Guideline on clinical evaluation of vaccines

疫苗临床评估指南

Executive summary 执行摘要

This guideline addresses the clinical evaluation of vaccines intended for the prevention of infectious  diseases . It includes considerations for trials intended to document the safety, immunogenicity and  efficacy of new candidate vaccines and to support changes in the prescribing information of licensed vaccines . It also considers the need for and use of vaccine effectiveness studies .

本指南针对用于预防传染病的疫苗进行临床评估。它包括对旨在记录新候选疫苗的安全性、免疫原性和有效性以及支持许可疫苗处方信息变更的试验的考虑。它还考虑了疫苗有效性研究的必要性和使用。

Since the adoption of EMEA/CHMP/VWP/164653/2005  many new vaccines have been approved in the EU or have received a positive opinion under Article 58 of Regulation (EC) No 726/2004,  including several intended to prevent infectious diseases for which there was previously no vaccine available .

自 EMEA/CHMP/VWP/164653/2005 号文件通过以来，许多新疫苗已在欧盟获得批准，或根据 (EC) No 726/2004 号法规第 58 条获得了肯定意见，其中包括几种用于预防以前没有疫苗可用的传染病的疫苗。

Some of these vaccines include antigens from multiple pathogens or from multiple subtypes of a single pathogen. These applications have raised several issues for vaccine clinical development programmes   that were not addressed in the previous guideline . Furthermore, there have been requests for scientific advice on vaccine clinical development programmes that have pointed to the need to provide updated   or additional guidance on some issues . For example, on considerations for conducting vaccine efficacy  trials, identification of immune correlates of protection, vaccines intended to be used in heterologous    prime-boost regimens and vaccines to be administered to pregnant women to protect their infants during the first months of life .

其中一些疫苗包括来自多种病原体或单一病原体多种亚型的抗原。这些应用为疫苗临床开发计划提出了一些问题，而这些问题在之前的指南中并未涉及。此外，还有人要求就疫苗临床开发计划提供科学建议，这表明有必要就某些问题提供更新或补充指导。例如，关于开展疫苗效力试验的考虑因素、确定保护的免疫相关性、打算用于异源原代强化方案的疫苗以及在婴儿出生后的头几个月中给孕妇注射以保护其婴儿的疫苗。

In response to recurring issues arising in scientific advice and in application dossiers, this revised guidance includes a discussion of disease and patient-related factors to consider when planning and interpreting the results of comparative immunogenicity trials . For example, the importance of considering the severity, mortality and/or risk of permanent sequelae of the infectious disease to be prevented as well as the robustness of the assays to determine the immune response when selecting    non-inferiority margins and assessing the clinical impact of failing to meet pre-defined criteria . In trials that compare candidate and licensed vaccines containing antigens from different numbers of subtypes  of the same organism consideration is given to interpretation of immune responses to non-shared subtypes .

针对科学建议和申请材料中反复出现的问题，本修订指南讨论了在规划和解释比较免疫原性试验结果时应考虑的疾病和患者相关因素。例如，在选择非劣效边际和评估未达到预定标准的临床影响时，必须考虑所要预防的传染病的严重程度、死亡率和/或永久性后遗症的风险，以及确定免疫反应的检测方法的稳健性......。在比较含有同一生物体不同亚型抗原的候选疫苗和许可疫苗的试验中，要考虑对非共享亚型免疫反应的解释。

The guideline also expands on considerations for the design of vaccine efficacy trials, including the selection of appropriate control groups in different circumstances . Moreover, the role of sponsors in the provision of vaccine effectiveness data in the post-authorisation period has been reconsidered to reflect the fact that effectiveness studies are often conducted by public health authorities .

该指南还扩展了疫苗有效性试验设计的考虑因素，包括在不同情况下选择适当的对照组。此外，还重新考虑了赞助商在授权后提供疫苗有效性数据方面的作用，以反映有效性研究通常由公共卫生机构进行这一事实。

There are some special considerations for the evaluation of vaccine safety in clinical trials, including the parameters to be documented in specific age sub-groups. The guideline addresses general considerations for the size of the pre-authorisation safety database, such as the vaccine construct and the use of antigens or adjuvants not previously included in licensed vaccines .

在临床试验中评估疫苗安全性有一些特殊的考虑因素，包括在特定年龄分组中需要记录的参数。该指南涉及授权前安全性数据库规模的一般考虑因素，如疫苗结构和使用以前未纳入许可疫苗的抗原或佐剂。

1.  Introduction (background)

1. 导言（背景）

The Guideline on clinical evaluation of vaccines (EMEA/CHMP/VWP/164653/2005)  covered the clinical development of vaccines intended to provide pre- and post-exposure prophylaxis against infectious diseases . The Guideline on adjuvants in vaccines for human use (EMEA/CHMP/VEG/134716/2004) included a section on the clinical evaluation of vaccines proposed to contain adjuvants . This revision   combines the clinical guidance provided in these two documents . In replacing them, it also addresses issues that have come to light since they came into operation.

疫苗临床评估指南》（EMEA/CHMP/VWP/164653/2005）涵盖了旨在提供接触前和接触后预防传染病的疫苗的临床开发。人用疫苗佐剂指南》（EMEA/CHMP/VEG/134716/2004）中有一节涉及拟含佐剂疫苗的临床评估。本次修订合并了这两份文件中提供的临床指导。在取代这两份文件的同时，它还解决了自这两份文件生效以来出现的问题。

2.  Scope 2. 范围

This guideline is focussed on the clinical development of vaccines, where vaccines are defined as medicinal products intended for prevention, post-exposure prophylaxis and/or treatment of disease   caused by an infectious agent and which contain antigen(s) or genetic information for an antigen(s),  either of biological or synthetic nature, that induce a specific immune response against the causative infectious agent(s) or its toxins .

本指南的重点是疫苗的临床开发，疫苗被定义为用于预防、接触后预防和/或治疗由传染性病原体引起的疾病的医药产品，其中包含生物或合成性质的抗原或抗原的遗传信息，可诱导针对致病性传染性病原体或其毒素的特异性免疫反应。

The guidance is relevant to vaccines that contain one or more :

该指南适用于含有一种或多种......的疫苗：

•     Organisms that have been inactivated by chemical or physical means;

- 通过化学或物理手段灭活的生物体；

•     Live organisms that are naturally non-virulent in humans or that have been treated or genetically modified to attenuate their virulence ;

- 对人类天然无毒性的活生物体，或经过处理或基因改造以减弱其毒性的活生物体；

•     Antigens extracted from pathogens or secreted by them, which may be used in their native state, detoxified by chemical or physical treatments or aggregated, polymerised or conjugated to a carrier to increase their immunogenicity;

- 从病原体中提取或由病原体分泌的抗原，这些抗原可以原生状态使用，也可以通过化学或物理处理解毒，或聚集、聚合或与载体共轭以增加其免疫原性；

•     Antigens produced by genetic engineering or chemical synthesis ;

- 通过基因工程或化学合成生产的抗原 ；

•     Live bacterial or viral vector vaccines expressing foreign antigens;

- 表达外来抗原的活细菌或病毒载体疫苗；

•     Nucleic acid, including plasmids engineered to express specific antigens .

- 核酸，包括用于表达特定抗原的质粒。

The guideline addresses clinical development programmes to support the approval of candidate (i.e . unlicensed) vaccines, adjuvanted or non-adjuvanted, and to support modifications to vaccines in the post-approval period (e.g. changes in, or additions to, the posology, the age range for use or recommendations for concomitant vaccination).

该指南涉及临床开发计划，以支持候选疫苗（即未获许可的疫苗）、佐剂疫苗或无佐剂疫苗的批准，并支持在批准后阶段对疫苗进行修改（例如，改变或增加疫苗剂型、使用年龄范围或建议同时接种疫苗）。

The guidance addresses trials to document vaccine safety, immunogenicity and/or efficacy . It considers situations in which a pre-authorisation demonstration of vaccine efficacy would or would not be required, the design of pre-authorisation trials to evaluate vaccine efficacy and the assessment of vaccine effectiveness in the post-authorisation period.

该指南涉及记录疫苗安全性、免疫原性和/或有效性的试验。它考虑了在哪些情况下需要或不需要进行疫苗有效性的授权前证明，设计授权前试验以评估疫苗的有效性，以及在授权后评估疫苗的有效性。

It also considers the evidence that may be provided from nonclinical studies to support vaccine efficacy but it does not consider other types of nonclinical investigations . These are covered in other guidelines  relevant to vaccines .

它还考虑了可从非临床研究中获得的支持疫苗有效性的证据，但不考虑其他类型的非临床调查。与疫苗相关的其他指南中也有涉及。

Clinical pharmacokinetic studies are not addressed in this guideline since they are not required for vaccines . Although nonclinical pharmacokinetic studies might be applicable when new delivery systems are employed or when the vaccine contains novel adjuvants or excipients, such studies are not addressed in this guideline .

本指南不涉及临床药代动力学研究，因为疫苗不需要这些研究。虽然非临床药代动力学研究可能适用于采用新给药系统或疫苗含有新型佐剂或辅料的情况，但本指南不涉及此类研究。

In relation to vaccines, pharmacodynamic studies comprise the immunogenicity studies that characterise the immune response to the vaccine, which are addressed in section 4.

关于疫苗，药效学研究包括免疫原性研究，这些研究描述了疫苗免疫反应的特征，将在第 4 节中讨论。

Vaccine pharmacovigilance is not covered in this guideline because it is addressed in detail in separate CHMP guidance .

本指南不涉及疫苗药物警戒问题，因为 CHMP 另一份指南对其进行了详细阐述。

3.  Legal basis and relevant guidelines

3. 法律依据和相关准则

This Guideline should be read in conjunction with the introduction and general principles of Annex I to Directive 2001/83/EC, as amended, and all other relevant EU and ICH guidelines . These include, but   are not limited to:

本《指导原则》应与经修订的第 2001/83/EC 号指令附件 I 的导言和一般原则以及所有其他相关的欧盟和 ICH 指导原则一并阅读。这些准则包括但不限于

•     Guideline on good pharmacovigilance practices (GVP) Module VIII – Post-authorisation safety studies (EMA/813938/2011 Rev 3)

- 良好药物警戒规范指南 (GVP) 模块 VIII - 授权后安全性研究 (EMA/813938/2011 Rev 3)

•     ICH guideline E17 on general principles for planning and design of multi-regional clinical trials Step 5 (EMA/CHMP/ICH/453276/2016  Rev 1)

- 关于多区域临床试验规划和设计一般原则的 ICH 指导原则 E17 第 5 步（EMA/CHMP/ICH/453276/2016 Rev 1）

•     Guideline on strategies to identify and mitigate risks for first-in-man and early clinical trials with investigational medicinal products (EMA/CHMP/SWP/28367/07 Rev 1)

- 关于识别和降低研究用医药产品首次临床试验和早期临床试验风险的策略指南（EMA/CHMP/SWP/28367/07 Rev 1）

•     ICH topic E2A Clinical Safety Data Management: Definitions and Standards for Expedited Reporting (CPMP/ICH/377/95)

- ICH 专题 E2A 临床安全数据管理：快速报告的定义和标准（CPMP/ICH/377/95）

•     ICH guideline E8 (R1) on general considerations for clinical studies (EMA/CHMP/ICH/544570/1998)

- 关于临床研究一般注意事项的 ICH E8 (R1) 准则（EMA/CHMP/ICH/544570/1998）

•     ICH E11(R1) guideline on clinical investigation of medicinal products in the paediatric population (EMA/CPMP/ICH/2711/1999)

- ICH E11(R1) 儿科用药临床研究指南（EMA/CPMP/ICH/2711/1999）

•     ICH E7 Studies in Support of Special Populations: Geriatrics Q&A (EMA/CHMP/ICH/604661/2009)

- 支持特殊人群的 ICH E7 研究：老年医学问答》（EMA/CHMP/ICH/604661/2009）

•     ICH E2A Clinical safety data management: definitions and standards for expedited reporting (CPMP/ICH/377/95)

- ICH E2A 临床安全数据管理：快速报告的定义和标准（CPMP/ICH/377/95）

•     ICH E2E - Note for Guidance on Planning Pharmacovigilance Activities (CPMP/ICH/5716/03) •     Guideline on Influenza Vaccines; Non-clinical and Clinical Module (EMA/CHMP/VWP/457259/2014)

- ICH E2E--药物警戒活动规划指导说明（CPMP/ICH/5716/03）--流感疫苗指南；非临床和临床模块（EMA/CHMP/VWP/457259/2014）

•     Guideline on quality, non-clinical and clinical aspects of live recombinant viral vectored vaccines (EMA/CHMP/VWP/141697/2009)

- 重组病毒载体活疫苗质量、非临床和临床方面的指导原则（EMA/CHMP/VWP/141697/2009）

•     ICH Q2 (R1) Validation of analytical procedures: text and methodology (CPMP/ICH/381/95)

- ICH Q2 (R1) 分析程序的验证：文本和方法（CPMP/ICH/381/95）

•     ICH topic E9 Statistical principles for clinical trials – Note for Guidance on Statistical Principles for Clinical Trials (CPMP/ICH/363/96)

- ICH 议题 E9 临床试验统计原则--临床试验统计原则指导说明（CPMP/ICH/363/96）

•     ICH E9 (R1) addendum on estimands and sensitivity analysis in clinical trials to the guideline on statistical principles for clinical trials (EMA/CHMP/ICH/436221/2017)

- ICH E9 (R1)临床试验统计原则指南关于临床试验中估计值和敏感性分析的增编（EMA/CHMP/ICH/436221/2017）

•     Guideline on Missing Data in Confirmatory Clinical Trials (EMA/CPMP/EWP/1776/99  Rev . 1)

- 关于确认性临床试验中缺失数据的指南（EMA/CPMP/EWP/1776/99 Rev .）

•     Guideline on the Choice of the Non-Inferiority Margin (EMEA/CPMP/EWP/2158/99)

- 非劣效边际选择指南（EMEA/CPMP/EWP/2158/99）

•     Points to Consider on Switching between Superiority and Non-Inferiority (CPMP/EWP/482/99)

- 在 "优 "与 "非劣 "之间转换的注意事项（CPMP/EWP/482/99）

•     Points to Consider on Multiplicity  Issues in Clinical Trials (CPMP/EWP/908/99)

- 临床试验中多重性问题的考虑要点（CPMP/EWP/908/99）

•     Points to consider on application of 1. Meta-analyses 2. One pivotal study (CPMP/EWP/2330/99)

- 元分析的应用要点 2.一项关键性研究（CPMP/EWP/2330/99）

•     Guideline on adjustment for baseline covariates in clinical trials (EMA/CHMP/295050/2013)

- 临床试验中基线协变量调整指南（EMA/CHMP/295050/2013）

•     Guideline on the investigation of subgroups in confirmatory clinical trials (EMA/CHMP/539146/2013)

- 确证性临床试验亚组调查指南（EMA/CHMP/539146/2013）

•     Reflection Paper on methodological issues in confirmatory clinical trials planned with an adaptive design (CHMP/EWP/2459/02)

- 关于采用适应性设计的确证性临床试验方法问题的思考文件（CHMP/EWP/2459/02）

•     Guidance on format of the risk-management plan in the European Union – in integrated format (EMA/164014/2018 Rev.2.0.1 accompanying GVP Module V Rev.2)

- 欧盟风险管理计划格式指南 - 综合格式（EMA/164014/2018 Rev.2.0.1 附 GVP 模块 V Rev.2）

•     Guideline on Risk Management Systems for Medicinal Products for Human use (EMEA/CHMP 96286/2005)

- 人用医药产品风险管理系统指南》（EMEA/CHMP 96286/2005）

•     Guideline on good pharmacovigilance practices (GVP) - Product- or Population-Specific

- 良好药物警戒规范 (GVP) 指南 - 针对特定产品或人群

Considerations I: Vaccines for prophylaxis against infectious diseases (EMA/488220/2012 Corr)

考虑因素 I：用于预防传染病的疫苗 (EMA/488220/2012 Corr)

•     Guideline on good pharmacovigilance practices (GVP) Annex I - Definitions (EMA/876333/2011 Rev 4)

- 良好药物警戒规范 (GVP) 指南 附件 I - 定义 (EMA/876333/2011 Rev 4)

•     Guideline on good pharmacovigilance practices: Module V – Risk management systems (EMA/838713/2011 Rev 2).

- 良好药物警戒实践指南：模块 V - 风险管理系统 (EMA/838713/2011 Rev 2)。

4.  Immunogenicity 4. 免疫原性

4.1.   Characterisation of the immune response

4.1.免疫反应的特征

For each antigenic component in a candidate vaccine, and depending on any available information on  immune responses to the same or similar antigenic components in licensed vaccines, characterisation of the immune response in sera, plasma, whole blood, peripheral blood mononuclear cells or occasionally other biological matrices (e.g. nasal swabs, nasal washes, mucosal samples) may include some of the following investigations :

对于候选疫苗中的每种抗原成分，并根据对许可疫苗中相同或类似抗原成分的免疫反应的任何可用信息，对血清、血浆、全血、外周血单核细胞或偶尔其他生物基质（如鼻拭子、鼻腔冲洗液、粘膜样本）中的免疫反应进行定性，可能包括以下一些调查：

•     Measurement of functional antibody (e.g. neutralising antibody, bactericidal activity or opsonophagocytic activity) and/or binding antibody (e.g. total binding IgG, IgA, Ig subclasses);

- 测量功能性抗体（如中和抗体、杀菌活性或溶血活性）和/或结合抗体（如总结合 IgG、IgA、Ig 亚类）；

•     Description of the kinetic of the immune response (e.g. time to reach peak antibody levels and the antibody decay curve);

- 免疫反应动力学描述（如达到抗体峰值的时间和抗体衰减曲线）；

•     Induction of immune memory;

- 诱导免疫记忆；

•     Exploration of immunological factors that could affect the humoral immune response (e.g. pre- vaccination antibody levels resulting from prior vaccination and/or natural exposure);

- 探索可能影响体液免疫反应的免疫学因素（如接种疫苗前因接种疫苗和/或自然暴露而产生的抗体水平）；

•     Evaluation of cross-reactive antibody (e.g. antibody elicited by an antigen that cross-reacts with antigen[s] of one or more other species or subtypes within a species);

- 交叉反应抗体评估（例如，抗原引起的抗体与一个或多个其他物种或一个物种内的亚型的抗原发生交叉反应）；

•     Evaluation of cross-priming (e.g. the ability of one antigen to induce immune memory to [an]other antigen[s]);

- 评估交叉刺激（例如一种抗原诱导对其他抗原产生免疫记忆的能力）；

•     Assessment of the cell-mediated immunity (CMI) component of the immune response (e.g. by quantifying T-cells specific for vaccine antigen[s] and/or antigens derived from wild-type organisms in vitro via direct labelling or based on cytokine release);

- 评估免疫反应的细胞介导免疫 (CMI) 部分（例如，通过直接标记或根据细胞因子释放情况，对疫苗抗原和/或野生型生物体抗原的特异性 T 细胞进行体外定量）；

•    Investigation of the correlation between cytokine or gene expression profiles (e.g. innate immune or plasma cell signatures) and an immune correlate of protection, antibody levels or clinical events, such as immune-mediated adverse effects .

- 研究细胞因子或基因表达谱（如先天免疫或浆细胞特征）与保护的免疫相关性、抗体水平或临床事件（如免疫介导的不良反应）之间的相关性。

Whenever possible, it is preferred that each immune parameter is assayed in a single central laboratory and that the same laboratories are used throughout the clinical development programme . If this is not possible, the potential impact of inter-laboratory variability on the results and conclusions of clinical trials should be addressed in the application dossier .

在可能的情况下，最好在一个中心实验室测定每种免疫参数，并在整个临床开发计划中使用相同的实验室。如果做不到这一点，则应在申请材料中说明实验室之间的差异对临床试验结果和结论的潜在影响。

Protocols should specify the assays to be used to evaluate immune parameters . The assays used in pivotal trials to measure immune parameters designated as primary and/or major secondary endpoints should be fully validated. If there is an internationally-accepted reference assay, any modifications to    the reference assay methodology that are made by a sponsor should be supported by an assay bridging study. Assays should be calibrated against the relevant International Standard(s) whenever these exist. If changes to assay methodologies occur during the clinical development programme, data should be provided to demonstrate no effect on the results or to support the use of a correction factor .

试验方案应明确规定用于评估免疫参数的检测方法。关键试验中用于测量被指定为主要和/或主要次要终点的免疫参数的化验方法应经过充分验证。如果有国际公认的参考检测方法，申办者对参考检测方法的任何修改都应得到检测桥接研究的支持。只要有相关的国际标准，就应根据这些标准对化验方法进行校准。如果在临床开发计划期间化验方法发生变化，应提供数据证明对结果没有影响或支持使用校正系数。

4.2.   Immune correlates of protection

4.2.保护的免疫相关性

In this guideline an immune correlate of protection (ICP) is defined as a type and amount of immunological response that correlates with vaccine-induced protection against an infectious disease  and that is considered predictive of clinical efficacy . Widely accepted and well-supported ICPs exist for a limited range of infectious diseases .

在本指南中，保护性免疫相关物 (ICP) 被定义为与疫苗诱导的传染病保护相关的免疫反应类型和数量，并被认为可预测临床疗效。在有限的几种传染病中，ICP 已得到广泛认可和充分支持。

When there is no established ICP for a specific infectious disease, the relationship between the immune response and protective efficacy (short-term and/or longer-term) should be investigated as the opportunity arises . For example, the relationship could be investigated during vaccine efficacy trials by collecting sera from all or a large subset of subjects in the test and control groups after completion of   the assigned regimen and comparing immune parameters between those who do and do not develop   the infectious disease to be prevented. Repeated sera collection and determination of vaccine efficacy  at timed intervals (e.g. annually) during follow-up may also be used to identify an ICP .

如果没有针对特定传染病的既定 ICP，则应在有机会时调查免疫反应与保护效力（短期和/或长期）之间的关系。例如，在疫苗疗效试验期间，可在完成指定方案后从试验组和对照组的所有受试者或一大部分受试者中采集血清，比较患上和未患上要预防的传染病的受试者的免疫参数，从而研究两者之间的关系。在随访过程中按时间间隔（如每年一次）重复采集血清并确定疫苗疗效，也可用于确定 ICP。

Alternatively, if a vaccine efficacy trial is not feasible (see section 5.1) or if no ICP has been identified  using efficacy trial data, it may be possible to derive an ICP from a prospective vaccine effectiveness   study (see section 6). Furthermore, an indication of the immune parameter of greatest importance for protection and sometimes a preliminary ICP may be obtained from one or more of nonclinical efficacy  studies, sero-epidemiological studies (i.e . examining natural protection) and human challenge trials .

另外，如果疫苗效价试验不可行（见第 5.1 节），或效价试验数据没有确定 ICP，则有可能从前瞻性疫苗有效性研究中得出 ICP（见第 6 节）。此外，还可以从一项或多项非临床有效性研究、血清流行病学研究（即检查自然保护）和人体挑战试验中获得对保护最重要的免疫参数的指示，有时还可以获得初步的 ICP。

An ICP may not be applicable beyond the vaccine and the population in which it was identified. For example, an ICP against a specific infectious disease that is based on a functional humoral immune    response cannot be applied to vaccines intended to prevent the same disease which confer protection via a different immune mechanism . Additionally, an ICP derived from an efficacy trial in infants may   not necessarily be applicable to adults, an ICP established for one subtype of a pathogen may not be  applicable to all subtypes and an ICP may not be applicable to all possible routes of administration of  the same antigens .

国际比较方案的适用范围可能超出疫苗和确定该方案的人群。例如，以功能性体液免疫反应为基础的针对特定传染病的 ICP 不能应用于通过不同免疫机制提供保护的旨在预防相同疾病的疫苗。此外，从婴儿疗效试验中得出的 ICP 不一定适用于成人，为病原体的一种亚型建立的 ICP 不一定适用于所有亚型，而且 ICP 不一定适用于相同抗原的所有可能给药途径。

In some cases, it may not be possible to identify an ICP but clinical trial data may point to a threshold value of a certain immune parameter that could serve for making comparisons between vaccines or population groups (e.g. as applied to serotype-specific IgG elicited by conjugated pneumococcal polysaccharides). Threshold values may be used as a benchmark when interpreting immunological data from further trials with a specific type of vaccine .

在某些情况下，可能无法确定 ICP，但临床试验数据可能会指出某一免疫参数的阈值，该阈值可用于疫苗或人群之间的比较（例如，适用于共轭肺炎球菌多糖诱导的血清型特异性 IgG）。在解释特定类型疫苗进一步试验的免疫学数据时，可将阈值作为基准。

4.3.   Design of comparative immunogenicity trials

4.3.免疫原性对比试验的设计

This section considers general principles for comparative immunogenicity trials regardless of the trial objectives .

本节将讨论比较免疫原性试验的一般原则，无论试验目标如何。

4.3.1. Primary and secondary endpoints

4.3.1.主要和次要终点

Primary and secondary endpoints reported from comparative immunogenicity trials may include some of the following:

免疫原性对比试验报告的主要和次要终点可能包括以下内容：

•     Percentages of subjects with an immune response to vaccination that is above the defined ICP (i.e . the seroprotection rate) or above a threshold level;

- 接种疫苗后免疫反应高于规定的 ICP（即血清保护率）或高于临界值的受试者百分比；

•     Percentages of subjects with a pre-defined increment (e.g. at least a 4-fold rise) in antibody concentration/titre from pre- to post-vaccination (i.e . the seroconversion rate);

- 抗体浓度/滴度从接种前到接种后出现预定增量（如至少上升 4 倍）的受试者百分比（即血清转换率）；

•     Percentages of seronegative or seropositive subjects (with a definition of serostatus that is justified in relation to the assay) pre-vaccination and post-vaccination;

- 接种疫苗前和接种疫苗后血清阴性或血清阳性受试者的百分比（血清状态的定义应与化验结果相符）；

•     Post-vaccination seroprotection and seroconversion rates separately for those who were seronegative or seropositive at study baseline;

- 研究基线时血清阴性或血清阳性者接种疫苗后的血清保护率和血清转换率；

•     Geometric mean antibody concentrations (GMCs) or titres (GMTs) and pre-/post-vaccination ratios (GMRs);

- 几何平均抗体浓度（GMCs）或滴度（GMTs）以及接种前后比率（GMRs）；

•     Pre- and post-vaccination numbers or percentages of subjects with sensitised (i.e . antigen- specific) T-cells (including sensitised CD4+ and CD8+ T-cells), presented according to the   antigen(s) used for stimulation and the cytokine(s) detected in the assay(s).

- 接种疫苗前和接种疫苗后，受试者体内敏化（即抗原特异性）T 细胞（包括敏化的 CD4+ 和 CD8+ T 细胞）的数量或百分比，根据用于刺激的抗原和在检测中检测到的细胞因子列出。

Primary vaccination 初级疫苗接种

If there is a relevant ICP or threshold value, the usual focus of interest is on the proportion of vaccinees likely to be protected after a single primary dose or after the last dose of a primary series . Therefore, the usual primary endpoint is the post-vaccination  seroprotection rate or the percentage  with an immune response at or above the threshold value . If there is no ICP or threshold value, the   primary endpoint is usually the seroconversion rate . The post-vaccination seropositivity rate and the  GMC or GMT may be informative secondary endpoints . Exceptions in which the GMC or GMT may be  the primary endpoint include, but may not be limited to, lot-to-lot consistency trials .

如果存在相关的 ICP 或阈值，通常关注的重点是接种单剂初级疫苗或接种初级系列疫苗最后一剂后可能得到保护的受种者比例。因此，通常的主要终点是接种后血清保护率或免疫反应达到或超过阈值的百分比。如果没有 ICP 或阈值，主要终点通常是血清转换率。接种后血清阳性率和 GMC 或 GMT 可能是有参考价值的次要终点。以 GMC 或 GMT 作为主要终点的例外情况包括（但不限于）批次间一致性试验 .

Post-primary vaccination 初级疫苗接种后

For vaccines that elicit immune memory during primary vaccination of naïve individuals (see sections  4.1 and 4.4.2), post-primary doses will usually result in very high seroprotection, seroconversion and seropositivity rates . Therefore, these endpoints are not usually sensitive for detecting any differences there may be between vaccines, it may be appropriate to designate the post-vaccination GMC or GMT or, occasionally, the GMR (pre-boost to post-boost) as the primary endpoint, in which case the seroconversion and/or seropositivity rates should be designated secondary endpoints .

对于在对未接种疫苗的个体进行初次接种时会产生免疫记忆的疫苗（见第 4.1 和 4.4.2 节），初次接种后的剂量通常会产生很高的血清保护率、血清转换率和血清阳性率。因此，这些终点对于检测不同疫苗之间可能存在的任何差异通常并不敏感，将接种后的 GMC 或 GMT 或（偶尔）GMR（从强化前到强化后）指定为主要终点可能是合适的，在这种情况下，血清转换率和/或血清阳性率应指定为次要终点。

If the vaccine does not elicit immune memory, the primary endpoint should be the same as that selected for assessing the immune response to primary vaccination.

如果疫苗不能引起免疫记忆，则主要终点应与评估初次接种免疫反应时所选择的终点相同。

4.3.2.Primary analyses 4.3.2.1 初级分析

Comparative immunogenicity trials conducted early in the development of a candidate vaccine (e.g. to   identify formulations, doses and regimens for further study) may plan for descriptive analyses . In trials that are designed to support hypothesis testing, CHMP guidance on statistical issues should be followed including, as appropriate, randomisation with stratification factors (e.g. age subgroups, region, prior vaccination history) and the possible need to adjust for multiplicity .

在候选疫苗开发早期进行的免疫原性比较试验（如确定进一步研究的配方、剂量和方案）可计划进行描述性分析。在为支持假设检验而设计的试验中，应遵循 CHMP 关于统计问题的指导，包括酌情使用分层因素（如年龄分组、地区、先前疫苗接种史）进行随机化，以及可能需要根据多重性进行调整。

When the primary aim is to demonstrate non-inferiority of the test group(s) vs . the reference group(s) with respect to immune responses to each or specific antigen(s) of interest, CHMP guidance on selection of non-inferiority margins should be consulted. The clinical considerations for selection of the non-inferiority margin should include the mortality rate and the risk of serious permanent sequelae for the disease to be prevented. In addition, selection of the non-inferiority margin could consider the expected precision of the measurement and the performance characteristics of the assay (e.g. lower limit of detection or quantification, reproducibility) applied to the primary immune parameter .

当主要目的是证明试验组与参照组在对每种或特定抗原的免疫反应方面的非劣效性时，应参考 CHMP 关于选择非劣效性临界值的指导意见。选择非劣效边际的临床考虑因素应包括死亡率和所预防疾病的严重永久性后遗症风险。此外，在选择非劣效边际时，可考虑测量的预期精度和适用于主要免疫参数的检测方法的性能特征（如检测或定量的下限、再现性）。

Comparative immunogenicity trials may aim to demonstrate superiority of the immune response to one or more antigen(s) in a test group compared to a reference group. For example, when the reference group does not receive the antigen(s) in question, when comparing doses or regimens of the same candidate vaccine and when the effect of adding an adjuvant is under evaluation. Alternatively, the same trial may be designed to demonstrate non-inferiority of immune responses to some antigens and superiority for responses to others or may plan to test for non-inferiority and, if the criterion is met, to sequentially test for superiority . For example, when a candidate vaccine contains antigens from more   pathogen subtypes compared to a licensed vaccine, the aim may be to demonstrate non-inferiority for  shared subtypes and superiority for non-shared subtypes .

免疫原性比较试验的目的可能是证明试验组对一种或多种抗原的免疫反应优于参照组。例如，当参照组未接种相关抗原时，当比较同一候选疫苗的剂量或方案时，以及当正在评估添加佐剂的效果时。或者，同一试验的设计可以证明对某些抗原的免疫反应的非劣效性和对另一些抗原的免疫反应的优效性，或者可以计划先进行非劣效性试验，如果符合标准，再依次进行优效性试验。例如，当候选疫苗与许可疫苗相比含有更多病原体亚型的抗原时，其目的可能是证明共享亚型的非劣效性和非共享亚型的优效性。

4.4.   Formulation, dose and schedule

4.4.配方、剂量和时间表

4.4.1.Formulation and dose

4.4.1.配方和剂量

Different considerations will apply according to whether the vaccine contains i) an antigen that has not previously been included in a licensed vaccine; ii) one or more antigens that have not previously been  combined in a licensed vaccine; iii) an adjuvant.

根据疫苗是否包含 i) 以前未被纳入许可疫苗的抗原；ii) 以前未被合并纳入许可疫苗的一种或多种抗原；iii) 佐剂，将适用不同的考虑因素。

i) For an antigen that has not previously been included in a licensed vaccine the  relationship between a range of doses and immune responses should be explored in clinical trials, considering that data from   in-vivo non-clinical studies are not usually helpful for selecting the human dose . If it is not known what might constitute a protective immune response, it may be possible to select an antigen dose above which there is no appreciable increment in the immune response unless there are dose-limiting safety issues associated with that dose . For candidate vaccines that include vectored antigens the dose-finding trials should evaluate the potential effect of pre-existing as well as vaccine-elicited immune responses to the vector on the immune responses to the antigens derived from the target pathogens .

i) 对于以前未被纳入许可疫苗的抗原，应在临床试验中探讨一系列剂量与免疫反应之间的关系，考虑到体内非临床研究的数据通常无助于选择人体剂量......。如果不知道什么可能构成保护性免疫反应，则有可能选择一个抗原剂量，在该剂量之上免疫反应不会明显增加，除非该剂量存在剂量限制性安全问题。对于包含载体抗原的候选疫苗，剂量测定试验应评估原有的以及疫苗引发的对载体的免疫反应对目标病原体抗原免疫反应的潜在影响。

ii) For candidate vaccines that contain one or more antigens that have not previously been combined in a licensed vaccine, the immune responses may be compared with those observed after separate administrations of the individual antigens to evaluate any impact of new combinations on immune responses . However, an evaluation of the effects of combining individual antigens may not be necessary or feasible if a) a very large number of antigens are to be combined (e.g. multiple subtypes of a pathogen); b) the antigen(s) in question will be added to a licensed combination vaccine, in which case the trial may compare the candidate combination vaccine with separate administrations of the licensed combination vaccine and the additional antigen(s); c) the candidate combined vaccine includes only antigens already included in other licensed vaccines, in which case the candidate could be compared with separate administrations of the licensed vaccines or, if they are already approved for co-administration, the candidate could be compared with concomitant administration of the licensed vaccines . Other scenarios may be foreseen and the need for, and extent of, the trials should be decided on a case by case basis .

ii) 对于含有一种或多种抗原的候选疫苗，如果这些抗原以前未在许可疫苗中进行过组合，则可将免疫反应与单独施用单个抗原后观察到的免疫反应进行比较，以评估新组合对免疫反应的任何影响。然而，如果出现以下情况，对单个抗原组合的影响进行评估可能既无必要也不可行 a) 要组合的抗原数量非常多（如病原体的多个亚型b) 有关抗原将添加到已获许可的联合疫苗中，在这种情况下，试验可将候选联合疫苗与分别接种已获许可的联合疫苗和额外抗原进行比较；c) 候选联合疫苗只包括其他已获许可的疫苗中的抗原，在这种情况下，候选疫苗可与单独接种已获许可的疫苗进行比较，或者，如果这些疫苗已被批准联合接种，候选疫苗可与同时接种已获许可的疫苗进行比较。还可能出现其他情况，应根据具体情况决定试验的必要性和程度。

Unpredictable effects on immune responses have been observed when some protein-saccharide conjugates have been included in candidate combination vaccines with certain other antigens, including other conjugates . For example, immune responses to antigens that are the same as (e.g. tetanus toxoid) or closely resemble (e.g. diphtheria toxoid and CRM197) the carrier protein in the conjugate may be enhanced. The potential for increases or decreases in immune responses to the conjugated  antigens and to the conjugative proteins should be carefully explored.

当某些蛋白-多糖共轭物与某些其他抗原（包括其他共轭物）一起被纳入候选联合疫苗时，已经观察到了对免疫反应的不可预测的影响。例如，对与共轭物中载体蛋白相同（如破伤风类毒素）或近似（如白喉类毒素和 CRM197）的抗原的免疫反应可能会增强。应仔细研究对共轭抗原和共轭蛋白的免疫反应增加或减少的可能性。

iii) Whenever an adjuvant is to be included in a vaccine, whether or not the adjuvant is a component of licensed vaccines, the available safety and immunogenicity data should support the amount of the adjuvant that is provided in each dose . Prior experience with the same adjuvant may be used as supportive evidence .

iii) 无论疫苗中是否含有佐剂，现有的安全性和免疫原性数据都应支持每剂疫苗中佐剂的用量..........................以前使用相同佐剂的经验可作为支持性证据。

The justification for inclusion of an adjuvant in a candidate vaccine may be based on a combination of nonclinical and clinical data . In most cases, enhancement of the immune response to one or more of the antigenic components should be demonstrated in a clinical trial that directly compares adjuvanted and non-adjuvanted formulations . Alternatively, or in addition, inclusion of an adjuvant may serve to   reduce the amount of the antigenic component(s) required to achieve a target immune response . This strategy may be important when there are vaccine supply limitations related to manufacture of the antigenic component(s) and there is anticipation of a need to provide large numbers of doses within a limited time frame (e.g. to address pandemic influenza).

在候选疫苗中加入佐剂的理由可基于非临床和临床数据的组合。在大多数情况下，应在直接比较添加佐剂和不添加佐剂的制剂的临床试验中证明对一种或多种抗原成分的免疫反应增强。另外，加入佐剂还可以减少达到目标免疫反应所需的抗原成分的用量。当疫苗供应受到抗原成分生产的限制，并且预计需要在有限的时间内提供大量剂量（如应对流感大流行）时，这种策略可能非常重要。

4.4.2.Schedule

Primary vaccination 初级疫苗接种

The immunogenicity data should suffice to identify the minimum number of doses required to elicit   immune responses at or above the ICP or threshold value or, if neither is available, to maximize the immune response that can be safely achieved in the target population or sub-populations (e.g. age  sub-groups). The appropriate dose interval(s) should be explored considering available data on the  kinetic of the immune response to each sequential dose .

免疫原性数据应足以确定引起达到或超过 ICP 或阈值的免疫反应所需的最小剂量数，或在两者均不具备的情况下，最大限度地提高目标人群或亚人群（如年龄亚组）可安全达到的免疫反应。在确定适当的剂量间隔时，应考虑到有关每个连续剂量的免疫反应动力学的现有数据。

In infants, it is often important to identify a schedule that provides protective immune responses as early as possible . The possibility that maternal antibody might reduce the  magnitude of the infant immune response to vaccination should be evaluated by exploring the relationship between pre-dose and post-dose antibody levels . If pre-existing maternal antibody has a potentially clinically important negative effect, it may be appropriate to investigate infant immune responses when primary immunisation starts or is completed at a slightly later age . Furthermore, it may be useful to assess whether priming still occurred despite lower infant immune response when determining the earliest age at which the first dose may be given.

对于婴儿来说，确定一个能尽早提供保护性免疫反应的接种程序通常很重要。母体抗体可能会降低婴儿对疫苗接种的免疫反应程度，这一点应通过探索接种前和接种后抗体水平之间的关系来评估。如果预先存在的母体抗体会产生潜在的重要临床负面影响，那么当初次免疫接种开始或完成的年龄稍晚时，调查婴儿的免疫反应可能是合适的。此外，在确定最早可接种第一剂的年龄时，评估尽管婴儿免疫反应较低但是否仍有启动作用可能是有用的。

It is not necessary to evaluate immune responses to a candidate vaccine at multiple infant immunisation schedules in routine use . For example, if it is concluded that 2 doses are likely required, an evaluation of immune responses at 2 and 4 months would suffice to support a schedule that starts  and/or ends at a later age since immune responses are generally higher rather than lower as age at    time of vaccination increases within infancy . An evaluation of immune responses at 2 and 4 months of age would not support a schedule starting before 2 months of age or using a 1-month dose interval. Different schedules may have to be established for various target populations (e.g. premature infants, the elderly, the immunosuppressed and haemodialysis patients). Specific schedules may also be needed for populations in which a single dose or short schedule is needed for practical reasons (e.g. travellers and pregnant women).

没有必要在常规使用的多个婴儿免疫程序中评估候选疫苗的免疫反应。例如，如果得出结论认为可能需要接种 2 剂，那么对 2 个月和 4 个月时的免疫反应进行评估就足以支持在较晚年龄开始和/或结束的免疫接种计划，因为随着婴儿期接种年龄的增加，免疫反应通常会更高而不是更低。对 2 个月和 4 个月时免疫反应的评估不支持在 2 个月前开始接种或间隔 1 个月接种的接种程序。不同的目标人群（如早产儿、老年人、免疫抑制者和血液透析患者）可能需要制定不同的接种计划。出于实际原因需要单剂量或短疗程的人群（如旅行者和孕妇）也可能需要特定的疗程。

Post-primary vaccination 初级疫苗接种后

The ability of a primary series to elicit immune memory may be demonstrated by administration of a   post-primary dose of the same vaccine at least 6 months after completion of the primary series . If the post-dose GMC or GMT is higher than the  post-primary value and/or is higher in a group that previously received a primary series than in a previously unvaccinated age-matched group receiving a single dose, it may be inferred that the primary series elicited a T-cell-dependent immune response    leading to an anamnestic response to the post-primary (booster) dose .

在完成初级系列接种至少 6 个月后接种同一疫苗的初级后剂量，可证明初级系列接种激发免疫记忆的能力。如果接种后的 GMC 或 GMT 值高于初次接种后的值，和/或以前接种过初次接种系列疫苗的组别高于以前未接种过疫苗的年龄匹配组别，则可以推断初次接种系列疫苗引起了依赖 T 细胞的免疫反应，导致了对初次接种（加强）后剂量的过敏反应。

If it is known that additional doses will be needed to maintain protection, the immune responses to one or more post-primary doses should usually be investigated in the pre-authorisation trials . If it is not already known that additional doses are needed to maintain protection against the target pathogens the need for and timing of an additional dose(s) after the primary series should be investigated. It is recognised that the need for additional doses may have to be determined after initial authorisation.

如果已知需要额外剂量来维持保护作用，通常应在授权前试验中调查一次或多次初次剂量后的免疫反应。如果还不知道是否需要额外剂量来维持对目标病原体的保护，则应调查在初次系列治疗后是否需要额外剂量以及额外剂量的时间。我们认识到，追加剂量的必要性可能需要在首次授权后才能确定。

For some vaccines that elicit immune memory in the primary series it may not be necessary to administer the same dose for boosting. Therefore, it may be appropriate to investigate the safety and immunogenicity of lower antigen doses for boosting than were used for priming, or to boost with a formulation that does not include an adjuvant.

对于某些在初次接种时可产生免疫记忆的疫苗，可能没有必要在加强接种时接种相同剂量的疫苗。因此，可能需要研究加强接种的抗原剂量低于初免剂量的安全性和免疫原性，或使用不含佐剂的配方进行加强接种。

Generally, it is not recommended to draw conclusions on the need for post-primary doses based only on waning antibody levels . For some pathogens, a decline in antibody, including levels below a putative ICP, may not necessarily indicate loss of protection if immune memory has been elicited (e.g. hepatitis  B vaccines). In contrast, for some pathogens that rapidly invade after colonisation (e.g. N. meningitidis) it may be necessary to maintain a certain level of circulating antibody to ensure protection even if primary vaccination elicited immune memory . For these reasons, when applicable and feasible, it is preferred that the need for and the timing of further doses should be determined  from long term follow-up of subjects enrolled into vaccine efficacy trials and/or from vaccine effectiveness studies or disease surveillance data obtained during the post-authorisation period.

一般来说，不建议仅根据抗体水平的下降就得出是否需要接种初次免疫后剂量的结论。对于某些病原体，如果已经产生了免疫记忆，那么抗体水平的下降，包括低于假定的 ICP 的水平，并不一定意味着失去了保护作用（如乙型肝炎疫苗）。相反，对于一些在定植后迅速入侵的病原体（如脑膜炎双球菌），即使初次接种引起了免疫记忆，也有必要维持一定水平的循环抗体以确保保护。由于这些原因，在适用和可行的情况下，最好根据疫苗效力试验受试者的长期随访结果和/或疫苗效力研究或授权后期间获得的疾病监测数据来确定是否需要继续接种以及何时接种。

Use of different vaccines within schedules

在计划内使用不同的疫苗

The following considerations apply whenever sponsors wish to include specific statements in SmPC regarding the usages described :

当提案国希望在 SmPC 中纳入有关所述用途的具体说明时，应考虑以下因素： 1：

i)         To support the use of more than one vaccine to deliver the total number of doses required within the primary schedule, it should be demonstrated that similar immune responses are achieved using more than one vaccine compared to a single vaccine to complete the schedule ;

i) 为支持使用一种以上的疫苗来完成初级免疫程序所需的总剂量，应证明使用一种以上的疫苗与使用单一疫苗完成免疫程序相比，可获得相似的免疫反应；

ii)        To support the use of a vaccine to boost immune responses in subjects who received a primary series using a different vaccine, subjects primed with one vaccine could be randomised to receive a booster dose with the priming vaccine or the proposed alternative vaccine with the aim of demonstrating non-inferiority of immune responses;

ii) 为支持使用一种疫苗来增强曾接种过另一种疫苗的受试者的免疫反应，可将接种过一种疫苗的受试者随机分配到接种起始疫苗或拟议替代疫苗的受试者中，以证明免疫反应的非劣效性；

iii)        To support the use of different vaccine constructs to prime and to boost, the test regimen could be compared with a repeated dose of the first vaccine construct with the aim of demonstrating superiority of immune responses and/or broadening of the immune response (e.g. to multiple subtypes of a pathogen).

iii) 为支持使用不同的疫苗构建物进行诱导和增强，可将试验方案与重复剂量的第一种疫苗构建物进行比较，以证明免疫反应的优越性和/或免疫反应的广泛性（如对病原体的多种亚型）。

4.4.3. Route and/or method of administration

4.4.3.给药途径和/或方法

For a new candidate vaccine, the choice of route of administration should be justified (e.g. intramuscular, intradermal or subcutaneous) based on prior experience with the same type of vaccine and/or from clinical data generated in the initial dose, formulation and regimen studies . To support an alternative route of administration of a licensed vaccine without altering the vaccine formulation (e.g. to allow a vaccine licensed for intramuscular administration to be given intranasally    or using a new device, such as a microneedle patch), with or without changing the antigen dose(s), the possible need for an efficacy trial should be considered (see section 5).

对于新的候选疫苗，给药途径的选择（如肌内注射、皮内注射或皮下注射）应根据以往使用同类疫苗的经验和/或初始剂量、配方和方案研究中产生的临床数据进行论证。为了在不改变疫苗配方的情况下支持许可疫苗的替代给药途径（例如，允许肌肉注射的许可疫苗经鼻内注射或使用微针贴片等新装置），无论是否改变抗原剂量，都应考虑是否需要进行药效试验（见第 5 节）。

4.5.   Concomitant administration

4.5.同时用药

Concomitant administration of vaccines may result in higher or lower immune responses to certain antigenic components compared to separate administration.

与单独接种疫苗相比，同时接种疫苗可能会导致对某些抗原成分产生较高或较低的免疫反应。

At the time of initial authorisation of a vaccine, it is desirable but not required that there should be data on concomitant administration with vaccines that are most likely to be given at the same time for prevention of other diseases . When there are several licensed vaccines available that protect against    the same disease(s), a trial including concomitant administration of one of these vaccines may suffice

在疫苗初次授权时，最好但不要求提供与最有可能同时接种以预防其他疾病的疫苗同时接种的数据。当有几种获得许可的疫苗可预防同一种疾病时，包括同时接种其中一种疫苗的试验可能就足够了。

 to make a general statement about co-administration in the Summary of Product Characteristics (SmPC). However, variable enhancement or depression of immune responses to conjugated saccharides has been observed when the carrier proteins for co-administered products are the same or different so that the specific type of conjugate for which data are available should be stated in the SmPC.

在 "产品特征概要"（SmPC）中对联合给药进行一般性说明。不过，当联合给药产品的载体蛋白相同或不同时，对共轭糖类的免疫反应增强或抑制的情况也不尽相同，因此应在 SmPC 中说明已有数据的共轭物的具体类型。

For some vaccines, such as those intended for the primary series in infants, it may be necessary to ensure that all subjects in a clinical trial receive all the required antigens before reaching a certain age . To address this need, trials may need to compare concomitant administration with separate administrations made in a staggered fashion (e.g. to compare concomitant administration at 2 and 4   months with administration of routine infant vaccines at 2 and 4 months and the candidate vaccine at 3 and 5 months). In older age groups, it is more likely possible to find populations in which co- administration can be compared with separate administrations since it may be less critical to achieve protection against all antigens in a short timeframe . For some types of vaccine, such as those generally given before travel, it would also be important to assess immune interference at the most concentrated schedule that might be needed.

对于某些疫苗，例如用于婴儿初种系列的疫苗，可能有必要确保临床试验中的所有受试者在达到一定年龄之前接种所有必需的抗原。为了满足这一需要，试验可能需要比较同时接种和交错分别接种（例如，比较 2 个月和 4 个月同时接种与 2 个月和 4 个月接种常规婴儿疫苗和 3 个月和 5 个月接种候选疫苗）。在较大年龄组中，更有可能找到可将同时接种与单独接种进行比较的人群，因为在短时间内实现对所有抗原的保护可能并不那么重要。对于某些类型的疫苗，例如通常在旅行前接种的疫苗，在可能需要的最集中接种计划中评估免疫干扰也很重要。

If any co-administration studies identify important reductions in immune responses, further trials could explore the minimum dose interval that does not lead to any impact.

如果任何联合用药研究发现免疫反应会明显降低，那么进一步的试验可以探索不会产生任何影响的最小剂量间隔。

4.6.   Lot-to-lot consistency

4.6.地块与地块之间的一致性

A lot-to-lot consistency trial is not routinely required but may be considered useful under certain circumstances that should be considered on a case by case basis . If such a trial is conducted it is important to consider and justify the number of lots to be compared and the method of lot selection (e.g. consecutively produced or chosen at random). Careful consideration needs to be given to the   primary immune response endpoint and the pre-defined acceptance criteria .

批次与批次之间的一致性试验并非常规要求，但在某些情况下可能会被认为是有用的，应根据具体情况加以考虑。如果要进行这样的试验，必须考虑并证明需要比较的批次数量和选择批次的方法（如连续生产或随机选择）。需要仔细考虑主要免疫反应终点和预先确定的接受标准。

It is recommended that several lots of the candidate vaccine with a formulation comparable to that of  the final product intended for marketing should be tested during the clinical development programme . If this is not possible due to late stage manufacturing changes, the sponsor should justify the relevance of the clinical trial data to the lots intended for marketing based on quality attributes and/or should conduct a clinical comparison between lots .

建议在临床开发计划期间测试几批配方与最终上市产品相当的候选疫苗。如果由于后期生产变更而无法进行测试，申办者应根据质量属性证明临床试验数据与拟上市批次的相关性，并/或进行批次间的临床比较。

5.  Efficacy 5.功效

5.1.   Requirements for efficacy trials

5.1.药效试验的要求

Vaccine efficacy trials are not required if any of the following apply:

如果出现以下情况，则不需要进行疫苗效力试验：

•     It is possible to interpret immune responses to all the antigens in a candidate vaccine using well-established ICPs . In this case demonstration of non-inferiority to a licensed vaccine for immune responses to each antigen is not necessary . Nevertheless, it is recommended that comparative trials including randomisation to an appropriate licensed vaccine be performed to allow a descriptive comparison of safety profiles . Determination of immune responses to the comparator may be useful to put the  results into context in case the seroprotection rates in the candidate vaccine group are unexpectedly low or high (e.g. due to characteristics of the trial population and/or issues with the assay).

- 使用成熟的 ICP 可以解释候选疫苗中所有抗原的免疫反应。在这种情况下，没有必要证明对每种抗原的免疫反应不劣于许可疫苗。不过，建议进行比较试验，包括随机接种适当的特许疫苗，以便对安全性进行描述性比较。如果候选疫苗组的血清保护率出乎意料地偏低或偏高（例如，由于试验人群的特点和/或检测方法的问题），那么确定对参照物的免疫反应可能有助于将结果与背景情况联系起来。

•     There is/are no ICP(s) but vaccine efficacy can be inferred by demonstrating non-inferior immune responses between the candidate vaccine and a licensed vaccine for which efficacy and/or effectiveness has been established (i.e . an immunobridging strategy is possible). If the

- 没有 ICP，但可通过证明候选疫苗与已确定其效力和/或有效性的许可疫苗之间不存在劣效免疫反应来推断疫苗效力（即可以采用免疫桥接策略）。如果

 exact vaccine for which efficacy or effectiveness was determined is no longer available, the comparison may be made with a licensed vaccine that was itself approved via an immunobridging strategy and, preferably, has been widely used without any concerns regarding protection.

如果已确定效力或有效性的确切疫苗已不再供应，则可与本身已通过免疫桥接策略获得批准的许可疫苗进行比较，该疫苗最好已被广泛使用，且不存在任何保护问题。

•     Immune responses to all antigens in the candidate vaccine can be interpreted using a combination of the above approaches .

- 对候选疫苗中所有抗原的免疫反应可综合使用上述方法进行解释。

Vaccine efficacy trials may not be feasible if any of the following apply:

如果出现以下情况，则可能无法进行疫苗功效试验：

i.     The infectious disease to be prevented does not occur at present (e.g. smallpox) or occurs at too low a rate for a study to be performed in a reasonable timeframe (e.g. anthrax, brucellosis, Q fever).

i.要预防的传染病目前没有发生（如天花）或发生率太低，无法在合理的时间内进行研究（如炭疽、布鲁氏菌病、Q 热）。

ii.     The infectious disease to be prevented occurs in unpredictable short-lived outbreaks that, even if large numbers are affected, do not allow enough time to accrue sufficient cases for an assessment of vaccine efficacy (e.g. some viral haemorrhagic fevers).

ii. 需要预防的传染病会在不可预测的短时间内爆发，即使有大量患者，也没有足够的时间积累足够的病例来评估疫苗的效果（如某些病毒性出血热）。

When a demonstration of vaccine efficacy is considered necessary and it is feasible, a single pivotal vaccine efficacy trial may be acceptable, especially if there is a low incidence of the infectious disease to be prevented so that a very large trial is necessary to accumulate sufficient cases to estimate vaccine efficacy . In this case, considerations in the relevant CHMP guidance on application with a single pivotal trial (CPMP/EWP/2330/99) will apply at time of authorisation assessment.

当认为有必要证明疫苗效力且可行时，可以接受单一关键疫苗效力试验，特别是当需要预防的传染病发病率较低，因此有必要进行非常大规模的试验以积累足够的病例来估计疫苗效力时。在这种情况下，在进行授权评估时，CHMP 关于单次关键试验申请的相关指导（CPMP/EWP/2330/99）中的考虑因素将适用。

For pathogens that have multiple subtypes, it is possible that the cases that occur in an efficacy trial may be due to one or only a few subtypes of the pathogen. Sponsors could consider conducting the pivotal efficacy trial in regions selected to increase the likelihood that cases are due to a broad range of subtypes, although it would not be expected that the trial is designed to estimate subtype-specific efficacy . Alternatively, sponsors may consider conducting more than one vaccine efficacy trial in different regions where certain subtypes are known to predominate . Depending on the vaccine construct, nonclinical and/or other clinical evidence may also be used to support the likely consistency of efficacy across all subtypes .

对于有多种亚型的病原体，疗效试验中出现的病例有可能是由病原体的一种或仅有几种亚型引起的。申办者可以考虑在选定的地区进行关键疗效试验，以增加病例由多种亚型引起的可能性，尽管预计试验的目的不是为了估计特定亚型的疗效。或者，申办者可以考虑在已知某些亚型占主导地位的不同地区进行一次以上的疫苗效力试验。根据疫苗结构的不同，还可以使用非临床和/或其他临床证据来支持所有亚型的疗效一致性。

For some infectious diseases, there may be good scientific reasons to anticipate that the protective efficacy demonstrated in a pivotal efficacy trial in one population in a specific age range may not be extrapolated to other populations with the same age range . For example, in some regions there may be multiple co-infections in populations and/or there may be considerable boosting of the immune response due to natural exposure that could have positive or negative effects on the generalisability of the estimate of vaccine efficacy . In these cases, it may be necessary to conduct a pivotal trial that enrols representative samples of different populations or to conduct more than one trial in separate populations .

对于某些传染病，可能有充分的科学理由来预测，在某一特定年龄段人群中进行的关键疗效试验所显示的保护效力可能无法推断到相同年龄段的其他人群。例如，在某些地区，人群中可能存在多种并发感染，和/或由于自然暴露而导致免疫反应明显增强，这可能对疫苗效力估计值的普遍性产生积极或消极影响。在这种情况下，可能有必要对不同人群进行代表性样本的关键试验，或在不同人群中进行一次以上的试验。

5.2.   Efficacy trial designs

5.2.疗效试验设计

The absolute protective efficacy of vaccines is usually determined by comparing the reduction in the incidence of the infectious disease in question after vaccination with the candidate vaccine compared to the incidence in a group that receives placebo in a prospective randomised and double-blind trial. If a placebo control is considered inappropriate (e.g. because investigators and/or participants/care-givers would reject the possibility of randomisation to multiple placebo injections), a licensed vaccine without an effect on the disease to be prevented by the candidate vaccine could be administered to the control group.

在前瞻性随机双盲试验中，疫苗的绝对保护效力通常是通过比较接种候选疫苗后相关传染病发病率的降低与接种安慰剂组发病率的降低来确定的。如果认为安慰剂对照不合适（例如，因为研究人员和/或参与者/护理人员会拒绝随机注射多次安慰剂的可能性），则可在对照组接种对候选疫苗预防的疾病无影响的特许疫苗。

If the candidate vaccine prevents a severe and/or life-threatening infection and there is an EU- authorised vaccine that prevents the same disease, such that use of a placebo group is not

如果候选疫苗可预防严重和/或危及生命的感染，且有欧盟授权的疫苗可预防同一种疾病，则不需要使用安慰剂组。

 appropriate, the trial may be designed to estimate the relative efficacy of the candidate vs, licensed   vaccine . If the candidate vaccine has been developed to improve on one or more licensed vaccines, it may be appropriate to demonstrate that the efficacy of the candidate vaccine is superior to that of a  licensed vaccine . For example, this may occur when including a higher antigen dose compared to a licensed vaccine, when adding an adjuvant or when replacing the adjuvant with a more powerful adjuvant. If the candidate vaccine is intended to provide protection that it at least as good as that of an EU-authorised vaccine, the aim may be to demonstrate non-inferior efficacy . This design requires very careful justification of the non-inferiority margin, which may not be straightforward.

在适当的情况下，试验可设计为估算候选疫苗与许可疫苗的相对效力。如果开发候选疫苗是为了改进一种或多种许可疫苗，那么证明候选疫苗的效力优于许可疫苗可能是合适的。例如，与许可疫苗相比，如果抗原剂量更高、添加佐剂或用更强效的佐剂替代佐剂，就可能出现这种情况。如果候选疫苗旨在提供至少与欧盟授权疫苗一样好的保护效果，那么其目标可能是证明非劣效性。这种设计要求对非劣效差值进行非常仔细的论证，这可能并不简单。

Other efficacy trial designs are less preferable but may be considered appropriate in certain circumstances and on a case by case basis .

其他疗效试验设计不那么可取，但在某些情况下可根据具体情况考虑采用。

For example, secondary attack rate trials are sometimes used when the infection to be prevented is known or expected to be associated with a relatively high incidence of secondary cases . In these trials, an assumption is made that vaccinees and non-vaccinees have an equal chance of acquiring the infection from the index case . The preferred design would be to randomise the direct contacts, and sometimes secondary contacts, of a case on an individual basis to receive or not receive the candidate vaccine . Alternatives could include randomising individuals to immediate or delayed vaccination or randomising all the members of each ring to the same arm, i.e . a cluster-randomised approach.  In a randomised step-wedge trial, the candidate vaccine is administered sequentially to predefined groups such that each group is a unit of randomisation. Groups may be defined by host factors, location or    other factors . This design may be particularly appropriate when there are logistical reasons that preclude vaccination of large numbers of subjects with the candidate vaccine in a short interval.

例如，当已知或预期要预防的感染与相对较高的继发病例发生率相关时，有时会使用继发感染率试验。在这些试验中，假定接种者和非接种者从指数病例中感染的机会均等。首选的设计是随机分配病例的直接接触者，有时也包括继发接触者，让他们接种或不接种候选疫苗。其他方法包括随机分配个人立即接种或延迟接种，或随机分配每个接种圈的所有成员接种同一臂，即分组随机方法。在随机阶梯试验中，候选疫苗按顺序接种到预先确定的组别中，这样每个组别就是一个随机单位。各组可根据宿主因素、地点或其他因素确定。当由于后勤原因无法在短时间内为大量受试者接种候选疫苗时，这种设计可能特别合适。

5.3.   Case definitions 5.3.案例定义

Case definitions to be used for the primary analysis and any alternative case definitions for secondary   analyses usually comprise clinical signs and/or symptoms typical of the infectious disease together with laboratory confirmation of the aetiology . On occasion, case definitions for primary or secondary analyses may be based only on clinical features or laboratory investigations .

用于初级分析的病例定义和用于次级分析的任何替代病例定义通常包括传染病的典型临床症状和/或体征，以及病原学的实验室确认。有时，一级或二级分析的病例定义可能仅基于临床特征或实验室检查。

If an organism causes disease of variable severity or a range of clinical presentations (e.g. life- threatening invasive infections as well as localised infections) the clinical features of the case definition should be selected in accordance with the proposed indication(s). In these instances, separate efficacy trials using different case definitions may be necessary to support specific indications (e.g. prevention  of invasive pneumococcal disease vs . prevention of pneumococcal otitis media). In addition, for some   vaccines it may be important to compare the severity of vaccine breakthrough cases with cases that occur in the control group to determine whether prior vaccination ameliorates or possibly enhances the severity of the disease .

如果某种病原体引起的疾病严重程度不一或有多种临床表现（如危及生命的侵袭性感染和局部感染），则应根据拟议的适应症选择病例定义的临床特征。在这种情况下，可能需要使用不同的病例定义进行单独的疗效试验，以支持特定的适应症（如预防侵袭性肺炎球菌疾病与预防肺炎球菌中耳炎）。此外，对于某些疫苗，可能有必要比较疫苗突破性病例与对照组病例的严重程度，以确定先前接种疫苗是否会减轻或可能加重疾病的严重程度。

Laboratory confirmation of a case may be based on one or more of immunological tests, pathogen culture, pathogen detection by non-culture-based methods or histological findings . The laboratory methods used to confirm the diagnosis at local study sites and/or at central laboratories should be pre- defined and justified. If there are commercially available tests, the choice of laboratory method(s) should be based on the reported performance characteristics (i.e . the sensitivity and specificity of the   assay and whether it is deemed suitable for the trial population). In some cases, there may be interest in selecting an assay that can detect additional pathogens that may co-infect with the target pathogen and possibly affect the severity or course of the disease . It may also be necessary to apply additional   assays to detect such organisms if this is considered important for interpretation of the trial results.

病例的实验室确诊可基于一种或多种免疫学检测、病原体培养、非培养方法的病原体检测或组织学结果。当地研究机构和/或中央实验室用于确诊的实验室方法应预先确定并说明理由。如果有市售的检测方法，则应根据报告的性能特点（即检测的灵敏度和特异性以及是否适合试验人群）来选择实验室方法。在某些情况下，可能需要选择一种能检测其他病原体的检测方法，这些病原体可能与目标病原体同时感染，并可能影响疾病的严重程度或病程。如果认为这对解释试验结果很重要，也可能有必要采用其他检测方法来检测这些病原体。

On occasion, such as when there are no commercially available tests available with satisfactory performance characteristics, it may be appropriate to use experimental laboratory methods for establishing the presence of infection. In such cases, every effort should be made during the clinical    

在某些情况下，如没有性能令人满意的市售检测方法时，可能需要使用实验室实验方 法来确定是否存在感染。在这种情况下，在临床实验中应尽力

 development programme to evaluate the sensitivity, specificity and reproducibility of the methods used. If the case definition is based on histological findings, the criteria for staging and progression  should be pre-defined in the protocol and it is recommended that there is a quality control system in place and/or secondary readings conducted at an expert central laboratory facility .

制定方案，以评估所使用方法的灵敏度、特异性和可重复性。如果病例定义基于组织学结果，则应在方案中预先确定分期和进展标准，并建议建立质量控制体系和/或在专家中心实验室进行二次读数。

5.4.   Case ascertainment 5.4.病例确定

It is usual that there is active case ascertainment at least up to the time of conduct of the primary analysis . If there is to be further follow-up after the primary analysis the decision to switch to passive case ascertainment should consider the importance of obtaining reliable estimates of vaccine efficacy  in the longer term and information on the characteristics of cases that occur in previously vaccinated  and unvaccinated subjects over time .

通常情况下，主动病例确定至少要持续到进行初步分析时。如果在初步分析后还需要进一步的随访，那么在决定是否改用被动病例确定时，应考虑到获得长期可靠的疫苗效力估计值的重要性，以及关于以前接种过疫苗和未接种过疫苗的受试者随着时间推移出现的病例特征的信息。

When the primary endpoint is laboratory-confirmed clinical disease, the protocol should list the clinical signs and/or symptoms that trigger contact between trial subjects and trial site staff or designated healthcare facilities participating in the trial so that appropriate laboratory testing can be conducted to confirm the case . Regular personal or non-personal contact with trial staff may also be used to determine whether there have been any recent clinical signs or symptoms of potential relevance and to determine whether cases may have been missed. If any cases bypass the designated trial healthcare    facilities and present elsewhere, attempts should be made to retrieve available data that could be used to establish whether the case definition was met.

当主要终点是实验室确诊的临床疾病时，方案应列出引发试验对象与试验场地工作人员或参与试验的指定医疗机构接触的临床症状和/或体征，以便进行适当的实验室检测来确诊病例。与试验工作人员的定期个人或非个人接触也可用于确定近期是否出现任何可能相关的临床症状或体征，并确定病例是否可能被遗漏。如果任何病例绕过了指定的试验医疗机构而出现在其他地方，则应尝试检索可用于确定是否符合病例定义的可用数据。

If the primary endpoint is not a clinically manifest infection, trial visits should be sufficiently frequent to obtain the laboratory data of importance . Every effort should be made to minimize numbers that are lost to follow-up and to conduct trial visits within protocol-defined windows .

如果主要终点不是临床表现的感染，试验访视次数应足够频繁，以获得重要的实验室数据。应尽一切努力减少失去随访的人数，并在方案规定的时间窗口内进行试验访问 .

5.5.   Duration of follow-up for efficacy

5.5.疗效随访时间

The primary analysis of efficacy is usually conducted when a pre-defined number of total cases of disease have occurred. In some cases, when the background incidence of disease is well-documented, the primary analysis may be conducted when it is predicted that a certain number of cases can be expected. See section 5.6.2.

疗效的初步分析通常是在预设的总病例数已发生时进行的。在某些情况下，当疾病的背景发病率有据可查时，可在预测会出现一定数量的病例时进行初步分析。见第 5.6.2 节。

An evaluation of the duration of protection beyond the time at which the primary analysis is conducted is important when there is no prior information for vaccines against the targeted infectious disease but such information is not expected to be available at the time of approval. Data on longer-term protection may come from extensions of pre-authorisation trials and/or from data collected from various sources in the post-approval period.

如果事先没有关于目标传染病疫苗的信息，但预计在批准时无法获得此类信息，那么对进行主要分析时之后的保护持续时间进行评估就非常重要。有关长期保护的数据可能来自批准前试验的延长和/或批准后期间从各种来源收集的数据。

For example, the long-term efficacy of a vaccine and determination of the need for and timing of additional doses may be assessed by following trial subjects after conducting the primary analysis . Follow-up of subjects within an efficacy trial may also be important to fully document the severity and  aetiology of cases that occur in subjects that did and did not receive the candidate vaccine . These data can be used to assess the potential that vaccination reduces or enhances the severity of disease in breakthrough cases . Furthermore, even if vaccination reduces the risk of a clinical disease, documenting the aetiology of any cases that do occur may point to a change in aetiology (e.g. breakthrough cases may be confined to subtypes of a pathogen not included in the vaccine).

例如，在进行主要分析后，可通过跟踪试验对象来评估疫苗的长期疗效，并确定是否需要额外剂量以及额外剂量的时间安排。疗效试验中的受试者随访对于全面记录接种或未接种候选疫苗的受试者所发生病例的严重程度和病因也很重要。这些数据可用于评估接种疫苗是否有可能降低或提高突破性病例的疾病严重程度。此外，即使接种疫苗降低了临床疾病的风险，记录任何病例的病原学也可能表明病原学发生了变化（例如，突破性病例可能仅限于疫苗中未包含的病原体亚型）。

The value and feasibility of obtaining this information within the setting of a prolonged randomised controlled trial must be weighed against alternative methods, such as post-approval vaccine effectiveness studies and routine disease surveillance . Additionally, if the primary analysis indicates that a candidate vaccine is very effective, it may not be appropriate to maintain an unprotected control group. Nevertheless, it may be possible to follow up vaccinated subjects to assess whether there is waning efficacy over time by comparing numbers of cases that occur on an annual basis .                    

在长期随机对照试验的背景下获得这些信息的价值和可行性必须与其他方法（如批准后疫苗有效性研究和常规疾病监测）进行权衡。此外，如果主要分析表明候选疫苗非常有效，则可能不适合保留未受保护的对照组。尽管如此，仍有可能对接种过疫苗的受试者进行随访，通过比较每年发生的病例数来评估疫苗的效力是否会随着时间的推移而减弱。

 5.6.   Analyses of efficacy 5.6.疗效分析

5.6.1.Primary endpoint 5.6.1.主要终点

The primary endpoint is usually based on all cases of an infectious disease that meet the protocol-    defined case definition but may sometimes be based on laboratory events without  immediate clinical signs and symptoms .

主要终点通常基于符合方案定义的病例定义的所有传染病病例，但有时也可能基于没有直接临床症状和体征的实验室事件。

If a candidate vaccine contains antigens derived from several but not all known subtypes of a pathogen it may be acceptable that the primary endpoint is based on cases of disease due to any subtype included in the vaccine . This approach requires that causative pathogens can be subtyped and/or otherwise characterised to determine the degree of matching to the vaccine antigens . If nonclinical or prior clinical data indicate that the vaccine may be able to confer cross-protection against subtypes of a pathogen that are not included in the vaccine, the primary endpoint may be cases of disease due to any subtype of the pathogen.

如果一种候选疫苗包含的抗原来自病原体的几种但不是所有已知亚型，那么主要终点基于疫苗中包含的任何亚型引起的疾病病例可能是可以接受的。这种方法要求对致病病原体进行亚型和/或其他特征描述，以确定与疫苗抗原的匹配程度。如果非临床数据或先前的临床数据表明，疫苗可对未纳入疫苗的病原体亚型产生交叉保护作用，则主要终点可为因病原体的任何亚型而导致的疾病病例。

5.6.2.Primary analysis 5.6.2.1 初级分析

The primary analysis may be performed when :

在下列情况下可进行初级分析

•     The last subject enrolled reaches a specific time elapsed since vaccination or has previously withdrawn from the study This approach may be used when the background rate of disease is well described so that there is confidence regarding the number of cases likely to be observed in the control group during a pre-defined post-vaccination interval.

- 最后一名受试者在接种疫苗后达到特定的时间，或之前已退出研究。 如果对疾病的背景发病率有很好的描述，从而对接种疫苗后的预定间隔内对照组中可能观察到的病例数有信心，则可以使用这种方法。

•     The required number of events (i.e . cases) has been accumulated. This case-driven approach may be most appropriate when the rate of accumulation of cases is less certain.

- 已经积累了所需的事件（即案例）数量。当病例积累率不太确定时，这种病例驱动法可能最合适。

The primary analysis should be aligned to an agreed target of estimation (estimand) as determined by the trial objective . Examples of issues to consider when defining a target of estimation include the target population about which confirmatory conclusions are to be drawn and adherence to the treatment schedule . Depending on the specific situation there could be others, including events such as deaths clearly unrelated to the infectious disease to be prevented that preclude observation of the variable of interest.

主要分析应与试验目标确定的商定估算目标（estimand）保持一致。在确定估计目标时需要考虑的问题包括要得出确证结论的目标人群和治疗计划的坚持情况。根据具体情况，还可能有其他问题，包括与要预防的传染病明显无关的死亡等事件，这些事件排除了对相关变量的观察。

Depending on the infectious disease to be prevented, including factors such as the expected proportion of subjects who are already naturally protected prior to vaccination, different approaches to constructing an estimand and associated primary analysis could be acceptable . In each case the sponsor should fully justify the primary objective of the trial, which will determine the primary analysis population of major interest. Some considerations include the following:

根据要预防的传染病，包括疫苗接种前已自然受到保护的受试者的预期比例等因素，可以接受不同的方法来构建估计值和相关的主要分析。在每种情况下，申办者都应充分说明试验的主要目标，这将决定主要关注的主要分析人群。一些考虑因素如下：

•     When the major interest is to estimate the vaccine efficacy that could be expected in routine use, the primary analysis population would usually include all randomised subjects who receive at least one dose of assigned treatment. Whenever this is not the designated primary analysis  population, there should always be a pre-planned secondary analysis conducted in all randomised subjects who receive at least one dose of assigned treatment.

- 如果主要目的是估计疫苗在常规使用中的预期疗效，那么主要分析人群通常包括所有接受至少一剂指定治疗的随机受试者。如果这不是指定的主要分析人群，则应在所有接受至少一剂指定治疗的随机受试者中进行预先计划的二次分析。

•     When the major interest is to obtain an estimate of vaccine efficacy under full adherence to the allocated vaccine schedule, and assuming there are no systematic differences between subjects who complete the allocated vaccine schedule in each randomised group, the primary analysis    population could include only subjects who received all the allocated doses within pre-defined    windows . For some vaccines and infectious diseases, it may also be acceptable that the

- 如果主要目的是在完全遵守分配的疫苗接种计划的情况下获得疫苗效价的估计值，并假定每个随机分组中完成分配疫苗接种计划的受试者之间不存在系统性差异，则主要分析人群可仅包括在预定窗口内接种了所有分配剂量的受试者。对于某些疫苗和传染病，也可以接受以下情况

 primary analysis population includes only subjects who were seronegative or had no ongoing infection with the target pathogen at trial baseline .

主要分析人群仅包括试验基线时血清阴性或未持续感染目标病原体的受试者。

The primary analysis of efficacy may be based on all cases meeting the primary case definition that occur from randomisation or may be confined to cases that occur more than a specified number of days after the final vaccine dose, assuming there are no systematic differences between subjects who meet the case definition in the intervening period in each group. The post-dose interval before counting cases should be determined from information on the kinetic of the immune response . If the latter approach is taken there should be secondary analyses of all cases that occur from the time of   randomisation. Where relevant, analyses should also be conducted in secondary analysis populations defined, for example, according to the number of vaccine doses actually received.

疗效的主要分析可以基于随机化后发生的符合主要病例定义的所有病例，也可以仅限于最后一剂疫苗接种后超过规定天数的病例，前提是各组间符合病例定义的受试者在间隔期内没有系统性差异。计算病例前的剂量后间隔时间应根据免疫反应动力学信息来确定。如果采用后一种方法，则应对随机分组后发生的所有病例进行二次分析。在相关情况下，还应在二次分析人群中进行分析，例如，根据实际接种的疫苗剂量来定义。

5.6.3.Other issues for the interpretation of vaccine efficacy

5.6.3.解释疫苗效力的其他问题

Vaccine efficacy can only be demonstrated in regions where there is sufficient disease to enable a trial to be conducted within a reasonable time frame . Therefore, use of a vaccine to prevent a disease that occurs rarely within EU countries will be based solely on clinical data generated in regions of high endemicity .

只有在有足够疾病的地区才能证明疫苗的有效性，以便在合理的时间框架内进行试验。因此，使用疫苗来预防一种在欧盟国家很少发生的疾病，将完全基于高流行地区产生的临床数据。

If the pivotal clinical efficacy trial was conducted in endemic regions outside of the EU where there was considerable natural priming before vaccination and/or cross-priming following vaccination against closely related pathogens, the data obtained from subjects who were naïve to the relevant pathogen(s) at trial baseline may be of most relevance to EU residents. In these cases, sponsors should consider whether an assessment of the benefit in EU residents should be supported by a comparison of immune responses to vaccination between seronegative subjects who are resident in an endemic area and age- matched EU residents .

如果关键性临床疗效试验是在欧盟以外的地方病流行地区进行的，而这些地区在接种疫苗前存在大量自然诱导和/或接种疫苗后存在针对密切相关病原体的交叉诱导，那么从试验基线时对相关病原体不敏感的受试者那里获得的数据可能与欧盟居民最相关。在这种情况下，申办者应考虑是否应通过比较居住在流行区的血清阴性受试者和年龄匹配的欧盟居民对接种疫苗的免疫反应来支持对欧盟居民获益的评估。

A further issue may arise if a vaccine was shown to be efficacious in a region where the circulating pathogen subtypes were substantially different to those most common in the EU and existing data indicate that cross-protection across all subtypes cannot be assumed. In this case it may be useful to assess the degree of cross-protection that can occur in vitro to support the expected efficacy of the    vaccine in different regions . For example, depending on the pathogen, functional immune responses  elicited by the vaccine could be assessed for magnitude and durability using a range of circulating organisms isolated from EU cases .

如果疫苗在某一地区被证明有效，而该地区流行的病原体亚型与欧盟最常见的病原体亚型有很大不同，并且现有数据表明不能假定所有亚型都有交叉保护作用，则可能会出现另一个问题。在这种情况下，可能需要评估体外交叉保护的程度，以支持疫苗在不同地区的预期效力。例如，根据病原体的不同，可以使用从欧盟病例中分离出来的一系列循环生物来评估疫苗引起的功能性免疫反应的程度和持久性。

5.7.   Other approaches for estimating vaccine efficacy

5.7.估算疫苗效力的其他方法

For some infectious diseases, there may be i) no possibility of comparing immune responses between a candidate vaccine and a licensed vaccine for which there is documented efficacy or effectiveness; ii) no possibility of conducting a vaccine efficacy trial; and iii) no ICP or threshold value that could be applied to interpret immune responses . In such situations, other approaches to estimating vaccine efficacy could be considered.

对于某些传染病，可能存在以下情况：i) 无法比较候选疫苗与有效力或有效性记录的许可疫苗之间的免疫反应；ii) 无法进行疫苗效力试验；iii) 没有可用于解释免疫反应的 ICP 或阈值。在这种情况下，可以考虑采用其他方法来估计疫苗效力。

For example, consideration could be given to conducting a human challenge trial. Such trials may be conducted quite early in clinical development to provide proof of concept and/or to assist in dose and/or regimen selection. In some instances, such trials may be all that is feasible in terms of assessing clinical efficacy in the pre-approval period. Nevertheless, there are recognised limitations of human challenge trials for predicting protection against natural infection with wild-type pathogens . These include, but are not limited to:

例如，可以考虑进行人体挑战试验。此类试验可在临床开发的早期进行，以提供概念验证和/或协助剂量和/或治疗方案的选择。在某些情况下，此类试验可能是批准前评估临床疗效的唯一可行方法。然而，在预测对野生型病原体自然感染的保护作用方面，人体挑战试验存在公认的局限性。这些限制包括但不限于

i) the need to use attenuated strains of some pathogens; ii) the uncertain or unknown relevance of the challenge doses compared to natural infecting doses; iii) the relevance of the population studied, which is usually healthy adults commonly less than 50 years old, to the entire target population for the

i) 需要使用某些病原体的减毒株；ii) 与自然感染剂量相比，挑战剂量的相关性不确定或未知；iii) 所研究的人群（通常是 50 岁以下的健康成年人）与整个目标人群的相关性。

 vaccine; iv) early intervention with antimicrobial treatment based on first possible sign(s) of clinical disease, such that efficacy against preventing the disease itself is not determined; v) reliance on laboratory data (such as difference in viral loads between vaccinated and unvaccinated groups) because clinical disease is very unlikely to occur in the trial population.

v) 依靠实验室数据（如接种疫苗组和未接种疫苗组之间病毒载量的差异），因为临床疾病在试验人群中发生的可能性很小。

On occasion, the only option for assessing the efficacy of candidate vaccines may be the use of appropriate animal models of infection, which may include post-vaccination challenge studies and studies of passive immunisation using sera or T-cells from vaccinated or naturally infected animals and/or humans . The choice of model(s) requires careful justification.  In this situation of no ICP being available, the extrapolation of vaccine efficacy observed in animals to humans at least requires an understanding of the immune parameter(s) that are most important for mediating protection. In this situation, safety and immunogenicity clinical trials would still be required. The interpretation of the human immunogenicity data would take into account the nonclinical findings and should be discussed on a case by case basis .

有时，评估候选疫苗疗效的唯一选择可能是使用适当的动物感染模型，其中可能包括疫苗接种后的挑战研究以及使用接种疫苗或自然感染的动物和/或人类的血清或 T 细胞进行的被动免疫研究。模型的选择需要仔细论证。在没有 ICP 的情况下，要将在动物身上观察到的疫苗效力推断到人类身上，至少需要了解对介导保护最重要的免疫参数。在这种情况下，仍然需要进行安全性和免疫原性临床试验。对人体免疫原性数据的解释应考虑到非临床研究结果，并应根据具体情况进行讨论。

Whenever authorisation is based on such data, plans to estimate vaccine efficacy and/or vaccine effectiveness if the opportunity arises should be in place at the time of approval.

在根据此类数据进行授权时，应在批准时制定计划，以便在有机会时对疫苗效力和/或疫苗有效性进行估计。

 6.  Effectiveness 6. 成效

Estimates of vaccine effectiveness reflect direct (vaccine induced) and indirect (population related) protection during routine use . Vaccine effectiveness may be estimated from studies that describe the   occurrence of the disease to be prevented in the vaccinated target population over time . For example, these may be observational cohort studies, case-control or case-cohort studies . Alternatively, effectiveness may be estimated from data collected during phased (e.g. in sequential age or risk groups) introduction of the vaccine into the target population and on occasion, using other study designs, disease surveillance networks or disease registries .

疫苗有效性的估计反映了常规使用过程中的直接（疫苗诱导）和间接（与人群相关）保护。疫苗效果可通过描述接种目标人群在一段时间内所预防疾病发生情况的研究来估算。例如，这些研究可以是观察性队列研究、病例对照或病例队列研究。或者，也可通过在目标人群中分阶段（如按年龄或风险组别顺序）接种疫苗期间收集的数据，有时也可利用其他研究设计、疾病监测网络或疾病登记册来估算有效性。

Vaccine effectiveness studies are not always necessary but may be particularly useful in some situations and/or to address certain issues, including but not limited to the following:

疫苗有效性研究并非总是必要的，但在某些情况下和/或在解决某些问题时可能特别有用，包括但不限于以下情况：

•     Authorisation was based on nonclinical efficacy data and a comparison of immune responses between protected animals and vaccinated humans and/or on a human challenge trial;

- 授权的依据是非临床疗效数据以及受保护动物与接种疫苗的人类之间的免疫反应比较和/或人类挑战试验；

•     It is not known how long protection will last after the primary series and/or after post-primary dose(s);

- 目前尚不清楚初级系列和/或初级剂量后的保护作用能持续多久；

•     It is proposed to use the data collected to address long-term protection to support identification of an ICP;

- 建议利用收集到的数据来解决长期保护问题，以支持国际比较方案的确定；

•     There are unanswered questions regarding the efficacy of a vaccine against a wide range of pathogen subtypes ;

- 关于疫苗对多种病原体亚型的疗效，还存在一些未解之谜；

•     There are scientific reasons to suspect that an estimate of vaccine efficacy documented in a    pre-authorisation trial may not be widely applicable to other populations (e.g. to subjects who are resident in different endemic or non-endemic regions);

- 有科学理由怀疑，授权前试验中记录的疫苗疗效估计值可能无法广泛适用于其他人群（例如居住在不同流行或非流行地区的受试者）；

•     Different vaccine implementation strategies are in use in different countries or regions that may impact on the estimate of vaccine effectiveness (e.g. when introduction of routine use in infants is accompanied by a catch-up programme in older subjects and the upper age of the catch-up). In these instances, estimates of vaccine effectiveness obtained using different strategies can inform the optimal strategy to achieve rapid and efficient control of the disease ;

- 不同的国家或地区采用不同的疫苗实施策略，这可能会对疫苗效果的估计值产生影响（例如，在对婴儿进行常规接种的同时，对年龄较大的接种对象实施补种计划，以及补种的最高年龄）。在这种情况下，使用不同策略获得的疫苗有效性估计值可以为快速有效地控制疾病提供最佳策略；

•     There is reason to suspect that widespread use of a vaccine could result in a change in the subtypes of a pathogen causing disease compared to the pre-vaccination era .

- 有理由怀疑，与接种疫苗前相比，疫苗的广泛使用可能会导致致病病原体亚型的改变。

Vaccine effectiveness studies require a suitable infrastructure to be in place for case ascertainment and confirmation of cases in accordance with clinical and laboratory criteria and it may not be possible to obtain reliable data in all countries or regions . In addition, for some infectious diseases an estimate of   vaccine effectiveness is possible only in case of a naturally occurring epidemic or a deliberate release    of a pathogen in the context of bioterrorism . Furthermore, the conduct of a vaccine effectiveness study requires that a policy decision has been made to vaccinate a sufficiently large population to support the analysis .

疫苗有效性研究需要建立适当的基础设施，以便根据临床和实验室标准确定和确认病例，而且可能无法在所有国家或地区获得可靠的数据。此外，对于某些传染病，只有在自然发生的流行病或在生物恐怖主义背景下故意释放病原体的情况下，才有可能估计疫苗的有效性。此外，要进行疫苗有效性研究，就必须做出政策决定，为足够多的人口接种疫苗，以支持分析。

Whenever it is perceived that valuable information could be gained from conducting a vaccine effectiveness study it is important that plans are in place to enable its initiation whenever a suitable opportunity arises in the post-authorisation period.

只要认为可以通过开展疫苗有效性研究获得有价值的信息，就必须制定计划，以便在获得授权后的适当时机启动研究。

The role of the licence holder in designing vaccine effectiveness studies and specifying the target of,   and the population for analysis, generating protocols, and collecting and analysing the data requires  consideration on a case by case basis . In most cases, unless the incidence of the infectious disease is very high in some regions so that a relatively small and short study is possible, a study sponsored by the licence holder is not a practical undertaking. The only feasible way to evaluate vaccine effectiveness is often from studies put in place by public health authorities when initiating large vaccination programmes . Nevertheless, licence holders have a responsibility to ensure that relevant data made available to them and/or reported in the literature from non-sponsored studies are reported to EU Competent Authorities . Consideration should be given to  updating the SmPC if the  results have   clear implications for the advice given (e.g. on the need for additional doses to maintain protection).

许可证持有人在设计疫苗有效性研究、确定分析对象和人群、制定方案以及收集和分析数据方面的作用需要根据具体情况进行考虑。在大多数情况下，除非某些地区的传染病发病率非常高，因此可以进行相对较小和较短时间的研究，否则由许可证持有人赞助的研究是不切实际的。评估疫苗有效性的唯一可行方法往往是公共卫生当局在启动大型疫苗接种计划时开展的研究。尽管如此，许可证持有者仍有责任确保向欧盟主管当局报告向其提供的相关数据和/或文献中报告的非赞助研究数据。如果研究结果对所提供的建议有明显影响（例如，需要增加剂量以维持保护），则应考虑更新 SmPC。

 7.  Safety 7. 安全

7.1.   Assessment of safety in clinical trials

7.1.临床试验的安全性评估

The main considerations for the assessment of safety in vaccine trials are the same as those for other types of medicinal products . All available and relevant CHMP guidance should be followed. Some additional considerations for the assessment of vaccine safety in clinical trials follows .

疫苗试验安全性评估的主要考虑因素与其他类型的医药产品相同。应遵循所有可用的相关 CHMP 指南。以下是在临床试验中评估疫苗安全性的一些额外注意事项。

Since most adverse reactions to vaccines occur within the first few days after each dose, it is common  practise that solicited local and systemic symptoms are collected for approximately 5-7 days after each dose . A longer post-dose period of collection of solicited symptoms may be applicable for replication- competent live vaccines (e.g. 10-14 days or sometimes more), depending on what is known about the   duration of shedding of the vaccine (s). The duration of shedding also has implications for any potential risks to contacts of vaccinees .

由于疫苗的大多数不良反应都发生在每次接种后的最初几天内，因此通常的做法是在每次接种后收集约 5-7 天的局部和全身症状。对于具有复制能力的活疫苗，可能需要更长的剂量后症状收集时间（如 10-14 天，有时甚至更长），这取决于对疫苗脱落持续时间的了解。脱落持续时间也会对接种者接触者的任何潜在风险产生影响。

The list of solicited symptoms may vary with age (e.g. between infants, toddlers and older children or adults). Appropriate grading systems to assess severity should be pre-defined in protocols .

所征集的症状清单可能因年龄而异（如婴儿、学步期儿童和年长儿童或成人）。应在方案中预先确定评估严重程度的适当分级系统。

Details of all other (i.e . unsolicited) post-dose adverse events should be obtained at trial visits and/or using remote contact. During long-term follow-up it may be acceptable that only serious adverse events and adverse events of special interest are captured.

所有其他（即主动提出的）用药后不良事件的详情应在试验访视时和/或通过远程联系获得。在长期随访期间，可以只记录严重不良事件和特别关注的不良事件。

The duration of safety follow-up after the last dose has been given should be justified based on the    candidate vaccine construct, the inclusion of a new adjuvant and prior data of relevance to any of the components .

最后一剂疫苗接种后的安全随访时间应根据候选疫苗的结构、新佐剂的加入情况以及与任何成分相关的先前数据来确定。

If the target population for a candidate vaccine includes paediatric subjects the need for an age de- escalation programme (e.g. so that safety is first assessed in adolescents before moving to 6-12 years, 2-5 years, 1-2 years and less than one year) should be considered on a case by case basis depending on the age range of the target population and the relevance of safety data collected in older sub-populations to younger sub-populations .

如果候选疫苗的目标人群包括儿科受试者，则应根据目标人群的年龄范围以及在年龄较大的亚人群中收集的安全性数据与年龄较小的亚人群的相关性，逐一考虑是否需要实施年龄递增计划（例如，首先评估青少年的安全性，然后再评估 6-12 岁、2-5 岁、1-2 岁和 1 岁以下儿童的安全性）。

For example, age de-escalation may be necessary because it is expected that different vaccine formulations will be required for different age sub-groups, in which case the safety and immunogenicity data from one age subgroup are analysed before moving to the next group.

例如，由于预计不同年龄亚组需要不同的疫苗配方，因此可能需要进行年龄降级，在这种情况下，先分析一个年龄亚组的安全性和免疫原性数据，然后再分析下一个年龄亚组的数据。

Furthermore, if the antigen(s) and/or adjuvant in a vaccine differ from those in licensed vaccines then a more cautious approach may be appropriate .

此外，如果疫苗中的抗原和/或佐剂与许可疫苗中的抗原和/或佐剂不同，则可能需要采取更加谨慎的方法。

Age de-escalation may not be necessary if the candidate vaccine contains only antigen(s) ± an adjuvant already included in licensed vaccine(s), in which case the available safety information of relevance could be considered. Moreover, no or negligible benefit can be expected for some vaccines in certain paediatric age subgroups, which may lead to some degree of reluctance to enroll such children  into clinical trials . If supported by the  nonclinical data and information obtained in adult studies, a modified age-de-escalation approach could be appropriate in certain circumstances . For example, it may be justifiable to proceed from adults to toddlers provided that a cautious approach is taken to  choosing the initial doses and fully evaluating all data from small cohorts before enrolling the next  cohort.

如果候选疫苗仅含有抗原±一种佐剂，且已包含在许可疫苗中，则可能没有必要进行年龄降级，在这种情况下，可考虑现有的相关安全性信息。此外，某些疫苗在某些儿童年龄亚群中可能没有益处或益处微乎其微，这可能导致在某种程度上不愿意将这些儿童纳入临床试验。如果得到成人研究中获得的非临床数据和信息的支持，在某些情况下，修改后的年龄降级方法可能是合适的。例如，如果在选择初始剂量时采取谨慎的态度，并在招募下一批患者之前充分评估来自小群体的所有数据，那么从成人到幼儿的试验可能是合理的。

7.2.   Size of the safety database

7.2.安全数据库的规模

The size of the pre-authorisation safety database must be decided on a case by case basis . If a candidate vaccine contains components not previously included in licensed vaccines it would be usual to aim for a safety database that is sufficient to estimate the frequency of uncommon adverse    events (occurring in between 1/100 and 1/1000 vaccinated persons). Nevertheless, this should not be regarded as a generally applicable target since there may be special concerns that need to be addressed for which a larger database would be needed.

授权前安全数据库的规模必须根据具体情况而定。如果候选疫苗中含有以前未在许可疫苗中使用过的成分，通常会将安全数据库的目标设定为足以估计不常见不良事件的发生频率（发生率在 1/100 至 1/1000 接种者之间）。不过，这不应被视为一个普遍适用的目标，因为可能存在需要解决的特殊问题，为此需要更大的数据库。

For example, if there are concerns arising from the nonclinical data, from historical experience with a similar vaccine or from the available clinical safety data it may be considered necessary that the pre- authorisation safety database is adequate to provide a relatively precise estimate of the risk of uncommon or even rare adverse events . Furthermore, it may be required that the safety database is of sufficient size to estimate the risk of experiencing a specific adverse event after vaccination.

例如，如果非临床数据、类似疫苗的历史经验或现有临床安全数据引起了担忧，则可能需要授权前安全数据库足以对不常见甚至罕见不良事件的风险提供相对精确的估计。此外，可能还要求安全数据库的规模足以估计接种疫苗后发生特定不良事件的风险。

Special considerations for the pre-authorisation safety database may be applicable if i) a candidate vaccine combines antigens ± adjuvant that are all included in licensed vaccines or ii) contains additional antigens compared to a licensed vaccine but all are derived from the same pathogen and manufactured in a similar fashion. In such cases information on the exact mode of manufacture of the various antigens or adjuvants in the candidate vs . licensed vaccine(s) could be taken into account when considering requirements for the pre-authorisation safety database .

授权前安全数据库的特殊考虑可能适用于以下情况：i) 候选疫苗结合了全部包含在许可疫苗中的抗原± 佐剂，或 ii) 与许可疫苗相比含有更多抗原，但所有抗原均来自同一病原体，并以类似方式制造。在这种情况下，在考虑授权前安全数据库的要求时，可以考虑候选疫苗与许可疫苗中各种抗原或佐剂的确切生产方式的信息。

In general, the considerations above apply to the total safety database, i.e . regardless of numbers or proportions within age or other population sub-groups. Depending on the vaccine and target population, it would usually be expected that at least some safety data are available from all target groups for the vaccine (e.g. age sub-groups) and it some cases it may be required that the total safety database comprises a minimum number of subjects within a certain age range or with specific host characteristics .

一般来说，上述考虑因素适用于整个安全性数据库，即不考虑年龄或其他人口亚群的数量或比例。根据疫苗和目标人群的不同，通常希望至少能从疫苗的所有目标人群（如年龄分组）中获得一些安全性数据，在某些情况下，可能要求总安全性数据库包含一定年龄范围内或具有特定宿主特征的受试者的最低数量。

8.  Special populations 8.特殊人群

8.1.   Pregnant women 8.1.孕妇

Not all vaccines are suitable for administration to pregnant women. This section assumes that candidate vaccines proposed for administration during pregnancy will have been assessed in appropriate nonclinical studies and will be comprised of antigen(s) ± adjuvant not known to pose a risk to the pregnant woman or foetus .

并非所有疫苗都适合孕妇接种。本节假定，拟在孕期接种的候选疫苗已在适当的非临床研究中进行了评估，其抗原和佐剂不会对孕妇或胎儿构成风险。

Vaccination during pregnancy may have one or more of the following aims: i) to protect the pregnant woman; ii) to protect the fetus from intra-uterine infection; iii) to protect the infant for as long as protective levels of maternal antibody persist in the post-natal period.

孕期接种疫苗可能有以下一个或多个目的：i) 保护孕妇；ii) 保护胎儿免受宫内感染；iii) 只要母体抗体保护水平在产后持续存在，就能保护婴儿。

If the candidate vaccine is not approved for use in non-pregnant adults, safety and immunogenicity data should be obtained from non-pregnant women of childbearing age before proceeding to trials in    pregnant women. Safety and immunogenicity trials to support selection of dose regimens should enrol individuals at a stage of pregnancy appropriate to the primary objective, i.e . as early as possible in pregnancy to protect the mother and/or fetus and later in pregnancy to maximize maternal antibody levels in the neonate .

如果候选疫苗未被批准用于非怀孕成人，则应先从非怀孕育龄妇女处获得安全性和免疫原性数据，然后再在孕妇中进行试验。为支持剂量方案选择而进行的安全性和免疫原性试验应在与主要目标相适应的妊娠阶段进行，即在妊娠早期进行试验以保护母亲和/或胎儿，在妊娠晚期进行试验以最大限度地提高新生儿的母源抗体水平。

If the primary aim of vaccination during pregnancy is to protect the infant in the first months of life the dose-finding trials should include measurement of antibody levels in cord blood samples taken at delivery . The data should be sufficient to provide an estimate of inter-individual variability and to assess the effect of time interval between vaccination and delivery on maternal antibody levels in infants . The persistence of antibody directed against the target pathogen should be evaluated and compared between infants born to vaccinated vs . unvaccinated mothers as part of the dose-finding process . If the overall strategy involves vaccinating pregnant women followed by active vaccination of their infants against the same antigen(s), the antibody decay curve in infants may provide a preliminary indication of the timing of the first infant dose .

如果孕期接种疫苗的主要目的是在婴儿出生后的头几个月为其提供保护，则剂量测定试验应包括对分娩时采集的脐带血样本中抗体水平的测定。这些数据应足以估计个体间的差异，并评估接种和分娩之间的时间间隔对婴儿体内母体抗体水平的影响。应评估针对目标病原体的抗体的持久性，并在接种疫苗的母亲与未接种疫苗的母亲所生的婴儿之间进行比较，作为剂量测定过程的一部分。如果总体策略包括先为孕妇接种疫苗，然后再为婴儿接种针对相同抗原的疫苗，那么婴儿的抗体衰减曲线可为婴儿首次接种的时间提供初步指示。

If an ICP is established for the infectious disease to be prevented, and depending on the primary objective and the safety profile, the maternal vaccination regimen should maximise the proportions of pregnant women or cord blood samples with antibody that exceeds the ICP . If there is no ICP and there is no licensed vaccine of known efficacy to which the candidate vaccine could be compared (i.e . using immunobridging to infer efficacy), a vaccine efficacy trial would usually be necessary .

如果确定了要预防的传染病的 ICP，根据主要目标和安全性，母体疫苗接种方案应使抗体超过 ICP 的孕妇或脐带血样本比例最大化。 如果没有 ICP，也没有已知效力的许可疫苗可与候选疫苗进行比较（即使用免疫桥接推断效力），通常需要进行疫苗效力试验。

In all trials conducted in pregnant women, adequate mechanisms should be in place to document the  outcome of the pregnancy . For example, information should be collected on the duration of gestation, the condition of the infant at birth and any congenital conditions .

在对孕妇进行的所有试验中，都应建立适当的机制来记录妊娠结果。例如，应收集有关妊娠持续时间、婴儿出生时的状况和任何先天性疾病的信息。

It is important that vaccines proposed for use during pregnancy have very benign safety profiles, including low systemic reactogenicity . If the safety profile in non-pregnant women raises any safety concerns it may be necessary to conduct larger studies in this population to quantify the risk before deciding whether to proceed to pregnant women.

重要的是，建议在孕期使用的疫苗应具有非常良性的安全性，包括低全身反应性。如果非孕妇的安全状况引起了任何安全问题，可能有必要在这一人群中进行更大规模的研究，以量化风险，然后再决定是否对孕妇使用。

8.2.   Elderly subjects 8.2.老年人

For most vaccines, elderly subjects have lower responses to vaccination compared to younger subjects, which may reflect immunosenescence and/or the prevalence of specific underlying diseases or medications that have a negative impact on the immune system . On occasion, immune responses may be higher in the elderly if they are more likely than younger adults to have been primed by natural exposure or prior vaccination. Therefore, it is important that adequate dose-finding studies are conducted for vaccines proposed for use in the elderly and that all age subgroups are investigated (e.g. 65-74 years, 75-84 years and 85 years or more) to determine whether different doses and/or

对于大多数疫苗，老年受试者对疫苗接种的反应低于年轻受试者，这可能反映了免疫衰老和/或对免疫系统有负面影响的特定潜在疾病或药物的流行。有时，如果老年人比年轻人更有可能通过自然暴露或之前的疫苗接种产生免疫反应，那么老年人的免疫反应可能会更高。因此，必须对拟用于老年人的疫苗进行充分的剂量试验研究，并对所有年龄分组（如 65-74 岁、75-84 岁和 85 岁或以上）进行调查，以确定不同的剂量和/或剂量是否会对免疫系统产生负面影响。

regimens are needed as age increases . If efficacy trials are to be conducted in elderly subjects it is recommended to stratify randomisation by age sub-groups . Furthermore, the impact of any underlying conditions or medications known or likely to affect immune responses should be investigated during the clinical trials . The safety of vaccines in the elderly should be documented in subsets with certain underlying conditions and levels of frailty to determine whether the safety profile is broadly acceptable .

随着年龄的增长，需要更多的治疗方案。如果要对老年受试者进行疗效试验，建议按年龄分组进行随机分层。此外，在临床试验期间，应调查已知或可能影响免疫反应的任何基础疾病或药物的影响。疫苗对老年人的安全性应在有某些基础疾病和虚弱程度的子群中进行记录，以确定安全性是否可被广泛接受。

8.3.   Immunodeficient subjects

8.3.免疫缺陷者

Due to the wide range of types of immunodeficiency that may result from congenital or acquired conditions or from iatrogenic intervention, only some of which may impact on the immune response to a specific type of vaccine, trials that assess safety, immunogenicity or efficacy in a broad immunodeficient population are not recommended.

由于先天性或后天性疾病或先天性干预可能导致多种类型的免疫缺陷，其中只有部分可能会影响对特定类型疫苗的免疫反应，因此不建议在广泛的免疫缺陷人群中进行安全性、免疫原性或有效性评估试验。

Trials intended to support dose recommendations for immunodeficient subjects should plan to enrol well-defined sub-populations of subjects with immune deficiencies that have been selected based on those most likely to affect the immune response to a specific vaccine . Unless there is a well-established ICP that can be applied to the data, the  usual aim of such trials will be to identify a posology that achieves comparable immune responses to those observed in immunocompetent subjects .

旨在支持免疫缺陷受试者剂量建议的试验应计划招募定义明确的免疫缺陷受试者亚群，这些亚群是根据最有可能影响特定疫苗免疫反应的因素选择的。除非有可以应用于数据的成熟的 ICP，否则此类试验的通常目的将是确定一种姿势，以获得与在免疫功能正常受试者中观察到的免疫反应相当的免疫反应。

It is not expected to be feasible to study all immunodeficient sub-populations . The extent to which any one posology may be recommended beyond the exact population in which it was studied must be decided based on what is known about the relative importance of different immunological parameters for protection.

对所有免疫缺陷亚群进行研究预计是不可行的。必须根据对不同免疫参数对保护作用的相对重要性的了解，决定在研究的特定人群之外推荐使用任何一种体位疗法的程度。