1 2 3 WHO/EV71/DRAFT/042020 4 ENGLISH ONLY 5 Recommendations to assure the quality, safety and 6 efficacy of Enterovirus 71 vaccines (inactivated) 7 Proposed new recommendations 8 (Draft-version public consultation) 9 10 NOTE: 11 This document has been prepared for the purpose of inviting comments and suggestions on the 12 proposals contained therein, which will then be considered by the Expert Committee on Biological 13 Standardization (ECBS). Publication of this early draft is to provide information about the proposed 14 WHO Recommendations to assure the quality, safety and efficacy of Enterovirus 71 vaccines 15 (inactivated) to a broad audience and to improve transparency of the consultation process. 16 These Recommendations were developed based on the outcomes and consensus of the WHO working 17 group meeting convened in 2018 with participants from national regulatory authorities, national control 18 laboratories, vaccine manufacturers and academia researchers. 19 The text in its present form does not necessarily represent an agreed formulation of the Expert 20 Committee. Written comments proposing modifications to this text MUST be received 21 by 28 May 2020 in the Comment Form available separately and should be addressed to the World 22 Health Organization, 1211 Geneva 27, Switzerland, attention: Department of Health Products Policy 23 and Standards. Comments may also be submitted electronically to the Responsible Officer: 24 Dr Dianliang Lei at email: [email protected]. 25 The outcome of the deliberations of the Expert Committee will be published in the WHO Technical 26 Report Series. The final agreed formulation of the document will be edited to be in conformity with 27 the "WHO style guide, second edition" (KMS/WHP/13.1). 28 29 © World Health Organization 2020 30 All rights reserved. Publications of the World Health Organization can be obtained from WHO Press, World 31 Health Organization, 20 Avenue Appia, 1211 Geneva 27, Switzerland (tel.: +41 22 791 3264; fax: +41 22 791 32 4857; e-mail: [email protected]). Requests for permission to reproduce or translate WHO publications – 33 whether for sale or for noncommercial distribution – should be addressed to WHO Press, at the above address 34 (fax: +41 22 791 4806; email: [email protected]). 35 1 1 The designations employed and the presentation of the material in this publication do not imply the 2 expression of any opinion whatsoever on the part of the World Health Organization concerning the legal status 3 of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or 4 boundaries. Dotted lines on maps represent approximate border lines for which there may not yet be full 5 agreement. 6 7 The mention of specific companies or of certain manufacturers’ products does not imply that they are 8 endorsed or recommended by the World Health Organization in preference to others of a similar nature that 9 are not mentioned. Errors and omissions excepted, the names of proprietary products are distinguished by 10 initial capital letters. 11 12 All reasonable precautions have been taken by the World Health Organization to verify the information 13 contained in this publication. However, the published material is being distributed without warranty of any 14 kind, either expressed or implied. The responsibility for the interpretation and use of the material lies with the 15 reader. In no event shall the World Health Organization be liable for damages arising from its use. 16 17 The named authors [or editors as appropriate] alone are responsible for the views expressed in this 18 publication. 19 20 2 1 Contents 2 Introduction ............................................................................................................................... 5 3 Scope .......................................................................................................................................... 6 4 Terminology ............................................................................................................................... 6 5 General considerations .............................................................................................................. 8 6 International reference materials ............................................................................................ 10 7 Part A. Manufacturing recommendations ............................................................................. 11 8 A.1 Definitions ................................................................................................................. 12 9 A.2 General manufacturing recommendations ............................................................... 12 10 A.3 Control of source materials ....................................................................................... 12 11 A.4 Control of vaccine production ................................................................................... 16 12 A.5 Filling and containers ................................................................................................ 24 13 A.6 Control tests on the final lot ..................................................................................... 24 14 A.7 Records ...................................................................................................................... 26 15 A.8 Retained samples ...................................................................................................... 27 16 A.9 Labelling .................................................................................................................... 27 17 A.10 Distribution and shipping .......................................................................................... 27 18 A.11 Stability, storage and expiry date.............................................................................. 27 19 Part B Nonclinical Evaluation of EV71 vaccines ....................................................................... 28 20 B.1 Product characterization and process development ..................................................... 29 21 B.2 Primary pharmacodynamics studies .............................................................................. 29 22 B.3 Nonclinical safety studies ............................................................................................... 30 23 Part C. Clinical evaluation of inactivated EV71 vaccines ......................................................... 30 24 C.1 Introduction............................................................................................................... 30 25 C.2 Assays ........................................................................................................................ 31 26 C.3 Immunogenicity ........................................................................................................ 32 27 C.4 Efficacy ...................................................................................................................... 33 28 C.5 Safety ......................................................................................................................... 36 29 Part D. Recommendations for NRAs ........................................................................................ 37 30 D.1 General recommendations ....................................................................................... 37 31 D.2 Official release and certification ............................................................................... 37 32 Authors and acknowledgements ............................................................................................. 38 33 References ............................................................................................................................... 39 3 1 Appendix 1 Model Summary protocol for the manufacturing and control of Enterovirus 71 2 vaccines (inactivated) .............................................................................................................. 45 3 Appendix 2 Model NRA Lot Release Certificate for Enterovirus 71 vaccines (inactivated) .... 48 4 5 4 1 Introduction 2 3 Enterovirus (EV)71 was first isolated from the faeces of a female suffering from encephalitis 4 in 1969 in California (1) although a retrospective study in The Netherlands suggests that it 5 could have emerged as early as 1963 (2), consistent with reports of possible epidemics due to 6 EV71 in the late twentieth century across the world (3). EV71 has since been associated with 7 a range of diseases, including Hand Foot and Mouth Disease (HFMD) throughout the world 8 and with epidemics in Asia, Europe and America. The virus causes a range of effects from 9 asymptomatic infection and mild HFMD, to neurological disease with severe central nerve 10 system (CNS) complications and cardiopulmonary failure. In severe cases, mortality rates can 11 be high, especially in children of 5 years age and younger. EV71 is considered to be the most 12 severe neurotoxic enterovirus. Indeed, severe EV71 disease has become a major public health 13 problem in China. In 2011, the WHO Western Pacific Regional Office issued a “Guide to 14 clinical Management and Public Health Response to Hand, Foot and Mouth Disease(HFMD)” 15 (4) to support the treatment, prevention and control of HFMD. 16 Several vaccines against EV71 virus are under development and three inactivated EV71 17 vaccines have already been licensed in China (5-10). The WHO Expert Committee on 18 Biological Standardization (ECBS), at its 67th