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Recommendations to Assure the Quality, Safety and Efficacy of Enterovirus 71 Vaccines

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Recommendations to Assure the Quality, Safety and Efficacy of Enterovirus 71 Vaccines 1 2 3 WHO/BS/2020.2388 4 ENGLISH ONLY 5 6 Recommendations to assure the quality, safety and efficacy of enterovirus 7 71 vaccines (inactivated) 8 9 10 Proposed new Recommendations 11 12 13 14 NOTE: 15 16 This draft document has been prepared for the purpose of inviting comments and suggestions 17 on the proposals contained therein, which will then be considered by the Expert Committee 18 on Biological Standardization (ECBS). The distribution of this document is intended to 19 provide information on the proposed WHO Recommendations to assure the quality, safety 20 and efficacy of enterovirus 71 vaccines (inactivated) to a broad audience and to ensure the 21 transparency of the consultation process. 22 23 These WHO Recommendations were developed based on the outcomes and consensus of a 24 WHO working group meeting and informal consultation convened in 2019 and 2020 25 respectively, involving participants from national regulatory authorities, national control 26 laboratories, vaccine manufacturers and research institutes. 27 28 The text in its present form does not necessarily represent the agreed formulation of the 29 ECBS. Written comments proposing modifications to this text MUST be received by 30 2 October 2020 in the separately available comment form and should be addressed to the 31 Department of Health Products Policy and Standards, World Health Organization, 20 Avenue 32 Appia, 1211 Geneva 27, Switzerland. 33 34 Comments may also be submitted electronically to the Responsible Officer: Dr Dianliang Lei 35 at: [email protected]. 36 37 The outcome of the deliberations of the ECBS will be published in the WHO Technical 38 Report Series. The final agreed formulation of the document will be edited to be in 39 conformity with the second edition of the WHO style guide (KMS/WHP/13.1). 40 WHO/BS/2020.2388 Page 2 1 2 © World Health Organization 2020 3 4 All rights reserved. 5 6 The designations employed and the presentation of the material in this draft document do not imply the 7 expression of any opinion whatsoever on the part of the World Health Organization concerning the legal status 8 of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or 9 boundaries. Dotted lines on maps represent approximate border lines for which there may not yet be full 10 agreement. 11 12 The mention of specific companies or of certain manufacturers’ products does not imply that they are endorsed 13 or recommended by the World Health Organization in preference to others of a similar nature that are not 14 mentioned. Errors and omissions excepted, the names of proprietary products are distinguished by initial capital 15 letters. 16 17 All reasonable precautions have been taken by the World Health Organization to verify the information 18 contained in this draft document. However, the printed material is being distributed without warranty of any 19 kind, either expressed or implied. The responsibility for the interpretation and use of the material lies with the 20 reader. In no event shall the World Health Organization be liable for damages arising from its use. 21 22 This draft document does not necessarily represent the decisions or the stated policy of the World Health 23 Organization. The named authors [or editors as appropriate] alone are responsible for the views expressed 24 herein. 25 WHO/BS/2020.2388 Page 3 1 Recommendations to assure the quality, safety and efficacy of enterovirus 2 71 vaccines (inactivated) 3 4 5 6 Introduction 7 7 8 Purpose and scope 8 9 10 Terminology 8 11 12 General considerations 10 13 14 International reference materials 12 15 16 Part A. Manufacturing recommendations 13 17 18 A.1 Definitions 13 19 A.2 General manufacturing recommendations 14 20 A.3 Control of source materials 14 21 A.4 Control of vaccine production 18 22 A.5 Filling and containers 28 23 A.6 Control tests on the final lot 29 24 A.7 Records 31 25 A.8 Retained samples 31 26 A.9 Labelling 31 27 A.10 Distribution and transport 32 28 A.11 Stability testing, storage and expiry date 32 29 30 Part B. Nonclinical evaluation of enterovirus 71 vaccines (inactivated) 33 31 32 B.1 Product characterization and process development 33 33 B.2 Nonclinical immunogenicity and protection studies 34 34 B.3 Nonclinical safety studies 35 35 36 Part C. Clinical evaluation of enterovirus 71 vaccines (inactivated) 35 37 38 C.1 Introduction 35 39 C.2 Assays 36 40 C.3 Immunogenicity 37 41 C.4 Efficacy 38 42 C.5 Safety 42 43 WHO/BS/2020.2388 Page 4 1 Part D. Recommendations for NRAs 42 2 3 D.1 General recommendations 42 4 D.2 Official release and certification 43 5 6 Authors and acknowledgements 43 7 8 References 44 9 10 Appendix 1 Model summary protocol for the manufacturing and control of 11 enterovirus 71 vaccines (inactivated) 54 12 13 Appendix 2 Model NRA Lot Release Certificate for enterovirus 71 vaccines 14 (inactivated) 64 15 16 WHO/BS/2020.2388 Page 5 1 Recommendations published by the World Health Organization (WHO) are intended to be 2 scientific and advisory in nature. Each of the following sections constitutes recommendations 3 for national regulatory authorities (NRAs) and for manufacturers of biological products. If an 4 NRA so desires, these WHO Recommendations may be adopted as definitive national 5 requirements, or modifications may be justified and made by the NRA. It is recommended 6 that modifications to these WHO Recommendations are made only on condition that such 7 modifications ensure that the product is at least as safe and efficacious as that prepared in 8 accordance with the recommendations set out below. The parts of each section printed in 9 small type are comments or examples intended to provide additional guidance to 10 manufacturers and NRAs. 11 12 WHO/BS/2020.2388 Page 6 1 Abbreviations 2 3 4 BPL beta-propiolactone 5 ELISA enzyme-linked immunosorbent assay 6 EV71 enterovirus 71 7 HFMD hand, foot and mouth disease 8 ICP immune correlate of protection 9 Ig immunoglobulin 10 IPV inactivated poliomyelitis vaccine 11 MCB master cell bank 12 NAT nucleic acid amplification technique 13 NCL national control laboratory 14 NIBSC National Institute for Biological Standards and Control 15 NIFDC National Institutes for Food and Drug Control 16 NRA national regulatory authority 17 PCR polymerase chain reaction 18 PSGL-1 P-selectin glycoprotein ligand-1 19 RD rhabdomyosarcoma 20 SCARB2 scavenger receptor class B member 2 21 SCARB2 scavenger receptor class B member 2 (gene) 22 WCB working cell bank 23 WHO/BS/2020.2388 Page 7 1 Introduction 2 3 Enterovirus 71 (EV71) was first isolated from the faeces of a female suffering from 4 encephalitis in 1969 in California (1). However, a retrospective study conducted in the 5 Netherlands indicated that the virus could have emerged as early as 1963 (2); a finding 6 consistent with reports of possible worldwide EV71 epidemics in the late twentieth century 7 (3). EV71 has since been associated with a range of diseases, including hand, foot and mouth 8 disease (HFMD), throughout the world and with epidemics in Asia, Europe and the 9 Americas. The virus causes a range of effects from asymptomatic infection and mild HFMD 10 to neurological disease with severe central nervous system complications and 11 cardiopulmonary failure. In severe cases mortality rates can be high, especially in children 12 aged 5 years and younger. EV71 is considered to be the most severe neurotoxic enterovirus 13 and severe EV71 disease has become a major public health problem in China. In 2011, the 14 WHO Regional Office for the Western Pacific issued A guide to clinical management and 15 public health response for hand, foot and mouth disease (HFMD) (4) to support the 16 treatment, prevention and control of HFMD. 17 18 Several vaccines against EV71 are currently under development and three inactivated EV71 19 vaccines have been licensed in China (5–10). The WHO Expert Committee on Biological 20 Standardization discussed the EV71 situation at its 67th meeting in 2016 and considered it to 21 be of major regional significance (11). The Committee noted that the joint efforts of the 22 National Institutes for Food and Drug Control (NIFDC) and the National Institute for 23 Biological Standards and Control (NIBSC) had resulted in the development of the First WHO 24 International Standard for anti-EV71 serum (human), and recommended that consideration 25 also be given to the development of a WHO written standard for EV71 vaccines. In addition, 26 the First WHO International Standard for EV71 inactivated vaccine was established by the 27 Committee in October 2019 following a collaborative study led by NIBSC and NIFDC (12, 28 13). National standards for antigen content and neutralizing antibody responses for evaluating 29 EV71 vaccines are also available in China (14) where they have supported the development 30 and clinical assessment of such vaccines. In 2018, the Committee also endorsed a proposal to 31 develop WHO international standards for enterovirus RNA for nucleic acid amplification 32 technique (NAT)-based assays for EV71 (15, 16). 33 34 Following requests from regulators and other stakeholders for WHO to develop 35 recommendations to assure the quality, safety and efficacy of EV71 vaccines, a series of 36 meetings was convened by WHO to review the current status of their development and 37 licensure (17). These meetings were attended by experts from around the world involved in 38 the research, manufacture, regulatory assessment and approval, and control testing and 39 release of EV71 vaccines. Participants were drawn from academia, national regulatory 40 authorities (NRAs), national control laboratories (NCLs) and industry.
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