bill & Melinda Gates Foundation

Back to Table of Contents

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Scientific & Organizing CommitteesSCIENTIFIC COMMITTEE

CO-CHAIRSWarren Casey, National Toxicology Program Interagency Center for the Evaluation of Alternative Toxicological Methods (NICEATM)Robin Levis, Food and Drug Administration (FDA)Richard Hill, International Alliance for Biological Standardization-North America (IABS-NA)

MEMBERSJuan Arciniega, Food and Drug Administration (FDA)(ret)Geetha Srinivas, USDA - Center for Veterinary BiologicsYvette Diamondidis, Zoetis Inc.Cynthia Allen, Health Canada - Biologics and Genetic Therapies Directorate, Viral Vaccines DivisionOksana Yarosh, Canadian Food Inspection Agency - Canadian Centre for Veterinary BiologicsLaurent Mallet, Sanofi PasteurRodney Christmas, Boehringer Ingelheim Animal HealthJames Roth, Institute for International - Cooperation in Animal Biologics/ Center for Food Security and Public HealthLaura Viviani, Humane Society InternationalGautam Sanyal, Vaccine Analytics, LLCJeffrey Brown, PETA International Science Consortium

ORGANIZING COMMITTEEDave Allen, Integrated Laboratory Systems, Inc. (ILS)Rebecca Poston, Integrated Laboratory Systems, Inc. (ILS)(Consultant)Steven Morefield, Integrated Laboratory Systems, Inc. (ILS)Rebecca Sheets, International Alliance for Biological Standardization (IABS)

About the ConferenceVaccines improve human and animal health and welfare by preventing the spread of infectious diseases. However, testing to ensure effectiveness and safety of these products often requires the use of large numbers of animals. Technological advances have led to the development of methods that could reduce or eliminate the need for animal testing for vaccines. This workshop will bring together scientific and regulatory leaders from government, academia and industry to develop recommendations to advance alternative methods for human and veterinary rabies vaccine testing. Additional workshop sessions will also spotlight state-of-the-science animal alternatives for other antigens and future possibilities for advancing animal reduction and replacement initiatives.

REVIEW relevant scientific advancements, state-of-the-art technologies and regulatory success stories for alter-native testing strategies; with a focus on replacement strategies.

EXPLORE application of these new principles for human and animal rabies vaccine testing

CHART and prioritize recommendations for implementing nonanimal approaches for rabies vaccine testing in North America and discuss future planning needs to address their implementation for target antigens at the international level

A series of pre-workshop webinars were held to address foundational principles and practices relevant for work-shop participants.





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Day 1 October 16, 2018

Speaker Abstracts begin on Page 10

7:30 Registration Poster Set Up

Session 1 - Welcome from the Organizers Moderator : Robin Levis, Food and Drug Administration (FDA)

8:30 Warren Casey, National Toxicology Program Interagency Center for the Evaluation of Alternative Toxicological Methods (NICEATM)

8:45 Richard Hill, International Alliance for Biological Standardization – North America (IABS)

Session 2 - Setting the Stage for Alternatives to In Vivo Release Testing for Animal and Human Vaccines

Moderator : Richard Hill, International Alliance for Biological Standardization – North America (IABS-NA)

9:00 Human Biologics - North American Regulatory Perspective Robin Levis, Food and Drug Administration (FDA)

9:30 Animal Biologics - North American Regulatory Perspective Geetha Srinivas, U.S. Department of Agriculture (USDA) - Center for Veterinary Biologics (CVB)

10:00 The “Consistency Approach”: Concept and Progress Since the 2015 Congress Marlies Halder, European Commission Joint Research Center (JRC)

10:20 Rabies and the Innovative Medicines Initiative, Vaccine Lot to Vaccine Lot Comparison by Consistency Testing (IMI Vac2Vac) Catrina Stirling, Zoetis Inc.

10:40 Break Posters available for viewing

11:00 Drivers and Barriers to Replacing the NIH Test for Rabies Vaccine Potency Testing Marie-Jeanne Schiffelers, Utrecht University School of Governance

11:20 A Success Story of Alternatives to In Vivo Testing: Pertussis Vaccine Histamine Sensitization Test (HIST) Waiving and Replacement Juan Arciniega, Food and Drug Administration (FDA)(retired)

11:40 Substitutions for In Vivo Methods and Potency Test Acceptability: The Fear Factor Dean Smith, Health Canada, Centre for Biologics Evaluation




Scientific ProgramBack to Table of Contents

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Session 3 - Rabies Vaccines Alternative Testing State of the Art and Reagent Availability

Moderator : Robin Levis, Food & Drug Administration (FDA)

12:00 Reagents and Serology Marc Fiorucci, Boehringer Ingelheim Animal Health

12:20 Animal Health Institute (AHI) Veterinary Biologics Section (VBS) Rabies Potency Test Working Group - Technical and Procedural Perspectives Nancy Oien, Zoetis Inc.

12:40 Lunch and Posters available for viewing

13:40 Overview of European Partnership for Alternatives to Animal Testing (EPAA) Efforts on Replacement of Animal Testing for Rabies Vaccine and Reagent Availability JM Chapsal, The European Partnership for Alternative Approaches to Animal Testing (EPAA)

14:00 Overview of European Directorate for the Quality of Medicines and Healthcare (EDQM) - Efforts in the Rabies Space Eriko Terao, Council of Europe, EDQM

14:20 An ELISA for Human Rabies Vaccine - Method Validation Leading to Selection for EDQM Audrey Toinon, Sanofi Pasteur.

14:40 Use of ELISA for a New Human Rabies Vaccine: Clinical Trial for a Dose Ranging Study Francoise Guinet-Morlot, Sanofi Pasteur

15:00 Break and Posters available for viewing

15:20 An ELISA for Veterinary Vaccine: Validation and Acceptance by EMA as an Alternative to NIH Rabies Test Marc Fiorucci, Boehringer Ingelheim Animal Health

15:40 Development of In Vitro and In Vivo Rabies Virus Neutralization Assays Based on a High Titer Pseudovirus System Sean (Xuguang) Li, Health Canada, Regulatory Research Division

Session 4 - Charting the Path Forward for Alternative Testing for Rabies Vaccines

Moderator : Laurent Mallet, Sanofi Pasteur

16:00 Roundtable 1 - Setting the Stage - Aspirational Outcomes for the Workshop and Roundtables Introductory Comments - Laurent Mallet, Sanofi Pasteur Moderators : Veterinary Rabies Focus - Catrina Stirling, Zoetis Inc. Human Rabies Focus - Cynthia Allen, Health Canada, Centre for Biologics Evaluation

17:00 - 18:00 Poster Session - Alternatives to Vaccine Testing in Animals - Beyond Rabies




Scientific Program

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Session 4 - con’t. (Charting the Path Forward for Alternative Testing for Rabies Vaccines)(Veterinary and human focus groups will meet separately for majority of Roundtables)

Moderator : Laurent Mallet, Sanofi Pasteur

8:30 Keynote address: Alternatives to Animal Testing - Rabies and Beyond Donna Gatewood, EDGE Veterinary Vaccines Consulting Group

9:00 Brief review of Day 1 Progress and Refinements on Roundtable Goals for Day 2 Veterinary Rabies Focus - Catrina Stirling, Zoetis Inc. Human Rabies Focus - Cynthia Allen, Health Canada, Centre for Biologics Evaluation

9:15 Roundtable 2 - Ideation and Action - (V and H workgroups meet separately) Moderators :

Veterinary Rabies Focus - Donna Gatewood, EDGE Veterinary Vaccines Consulting Group, LLC Human Rabies Focus - Dean Smith, Health Canada, Centre for Biologics Evaluation

12:00 Lunch and Posters breakdown

13:20 Joint Session - Regulatory and Industry speakers will highlight specific challenges, methods to expedite research and regulatory changes

13:20 Regulatory Considerations from the Veterinary and Human Perspective Veterinary Regulatory - Oksana Yarosh, Canadian Food Inspection Agency, Centre for Veterinary Biologics Human Regulatory - Philip Krause, Deputy Director, Office of Vaccines Research and Review, CBER/FDA

13:40 Industry Considerations from the Veterinary and Human Perspective Veterinary Industry - Catrina Stirling, Zoetis Inc. Human Industry - Laurent Mallet, Sanofi Pasteur

14:00 Roundtable 3 - Drafting the Roadmap - (V and H workgroups meet separately) Co-moderators from Roundtables 1&2 : Veterinary Rabies Focus - Donna Gatewood, EDGE Veterinary Vaccines Consulting Group, LLC and Catrina Stirling, Zoetis Inc. Human Rabies Focus - Dean Smith, Health Canada, Centre for Biologics Evaluation and Cynthia Allen, Health Canada, Centre for Biologics Evaluation

15:30 Break




Scientific Program

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Session 5 - Rabies Alternative Testing Wrap-up Global Perspective and Future Considerations

Moderator : Warren Casey, National Toxicology Program Interagency Center for the Evaluation of Alter-native Toxicological Methods (NICEATM)

15:45 Veterinary and Human Roadmaps Veterinary Rabies Focus - Donna Gatewood, EDGE Veterinary Vaccines Consulting Group; and Catrina Stirling, Zoetis Inc. Human Rabies Focus - Dean Smith; Cynthia Allen, Health Canada, Centre for Biologics Evaluation

16:20 Global Perspective and Future Considerations for Decreasing Testing in Animals Rebecca Sheets, IABS

16:40 Closing Conference Comments Warren Casey, National Toxicology Program Interagency Center for the Evaluation of Alternative Toxico-logical Methods (NICEATM) Richard Hill, International Alliance for Biological Standardization-North America (IABS-NA) Robin Levis, Food and Drug Administration (FDA)

Scientific Program

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Speaker Abstracts



Juan Arciniega, DSc Food and Drug Administration (FDA)(ret)

Jean-Michel Chapsal, Ph.D. European Partnership for Alternative Approaches to Animal Testing ( EPAA)

Marc Fiorucci, Ph.D. Boehringer Ingelheim Animal Health

Donna Gatewood, DVM EDGE Veterinary Vaccines Consulting Group

Françoise Guinet-Morlot, Ph.D. Sanofi Pasteur

Marlies Halder, VMD European Commission Joint Research Center

Richard Hill, DVM / MS / Diplomate ACVPM International Alliance for Biological Standardization-North America (IABS-NA)

Robin Levis, Ph.D. Food and Drug Administration (FDA)

Sean (Xuguang) Li, M.D. / Ph.D. Health Canada: Center for Biologics Evaluation

Nancee Oien, M.S. Zoetis Inc.

Marie-Jeanne Schiffelers, MSc / Ph.D. Utrecht University School of Governance

Rebecca Sheets, Ph.D. International Alliance for Biological Standardization (IABS)

Dean Smith, Ph.D. Health Canada, Centre for Biologics Evaluation

Geetha Srinivas, DVM U.S. Department of Agriculture (USDA) Center for Veterinary Biologics (CVB)

Catrina Stirling, Ph.D. Zoetis Inc.

Eriko Terao, Ph.D. Council of Europe, EDQM

Dr. Audrey Toinin, MSc Sanofi Pasteur



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Speaker Abstracts

Juan Arciniega, DSc A Hopeful Story of Replacement or Waiving of In Vivo Testing: The Histamine Sensitization Test (HIST) for Final Bulk Acellular Pertussis Vaccines. Juan L. Arciniega, DSc*.

Despite recent setbacks interrupting transmission, pertussis vaccines have substantially prevented severe disease in infants worldwide. Two types of pertussis vaccines are available: whole-cell (wP), containing killed, partially detoxified Bordetella pertussis organisms; and acellular (aP), containing one or more purified pertussis proteins. wP vaccines were intro-duced to industrialized countries in the mid-20th century, but as early as 1981 many replaced wP with aP vaccines to decrease pertussis vaccine reactogenicity. All aP vaccines include pertussis toxin (PTx) chemically inactivated by different means (glutaraldehyde, formaldehyde - alone or in combination - or H2O2). Mice are naturally resistant to the effects of histamine but become sensitive upon injection of minute amounts of PTx, allowing for the development of the histamine sensitization test (HIST), which measures residual PTx activity. Although originally designed for wP vaccines, HIST, using either lethal or nonlethal endpoints to meas-ure mouse sensitization, has successfully ensured the release of aP vaccines with acceptable residual PTx activity. Nevertheless, a 2010 international decision to replace HIST with an in vitro test culminated in a 2018 proposal to include the CHO cell clustering assay in the Euro-pean Pharmacopeia. A personal summary of the roadmap that led to this successful outcome involved:

1. Establishing, by consensus, the test as a priority for replacement

2. Forming a group with a diverse base of knowledge in pertussis to bring about the transi-tion

3. Clearly defining the characteristics of the test to be replaced and of the candidate replace-ments

4. Holding periodic meetings to regularly review advances

5. Selecting the simplest candidate replacement that performs at least as well as the test it’s replacing

6. Considering the possible uses of candidates not selected, instead of dismissing them, while pursuing consolidated steps if more than one protocol for the chosen replacement is available

* Biologics Consulting (Affiliate). [email protected]. 301-873-0315 (Mobile)




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Speaker Abstracts

Jean-Michel Chapsal, Ph.D. Human Rabies vaccine glycoprotein G ELISA as an alternative to the challenge test: selection of a candidate method and future strategiesJean-Michel CHAPSAL 1, Sylvie MORGEAUX 2, Eriko TERAO 3

(1) EPAA - (2) Control Laboratory Department, ANSM, France - (3) EDQM, DBO/BSP, Council of Europe

Immunization with the native trimeric form of the rabies glycoprotein G induces the production of neutralising antibodies and protection against lethal challenge. In human rabies vaccines manufac-turing, antigen quantification is used for the formulation of the final vaccine lot. Official release con-trol of human rabies vaccines relies upon an in vivo potency test in mice, the NIH test (1). The NIH as-say is a significantly variable test based on immunisation followed by an intracranial virus challenge and is using a large number of mice of which many suffer tetany symptoms. The replacement of the NIH test is thus a high priority for the implementation of the 3R concept. Following the International workshop on Alternative Methods for Human and Veterinary Rabies Vac-cine Testing : State of the Science and Planning the Way Forward organised by NICEATM and ICCVAM in Ames in 2011, an EPAA meeting in 2012 focused on gaps in technical knowledge and validation of in vitro G antigen quantification methods for potency testing, with the view to propose a strategy for the replacement of the NIH test. Participants stressed out that the current in vivo assay should not be used for correlation with the in vitro methods since it is highly variable, and that an agreement strategy should therefore follow. It was also agreed that the alternative glycoprotein G ELISA method should be able to discriminate between potent and sub-potent batches. An International Working Group including regulators, rabies science specialists and vaccine manu-facturers was formed to coordinate an inter-laboratory study aiming at identifying the most suitable replacement assay. A protocol was established to compare several ELISA methods, using potent and sub potent human rabies vaccine lots. The data from this study indicated a good agreement be-tween the ELISA and the NIH test. One of the tested ELISAs was selected for its ability to discriminate potent from sub-potent lots but also to detect the main virus strains used in vaccine manufacturing (2, 3). The results of this study were presented in 2015 at an EPAA group workshop and were pub-lished (3). Based on these results, an international collaborative study (coded BSP148) was launched by the Biological Standardisation Programme of the Council of Europe and the EU Commission to further validate the transferability and robustness of the selected ELISA. This BSP study should support to the global replacement of the in vivo NIH test by an in vitro method for the official release potency test of human rabies vaccines.References1. Laboratory techniques in rabies: the NIH test for potency. Seligmann EB. Monogr Ser World Health Organ., 1973,(23):279–86.2. G-protein based ELISA as a potency test for rabies vaccines. Chabaud-Riou M, Moreno N, Guinchard F, Nicolai MC, Niogret-Siohan E, Sève N, Manin C, Guinet-Morlot F, Riou F. Biologicals, 2017,46:124-29.3. Replacement of in vivo human rabies vaccine potency testing by in vitro glycoprotein quantification using ELISA - Results of an international collaborative study. Morgeaux S, Poirier B, Ragan I, Wilkinson D, Arabin U, Guinet-Morlot F, Levis R, Meyer H, Riou P, Shaid S, Volokhov D, Tordo N, Chapsal JM. Vaccine, 2017, 40(5):369-81




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Speaker Abstracts

Marc Fiorucci, Ph.D. Reagents-ELISA-Specification- How do we get away from In Vivo potency for RABIES Veterinary Products ?Significant evolutions have been made in the rabies manufacturing and the quality guidelines over the past decades.

The mouse challenge test, developed in the mid 50’s, still remains the historical method for the potency determination and it is still widely used throughout the world. In order to reduce the distress brought by vaccination/challenge model and the number of animals used, Eu-ropean Phramacopoeia has recently recognised the use of Potency Serological Assay as an alternative to this challenge test.

However, nowadays, the work for a total replacement of the use of animals for releasing rabies product is still in progress.

This presentation will highlight the singularity of veterinary Rabies vaccines, the selection of rabies antibodies for the development of an immunoassay and the different ways that can be implemented to release a veterinary rabies vaccine with a full In Vitro approach.




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Speaker Abstracts

Marc Fiorucci, Ph.D. A Rabies ELISA for veterinary vaccine: validation and acceptance by European authorities as an alternative to the vaccination/challenge modelIn the European pharmacopoeia, regulatory potency test for rabies vaccines requires either mice vaccination followed by challenge or vaccination followed by a serum virus neutraliza-tion assay.

With the aim of replacing the usage of animals for releasing rabies vaccines, Boehringer-In-gelheim Animal Health has developed, validated and implemented an ELISA targeting the glycoprotein G of the rabies virus. The selection of antibodies as well as the relevance of this ELISA and the comparison between this immunoassay and the In Vivo Potency historical methods will be highlighted.

Regulatory pathway followed in order to remove the vaccination/challenge test from the specification of Rabisin® in Europe will be featured.

Last, the main challenges regarding the worldwide acceptance of this full In Vitro approach will be discussed.




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Speaker Abstracts

Donna Gatewood, DVM Alternatives to Animal Testing - Rabies and BeyondThree R (reduce/refine/replace) efforts to reduce animal use and suffering in product testing have been underway for decades. While there have been some notable successes, the fact remains that extensive animal testing continues, particularly in the area of veterinary vac-cines.

Animal testing served an important purpose in the early days of veterinary vaccine produc-tion. Manufacturing processes were in many cases quite crude, and extensive final product testing was critical to confirm the safety, purity, and potency of the vaccine. Consider for ex-ample rabies vaccines. It was not so long ago that these vaccines were produced by inocu-lating live virus into mouse or sheep brains, harvesting the infected brains, homogenizing the tissue, and then, in the case of killed vaccine, using an inactivating agent to kill the virus. The inherent variability of these processes warranted comprehensive testing of the final product in animals, and there were no reasonable alternatives.

Fortunately, advancements in science and technology have allowed manufacturers to refine their production processes to the point that consistency in production is achievable. Pro-cesses can be very closely monitored and controlled, and in-process testing of antigen can provide substantial information about antigenic content and quality. Concurrent with the advances in science and technology, manufacturers have established robust quality manage-ment systems to ensure that appropriate manufacturing controls are in place, adhered to, and documented at every step of the production process.

Traditional regulatory dogma calls for a single assay on final product to confirm product po-tency. Advancing Three R efforts requires a fresh approach to the way we think about imple-menting in vitro replacement testing. Recognition of consistency in production, utilization of new and emerging technologies, use of in-process testing, and consideration of assay panels rather than a single test on final product could allow for further successes in reduction of animal use and suffering.

[email protected] Maxwell AvenueAmes, Iowa 50010515 231 3610




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Speaker Abstracts

Françoise Guinet-Morlot, Ph.D. G protein content measured by ELISA correlates with immune response: results from a randomized dose- ranging Phase II studyF. Guinet-Morlot, P. Riou, S. PichonSanofi Pasteur has a longstanding commitment to constantly improve quality standards for its com-mercialized vaccines. The next generation of rabies vaccine PVRV-NG2 has been developed with an improved and innovative manufacturing technology resulting in a highly purified vaccine that lacks antibiotic and components of human and animal origin. As part of global efforts to reduce animal experimentation and to comply with Sanofi Pasteur internal 3R policy, the ambition is to register PVRV-NG2 without any tests on animals. As of today, all in vivo tests have been replaced by in vitro alternatives, except for the NIH test (based on mice immunization followed by intracerebral viral challenge). This NIH test currently measures human rabies vaccine potency, a key criterion for vac-cine release, since it is considered to be predictive of an adequate immune response in humans (1). To replace this NIH test, we develop an ELISA (2) able to quantify Glycoprotein G and detect structur-al alterations (3). This ELISA is used to monitor the process, follow the vaccine stability, and define at the formulation step the final antigen content per dose of vaccine.

To select the dose of antigen in the PVRV-NG2 formulation we compared in a randomized controlled Phase II dose ranging study (NCT03145766) the immune response of 3 batches of PVRV-NG2 at a low, medium, and high antigen content with the licensed Imovax® rabies vaccine and with a previous formulation named, PVRV-NG1.

In this descriptive study, 320 healthy adults were vaccinated according to a 5-dose, post-exposure regimen at day (D)0, 3, 7, 14, and 28 by intramuscular (IM) route. All adults received human rabies im-munoglobulin (HRIG) at D0 (IM route, simulated conditions). Participants were followed for 6 months after final vaccination and immunogenicity was assessed using the RFFIT test. Results showed that at each time-point, the geometric mean titers (GMTs) increased with PVRV-NG2 antigen content, and the highest dose of PVRV-NG2 investigated compared favorably to Imovax® Rabies.

This study demonstrates a dose effect of antigen content at all time-points, and confirms that G pro-tein content measured by ELISA was an accurate predictor of the human immune response. This test was selected by an International Working group under the leadership of EPAA to be the most prom-ising candidate to replace the NIH test (4) and EDQM is currently organizing an international collabo-rative study for assessing the transferability and the intra- and inter-laboratory variability of this test. Upon successful completion of this study, this ELISA will be introduced as an alternative to the NIH method in the Pharmacopoeia monograph.(1):WHO TRS 941

(2) Chabaud-Riou M, Moreno N, Guinchard F, Nicolai MC, Niogret-Siohan E, Sève N, Manin C, Guinet-Morlot F, Riou P. G-protein based ELISA as a potency test for rabies vaccines. Biologicals. 2017 Mar;46:124-129

(3) Audrey Toinon, Nadege Moreno, Heloise Chausse, Emilie Mas, Marie Claire Nicolai, Fabien Guinchard, Isabelle Jaudinaud, Françoise Guinet-Morlot, Patrice Riou and Catherine Manin, Potency tests to discriminate between differentially over-inactivated rabies vaccines: Agreement between the NIH assay and the Sanofi Pasteur ELISA, submitted for publication

(4) Sylvie Morgeaux, Bertrand Poirier , C. Ian Ragan c,⇑, Dianna Wilkinson d, Ulrich Arabin e,Françoise Guinet-Morlot f, Robin Levis g, Heidi Meyer h, Patrice Riou f, Shahjahan Shaid e, Dmitriy Volokhov g,Noël Tordo i,j, Jean-Michel Chapsal, Replacement of in vivo human rabies vaccine potency testing by in vitro glycopro-tein quantification using ELISA – Results of an international collaborative study, Vaccine 35 (2017) 966–971




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Speaker Abstracts

Marlies Halder The “Consistency Approach”: Concept and Progress Since the 2015 CongressEuropean Commission Joint Research Centre; Ispra (VA), Italy

The consistency approach aims to ensure the uninterrupted release of safe and efficacious products. Vaccine batches / lots are regarded as one of a series. DeMattia et al (2011) defined the consistency approach as follows: “The consistency approach is a concept which includes the strict application of GMP rules and guidelines, process validation and in process and final product tests and is aimed at verifying if a manufacturing process produces final batches which are consistent with one that fulfils all the criteria of Quality, Safety and Efficacy as defined in the marketing authorization, ultimately resulting in replacement of routinely used in vivo tests.”

The presentation will give an overview on the consistency approach, current discussions and recent developments towards its implementation for established vaccines (e.g. IMI2 VAC2VAC project).

*Corresponding author: Marlies Halder, [email protected], European Commission Joint Research Centre; Ispra (VA), Italy; phone: +39-0332-785550

Hendriksen C, Arciniega JL, Bruckner L et al. The consistency approach for the quality control of vaccines. Biologicals 2008; 36(1): 73-77.

De Mattia F, Chapsal JM, Descamps J et al. The consistency approach for quality control of vaccines - a strategy to improve quality control and implement 3Rs. Biologicals 2011; 39(1):59-65.

De Mattia F, Hendriksen C, Buchheit K-H et al. The Vaccines Consistency Approach Project: an EPAA initiative: Pharmeuropa Bio&SN | May 2015 30-58.




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Speaker Abstracts

Richard E. Hill, Jr., DVM / MS / Diplomate ACVPM Welcome from the International Alliance for Biological StandardizationThe International Alliance for Biological Standardization (lABS) is a nonprofit professional organization that was established in 1955 and is headquartered in Geneva, Switzerland. For more than 60 years, IABS has had an impact on scientific and regulatory processes world-wide through collaborative scientific meetings and publications in the journal Biologicals. Together, with conference partners and collaborators (private industry, academia, regulatory officials) IABS has held a variety of conferences on a broad spectrum of topics concerning the veterinary and human biological and biopharmaceutical arenas. IABS’ unique role and strength reside in its ability to bring together interested parties for scientific discussions of important unresolved or emerging issues to assist in developing a consensus and an action plan to achieve regulatory progress. In 2015, an IABS North American Affiliate (IABS-NA) was created with a similar organizational mission; with emphasis on biological standardization issues in North America. The topic of “3Rs” was selected as the inaugural conference for IABS-NA. This introductory presentation will briefly review the organizational history of IABS-NA and the genesis of this workshop in collaboration with the National Toxicology Program Interagency Center for the Evaluation of Alternative Toxicological Methods (NICEATM).




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Speaker Abstracts

Robin Levis, Ph.D. Alternatives for the NIH Potency Assay for Rabies Virus Vaccines: Past and PresentDivision of Viral Products/Office of Vaccines Research and Review

Center for Biologics Evaluation and Research/Food and Drug Administration

Human rabies virus vaccine potency is currently assessed using the NIH potency test, a test which measures protection against rabies virus challenge in immunized mice. While the test is well accepted as a measure of vaccine potency/efficacy, the assay has several criti-cal problems. These include; the expense and length of the test, the use of many animals, a lethal challenge step, and a high degree of variability between assays. Vaccine manufactur-ers and regulatory authorities for both veterinary and human vaccines have been working for some time (decades) to develop an alternative assay to measure vaccine potency. This presentation will provide a historical perspective to alternate test development for human rabies virus vaccines and introduce considerations for an alternative potency assay based on an ELISA assay to measure rabies G glycoprotein.




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Speaker Abstracts

Sean (Xuguang) Li, M.D. / Ph.D. Development of in vitro and in vivo rabies virus neutralization assays based on a high-titer pseudovirus systemJianhui Nie 1#, Xiaohong Wu 2#, Jian Ma 1, Shouchun Cao 2, Weijin Huang 1, Qiang Liu 1, Xuguang (Sean) Li 3,4, Yuhua Li 2*, Youchun Wang 1*

(1) Division of HIV/AIDS and Sex-transmitted Virus Vaccines, National Institutes for Food and Drug Control (NIFDC), No.2 Tiantanxili, Beijing 100050, China. (2) Division of Arboviral Vaccines, National Institutes for Food and Drug Control (NIFDC), No. 2 Tiantanxili, Beijing 100050, China.(3) Centre for Biologics Evaluation, Biologics and Genetic Therapies Directorate, Health Canada, Ottawa, On K1A 0K9, Canada.(4) Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, On, Canada.(#) These authors contributed equally to this work. (*) Correspondence and requests for materialsshould be addressed to Y.L. ([email protected]) or Y.W. ([email protected]). Presented by Dr. Xuguang (Sean) Li, Centre for Biologics Evaluation, Biologics and Genetic Therapies Directorate, Health Canada

Pseudoviruses are useful virological tools because of their safety and versatility; however the low titer of these viruses substantially limits their wider applications. We developed a highly efficient pseudovirus production system capable of yielding 100 times more rabies pseudovi-rus than the traditional method. Employing the high-titer pseudoviruses, we have developed robust in vitro and in vivo neutralization assays for the evaluation of rabies vaccine, which traditionally relies on live-virus based assays. Compared with current rapid fluorescent focus inhibition test (RFFIT), our in vitro pseudovirus-based neutralization assay (PBNA) is much less labor-intensive while demonstrating better reproducibility. Moreover, the in vivo PBNA assay was also found to be superior to the live virus based assay. Following intravenous administration, the pseudovirus effectively infected the mice, with dynamic viral distributions being sequentially observed in spleen, liver and brain. Furthermore, data from in vivo PBNA showed great agreement with those generated from the live virus model but with the experi-mental time significantly reduced from 2 weeks to 3 days. Taken together, the effective pseu-dovirus production system facilitated the development of novel PBNA assays which could replace live virus-based traditional assays due to its safety, rapidity, reproducibility and high throughput capacity.




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Speaker Abstracts

Nancee L. Oien, M.S. Animal Health Institute (AHI)/Veterinary Biologics (VBS) Rabies Potency Test Working Group: Technical and Procedural PerspectiveNancee L. Oien 1, Marc Fiorucci 3, Tom Evans 1, Jennifer Johnson 5, Alethea Fry 5, Geetha Srinivas 5, Paul Hauer 5, Andrew Pratt 1,Jennifer Develbess 2, Sue Bonk 2,Kris Fairbanks 1, Robert Mandell 3, James McCord 2, Helen Smith 3, Brett Webster 4, Will McCauley 6

(1) Zoetis Inc, Kalamazoo, MI, (2) Merck, (3) BIVI, (4) ELANCO, (5) APHIS, USDA,(6) Animal Health Institute

The in vitro rabies potency assay working group, comprised of industry representatives affil-iated with the Animal Health Institute (AHI), was established in ca. 2012 and, in collaboration with the Center for Veterinary Biologics-USDA, has been working to replace the NIH Rabies Mouse Potency Test with an in vitro assay. The working group has been evaluating approach-es similar to those described by the EPAA (European Partnership for Alternatives to Animal Testing) and VAC2VAC and has identified two additional monoclonals that are more readily available in the US but are not being considered by either EPAA or VAC2VAC. These neutral-izing rabies glycoprotein G specific monoclonal antibodies, 509-6 and 523-11 (developed by the Wistar Institute), have been shown to differentiate antigens that have been altered by temperature, deglycosylation, and low pH in an indirect EIA format. As the working group continues to characterize and optimize the proposed EIA, the group has begun to outline the procedural aspect for gaining regulatory and public confidence of an in vitro potency assay for release of rabies vaccines. This talk will focus on these key technical and regulatory as-pects as they relate to veterinary vaccines.




21

Speaker Abstracts

Marie-Jeanne Schiffelers, MSc / Ph.D. Drivers and Barriers to Replacing the NIH Test for Rabies Vaccine Potency TestingUtrecht University School of Governance: [email protected]

The use of animals in batch release testing of vaccines very often is a regulatory obligation and represents around 80% of the total number of animals used in the vaccine industry. This heavy reliance on animal experimentation meets serious ethical, scientific and economic ob-jections. Additionally the use of 3R models is stimulated through (European) legislation. None-theless, the acceptance and use of available 3R methods is highly challenging, raising the question which factors influence the acceptance and use of 3R models for regulatory pur-poses and how to optimise this process? To examine the influencing variables and to define optimizing options, this presentation focusses on a survey (1.) and a case study (2.) regarding rabies vaccine potency testing to elucidate the factors influencing the acceptance and use of 3R models for rabies vaccine potency testing purposes in general and the Serum Neutralisa-tion Test developed by the Paul Ehrlich Institut in Germany, in particular. The findings are put into the broader perspective of technology transition. Through this additional step, the broad-er mechanism behind the existing inertia is described and input is given for the discussion between regulatory authorities and industry on how to enhance the regulatory acceptance and use of 3R models.References

1. Schiffelers, M.J., Blaauboer, B., Bakker, W. and Hendriksen, C. (2014). Replacing the NIH test for rabies vaccine potency testing: a synopsis of drivers and barriers, Biologicals 42, 4, 205-217.

2. Schiffelers, M.J.W.A., Blaauboer, B.J, Bakker, W.E., Hendriksen C.F.M. (2015). Regulatory acceptance & use of serology for inactivated veterinary rabies vaccines: a process reconstruction and lessons learned. ALTEX 32(3)




22

Speaker Abstracts

Rebecca Sheets, Ph.D. Global Perspective and Future Considerations for Decreasing Testing In Animals

IABS-NA Vice President

Around the world, many countries have policies or legislation that encourage reduction, replace-ment, or refinement of use of animals in product testing. Within the EU, this 3R’s approach is mandatory, whereas in the US, the approach is encouraged, but not thoroughly enforced. In many countries in the rest of the world, there is no legislation at all to even encourage the 3R’s. This uneven approach makes it very challenging for multinational companies, like most vaccine companies are, to comply with requirements in all markets. For European companies, they can-not conduct the animal testing with in vitro alternatives are accepted so it becomes essentially illegal for them to comply with countries’ requirements that have not abandoned the animal tests. In addition, double testing is not consistent with a Quality approach.In addition to potency and certain safety testing (e.g., completion of inactivation), additional tests should be considered for application of the 3R’s. Most vaccines are still required to con-duct abnormal toxicity testing (e.g., the target animal batch safety test) even though many coun-tries have eliminated them. All viral vaccines are tested for adventitious agents, even though there are acceptable in vitro alternatives that have been in existence for decades and new al-ternatives that are ostensibly broader and potentially as sensitive or suitably sensitive are being validated. Many of the old animal methods are accepted despite having never been validated in accord-ance with the principles exposed in ICH Q2(R1), which are now expected. New in vitro methods cannot be directly compared to old animal methods because the read-outs differ significant-ly as well as other reasons. Thus, it will take leadership on the part of regulators throughout the world to let go of old-fashioned and accepted animal tests in favor of more modern, more complex, and less wide-spread technologies. But, in this century, there is a mandate to reduce, replace, and refine the use of animals in product testing.




23

Speaker Abstracts

Dean Smith, Ph.D. Substituting In Vitro for In Vivo Vaccine Potency and Safety Assays: Science Versus the Fear Factor

An almost five decade long effort to implement an in vitro alternative to the in vivo NIH rabies vaccine potency assay is but one example of challenges confronting manufacturers, national control laboratories and regulatory authorities in our collective efforts to establish more appro-priate and effective in vitro potency and safety quality control (QC) assays for licenced vaccines. In contrast, there are several examples (including adjuvanted viral vaccines and adjuvanted bacterial conjugate vaccines), where key quality attributes are monitored during production and lot release using only physical chemical methods, including or excluding in vitro bioassays. Why then has innovation in assay development for several viral and bacterial vaccines critical public health been such a challenge? While technical issues include the high variability inherent of in vivo methods, an equally important barrier has been an over evaluation of what in vivo assays are capable of and, therefore, a fear of losing these tests. Additionally, there is an undervalua-tion of the more precise insights into product QC that well-designed in vitro methods can offer. Recently, the European Pharmacopeia (Eur. Ph.) human and veterinary vaccine working groups have developed General Chapter 5.2.14. This guidance introduces “substitution” as a new ap-proach to facilitate the transition from in vivo to in vitro methods, where one-to-one compari-sons are not feasible or scientifically justified (e.g., the NIH test for approved products). Eur. Ph. 5.2.14 describes in vivo assays as “less suitable” methods compared to well-designed in vitro QC, strategies and an absence of scientific justification for the General Safety Test resulted in its deletion from the Eur. Ph. Other in vivo so called “safety tests” are being reconsidered. While independently developed, this approach is also in line with subsequent efforts to develop al-ternative vaccine characterization and QC assays through VAC2VAC under the European-based Innovative Medicines Initiative.




24

Speaker Abstracts

Catrina (Cat) Stirling, Ph.D. Vaccine batch to vaccine batch comparison by consistency testing (VAC2VAC)

Authors: Catrina Stirling 1, Denis Lambrigts 2, Sylvie Uhlrich 3, Coenraad Hendriksen 4, Odile Leroy 5, Paul Sticking 6, Elisabeth Balks 7, Anke Huckriede 8, Arjen Sloots 4, Marlies Halder 9, Joris Vandeputte 10, Hilde Depraetere 5

VAC2VAC brings together a unique One Health consortium of human and animal health pharma-ceutical companies, academia, translational research organisations, Official Medicines Control Laboratories and regulatory bodies with the overall objective to demonstrate proof of concept of the consistency approach for batch release testing of established vaccines. This means that an-imal-free assays - instead of animal tests - can be used to ensure that each vaccine batch pro-duced is consistent with a batch already proven to be safe and efficacious in registration studies or in clinical use. Hence the name “consistency approach”. It covers vaccine potency, safety and animal welfare. The project aims to promote global understanding and acceptance of these new non-animal methods to facilitate international harmonisation and improved vaccine availability globally.

The three main steps to reach these objectives are:

1) Development of new or optimisation of existing non-animal methods for consistency testing This is the core activity of the project, with a focus on development and optimisation of physico-chemical methods, immunochemical methods, cell-based assays, and multi-parametric assays & bioinformatics.

2) Pre-validation of selected methodsFor selected methods developed in VAC2VAC, small-scale multi-centre studies will be set up to assess the transferability and inter-laboratory reproducibility of the methods. Methods that are successful in these pre-validation studies and that are proposed for inclusion in regulatory mon-ographs, will be submitted to the EDQM Biological Standardisation Programme to be considered for further validation studies.

3) Regulatory acceptance of the consistency approachTo maximise the chances of regulatory acceptance and implementation of the consistency approach for batch release, the development of methods in VAC2VAC will involve close coopera-tion between public partners and industry partners in consultation with the regulatory bodies. The presentation will outline the project in detail and discuss some early results and end with a summary of the approach, progress and next steps for Rabies vaccines.(1) Zoetis Belgium SA, (2) GSK Biologicals, (3) Sanofi Pasteur, (4) Institute for Translational Vaccinology, (5) European Vaccine Initiative, (6) National Insti-tute for Biological Standards and Control, (7) Paul-Ehrlich Institut, (8) University Medical Center Groningen, (9) European Commission, Joint Research Centre, (10) International Alliance for Biological Standardization for Europe

The project is supported by the EU/ European Federation of Pharmaceutical Industries and Associations (EFPIA)/Innovative Medicines Initiative (IMI2) Joint Undertaking (VAC2VAC grant n° 115924).




25

Speaker Abstracts

Eriko Terao, Ph.D. Moving towards a global replacement of the animal test for human rabies vac-cines by an ELISA: an international collaborative study (BSP148)

S. Morgeaux (Agence National de Sécurité des Médicaments et Soins de Santé, ANSM, France)JM. Chapsal (European Partnership for Alternatives to Animal Testing, EPAA)E Terao (EDQM, Council of Europe, France)Regulatory texts for human rabies vaccines require that the potency of each final lot is estimat-ed by a mouse challenge assay (NIH test). The NIH test is, among the remaining compendial in vivo assays, one of the most challenging to replace. It is a painful, scientifically disputable, high-ly variable and costly test that is contrary to the 3R strategy of the European Pharmacopoeia (Ph. Eur.). Despite many efforts, the global replacement of the NIH test by an in vitro assay is hindered by the absence of a common standardised method. One of the latest initiatives is the international study run by the European Partnership for Alternative Approaches to Animal Test-ing (EPAA). The project identified the currently most promising ELISA method [1]. It is a method which uses highly-characterised monoclonal antibodies, is specific to conformational epitopes responsible for the protection conferred by the vaccines, recognises most virus strains used for vaccine production and discriminates test sub-potent vaccines produced by various methods. With a view to proposing a global replacement of the NIH test, an international collaborative study was set up to evaluate the large-scale transferability and robustness of the selected method. The coordination of the study is ensured by the European Directorate for the Quality of Medicines & HealthCare (EDQM, Council of Europe) in the frame of the Biological Standardisation Programme (BSP) financed by the Council of Europe and the European Union Commission.The study will include 3 phases: a preparatory Phase 1, a collaborative Phase 2 involving labora-tories worldwide testing a common set of samples with various virus strains and potencies with a standardised protocol. Data will be centrally analysed at the EDQM. The Phase 3 of the study will aim at collecting data from commercial batches tested with the standardised protocol. These data will support the evaluation of the applicability of the method to routine testing and of the potency requirements in view of the revision of compendial texts.

[1] Replacement of in vivo human rabies vaccine potency testing by in vitro glycoprotein quantification using ELISA - Results of an international collab-orative study. Morgeaux S, Poirier B, Ragan I, Wilkinson D, Arabin U, Guinet-Morlot F, Levis R, Meyer H, Riou P, Shaid S, Volokhov D, Tordo N, Chapsal JM. Vaccine, 2017, 40(5):369-81

* Corresponding author: E. Terao, [email protected], European Directorate for the Quality of Medicines & HealthCare (EDQM), Council of Europe, Strasbourg, France, +33 3 90 21 42 00




26

Speaker Abstracts

Audrey Toinon, MSc An ELISA for Human Rabies Vaccine - Method Validation Leading to Selection for EDQMA. Toinon*1, P. Riou 1, F. Guinet-Morlot1

Sanofi Pasteur has improved the current Verorab® vaccine to develop a next generation, highly-purified Vero cell rabies vaccine (PVRV-NG). During vaccine development, Sanofi Pas-teur has also developed and validated an ELISA to detect and quantify rabies virus Glycopro-tein G structural alterations [1]. This ELISA is based on two neutralizing monoclonal antibodies that target the well-conformed G-protein sites II [2, 3] and III [4, 5]. Both sites have been identified as important in triggering a protective immune response against rabies. To demonstrate that this ELISA may be a candidate replacement for the NIH potency test, several assays have been conducted that demonstrate the capability of the ELISA to monitor key quality attrib-utes of the vaccine. Experimental vaccines subjected to different types of stress conditions (i.e. thermodegradation, hyperinactivation [6]) were analysed with both the ELISA and NIH tests. The results showed that the ELISA is more precise in detecting structural alteration of the virus than the NIH test and that there is agreement between the ELISA and NIH results for the altered experimental vaccines tested demonstrating that the Sanofi Pasteur ELISA may be a suitable candidate for the replacement of the NIH potency test. Considering this da-ta, the Sanofi Pasteur ELISA has been selected by EDQM (European Directorate for the Qual-ity of Medicines) for a collaborative international study [7] (Biological Standardization Program 0148 study).

[1] Chabaud-Riou M. et al, G-protein based ELISA as a potency test for rabies vaccines. Biologicals. 2017 Mar;46:124-29.[2] Gamoh K et al, Use of ELISA for in vitro potency test of rabies vaccines for animal use. Biologicals: Journal of the International Association of Biological Standardization. 1996;24:95-101.[3] Luo TR et al, Antigenic and functional analyses of glycoprotein of rabies virus using monoclonal antibodies. Microbiol Immunol. 1998;42:187-93.[4] Nagarajan T et al, A simple immuno-capture ELISA to estimate rabies viral glycoprotein antigen in vaccine manufacture. Biologicals. 2006;34:21-7.[5] Gibert R et al, A relevant in vitro ELISA test in alternative to the in vivo NIH test for human rabies vaccine batch release. Vaccine. 2013;31:6022-9.[6] Toinon A et al. Potency tests to discriminate between differentially over-inactivated rabies vaccines: Agreement between the NIH assay and the Sanofi Pasteur ELISA, submitted for publication. [7] Morgeaux S et al, Replacement of in vivo human rabies vaccine potency testing by in vitro glycoprotein quantification using ELISA – Results of an international collaborative study. Vaccine. 2017;35 966–71.

*Corresponding Author: Audrey Toinon, [email protected], +33 4 37 37 56 28

1Sanofi Pasteur, Research & Development, 1541 Avenue Marcel Merieux, 69280 Marcy l’Etoile, France




27

Round Table Starter Questions for Sessions 4




Roundtable 11) What makes an alternative test method(s) acceptable or not for stakeholders?2) What are the most appropriate stability indicating in vitro potency test methods for lot release and stability testing of Rabies vaccines?3) What challenges must be addressed to facilitate use of alternative tests by stakeholders? 4) What considerations can/should be made for mutual recognition of an acceptable alternative test among different regulatory bodies/jurisdictions?

Roundtable 2ELISA and other Alternative Test MethodsWith the understanding that at an ELISA method has been accepted as an alternative test for the NIH Rabies potency test for an animal vaccine in the EU and, a single stability indicating ELISA is currently being evaluated for several approved human Rabies vaccines 1) Is there agreement that glycoprotein (GP) ELISAs are the preferred alternative to the currently licenced in vivo Rabies vaccine potency assays? Why or Why not?2) What are the challenges for moving forward with alternative Rabies vaccine tests in North Amer-ica (NA)? What about other jurisdictions beyond the EU and NA?3) Can a single ELISA function as an alternative test for multiple vaccine strains? For human vac-cines? For animal vaccines? 4) What are data expectations for an ELISA (or in vitro neutralization test, or other alternative test method etc.). For lot release and stability testing? 5) Can an alternative test for in vivo Rabies potency test be accepted/harmonized across different regulatory jurisdictions? Why or why not? 6) Can regulatory authorities accept different companies using different alternative tests?7) Is there a need for a single format ELISA? Benefits and drawbacks? 8) In addition to vaccine manufacturer’s in-house alternative test method, is a common or interna-tional standard needed? What are the benefits and drawbacks for various stakeholders?9) What additional data/studies might be required by NA regulators


28

Round Table Starter Questions for Sessions 4

Tackling reagent availabilityReagent availability has historically been one of the rate-limiting steps for the implementation of alternative tests that are applicable to the same vaccine produced by several manufacturers.1) What are the options to ensure reagent availability? What are the challenges for different stakeholders? 2) What are current best practices or new ways to address availability of reagents? 3) What potential processes can be put into place to ensure cooperation between stakeholders to develop reagents and assays for implementing alternatives to in vitro testing for rabies? 4) When could such models/processes be practically used for other vaccines?

Best practices for increasing confidence of alternative Rabies vaccine potency tests for lot release and stability testing1) What is best practice for stakeholders to ensure the alternative test is relevant/indicative of potency? If an alternate in vitro method is not fully stability indicating, how can a manufacturer avoid the need to maintain an in vivo test to characterize a product after and major manufactur-ing change. 2) What combination(s) of non-animal alternative test methods would be optimal for Rabies po-tency and stability indication? Why?3) For various methods, what alternative test validation data must be generated in order to con-fidently demonstrate vaccine potency and stability by alternative tests? a) Data from sub-formulated and sub-potent batches (accelerated stability)b) How does the presence or absence of adjuvants affect ability to use the alternative tests?

Roundtable 3Roadmap for successful implementation of replacement tests for current Rabies vaccines, next generation Rabies vaccines1. WHICH TESTS? Gain consensus on best suited replacement test alternatives to in vivo test methods for Rabies vaccine safety and potency release testing. a. Consideration for methods most likely to lead to regulatory harmonization2. WHAT’S NEEDED? Generate a “high level” requirements list for successful implementation. a. Example requirements may include key steps to the process, key scientific requirements, key data packages, key approvals. 3. WHEN CAN IT HAPPEN? Generate a “high level” timeline for delivery of “requirements list.”a. Include approximate time for each deliverable, including different stakeholder perspectivesb. Which deliverables can be generated simultaneously?4. WHO DOES IT? Discuss and identify stakeholder responsibilities in the context of “require-ments list”. a. Identify and discuss differences in stakeholder viewpoints related to responsibilities (gray are-as) or other likely obstacles to success. b. Discuss potential solutions




29

Poster Abstracts


National Institutes of Health - William H. Natcher Building - Bethesda, Maryland - October 16-17, 2018


Ulrich Arabin GSK Vaccines GmbH

Erika Molica Colella Istituto Zooprofilattico Sperimentale della Lombardia e dell’Emilia Romagna- IZSLER

Rebecca Duit National Institute for Biological Standards and Control (NIBSC)

Katherine Groff People for the Ethical Treatment of Animals (PETA)

Marlies Halder European Commission, Joint Research Center

Marin Ming Sanofi Pasteur

Kathy L. Rowlen InDevR Inc.

Y. Bruce Yu University of Maryland


30

Poster Abstract

Replacing the required LD50 by a TCID50 for infectious virus challenge

Ulrich Arabin Roman Adamczyk, Ulrich Arabin* * Corresponding Author: Ulrich Arabin

GSK

Emil von Behring Strasse 76,

35041 Marburg, Germany,

[email protected]

+491622348685

At GSK, animal studies, which are conducted with high standards of humane care and treat-ment, represent a small but vital part of our procedures in the release and development of vaccines. While GSK continues to work toward an era of non-animal based research and development, we remain committed to acting ethically and practicing good animal welfare when animal use is still required.Within GSK Vaccines, the Rabies potency assay is identified as one of the most animal con-suming tests in the quality control department. This is mainly caused by the fact that two independent performed assays are necessary to prove the effectiveness. A single dilution assay, which can potentially quarter the number of animals and is well known, as described by WHO TRS 941 is not applicable for the rabies potency assay. Although a simple reduction of animals will increase the variance of the in-vivo assay. There-fore the 2+1 approach would half the number of animals within the groups and perform up to three assays. Within this design, two assays remain the minimum. The third assay is only performed if the combined potency result of the first two assays is not significantly above the specification (LCL ≥ 2.5 IU/ml). If this criterion is not met, the third assay is performed. The result (estimated potency) is reported as release value. To measure the amount of infectious Challenge Virus Suspension (CVS) a LD50 determination is not necessary in each routine test. A Tissue Culture Infectious Dose (TCID50) determina-tion as already implemented for the quantification of Rabies virus in the production process can be used to measure the consistency of the CVS preparation. To implement a new batch of CVS or after e.g. invalid test with conspicuous survival rates, a LD50 determination can be performed. This measure will reduce the animal consumption by 40 mice per test.




31

Poster Abstract

An alternative in vitro method to evaluate IL-1ß for toxicity test of autogenous vaccines

Erika Molica Colella Erika Molica Colella*1, Silvia Dotti1, Riccardo Villa1, Guerino Lombardi1 and Massimo Amadori1(1) Istituto Zooprofilattico Sperimentale della Lombardia e dell’Emilia Romagna, IZSLER.

In Italy the legislation provides that Experimental Zooprophilactic Institutes (II.ZZ.SS.) are the only agencies authorized by the Ministry of Health for the production of veterinary au-togenous and autologous vaccines. Autogenous vaccines are prepared for immunization against pathogenic microorganisms isolated from sick animals of one herd and only usable in the same farm. The II.ZZ.SS. must perform the in vivo toxicity test for each lot of vaccine produced as laid down in the Decree of 17 March 1994 [1]. According to the 3R principle (Re-placement, Refinement, Reduction), we have proposed an alternative in vitro method for testing toxicity of autogenous vaccines. The method described in this work measures IL-1ß production by macrophages in response to vaccine antigens. In this study, macrophages were obtained after differentiation from pig monocytes in peripheral blood mononuclear cells (PBMC) frozen in liquid nitrogen, using 10 ng/ ml of Macrophage-Colony Stimulating Factor (M-CSF). Differentiated macrophages were reacted with the antigens at different dilutions for 24 hours, followed by quantification of released IL-1ß. Samples were analyzed for IL-1ß by “Duo set ELISA for Porcine IL-1ß/IL-1F2” (R&D System) [2]. Preliminary results indicate different levels of activation of each macrophage population, which bears on sensitivity to vaccine an-tigens. It is therefore crucial for standardization to start from a single batch of low-activation cells, to standardize the period of cell differentiation and to choose a batch of suitable FCS, in order to have representative and replicable data. The study aims to present the potential of this methodology for replacement of the current in vivo test. It can be used in association with other in vitro tests to get an overview of the potential toxicity of the vaccines.[1] Ministerial Decree 17 March 1994. [2] Fabio Martinon, Kimberly Burns, and Jürg Tschopp. The Inflammasome: A Molecular Platform Triggering Activation of Inflammatory Caspases and Processing of pro- IL-1ß. Molecular Cell, Vol. 10, 417–426, August, 2002

*Erika Molica Colella, [email protected], IZSLER: Via Bianchi 9, 25124 Brescia (Italy), Telephone number: +390302290249




32

Poster Abstract

Rebecca Duit Rebecca Duit*, Laura Hassall, Paul Stickings

National Institute for Biological Standards and Control (NIBSC)

Blanche Lane, South Mimms, Potters Bar, Hertfordshire, EN6 3QG, UK

One objective of the VAC2VAC [1] project is to determine whether an immunoassay can po-tentially replace current in vivo tests for determining the potency of tetanus vaccines. NIBSC has previously developed a capture ELISA method using a specific monoclonal antibody to capture the tetanus toxoid antigen. This assay has been applied to different tetanus vaccines for human use and shown to be suitable for specifically and quantitatively detecting the tetanus toxoid antigen in these vaccines [2] and it will be evaluated further in the VAC2VAC project. However, this method has not previously been applied to tetanus vaccine for veteri-nary use. Tetanus vaccines for veterinary use contain a tetanus toxoid antigen that is similar to that used in production of vaccines for human use but with additional components and/or adjuvants that are not found in tetanus vaccines for human use. These include other clostrid-ial antigens that have a greater potential to show cross-reactivity with an antibody to teta-nus, and non-aluminium adjuvants that might interfere with antigen detection. The results obtained for a number of tetanus vaccines from different veterinary manufacturers suggest that the immunoassay is suitable for use with veterinary tetanus vaccines. No cross-reactiv-ity for a large number of non-tetanus antigens was observed. Non-aluminium adjuvants did not interfere with antigen detection but, as previously observed for human vaccines, alumin-ium adjuvants did interfere with the assay and a desorption step can increase the amount of antigen available for detection. Further work will now focus on whether this method, or a modification of it, is stability indicating (for both human and veterinary tetanus vaccines) and to what extent the assay can discriminate between compliant and altered batches.

[1] http://www.vac2vac.eu/

[2] Coombes L, Tierney R, Rigsby P, Sesardic D, Stickings P. In vitro antigen ELISA for quality control of tetanus vaccines. Biologicals. 2012 Nov;40(6):466-72.




33

Poster Abstract

The State-of-the-Science of Alternative Methods for Evaluating the Toxicity and Efficacy of Ectoparasiticides

Katherine Groff Katherine Groff* and Patricia Bishop, People for the Ethical Treatment of Animals

The development of veterinary ectoparasiticides involves the use of large numbers of animals to evaluate toxicity and efficacy. Regulatory guidelines state that a variety of health effects tests must be conducted for new flea and tick control products intended to be applied to companion animals, including acute, subchronic, and chronic toxicity; mutagenicity; carcinogenicity; reproduc-tive toxicity; and margin of safety determinations. Regulatory requirements further include that active ingredients and product formulations must be assessed for efficacy using dogs and cats. La-bel claims, such as duration of parasite control and efficacy when combined with other products, must be supported with data, which are usually obtained from tests on animals.Alternative methods for toxicity testing, including an additive equation for predicting the acute systemic toxicity of formulated products based on the toxicity of its ingredients and in vitro meth-ods for eye irritation, skin irritation, and skin sensitization, are currently under evaluation or have already been approved for use to satisfy many endpoints. For efficacy testing, artificial membrane systems have been developed to evaluate both oral and topical ectoparasiticides that are added to the blood in the in vitro system or applied to the membranes. Studies demonstrate the scientif-ic advantages of membrane systems, such as greater control and standardization and the direct observation of the attachment, feeding, reproductive output, and mortality of parasites. However, there remain many challenges to implementation of artificial membrane systems. This poster provides a review of the state-of-the-science of alternative methods, examples of the use of non-animal methods in scientific publications and regulatory applications, and recommen-dations for steps that can be taken to transition to non-animal methods. Key references:• Andrade, J.J., Xu, G., Rich, S.M., 2014. A silicone membrane for in vitro feeding of Ixodes scapularis (Ixodida: Ixodidae). J. Med. Entomol. 51, 878-879.• Bouhsira, E., et al. 2013. Ctenocephalides felis an in vitro potential vector for five Bartonella species. Comp. Immunol. Microbiol. Infect. Dis. 36, 105-111. • Groff, K., Bishop, P. 2017. Itching for change: Embracing modern flea and tick product development. Regul Toxicol Phar-macol 88, 349-355.• Kernif, T., et al. 2015. Responses of artificially reared cat fleas Ctenocephalides felis felis (Bouche, 1835) to different mammalian bloods. Med. Vet. Entomol. 29, 171-177. • Krober, T., Guerin, P.M. 2007c. In vitro feeding assays for hard ticks. Trends Parasitol. 23, 445-449. • Krull, C., et al. 2017. Optimization of an artificial tick feeding assay for Dermacentor reticulatus. Parasites Vectors 10, 60-68. • Kuhnert, F. 1996. Feeding of hard ticks in vitro: new perspectives for rearing and for the identification of systemic aca-ricides. ALTEX 13, 76-87.• Li, A.Y., Meng, H., Palma, K. 2015. In vitro membrane feeding of the lone star tick (Amblyomma americanum) and its use in evaluation of acaricidal compounds. In: Proceedings of Annual AAVP-LIWC-ISEP Joint Conference 103.

* Katherine Groff, [email protected], 501 Front St. Norfolk, VA 23510, 937-475-3884




34

Poster Abstract

International harmonisation: Progress in establishing VICH guidelines on wai-ving criteria for general batch safety tests of veterinary vaccines

Marlies Halder Marlies Halder 1,* and Esther Werner 2(1) European Commission Joint Research Centre; Ispra (VA), Italy; - (2) Paul-Ehrlich-Institut, Langen, Germany

General batch safety tests for veterinary vaccines as the Laboratory Animal Batch Safety Test (LABST) or the Target Animal Batch Safety Test (TABST) are supposed to demonstrate that a vaccine does not cause abnormal local or systemic reactions. However, over the last 25 years, the relevance of the TABST and LABST was questioned due to the introduction of more specific safety and purity tests, strict control of starting material and the introduction of Good Manufacturing Practice. Retrospective analysis of LABST and TABST data revealed that both tests are not able to detect batches causing safety problems and therefore are no longer justifiable. The LABST (or abnormal toxicity test) had already been removed from Euro-pean Pharmacopoeia monographs for veterinary vaccines in 1997, and the TABST in a step-wise approach until its complete deletion in 2013. However, outside of Europe and European Pharmacopoeia countries, general safety tests may still be required for batch release.

In 2008, Europe proposed to The International Cooperation on Harmonisation of Technical Re-quirements for Registration of Veterinary Medicinal Products (VICH) to aim at harmonisation of general batch safety tests across the VICH regions (USA, Japan, Europe) in order to mini-mise the need to perform separate studies for regulatory authorities of different countries. However, due to the great divergence in requirements between the regions it was agreed to adopt a phased approach. In 2014, VICH GL50 establishing harmonised criteria on data re-quirements for waiving of the TABST for inactivated vaccines came into force. A comparable guideline for live vaccines (VICH GL55) together with an updated GL50(R) were published in 2017 and came into force in May 2018. Since 2016, the VICH experts are working on a guide-line on harmonisation of criteria for waiving the LABST for veterinary vaccines. The poster will summarise these developments.References: VICH (2017) VICH GL50 Harmonisation of criteria to waive target animal batch safety testing for inactivated vac-cines for veterinary useVICH (2017) VICH GL55 Harmonisation of criteria to waive target animal batch safety testing for live vaccines for veterinary use

*Corresponding author: Marlies Halder, [email protected], European Commission Joint Research Centre; Ispra (VA), Italy; phone: +39-0332-785550




35

Poster Abstract

Replacing the Lethal Guinea Pig Challenge with an in vitro Potency Assay for Diphtheria

Marin Ming Marin Ming 1*, Judy Caterini 1, Luciano Ettorre 1, Martha Schreiber 1, Mei Tang 1, Carmen Dali 2, Navreet Deol 2, Olivier Faure 2, Sue Nelson 3, Jim Yu 3, Dave Jaipersad 4, Aarti Miryala 4, Lucy Gisonni-Lex 1(1) Sanofi Pasteur, Toronto, Immunology Platform, Analytical R&D(2) Sanofi Pasteur, Toronto, Quality Control(3) Sanofi Pasteur, Toronto, Global Analytical Process and Technology(4) Sanofi Pasteur, Toronto, Site Quality Operations

The US Diphtheria potency test (USPHS) is used for release of multiple diphtheria toxoid containing combination vaccines produced by Sanofi Pasteur. In the USPHS test, serum from guinea pigs immunized with the vaccine is mixed with a lethal dose of diphtheria toxin and subsequently injected into naive guinea pigs, with a readout of survival/death. Potent vaccine products are expected to elicit neutralizing antibodies that protect animals from the lethal effect of diphtheria toxin, while negative control animals will not survive.

As part of the 3R initiative to reduce, refine, and replace the use of animals in testing, we developed an in vitro assay to replace the lethal challenge portion of the USPHS.

The Diphtheria Vero cell (DVC) assay was developed as a sensitive, semi-quantitative cell-based test that directly demonstrates the mechanism of action of the diphtheria component of the vaccine. It is an endpoint titre assay which measures the neutralization titre of serum from immunized guinea pigs thus negating the need for lethal challenge. The DVC assay is precise, robust and less variable than the in vivo lethal challenge in USPHS assay.

The assay aligns with the USPHS in terms of reportable value (Units/mL) to the US reference antiserum so that existing product specifications can be used. The DVC Assay is currently undergoing concordance testing using diphtheria vaccines manufactured in SP Toronto. When accepted, the use of the DVC assay will have a huge impact on reducing animal use in the USPHS compendial test with expected reduction of animal use by 22% per test plus the costs associated with the use of animals.*Corresponding author: Marin Ming, [email protected], +1-416-667-2700 ext. 3816.

Note: All animal use was carried out in accordance with all applicable animal care and use laws, regulations, and guidelines. The study was approved by Animal Care and Use Committee.




36

Poster Abstract

VaxArray: Eliminating the Need for Animals for Vaccine Potency Testing

Kathy L. Rowlen The VaxArray platform is based on a multiplexed immunoassay and is designed to replace animal testing of vaccine potency. The first application of this technology focused on influ-enza vaccines. Specifically, the performance of rapid (2 hr) VaxArray assays for influenza hemagglutinin (HA) and neuraminidase (NA) was investigated. We evaluated the use of these assays to assess the potency of HA and NA of an A/H3N2 subunit vaccine by determining the correlation between the amounts measured by VaxArray and the immunogenicity in mice (all animal use was carried out in accordance with all applicable animal care and use laws, regulations, and guidelines, and that the study was approved by the appropriate Institutional Animal Care and Use Committee). The antibody response after one and two doses of five formulations of the vaccine ranging from 5 mg/mL to 80 mg/mL of HA, was measured by he-magglutination inhibition (HAI) and neuraminidase inhibition (NAI) assays. For hemagglutinin, vaccine potency determined by VaxArray was equivalent to potency measured single radial immunodiffision and these amounts were predictive of immunogenicity, with excellent cor-relation between potency measured by VaxArray and the HAI geometric mean titers (GMT). Likewise, the amount of NA measured by VaxArray was predictive of the NAI GMT. The Vax-Array NA assay reported non-detectable levels of intact NA for a sample that had been heat degraded at 56 C for 20 h, demonstrating that the assay measures the native, active form of NA. Importantly, the force degraded sample induced low HAI titers and the NAI titers were not measurable, supporting the conclusion that the VaxArray HA and NA assays measure the immunogenic forms of these A/H3N2 antigens. This study indicates that VaxArray assays can be used to assess the potency of HA and NA components in influenza vaccines as a proxy for immunogenicity.

Affiliation and Contact InformationK.L. Rowlen is the CEO & CSO of InDevR Inc.2100 Central Ave., Suite 106Boulder, CO 80301Ph: 303-402-9100Email: [email protected]




37

Poster Abstract

Noninvasive Analytics for Consistency of Biologics

Y. Bruce Yu Marc B. Taraban1, Katharine T. Briggs1, Christopher Fox2, Y. Bruce Yu1*

(1) Department of Pharmaceutical Sciences, Bio- and Nano-Technology Center, University of Maryland, Baltimore, MD 21201

(2) Infectious Disease Research Institute, Seattle, WA 98102

Rationale: The consistency approach to vaccine release testing rests on thorough analytical characterization of vaccine production. However, current analytical techniques have certain limitations due to their invasiveness. They are perturbative, which may result in misleading results; they are destructive, which makes 100% quantitative inspection of products impossi-ble; they are intrusive, making real-time in-line monitoring of production challenging. Because of these limitations, significant data gaps exist in vaccine characterization.

Scope: Physicochemical characterization of drug products and vaccine adjuvants

Approach: We developed a noninvasive quantitative analytical technology, called water pro-ton NMR (wNMR). wNMR involves no physical contact between the sample and the sensor and can be conducted using benchtop instruments in approximately 1 minute.

Results: We demonstrated the potential of wNMR through four examples. The first is a pair of FDA-approved brand and generic nanoparticle drug products, which were deemed equiv-alent by perturbative analysis. wNMR revealed >20% difference between brand and generic. The second is an FDA-approved insulin product, which had a recall in 2013 because a filling error led to insulin dose deviation by up to ⇑50% in 0.14% released cartridges. wNMR readily detects 10% insulin dose deviation. The third is alum, a common vaccine adjuvant that tends to sediment in water, making even filling of vials and re-dispersion challenging. Current ex situ methodologies include atomic emission microscopy for alum filling assessment and zeta potential for alum re-dispersion assessment. wNMR can rapidly assess alum filling, sedimen-tation and re-dispersion in an in situ fashion. The fourth is using wNMR to monitor protein concentration and aggregation under flow conditions, which paves the way for real-time in-line monitoring in biologics manufacturing.

Conclusion: Using wNMR, quantitative inspection of every vial in a batch and real-time in-line monitoring of the production process could be envisioned. wNMR could enhance the analyti-cal thoroughness of vaccine consistency testing.

* Corresponding author: Y. Bruce Yu, [email protected], 20 North Penn St., Rm. 635, Baltimore, MD 21201, USA. Tel: +1 410-706-7514




38

Webinars




A series of pre-workshop webinars were held to address foundational principles and practices relevant for workshop participants.

September 25 Regulatory 101- North American Regulatory Perspective for Vaccines

Moderator : Richard Hill, IABS Speakers :

Freyja Williams, DBPAP/OVRR/CBER/FDA

Replacing in vivo tests: A OVRR regulator’s perspective Dowload Slides

Alethea Fry, MS

NIH Test for Rabies Potency Dowload Slides

October 3 Rabies in the World Rabies in Vaccinology

Moderator : Robin Levis, FDA Speakers :

Charles Rupprecht, VMD, MS, PhD; CDC (ret)

Progress Towards the 2030 Goal: The Global Elimination of Human Rabies by Dogs (GEHRD)

Dowload Slides

Susan Moore, Kansas State

Rabies Vaccinology Dowload Slides

October 10 Animal usage in biologics development, production and testing

Moderator : Warren Casey, NTP Speakers :

Jeff Brown, PETA-International Science Consortium

Dowload Slides


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Bio Sketches



Cynthia Allen, Ph.D. Health Canada, Centre for Biologics Evaluation

Juan Arciniega, DSc FDA (ret)

Warren Casey, Ph.D. National Toxicology Program Interagency Center for the Evaluation of Alternative Toxicological Methods (NICEATM)

Jean-Michel Chapsal, Ph.D. European Partnership for Alternative Approaches to Animal Testing ( EPAA)

Marc Fiorucci, Ph.D. Boehringer Ingelheim Animal Health

Alethea Fry, MS U.S. Department of Agriculture (USDA) Center for Veterinary Biologics (CVB)

Donna Gatewood, DVM EDGE Veterinary Vaccines Consulting Group

Françoise Guinet-Morlot, Ph.D. Sanofi Pasteur

Marlies Halder, VMD European Commission Joint Research Center

Richard Hill, DVM / MS / Diplomate ACVPM International Alliance for Biological Standardization-North America (IABS-NA)

Robin Levis, Ph.D. Food and Drug Administration (FDA)

Sean (Xuguang) Li, MD / Ph.D. Health Canada: Center for Biologics Evaluation

Laurent Mallet, MSc / Ph.D. Sanofi Pasteur

Susan Moore, Ph.D.Kansas State University

Nancee Oien, MS Zoetis Inc.

Rebecca Poston, Ph.D.Consultant on assignment for Integrated Laboratory Systems

Charles Rupprecht, VMD / MS / Ph.D.LYSSA LLC

Marie-Jeanne Schiffelers, MSc / Ph.D. Utrecht University School of Governance

Rebecca Sheets, Ph.D. International Alliance for Biological Standardization (IABS)

Dean Smith, Ph.D. Health Canada, Centre for Biologics Evaluation

Geetha Srinivas, DVM U.S. Department of Agriculture (USDA) Center for Veterinary Biologics (CVB)

Catrina Stirling, Ph.D. Zoetis Inc.

Eriko Terao, Ph.D. Council of Europe, EDQM

Audrey Toinin, MSc Sanofi Pasteur

Freyja (Lynn) Williams, BS FDA, Center for Biologics Evaluation and Research

Oksana Yarosh, Ph.D. Canadian Centre for Veterinary Biologics, Canadian Food Inspection Agency



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Biosketch

Cynthia Allen, Ph.D. Senior Scientific EvaluatorOrganization: Health Canada – Centre for Biologics EvaluationOrganization Address: 100 Eglantine Drwy, Ottawa, ONEmail: [email protected] Tel: +1-613-617-8595Fax: +1-613-941-5841

Cynthia Allen is currently the rabies vaccine product lead and laboratory supervisor, over-seeing lot release activities of the Travel-Rabies vaccine lab at Health Canada’s Viral Vaccine Division. She has more than 10 years of regulatory science experience assessing both pre- and post-market chemistry and manufacturing product submissions.

Dr. Allen completed her graduate studies at the Université de Sherbrooke in Radiobiology with a specialization in Photodynamic Therapy. Her research focused on the elimination of viruses in blood products while maintaining the integrity of cellular components. Subse-quently, her focus progressed to photodynamic therapy as a cancer treatment dissecting cell signalling pathways. Her expertise in analytical method development directed her to the National Research Council Canada in Ottawa prior to joining Health Canada in the Pandemic Influenza Division in 2006. She was a key member of Health Canada’s regulatory team during the 2009 H1N1 influenza pandemic.

Dr. Allen’s multidisciplinary experience and knowledge of regulatory measures concerning the quality and safety of vaccines provides her with the specific skill set needed to lead the Travel-Rabies Vaccine lab.




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Biosketch

Juan L. Arciniega, DSc Email: [email protected]: +1 301-873-0315 (Mobile)

Dr. Juan L. Arciniega retired in April 2018, after working as a Microbiologist for 29 years at the Center for Biologics Evaluation and Research (CBER) of the FDA. He received a DSc degree in Clinical Biology in 1987 from the National School of Biological Sciences in Mexico City. Before joining CBER in 1989 as a Visiting Fellow, he worked for nine years at the Mexican National Public Health Laboratory, most recently as Deputy Director for Biological Control, in charge of two departments responsible for sanitary testing of food and biologics. He was also a found-ing member of the Permanent Commission of the Mexican Pharmacopoeia (Biologics and Bioassay and Statistics Committees).

His research and regulatory activities have focused on pertussis, diphtheria and anthrax vac-cines, and development of alternatives to animal tests. Dr. Arciniega’s last position at CBER was as a CMC consult reviewer, with special emphasis on methods development, validation, and quality control. He participated in other regulatory activities, including batch release. He acted as a CBER/FDA liaison with the US Pharmacopeia (Biologics and Biotechnology 2 Expert Committee, 2010-2015). He has published more than 30 papers in his field and refer-ees manuscripts for several journals. He has cooperated with the World Health Organization (WHO) and the Pan American Health Organization (PAHO) as a Temporary Advisor, and with the European Center for the Validation of Alternative Methods (ECVAM) and the European Directorate for the Quality of Medicines and Healthcare (EDQM). Dr. Arciniega mentored sev-eral young Latin American vaccine regulators and scientists.




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Biosketch

Warren Casey, Ph.D. Director – NICEATMTel 984-287-3118 [email protected]. Box 12233Mail Drop K2-16Durham, N.C. 27709

Warren Casey, Ph.D., is Director of the U.S. National Toxicology Program’s Interagency Center for the Evaluation of Alternative Toxicological Methods (NICEATM), National Institutes of En-vironmental Health Sciences (NIEHS). He received his undergraduate degree in biochemistry and his Ph.D. in microbiology from North Carolina State University (NCSU). Casey also serves as an Adjunct Associate Professor in the Department of Microbiology at NCSU and is Diplo-mate of the American Board of Toxicology (D.A.B.T.).

Prior to joining NICEATM, Casey was the Manager of Pharmaceutical Microbiology at Glaxo Inc. from 1994 to 1999; Head, Biomarker Development, at GlaxoWellcome, Inc., from 1999 to 2002; and a Senior Scientist, Discovery and Investigative Toxicology, at GlaxoSmithKline, Inc., from 2002 to 2009.

Casey is the author or co-author of over 28 publications in peer-reviewed journals, holds three patents, and has made presentations at scientific meetings.




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Biosketch

Jean-Michel Chapsal, Ph.D. European Partnership for Alternative Approaches to Animal Testing (EPAA)Avenue Herrmann-Debroux 40, 1160 Brussels, BelgiumEmail: [email protected]: +33 07 82485065

Dr. Jean Michel Chapsal has been working for 30 years at Sanofi Pasteur. Dr Chapsal has led a number of units, including Research and Development,Downstream Processing and Ana-lytical Services-Regulatory Affairs Interface. He has also served recently as Director in Global Analytical Services. His areas of expertise include technical method development for vaccine control, application of emerging technologies in vaccinology, 3Rs alternative methods devel-opment, and analytical services in biochemistry, microbiology.

Dr Chapsal received a PhD in Biochemistry from Compiègne University, France. He also

completed the general course of Virology at the Institut Pasteur in Paris and received an advanced postgraduate diploma in Virology at Université Paris Diderot. In 1986, he completed a postdoctoral fellowship in the laboratory of Dr Lenore Peirera at the University of California, San Francisco.

Dr Chapsal has been a member of the Working Group on Sera and Human Vaccines of the French Agency for the safety of Health Products (ANSM) and of the French Scientific Inter-est Group on Alternative methods (GIS). He was co-chair of the International Histamine Test Replacement Working Group for Pertussis vaccine in the frame of the consistency Vaccine Project of the EuropeanPartnership for Alternative Approaches to Animal Testing (EPAA). He is currently co-project leader for EDQM (BSP148) and EPAA for the Rabies NIH test replacement and co-chair of the international Rabies Test Replacement Working Group




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Biosketch

Marc Fiorucci, Ph.D. Analytical Manager and Project LeaderBoehringer Ingelheim Animal Health1730 Olympic DriveAthens, Georgia, 30601U.S.A.Email: [email protected]: +001 908 524 5954

Marc Fiorucci obtained a PhD in Virology from the “Ecole Normale Superieure de Lyon”, France in 2007. His PhD work was focused on the generation and characterization of recom-binant adenoviruses expressing hepatitis C proteins and supported by Transgene a French biotechnology company.

In 2007, he joined MERIAL in the USA, Athens GA, as a research scientist and was involved in the early development of new vaccines for US market.

In 2009, he became Laboratory Manager at MERIAL in R&D in the Analytical department in Lyon France. He led a team with the aim of developing, industrializing, validating and trans-ferring to industrial operations analytical methods for new MERIAL vaccines and for life cycle management vaccines.

He became a Project leader in addition to his Analytical Manager responsibilities in 2013 with the goal of replacing In Vivo potency tests by In Vitro potency tests for some marketed prod-ucts. Rabies vaccine was one significant work where he was involved.

He has pursued his career for MERIAL USA (now Boehringer-Ingelheim) in the R&D center in Athens, GA from October 2015.




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Biosketch

Alethea Fry, MS USDA, Center for Veterinary Biologics

Alethea is the Supervisor of the CVB Virology laboratory. She received her Master’s degree in Microbiology from South Dakota State University. She worked in, both human and veterinary diagnostic laboratories, a cytogenetics laboratory and the vaccine industry. She has been a Microbiologist with the Center for Veterinary Biologics for 15 years.




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Biosketch

Donna Gatewood DVM PresidentEDGE Veterinary Vaccines Consulting Group1928 Maxwell AvenueAmes, IowaEmail: [email protected]: + 1 515 231 3610

Dr. Gatewood has over 20 years of experience working toward the development and licen-sure of veterinary vaccines. She graduated from Tuskegee University’s College of Veterinary Medicine in 1986 and completed a Master’s Degree in Veterinary Microbiology and Immunol-ogy at Kansas State University in 1991. After completing her studies, she worked briefly at the National Veterinary Services Laboratories in a post doctorate position, and then joined Diamond Animal Health where she served as Manager of Research and Development work-ing on the development of a line of cattle vaccines. She later moved into Regulatory Affairs at Diamond to manage new product licensure. She rejoined USDA/APHIS in 1998, where she was a Senior Staff Reviewer at the Center for Veterinary Biologics until 2000, when she was named Section Leader for the Virology Section in the Licensing and Policy Development unit. She left the CVB in 2013 to found EDGE Consulting, where she is currently President and Chief Operating Officer. EDGE consultants provide regulatory support and guidance to researchers and commercial entities engaged in veterinary vaccine research and licensing.




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Biosketch

Françoise Guinet-Morlot, Ph.D. Global Project HeadSanofi Pasteur1541 Avenue Marcel Merieux69280 Marcy l’Etoile, FranceEmail: [email protected]: ++33 632 153 949

Dr Françoise Guinet-Morlot is a Global Project Head for New Rabies vaccine at Sanofi Pasteur, with a 30-year professional experience in R&D. She obtained her Ph.D. degree in Molecular Biology at the European Molecular Biology Laboratory (EMBL) in Grenoble, and previously she was graduated from the Ecole Nationale Supérieure de Chimie de Paris. She has been work-ing in the Rabies fields for 13 years.




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Biosketch

Richard E. Hill, Jr., DVM / MS / Diplomate ACVPM Board MemberInternational Alliance for Biological Standardization (IABS)Communication Committee ChairVeterinary Biologicals Committee MemberBiologicals Section EditorPresident, IABS-NA

Dr. Richard E. Hill, Jr., (Rick) received a D.V.M. degree from Michigan State University in 1983 and following graduation, worked in private veterinary practice. In 1985, he joined the USDA and worked as a field Veterinary Medical Officer before joining the Biologics Program in 1986. Rick worked as an Inspector, Epidemiologist, and Team Leader, for the Biologics Program where he was involved in regulatory compliance and coordination of the pharmacovigilance program. In 1990, he received an M.S. degree in Veterinary Preventive Medicine at Iowa State University and is a Diplomate in the American College of Veterinary Preventive Medicine. In 1995, Dr. Hill transferred to the position of Quality Assurance Manager, responsible for over-seeing the Quality Assurance Program at the National Veterinary Services Laboratories and Center for Veterinary Biologics Laboratory. In November 1998, he re-joined the Center for Veterinary Biologics as Director of Licensing and Policy Development and then served as the Center Director from 2005 through 2013. In 2013, Dr. Hill assumed the position of Executive Director for Veterinary Services, National Import and Export Services until his retirement in 2016 after 30+ years of Federal service. Dr. Hill remains active in veterinary medicine through volunteer positions with the American Veterinary Medical Association and as Exam Commit-tee Chair for the American College of Veterinary Preventive Medicine. Dr. Hill is a long-term member of IABS, Biologicals Section Editor, and served as inaugural member and Chair of the Veterinary Scientific Conference Committee (now the Veterinary Biologicals Committee).He is currently serving as Chair of the IABS Communications Committee and President of the North American Affiliate (IABS-NA).




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Biosketch

Marlies Halder, VMD Scientific OfficerEuropean Commission Joint Research CentreVia E. Fermi, 2749; TP126I-21027 Ispra (VA), ItalyEmail: [email protected]: +39-0332-785550

Dr. Halder studied veterinary medicine at the University of Munich (Germany) and obtained a VMD from the University of Munich in 1987 for research on crustaceans and fish diseas-es. She worked for several years as a research scientist at the University of Munich and the Akademie für Tierschutz, Neubiberg, Germany. Dr. Halder joined the European Commission in October 1995 and currently holds a position as a senior scientist at the European Commission’s Joint Research Centre, Directorate F – Health, Consumers and Reference Materials, Chemical Safety and Alternative Methods Unit / European Union Reference Laboratory for Alternatives to Animal Testing (EURL ECVAM) (F.3). She is responsible for EURL ECVAM’s activities related to replacement, reduction and refine-ment (3Rs) approaches to animal tests in the quality control of biologicals and environmental hazard assessments of chemicals.




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Biosketch

Robin Levis, Ph.D. Deputy Director, Division of Viral ProductsOVRR/CBER/FDA10903 New Hampshire AvenueBuilding 52/72 – Room 1208Silver Spring, Maryland 20993 Email: [email protected]: 240-402-9665

Dr. Levis received her PhD at Washington University in St Louis in 1988. She has worked at the US Food and Drug Administration since 1995. She is currently the Deputy Director of the Division of Viral Products in the Office of Vaccines Research and Review at CBER/FDA; a position she has held since 2006. Prior to this position, she served as the Regulatory Coor-dinator for the Division of Viral Products (2002-2006) and served as a Senior Staff Fellow in the Laboratory of Vector Borne Viral Diseases (1995-2002). Her initial research work at the FDA related to dengue virus replication. She then transitioned to be the lead subject matter expert and CMC reviewer for licensed rabies virus vaccine products and rabies vaccine and related products under development. Her laboratory work on rabies virus vaccines contin-ued the collaborative efforts underway to develop an alternative, in vitro based potency test for rabies virus vaccines. This work is ongoing in the Laboratory of Methods Development and in collaboration with a global working group.




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Sean (Xuguang) Li, MD / Ph.D. Senior Research ScientistDivision of Regulatory Research, Centre for Biologics Evaluation, Health Canada251 Sir Frederick Banting DrivewayEmail: [email protected]: + 613 954 2383Fax: + 613 941 8933

Dr. Sean (Xuguang) Li was trained as a physician in Medical College of Soochow University, China. He obtained his PhD from McGill University, Montreal, Canada. . He did his post-doctor-al fellowship at Harvard Medical School, Boston, MA, USA before he joined Health Canada in 2000. At the federal government of Canada, Dr. Li’s research work has been focussed on develop-ment of new technologies for the analyses of biotherapeutics and vaccines; investigation of potential adverse reactions associated with vaccines; determination of biomarkers for the analyses of immune responses to vaccines; contribution to international collaborations for the development of new assays for vaccines and biotherapeutic products. Dr. Li holds cross-appointment Professorship at Faculty of Medicine, University of Ottawa, where he teaches advanced immunology and supervises undergraduates and graduate stu-dents in their research studies of virus-induced disease and vaccine-elicited immune re-sponses. He has published over 100 papers in peer-reviewed international journals




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Biosketch

Laurent Mallet, MSC / Ph.D. Global Head, Analytical SciencesSanofi Pasteur1541, Avenue Marcel Merieux, Marcy L’Etoile, FranceEmail: [email protected]: +33 6 80 60 05 83

Dr. Laurent MALLET obtained his Master Degree of Science in Biochemistry from Claude Ber-nard Lyon University in France. He completed his PhD work in Virology and Molecular Biology under the co-direction of Pr Michèle Aymard (National Reference Center for Enterovirus, Ly-on, France) and Dr. François Pelloquin (Sanofi Pasteur, formerly Pasteur Mérieux Connaught). He obtained his PhD in 1996. After several positions within Sanofi Pasteur in France and in Canada, he is currently Global Head of Analytical Sciences for Sanofi Pasteur.He is also a member of several expert committees, EDQM Group 15 “Human vaccines and sera” at European Pharmacopoeia and stakeholder at the French Pharmacopoeia Committee “Biological Products and Innovative Therapies”. In addition, he has been involved in several WHO working groups on vaccines including the WHO Study Group on Cell Substrates.




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Biosketch (Webinar)

Susan M. Moore, Ph.D. Clinical Assistant Professor/Rabies Laboratory DirectorKansas State University/College of Veteirnary Medicine/Veterinary Diagnostic Laboratory2005 Research Park CircleManhattan, Kansas 66502U.S.A.Email: [email protected]: +1 785 532 4472Fax: +1 785 532 4474

Susan M. Moore, PhD, is a Clinical Assistant Professor/Rabies Laboratory Director in the Vet-erinary Diagnostic Laboratory at the College of Veterinary Medicine of Kansas State University (KSU). In 1981, she received her BS in Medical Technology from KSU and her American Soci-ety of Clinical Pathologists (ASCP) certification as a Medical Technologist at Providence-St. Margaret School of Medical Technology in Kansas City, KS. She stared out in clinical labora-tory medicine, first as a medical technologist in in Kansas and Missouri hospitals, and from 1990-1998, after obtaining her Specialist in Blood Banking certification through ASCP in 1989, as the Supervisor of the American Red Cross Blood Services immunohematology laboratory in Buffalo, New York. While working as Supervisor, then Managing Director of the KSU Rabies Laboratory, Dr. Moore obtained her MS (2005) and PhD (2015), in Pathobiology, and joined the faculty as a Clinical Assistant Professor in 2015. In 2017, she passed the American Associa-tion of Bioanalysis exam to become a qualified as a CLIA Laboratory Director. She instructs veterinary and graduate students on rabies and emerging infectious diseases. As the Director of the Rabies Laboratory, one of the largest rabies serology labs in the world, she consults with pharmaceutical clients on rabies vaccine clinical trial/product testing results produced by the laboratory, and provides clinical consultation to patients and physicians regarding rabies pre and post exposure prophylaxis. Dr. Moore is very active in outreach activities on rabies serology, including the World Health Organization, USDA, and the World Health Organi-sation for Animal Health (OIE).




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Nancee L. Oien, MS Research DirectorZoetis Inc.333 Portage StreetKalamazoo, MichiganU.S.A.Email: [email protected]: + 1-269-359-9406

Nancee has been an active researcher in the human pharmaceutical/biologics and veteri-nary vaccine industries for >30 years. Nancee is formally trained as an immunologist and has extensive experience as a virologist and molecular biologist, leading the development of both therapeutics and vaccines. Nancee has published in key journals in both human and animal health vaccine research and development. She has also served as a chair-person in creating the ANSI/ATCC standards for Species-Level Identification of Animal Cells through Mitochon-drial Cytochrome c Oxidase Subunit 1 (CO1) DNA barcodes. Nancee has been leading a group of scientists dedicated to the development of in vitro potency release assays for veterinary vaccines for the past ten years. She is currently an active participant in the Animal Health Institute’s (AHI) collaboration with Center for Veterinary Biologics (USDA) with the goal of replacing the rabies in vivo potency assays for veterinary vaccines.




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Rebecca Poston, Ph.D. Consultant Bio Business Consultants - on assignment for Integrated Laboratory SystemsE mail: [email protected]: +1.919.450.5698

Dr. Poston is an experienced consultant with over 20 years of experience in vaccine R&D and Business Development for the animal health industry. Her education started at Louisiana State University where she received her Bachelor of Science in Medical Technology (MT-AS-CP), and she earned her PhD in Immunology and Microbiology from Medical University of South Carolina. She conducted post graduate vaccine research on intracellular pathogens at Duke University followed by her start in animal health vaccine R&D at Embrex, Inc. Her team developed and licensed the first in ovo, veterinary parasite vaccine in the mid-2000s. After Embrex was acquired by Pfizer Animal Health, she continued in vaccine R&D until moving into a Business Development/Strategic Alliance leadership role in 2010. She led key business and alliance initiatives on behalf of PAH and later Zoetis, the company formed from the spin out of Pfizer’s animal health business. In 2017, Dr. Poston left Zoetis and formed Bio Business Consultants which provides animal health and biotech clients with business development and other services tailored to client needs.




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Biosketch (Webinar)

Charles E. Rupprecht, VMD / MS / Ph.D. Position: CEOLYSSA LLC309 Pirkle Ferry Rd., Cumming GAEmail: [email protected]: +1 770 736 0217

Rutgers University B.A. 1977 EcologyUniversity of Wisconsin M.S. 1980 ZoologyUniversity of Pennsylvania, School of Veterinary Medicine V.M.D. 1985University of Wisconsin Ph.D. 1986 Biological Sciences1982-92: Research Associate/Post-doctoral Student/Assistant/Associate Professor, The WistarInstitute, Philadelphia, PA1992-93: Associate Professor, Thomas Jefferson University, Department of Microbiology andImmunology, Philadelphia, PA,1993-2012: Chief, Rabies Program, CDC, Atlanta, GA1993-2012: Director, World Health Organization (WHO) Collaborating Center for RabiesReference and Research, CDC, Atlanta, GA2003-2012: Adjunct Professor, Population Biology, Ecology, & Evolution Training Program,Emory University, Atlanta, GA2010-2012: Head, World Organization for Animal Health (OIE) International ReferenceLaboratory for Rabies, CDC2012-present: WHO, Expert Technical Advisor on Rabies2012-present: Adjunct Professor, Wistar Institute, Philadelphia, PA, USA.2012-present: CEO, LYSSA LLC2012-14: Director of Research, Global Alliance for Rabies Control, Manhattan, KS2013-14: Adjunct Professor, Auburn University, Auburn, AL2013-14: Associate Dean/Professor, Epidemiology & Public Heath, Ross University, Schoolof Veterinary Medicine, St. Kitts, West IndiesIo date, authored/Co-authored > 350 Peer-reviewed publications, several books, multiplechapters, hundreds of abstracts/conference talksConsultations in > 55 countries




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Marie-Jeanne Schiffelers, MSc / Ph.D. Senior consultant and ResearcherUtrecht University School of GovernanceBijlhouwerstraat 6Utrecht, The NetherlandsEmail: [email protected]: +31.(0)302539319Fax: +31.(0)302537200

Marie-Jeanne Schiffelers has a master’s degree in Environmental Policy Sciences and is a senior consultant, researcher and lecturer at the Utrecht University School of Governance. She works as a consultant and researcher in the field of policy science, organizational change and technology transitions.She has been involved in several projects in the field of acceptance and use of 3R methods for regulatory purposes e.g.:• Project manager research Regulatory Animal Testing (2005)• Member research team ‘Evaluation Ministerial Decision Biotechnology in Animals’ (2006)• Member research team ‘Impact Assessment for the revision of EU Directive 86/609 on the protection of animals used for experimental and other scientific purposes’ (2007)In 2008 she was rewarded with the ALTEX prize 2008 for the article:Factors that Stimulate or Obstruct the Implementation of 3Rs in the Regulatory Process.In 2016 she obtained her PhD degree for a research on the Acceptance and Use of 3R Meth-ods entitled:Animal Testing, 3R models and Regulatory Testing: Technology Transition in a Risk Averse Con-textThe central questions of this research project were:⇑ Which factors influence the acceptance and use of 3R models for regulatory purposes by regulatory authorities and industry?⇑ Which lessons can be learned from past experiences in order to optimize future processes of acceptance and use of 3R models?In order to answer these questions several case-studies were conducted amongst which a case study on the acceptance and use of 3R approaches to replace the NIH potency assay for veterinary rabies vaccines quality control purposes.




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Rebecca Sheets, Ph.D. Senior consultant and ResearcherRebecca Sheets is the principal consultant for Grimalkin Partners and an Adjunct Professor at Catholic Univer-sity of America, teaching core courses for a M.S. in Biotechnology Program in the Biology Department in the School of Arts and Sciences. She also serves on the boards of the International Alliance for Biological Standard-ization and Math Dojo STL. Dr. Sheets recently published a book by Elsevier’s Academic Press imprint entitled, “Fundamentals of Biologicals Regulation: Vaccines & Biotechnology Medicines” (https://www.elsevier.com/books/fundamentals-of-biologicals-regulation/sheets/978-0-12-809290-3).In 2013, Rebecca Sheets retired from the U.S. Public Health Service in which she served as the Vaccine Scientific and Regulatory Specialist at the National Institute of Allergy and Infectious Diseases at the National Institutes of Health. In this role, she formulated regulatory strategy for the Division of AIDS on pre-clinical development translating research concepts into HIV vaccine candidates suitable for human clinical trials. She also served as a subject matter expert on vaccine cell substrates and vaccine pre-clinical safety assessment, including toxicolo-gy. Further, she served the Vaccine Research Center in a similar capacity until 2012.Rebecca Sheets obtained her B.S. degree in Biology from the California Institute of Technology; M.S. degree in Cellular, Viral, and Molecular Biology from the University of Utah School of Medicine, and Ph.D. in Pathology from the University of Southern California School of Medicine.Dr. Sheets served for 9 years (1993-2002) as a Scientific Reviewer in the Viral Vaccines Branch of the Division of Vaccines and Related Products Applications, Office of Vaccines Research and Review, CBER/FDA. In 1994, to foster her commitment to public health, she became a Commissioned Officer in the U.S. Public Health Service (Scientist Category), in which she was promoted to the rank of Captain (CAPT) before retiring in 2013. She trans-ferred to NIH in 2002.Both at FDA and at NIH, she has striven to advance policy regarding vaccine cell substrates. Because of her virology background, a strong focus of this effort has been in regard to the adventitious agent tests. From 2006-2014, she served as Co-chair of the World Health Organization’s Study Group on Cell Substrates and as Chair of the Adventitious Agents Sub-committee. This Study Group was tasked with providing technical advice to revise the WHO’s guidance on the subject, which was adopted by their Expert Committee on Biological Standardiza-tion (ECBS) in Oct. 2010. In 2013, she was involved in Implementation Workshops for this guidance. In addition, a separate Risk Assessment document was also adopted by the ECBS in Oct. 2014. Dr. Sheets has served WHO in developing or updating and revising several additional guidelines including those for HIV vaccines, HPV vaccines (adopted by ECBS), clinical evaluation of vaccines (adopted by ECBS), and DNA vaccines (under preparation).CAPT (ret.) Sheets strives to implement the NIH policy and US mandates that researchers reduce, refine, or re-place (3 R’s) animals used for product safety testing. In this spirit, she completed research projects to determine how to achieve this goal with animals used in adventitious agent testing. In addition, she has considered means to streamline or more rationally assure preclinical safety of vaccine candidates than the standard toxicology (“drug-screening”) studies currently required. She is currently organizing a 3 R’s conference to be held in Oct. 2018.In addition to the recently published book, Dr. Sheets has published two book chapters, edited a book in a series, and published in peer-reviewed journal over 40 articles, including reviews, meeting reports, and primary data papers. She has also been responsible for drafting several government documents that have been promul-gated via the web or in print. Considering her expertise, she has been a frequent lecturer, speaker, chair, moder-ator, or discussant at international conferences on topics ranging from cell substrates and adventitious agents, vaccine adjuvants, and risk assessments, to Good “X” Practices, human challenge trials, and vaccine toxicology.




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Dean Smith, Ph.D. IABS-NA Affiliation: Presenter, Implementation non-animal approaches to human and vete-rinary vaccine testing: Achieving scientific and regulatory success for rabies and beyond, Bethesda Maryland, 16-17 October 2018

Centre for Biologics Evaluation, Health Canada

Ottawa, Ontario, Canada

Presentation: “Substituting in vitro for in vivo vaccine potency and safety assays: science versus the fear factor”. Tuesday, October 16, 2018, 10:30 to 10:50 AM.

Dean Smith, Ph.D., Immunologist and Senior Scientific Evaluator in the Center for Biologics Evaluation of Health Canada with over 20 years of experience in regulatory science in sup-port of innovation in vaccine development, manufacturing and quality control. Dedicated to uphold standards while striving to provide value to sponsors through regulatory engage-ments in his work with Health Canada, Dr. Smith is also engaged with the WHO on vaccine and vaccine stability guidance development and implementation. For the past eight years, he’s been Health Canada’s representative to the European Directorate of Quality of Medi-cines, Group 15 (Vaccines), which supports the European Pharmacopeia. He also serves on the Science and Ethics Advisory Committee for VAC2VAC under the European Vaccines Initia-tive. Dr. Smith’s graduate work was completed in the Department of Medical Microbiology and Immunology at University of Alberta, where his research focused on autoimmunity and viral vector-based gene therapy. Prior to joining Health Canada, he was a Research Associate within the Vaccine Design Division of the National Research Council (Ottawa) focusing on BCG based anti-cancer vaccines and T cell memory.When Dr. Smith initially joined Health Canada, it was to re-establish a Smallpox Vaccine Qual-ity Control Laboratory post-9/11. The work expanded to include rabies, flavivirus and rota-virus; transitioning to BCG, typhoid, cholera and other bacterial vaccines. He has worked in and managed both the Viral and Bacterial Vaccines Divisions, and the Hemostatic Agents and Blood Substitutes Division. As a result, he has a range of biologics based scientific and regu-latory experience.




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Geetha B. Srinivas, DVM Supervisory VMOSection Head, VirologyCenter for Veterinary Biologics1920 Dayton AveAmes, Iowa 50010Email: [email protected]: +5153376165Fax: +5153376120

Dr. Geetha Srinivas received her DVM degree from the College of Veterinary Medicine, Ban-galore, India. Dr. Srinivas pursued her graduate degree at the Virginia-Maryland Regional College of Veterinary Medicine, University of Maryland. Her research work for her MS degree was on the development and characterization of strain specific monoclonal antibodies to Newcastle disease virus. Dr. Srinivas earned her PhD degree in 1995 in Veterinary Microbiol-ogy and Immunology. Her dissertation work was on the development of receptors specific monoclonal antibodies and molecular characterization of enteric receptors in pigs. After a brief post-doctoral research fellowship from South Dakota State University, Brookings, SD, Dr. Srinivas joined a biologics firm, Fort Dodge Animal Health, Fort Dodge, IA, in 1996, as the Virology Section Manager in the Product Development Department. She joined the Center for Veterinary Biologics (CVB) in 2003 as a reviewer with responsibilities to review data pack-ages for licensure of veterinary biologics. She took the Supervisory VMO position in 2007 and heads the Virology Section in CVB since 2013.




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Catrina (Cat) Stirling, Ph.D. Associate Director - Regulatory AffairsZoetis IncMercuriusstraat 20Zaventem, Belgium 1930Email: [email protected]: +44 7970 977030

Cat has a research background with a degree in Virology from the University of Edinburgh and PhD in Veterinary Immunology conducted at the Pirbright Institute. She spent 4 years doing post doctoral research at the Pirbright Institute on DNA vaccines for FMD and the immune response to ASFV. Cat then moved into regulatory affairs for Veterinary medicines, working first as an immunologicals assessor for the UK Veterinary Medicines Directorate then moving to industry with Pfizer then Zoetis. She has over 10 years industry experience fo-cused on the full life cycle development of Veterinary Vaccines and Biopharmacuticals, having licensed over 15 new vaccines and the first Veterinary monoclonal antibody in the EU. Cat is actively involved in Animal Health Europe working groups and in the 3Rs area Cat is the Veterinary lead for the IMI2 VAC2VAC project as well as representing Zoetis within EPAA and other internal and external 3Rs projects.




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Eriko Terao, Ph.D. Project coordinatorCouncil of Europe/EDQM7 allée Kastner67081 Strasbourg, FranceEmail: [email protected]: +33 3 9021 4200

Eriko Terao is a scientific project coordinator at the European Directorate for the Quality of Medicines & HealthCare (EDQM, Council of Europe, Strasbourg, France) since 2007. She is specifically in charge of collaborative studies of the Biological Standardisation Programme (BSP) of the Council of Europe and the European Union Commission. The portfolio of her projects covers validation of new and alternative methods - including 3R methods for the replacement of animal use in the quality control testing of biological products - as well as calibration of official reference standards for the European Pharmacopoeia (Ph. Eur.).Prior to joining the Council of Europe, she received a PhD in Biological Sciences from the University of Louvain (UCL, Belgium) and was a teacher-researcher and researcher in neuro-sciences (academic and corporate) in Belgium, UK and France.




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Audrey Toinon, MSc ScientistSanofi Pasteur1541, Avenue Marcel Mérieux69280 Marcy l’Etoile, FranceEmail: [email protected]: +33(0)4 37 37 56 28

Audrey Toinon is analytical scientist in Analytical Research and Development department of Sanofi Pasteur France. Audrey has more than 10 years industry experience in human vac-cines, developing, validating and transferring analytical methods for the quality control of commercialized and new vaccines. After her biological master schedule at university of Cler-mont-Ferrand (2001-2004), Audrey joined Sanofi Pasteur where she held several positions as analytical scientist and more particularly in immunochemistry and biochemistry laboratories. As analytical project team member, she worked in transversal collaboration with all CMC functions (bioprocess, regulatory, quality…) to manage analytical strategy for new vaccine. Her work is mainly focused on hepatitis B, hepatitis A and rabies vaccines, and development of alternatives to animal tests. She is working with European institutions and Health Author-ities for developing and implementing non animal approaches to human Hepatitis A and Rabies vaccines by participating to EDQM BSP studies.In addition, as member of the Sanofi Pasteur France Animal Care Committee for more than 7 years, she is involved in several projects dealing with 3Rs and animal welfare programs.




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Freyja (Lynn) Williams, BS

Freyja (Lynn) Williams has been involved in the development, qualification and validation of bioassays for over 30 years and is considered an expert in the evaluation of immunologic correlates of protection. She currently oversees the review of bioassays for both clinical and CMC submissions in the Division of Bacterial, Parasitic and Allergenic Products, OVRR, CBER. She has published on immunologic responses to and diagnosis of Bordetella pertussis, patho-genic Neisseria, and Bacillus anthracis.




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Oksana Yarosh, Ph.D. Senior Veterinary Biologics EvaluatorCanadian Centre for Veterinary Biologics,Canadian Food Inspection Agency Email: [email protected]: +613-773-7415

Dr. Yarosh received her M.Sc. in molecular microbiology and her Ph.D. in virology and molecu-lar biology, both from McMaster University, Hamilton, Canada. Her dissertation work focused on developing wildlife vaccines against rabies using human adenoviral vectors. In 1995 Dr. Yarosh joined the Biologics Evaluation Laboratory, Canadian Food Inspection Agency, as a post-doctoral fellow to assess the safety of plasmid DNA vaccines and support BEL activities of pre- and post-licensure quality monitoring of veterinary biologics for use in Canada. Dr. Yarosh transferred to the Canadian Centre for Veterinary Biologics in 2002 as an evaluator of biotech-derived biologics. Her current roles include the regulatory and scientific review of veterinary vaccines and immunologic products, serial /lot/ release, risk assessments for use of experimental and/or novel biotech-derived products, and facility inspections. She also serves as Canada’s representative to the Biologics Quality Monitoring Working Group at the VICH.




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