• <tr id="yyy80"></tr>
  • <sup id="yyy80"></sup>
  • <tfoot id="yyy80"><noscript id="yyy80"></noscript></tfoot>
  • 99热精品在线国产_美女午夜性视频免费_国产精品国产高清国产av_av欧美777_自拍偷自拍亚洲精品老妇_亚洲熟女精品中文字幕_www日本黄色视频网_国产精品野战在线观看 ?

    Review on Drug Regulatory Science Promoting COVID-19 Vaccine Development in China

    2022-06-11 09:04:18ZhimingHungZhihoFuJunzhiWng
    Engineering 2022年3期

    Zhiming Hung, Zhiho Fu, Junzhi Wng,*

    a National Medical Products Administration, Beijing 100053, China

    b National Institutes for Food and Drug Control, Beijing 102629, China

    Keywords:Regulatory science COVID-19 vaccine Vaccine industry

    ABSTRACT Regulatory science is a discipline that uses comprehensive methods of natural science,social science,and humanities to provide support for administrative decision-making through the development of new tools, standards, and approaches to assess the safety, efficacy, quality, and performance of regulated products. During the pandemics induced by infectious diseases, such as H1N1 flu, severe acute respiratory syndrome (SARS), and Middle East respiratory syndrome (MERS), regulatory science strongly supported the development of drugs and vaccines to respond to the viruses. In particular, with the support of research on drug regulatory science, vaccines have played a major role in the prevention and control of coronavirus disease 2019(COVID-19).This review summarizes the overall state of the vaccine industry, research and development (R&D) of COVID-19 vaccines in China, and the general state of regulatory science and supervision for vaccines in China. Further, this review highlights how regulatory science has promoted the R&D of Chinese COVID-19 vaccines,with analyses from the aspects of nationallevel planning, relevant laws and regulations, technical guidelines, quality control platforms, and postmarketing supervision. Ultimately, this review provides a reference for the formulation of a vaccine development strategy in response to the current pandemic and the field of vaccine development in the post-pandemic era, as well as guidance on how to better respond to emerging and recurring infectious diseases that may occur in the future.

    1. Introduction

    Vaccines are one of the greatest achievements in the medical field in the history of humankind.Vaccination is the most effective and economical method for preventing infectious diseases. Since China began nationwide implementation of planned immunization in 1978, and after several adjustments and expansions, China’s national immunization programs include 14 vaccines to prevent 15 diseases, with a vaccination rate greater than 90% [1,2]. Vaccines have played an irreplaceable role in responding to public health emergencies, such as the pandemic H1N1 flu [3] and hand–foot–mouth disease [4,5]. Chinese vaccination has not only improved the overall health of Chinese people but also contributed to the progress of public health worldwide [1,2,6]. Since 2018, the vaccine management system, laws, and regulations in China have undergone major reforms.Further,vaccine supervision has become more scientific and stricter,effectively promoting the development of the vaccine industry.

    The coronavirus disease 2019 (COVID-19) pandemic has undoubtedly increased the speed of global vaccine research and development(R&D),including in China.In one year after the beginning of the epidemic,more than one dozen COVID-19 vaccine candidates entered phase 3 clinical trials. Among them, massage RNA(mRNA) vaccines developed by BioNTech (Germany)/Pfizer (USA)and Moderna,Inc.(USA);adenovirus vectored vaccines by CanSino Biologics Inc.(China)and AstraZeneca(UK);and inactivated vaccines by Sinopharm (China) and Sinovac Biotech Co., Ltd. (China)were approved for conditional marketing.However,multiple variants of severe acute respiratory syndrome coronavirus 2 (SARSCoV-2)have emerged successively and have spread rapidly worldwide since the beginning of the COVID-19 pandemic. Accordingly,this virus continues to challenge the vaccine industry and health system. As of 2021, five variants of concern (VOCs) were reported worldwide, including Alpha (B.1.1.7 and Q lineages), Beta(B.1.351 and descendent lineages), Gamma (P.1 and descendent lineages), Delta (B.1.617.2 and AY lineages), and the newly identified strain Omicron (B.1.1.529).

    Vaccine regulatory science is also developing rapidly,which has played an irreplaceable role in the R&D of safe and effective COVID-19 vaccines for humans in a short period. China’s vaccine industry has made rapid progress with the support of regulatory science,producing and providing effective preventive vaccines at home and abroad. As genetic lineages of SARS-CoV-2 emerge and circulate globally,scientific and efficient regulatory science is absolutely needed to support the entire life cycle of vaccine development in response to epidemics of new variants.

    2. Overall state of the vaccine industry and R&D of COVID-19 vaccines in China

    2.1. Overview of the vaccine industry in China

    China is one of the few countries that can guarantee planned immunization with its own capabilities, and domestic vaccines account for more than 95% of vaccinations in China [7,8]. By the end of 2020, China granted approval for 55 vaccines to prevent 35 infectious diseases. As of 2020, 47 domestic vaccines with lot release were generated by 38 domestic companies in China. The doses of lot release for domestic human vaccines was 651 million in 2020.Further,the total output value of human vaccines in China was more than 60 billion CNY in 2020.

    2.2. Progress in the internationalization of Chinese vaccines

    The internationalization level of vaccine industry and related standards in China continues to improve. China’s national vaccine regulatory system passed the assessment by the World Health Organization (WHO) in 2011 and 2014, and has been recognized by the WHO as a regulatory agency capable of fully performing its functions, which has laid the foundation for Chinese vaccines to enter the procurement catalog by the United Nations [9]. In 2013,the WHO Collaborating Center for Standardization and Evaluation of Biologicals was established in China for the first time,and the live attenuated Japanese encephalitis vaccine,which was made in China, became the first Chinese vaccine to pass the WHO Prequalification (PQ) [10]. Since then, China’s influenza, hepatitis A,bivalent oral polio, and human papillomavirus vaccines have passed the WHO PQ and have been included in the global vaccine procurement list of the United Nations. After the beginning of COVID-19, China rapidly developed and industrialized COVID-19 vaccines based on multiple technology platforms. To ensure the accessibility of COVID-19 vaccines and the fairness of global distribution, international organizations, such as the WHO, the Global Alliance for Vaccines and Immunization (GAVI), and the Coalition for Epidemic Preparedness Innovations (CEPI) established the‘‘COVID-19 Vaccines Global Access (COVAX).” Notably, China has joined the COVAX plan. The inactivated COVID-19 vaccines BBIBP-CorV of the Sinopharm (Beijing) [11] and CoronaVac of the Sinovac Biotech Co., Ltd. [12] have been listed for emergency use by the WHO.As of November 2021,China had provided more than 1.8 billion doses of COVID-19 vaccines and bulk to more than 110 countries or international organizations worldwide.

    2.3. Overview of international R&D of COVID-19 vaccines

    COVID-19 is the infectious disease that has had the greatest impacts on human health and society in a century. As of 3 December 2021, 262 866 050 COVID-19 cases were diagnosed,and 5 224 519 deaths from COVID-19 had been reported worldwide, according to the WHO data [13]. To rapidly respond to the COVID-19 pandemic, many countries have adopted multiple technical approaches for the development of different types of COVID-19 vaccines. With reference to the data published by the WHO, as of 30 November 2021, there were 329 COVID-19 vaccines under research worldwide, among which 135 have entered clinical trials[14]. More than ten COVID-19 vaccines have been approved for marketing or emergency use globally, including COVID-19 mRNA vaccines, inactivated COVID-19 vaccines, adenovirus vectored COVID-19 vaccines, and recombinant subunit vaccines for COVID-19 [15]. Further, by the end of November 2021, nearly 7.9 billion doses of COVID-19 vaccines had been administered globally[13],more than 2.5 billion doses had been administered and over 1 billion people were fully vaccinated against COVID-19 in China[16].

    2.4. Overview of COVID-19 vaccine R&D in China

    As early as February 2020, China deployed several technical routes in the R&D of COVID-19 vaccines,including inactivated vaccine, genetically engineered recombinant subunit vaccine, adenovirus vectored vaccine, nucleic acid vaccine, and attenuated influenza virus vectored vaccine [17]. China has conditionally approved the marketing of three inactivated COVID-19 vaccines developed by Sinopharm (Beijing), Sinopharm (Wuhan), and Sinovac Biotech Co., Ltd.; one adenovirus vectored COVID-19 vaccine developed by CanSino Biologics Inc.; and one recombinant protein subunit vaccine for COVID-19 developed by Zhifei Longcom(China).Among the inactivated vaccines,BBIBP-CorV developed by Sinopharm (Beijing) and CoronaVac developed by Sinovac Biotech Co., Ltd. finalized and passed the WHO PQ and supported global epidemic control[18](Table 1).The inactivated COVID-19 vaccines developed by Shenzhen Kangtai (China) and the Institute of Medical Biology, Chinese Academy of Medical Sciences (China)have been approved for emergency use in China. Twenty-five Chinese COVID-19 vaccines have entered clinical stages.

    3. Overview of the development of drug regulatory science

    3.1. Definition and research content of regulatory science

    Regulatory science is the basis of regulatory decision-making and aims to develop new tools,standards,and approaches to assessthe safety,efficacy,quality,and performance of regulated products throughout their life cycle. Regulatory science is a highly interdisciplinary discipline with an extensive research scope and application fields. This discipline resorts to the comprehensive methods of natural science, social science, and humanities to scientifically and effectively evaluate regulatory objects and provide support for administrative decision-making as society develops and new technologies and new products continuously emerge[19].Regulatory science originated in the field of international environmental protection. After decades of development, research in regulatory science is currently focused on areas closely related to public health, such as food safety, medicine and health, and life sciences.The main research content of regulatory science includes the following three aspects: research and establishment of assessment methods and standards to ensure product quality; research and formulation of the technical guidelines required to guide product development and evaluation; and research and formulation of relevant laws and regulations based on scientific research and specific practices.

    Table 1 COVID-19 vaccines on the WHO emergency using list/PQ list.

    3.2. General state of regulatory science in Chinese vaccines

    As vaccines are mainly used in healthy individuals,their evaluation and regulation are the most stringent among all medicines.Vaccines are also a key research topic in regulatory science.During the past 20 years,with the support of national projects in response to challenges faced in the evaluation of the safety and efficacy of vaccines,research has been carried out on quality control methods,quality specifications,related reference materials,and non-clinical safety evaluations for the target products to promote the type A H1N1 flu vaccine, EV71 vaccine for hand–foot–mouth disease,Ebola vaccine based on a mutant strain of Ebola virus in 2014,hepatitis E vaccine, and other innovative vaccines to be approved for marketing. At the critical moment of the 2009 H1N1 pandemic,China assumed the lead to successfully develop an H1N1 flu vaccine, which was approved for market use [20]. To support EV71 vaccine development, National Institutes for Food and Drug Control (NIFDC) worked closely with several laboratories at each step of R&D, including the screening of vaccine strains, establishment of reference standards for EV71 antigen and neutralizing antibodies, development of suitable evaluation methods for potency, and the statutory standards for quality control. China approved the EV71 vaccine in 2015 [21,22], which is the first vaccine available worldwide for hand–foot–mouth disease. The successful R&D of the H1N1 flu vaccine and EV71 vaccine developed in China are examples of regulatory science supporting innovative vaccine R&D[19],indicating that R&D and regulatory science study of Chinese vaccines has a solid foundation. In May 2019, China’s NMPA launched the Action Plan of Drug Regulatory Science, signifying that China’s drug regulatory science had entered a new stage.

    3.3. Scientific supervision of vaccines supported by regulatory science

    Regulatory science is the foundation of scientific supervision,which refers to the methods, guidelines, laws, and regulations formed on the basis of scientific research and emphasizes scientific research. While scientific supervision belongs to the category of administration to solve the problem of regulatory implementation.In 2019,on the basis of a comprehensive summary of the previous supervision experience in vaccines,China promulgated and implemented the Vaccine Administration Law of the People’s Republic of China [23], in accordance with the Opinions on Reforming and Improving the Vaccine Management System, launching the most stringent supervision, avoiding loopholes in supervision, and ensuring supervision responsibilities. The Vaccine Administration Law of the People’s Republic of China and the newly revised Drug Administration Law of the People’s Republic of China [24], implemented in December 2019, have had a significant and positive impact in the field of vaccines. To implement these two laws,China’s NMPA successively issued a series of supporting regulations and systems, established an inter-ministerial joint meeting system for vaccine management, dispatched inspectors to vaccine manufacturers, carried out routine inspections and patrols(additional risk-based inspection) at vaccine manufacturing sites to improve and implement vaccine lot release systems, and established and launched a vaccine tracking system.

    4. Regulatory science promotes R&D of Chinese COVID-19 vaccines

    COVID-19 vaccines R&D is the first R&D in history to involve hundreds of institutions or companies in the development of vaccines for a single disease.Further,multiple vaccine types are being developed in parallel.The rapid development of COVID-19 vaccines and successful vaccination over a short period have changed the mode of traditional vaccine R&D and applications. Such mass vaccination is also a unique event in the history of human vaccines and infectious disease prevention and control and is an embodiment of the achievements of modern molecular biotechnology and vaccine production technology.

    4.1. China’s national-level planning and multiple technical routes for the development of COVID-19 vaccines

    An extremely ideal COVID-19 vaccine may have the following features[25]:safety(low risk,tolerable),effectiveness(high protection rate,ideally ≥70%and minimum 50%),durability(titer maintained for a long time), flexibility (boosted multiple times),universality (suitable for all age groups, including elderly people and individuals with underlying diseases), accessibility (can be mass-produced in a short time with low cost and globally accessible),and convenience(long-term storage at 4°C or short-term stable storage at room temperature). However, at the beginning of the COVID-19 pandemic, it was impossible to predict the safety and effectiveness of various vaccine types for COVID-19 owing to the novelty of the pathogen. Therefore, China has deployed multiple strategies,including inactivated vaccine,recombinant subunit vaccine,adenovirus vectored vaccine,nucleic acid vaccine,and attenuated influenza virus vectored vaccine(Table 2).In China,inactivated vaccines and adenovirus type-5 vectored vaccines have been conditionally approved for marketing,and recombinant subunit vaccines have been approved for emergency use. Additional vaccine types,including mRNA,DNA,and attenuated influenza virus vectored vaccines,are at different stages of clinical trials[14].Owing to the progress in diversified R&D technical routes, China has obtained technical reserves for the R&D of vaccines against variant strains.An additional vaccine targeting VOCs developed by SinoCellTech Ltd.(China)has already entered phase 2/3 clinical trials[14].

    4.2. Relevant laws and regulations to promote the rapid development of vaccines in China

    The Vaccine Administration Law of the People’s Republic of China[23] stipulates that China supports basic and applied research on vaccines and promotes vaccine development and innovation by incorporating the development, production, and storage of vaccines for the prevention and control of major diseases into the national strategy. For vaccines that are urgently needed for major public health emergencies, the application for vaccine registration may be approved if the benefits of the vaccine are greater than the risks. Vaccines can be used urgently within a certain range and

    time limit in the event of a major public health emergency. The newly revised Drug Administration Law of the People’s Republic of China also stipulates the conditional approval of urgently needed drugs. The Management of lot release of biological products [26]implemented on 1 March 2021, in China stipulates that biological products needed for national disease prevention and emergency control can be released simultaneously. To cope with the COVID-19 pandemic, the NMPA established an accelerated approval and lot release system for COVID-19 vaccines in China.To ensure safety and efficacy,COVID-19 vaccine R&D processes are sped up by rolling the submission of application materials and accelerating the review and approval processes. At present, China has marketed seven COVID-19 vaccines through the emergency use authorization and accelerated approval system.

    Table 2 Technology platforms and major progress in COVID-19 vaccine development in China.

    4.3.Formulation of technical guidelines to promote COVID-19 vaccine R&D in China

    With reference to the WHO and China’s existing vaccine-related regulations and guidelines, combined with the characteristics of emergency R&D of Chinese vaccines for COVID-19, the NMPA issued five technical guidelines for COVID-19 vaccine R&D in China on 14 August 2020, including the Technical guidelines on research and development of COVID-19 prophylactic vaccines (trial edition)[27], the Technical guidelines on pharmaceutical research of COVID-19 prophylactic mRNA vaccines (trial edition) [28], the Technical points for non-clinical studies and evaluation of prophylactic COVID-19 vaccines (trial edition) [29], the Technical guidelines on clinical research of COVID-19 prophylactic vaccines (trial edition) [30], and the Technical guidelines on clinical assessment of COVID-19 prophylactic vaccines (trial edition) [31]. Since then, several guidelines for COVID-19 vaccine R&D have been formulated to promote COVID-19 vaccine R&D in China on the premise of ensuring safety and effectiveness without lowering standards.To maintain consistency between the Chinese vaccine R&D and international standards and consensus, the R&D and evaluation of the series of COVID-19 vaccines have referred to relative guidelines formulated by China and the WHO,and have been guided by constant communication with WHO, which ensured that the R&D of the vaccines was carried out on the basis of data related to quality, safety, and efficacy.

    4.4. Complete quality control and evaluation technology platform to ensure the safety and effectiveness of vaccines

    China relied on national vaccine quality control laboratories,related inspections, and scientific research institutions to study and develop relevant animal models[32–37],quality control methods [38], reference materials [39], and quality specifications for innovative vaccine R&D for COVID-19 immediately after the outbreak [40]. Through laboratory work, such as virus seed verification, cell bank verification, product verification, and clinical serum testing, Chinese researchers have ensured the safety and effectiveness and promoted the R&D of COVID-19 vaccines. The evaluation method of vaccine efficacy is important for vaccine quality control;for example,at the beginning of the COVID-19 epidemic, the NIFDC established a SARS-CoV-2 neutralization assay based on a pseudotyped SARS-CoV-2 virus[38,41]and a transgenic mouse model expressing humanized SARS-CoV-2 receptor angiotensin-converting enzyme 2 (ACE2) [32]. These evaluation tools have been widely used in preclinical and clinical evaluations of the COVID-19 vaccine candidates, which promotes the research and development of COVID-19 vaccines in China. Because of its flexibility and availability, the SARS-CoV-2 pseudovirus has also been widely employed in the investigation of infectivity and antigenicity of SARS-CoV-2 variants [42–45], which is helpful to illustrate the current vaccine efficacy against the circulating variants and to design future broad-spectrum vaccines for the continuing pandemic. To ensure the emergency use of COVID-19 vaccines,13 provincial drug quality control agencies were authorized to undertake the lot release task to provide quality assurance for vaccine inoculation in China.

    4.5. Strengthening post-marketing supervision to promote the quality and supply of Chinese vaccines for COVID-19

    Chinese vaccines for COVID-19 have brand-new characteristics,including the largest vaccine production,distribution,and administration in human history. China has promptly issued a workflow for increasing production and line expansion, as well as technical guidelines for COVID-19 vaccines, including regulatory requirements for COVID-19 vaccine expansion and production, workflow for post-marketing changes in the registration and management of COVID-19 vaccine expansion and production, research on postmarketing changes in the assurance of quality and supply of COVID-19 vaccines, key considerations for commissioned production technology, and key technical points for research on the increase of multiple doses of COVID-19 vaccines (without preservatives), to clarify the specific circumstances and workflow of the changes after the increase in production and expansion lines. The NMPA has implemented a stationed inspection system for vaccine manufacturers to coordinate the stationed work with the production plans of the companies and align the dispatched inspection with the production batches of the enterprises, thereby ensuring that enterprises fulfil their responsibility for vaccine quality under large-scale and heavy-duty conditions in China. In addition to establishing a tracking and regulatory system for vaccine information, China has urgently developed an independent tracking and regulatory system for COVID-19 vaccines to ensure that the sources and destinations of COVID-19 vaccines are traceable.

    5. Conclusions

    Since the beginning of COVID-19, the global vaccine R&D system,patterns,and capabilities have undergone significant changes.Further, vaccine R&D, production, and supervision in China have also markedly changed. The administration of COVID-19 vaccines has effectively reduced the number of hospitalizations, severe illnesses, and deaths from COVID-19. Authorities have accumulated experience in the global vaccine supply, distribution, administration, and real-world monitoring of the safety and efficacy of COVID-19 vaccines.

    To cope with the major threats to human health caused by new and recurring infectious diseases in the future, rapid vaccine R&D should be promoted under the overall framework of promoting regulatory science, where focus should be given to basic research on pathogens,pathogen epidemiology and molecular epidemiological research, basic vaccine research, key technologies for vaccine industrialization, vaccine evaluation and approval mechanisms,and the internationalization of vaccines.

    Compliance with ethics guidelines

    Zhiming Huang, Zhihao Fu, and Junzhi Wang declare that they have no conflict of interest or financial conflicts to disclose.

    极品教师在线免费播放| 久久久久免费精品人妻一区二区 | 精品不卡国产一区二区三区| 久久人人精品亚洲av| 亚洲精品美女久久久久99蜜臀| 色精品久久人妻99蜜桃| 欧洲精品卡2卡3卡4卡5卡区| 成人国产综合亚洲| 两个人免费观看高清视频| 免费观看人在逋| 国产极品粉嫩免费观看在线| 国产99久久九九免费精品| 国产视频一区二区在线看| 久久狼人影院| 亚洲av熟女| 99久久国产精品久久久| 亚洲人成网站高清观看| 一区二区三区国产精品乱码| 老司机深夜福利视频在线观看| 成人国产综合亚洲| 亚洲 国产 在线| 99re在线观看精品视频| 在线免费观看的www视频| 日本精品一区二区三区蜜桃| 免费高清视频大片| 国产精品精品国产色婷婷| 久久久久久久精品吃奶| 久久精品国产亚洲av高清一级| 久久久久九九精品影院| 色精品久久人妻99蜜桃| 精品久久久久久久末码| 90打野战视频偷拍视频| 免费高清视频大片| 在线永久观看黄色视频| 色在线成人网| 国产av在哪里看| 美女午夜性视频免费| 国产精品免费一区二区三区在线| 亚洲九九香蕉| 日韩av在线大香蕉| 国产色视频综合| 亚洲成人久久爱视频| 国内精品久久久久久久电影| 欧美色欧美亚洲另类二区| 女人被狂操c到高潮| 亚洲免费av在线视频| 性欧美人与动物交配| 亚洲午夜理论影院| 91九色精品人成在线观看| 少妇熟女aⅴ在线视频| 国产精品乱码一区二三区的特点| 激情在线观看视频在线高清| 中文字幕久久专区| 久久热在线av| 国产精品电影一区二区三区| 色综合婷婷激情| 一本大道久久a久久精品| 岛国在线观看网站| 一级黄色大片毛片| 妹子高潮喷水视频| 欧美+亚洲+日韩+国产| 一a级毛片在线观看| 国产一区二区激情短视频| 久久中文字幕一级| 日本a在线网址| 国产成人精品无人区| 一级作爱视频免费观看| 国产97色在线日韩免费| 亚洲国产精品久久男人天堂| 正在播放国产对白刺激| 可以在线观看的亚洲视频| 国产亚洲精品久久久久5区| 欧美成人性av电影在线观看| 久久久国产精品麻豆| 亚洲精品粉嫩美女一区| 久热这里只有精品99| 国产亚洲精品第一综合不卡| 久久精品91蜜桃| 女性被躁到高潮视频| 真人做人爱边吃奶动态| 国产片内射在线| 亚洲免费av在线视频| 欧美成狂野欧美在线观看| 日本免费a在线| 99热只有精品国产| 久久国产乱子伦精品免费另类| 国产午夜福利久久久久久| 欧美日韩瑟瑟在线播放| 日日爽夜夜爽网站| 成人18禁在线播放| 桃色一区二区三区在线观看| 桃红色精品国产亚洲av| 日韩欧美免费精品| 亚洲av成人av| 亚洲精品久久成人aⅴ小说| 国产av在哪里看| 国产成人欧美| 亚洲专区国产一区二区| 老司机深夜福利视频在线观看| 亚洲精品av麻豆狂野| 亚洲欧洲精品一区二区精品久久久| 老司机午夜十八禁免费视频| 香蕉国产在线看| 久久天躁狠狠躁夜夜2o2o| 国内毛片毛片毛片毛片毛片| 久久精品影院6| 欧美午夜高清在线| 精品久久久久久,| ponron亚洲| 一区二区三区激情视频| 欧美精品啪啪一区二区三区| 国产精品野战在线观看| 观看免费一级毛片| 欧美中文综合在线视频| 成年免费大片在线观看| 亚洲成人久久爱视频| 高清毛片免费观看视频网站| cao死你这个sao货| 欧美日韩亚洲综合一区二区三区_| av有码第一页| 久久中文看片网| 免费av毛片视频| 91av网站免费观看| 这个男人来自地球电影免费观看| 久久久久久久精品吃奶| 国产亚洲精品久久久久5区| 久久久国产精品麻豆| 亚洲精品色激情综合| av在线播放免费不卡| 亚洲欧美日韩无卡精品| 久久久久亚洲av毛片大全| 自线自在国产av| 悠悠久久av| 身体一侧抽搐| 日韩欧美 国产精品| 一区二区三区激情视频| 国产精品亚洲一级av第二区| 久久精品91蜜桃| 欧美成人午夜精品| 精品不卡国产一区二区三区| 成年版毛片免费区| 91九色精品人成在线观看| 黄色毛片三级朝国网站| 欧美三级亚洲精品| 色老头精品视频在线观看| 欧美国产精品va在线观看不卡| 亚洲国产日韩欧美精品在线观看 | 人人妻人人澡人人看| bbb黄色大片| 国产真实乱freesex| 俺也久久电影网| 亚洲国产欧美一区二区综合| 两个人视频免费观看高清| 久久久久久大精品| 国产成年人精品一区二区| 国产精品二区激情视频| 欧美黑人精品巨大| 久热这里只有精品99| 欧美黑人精品巨大| 男人舔女人下体高潮全视频| 天天躁狠狠躁夜夜躁狠狠躁| 亚洲 国产 在线| 18禁观看日本| 18禁观看日本| 欧美又色又爽又黄视频| 国产av在哪里看| 最好的美女福利视频网| 免费看a级黄色片| 亚洲专区中文字幕在线| 妹子高潮喷水视频| 一级黄色大片毛片| 午夜激情av网站| 亚洲一区中文字幕在线| 精品国产国语对白av| 一区二区三区国产精品乱码| 真人做人爱边吃奶动态| 淫妇啪啪啪对白视频| 淫妇啪啪啪对白视频| 日本在线视频免费播放| 欧美成人免费av一区二区三区| 桃色一区二区三区在线观看| tocl精华| 在线观看免费日韩欧美大片| 18美女黄网站色大片免费观看| 成人午夜高清在线视频 | 精品久久久久久久久久久久久 | 午夜日韩欧美国产| 久久精品亚洲精品国产色婷小说| 韩国av一区二区三区四区| 看片在线看免费视频| 日日爽夜夜爽网站| 黄片播放在线免费| 夜夜躁狠狠躁天天躁| 成人18禁高潮啪啪吃奶动态图| 成人18禁在线播放| 欧美大码av| 色综合欧美亚洲国产小说| 99久久精品国产亚洲精品| 久久香蕉激情| 一本一本综合久久| 久99久视频精品免费| 欧美日韩一级在线毛片| 国产真实乱freesex| 国产极品粉嫩免费观看在线| 禁无遮挡网站| 久久性视频一级片| 亚洲精华国产精华精| 欧美成人一区二区免费高清观看 | 亚洲午夜理论影院| 欧美性长视频在线观看| 一二三四在线观看免费中文在| 每晚都被弄得嗷嗷叫到高潮| 国产精品久久久久久亚洲av鲁大| 亚洲国产精品999在线| 18禁黄网站禁片免费观看直播| 国产精品久久久久久精品电影 | 日日摸夜夜添夜夜添小说| 女人爽到高潮嗷嗷叫在线视频| 日本熟妇午夜| 日本成人三级电影网站| 欧美亚洲日本最大视频资源| 午夜福利18| 一区二区日韩欧美中文字幕| 国产精品一区二区三区四区久久 | 麻豆成人午夜福利视频| 免费看日本二区| 国产在线精品亚洲第一网站| 亚洲中文日韩欧美视频| 欧美精品啪啪一区二区三区| 欧美成人午夜精品| 男女午夜视频在线观看| 在线视频色国产色| 亚洲精品久久成人aⅴ小说| 亚洲熟妇中文字幕五十中出| 免费观看人在逋| 桃红色精品国产亚洲av| 国产成人av教育| 亚洲成a人片在线一区二区| 久久香蕉精品热| 国产蜜桃级精品一区二区三区| 亚洲精品久久国产高清桃花| 久久久久久久久免费视频了| 国产精品98久久久久久宅男小说| 婷婷精品国产亚洲av在线| 黄色视频不卡| 99久久国产精品久久久| 精品久久久久久久久久免费视频| 亚洲熟女毛片儿| 1024香蕉在线观看| 午夜亚洲福利在线播放| 国产成人一区二区三区免费视频网站| 日日夜夜操网爽| 看免费av毛片| 91大片在线观看| 成人亚洲精品av一区二区| 欧美中文日本在线观看视频| 国产日本99.免费观看| 一本久久中文字幕| 欧美zozozo另类| videosex国产| 长腿黑丝高跟| 国产精品,欧美在线| 久久久国产欧美日韩av| 18禁观看日本| 成人av一区二区三区在线看| 在线国产一区二区在线| 亚洲人成网站高清观看| 日本在线视频免费播放| 91麻豆av在线| 免费在线观看亚洲国产| 成年人黄色毛片网站| 男人的好看免费观看在线视频 | 国内揄拍国产精品人妻在线 | 黄片大片在线免费观看| 欧美中文日本在线观看视频| 久久久久久久久中文| 久久婷婷成人综合色麻豆| 国产不卡一卡二| 天天添夜夜摸| 三级毛片av免费| 国产又黄又爽又无遮挡在线| 曰老女人黄片| 大型黄色视频在线免费观看| АⅤ资源中文在线天堂| 母亲3免费完整高清在线观看| 热99re8久久精品国产| 午夜免费鲁丝| 曰老女人黄片| 最好的美女福利视频网| 男女床上黄色一级片免费看| 久久亚洲真实| 最新在线观看一区二区三区| 久久人妻av系列| 老司机在亚洲福利影院| 女人高潮潮喷娇喘18禁视频| 欧美日韩亚洲综合一区二区三区_| 在线看三级毛片| 成人欧美大片| 久久婷婷成人综合色麻豆| 中文字幕人妻丝袜一区二区| a在线观看视频网站| 成人亚洲精品av一区二区| av电影中文网址| 国产爱豆传媒在线观看 | 91成人精品电影| 欧美激情 高清一区二区三区| 黄片大片在线免费观看| 亚洲天堂国产精品一区在线| 精品福利观看| 国产精品香港三级国产av潘金莲| 性色av乱码一区二区三区2| 一边摸一边抽搐一进一小说| 久久热在线av| 国内少妇人妻偷人精品xxx网站 | 欧美激情久久久久久爽电影| 欧美午夜高清在线| 久久香蕉激情| 欧美 亚洲 国产 日韩一| 自线自在国产av| 亚洲精品国产精品久久久不卡| www.www免费av| 精品午夜福利视频在线观看一区| 看片在线看免费视频| 12—13女人毛片做爰片一| 免费高清视频大片| 午夜免费激情av| 国产1区2区3区精品| 夜夜看夜夜爽夜夜摸| 美女高潮到喷水免费观看| 中文字幕人妻熟女乱码| 人人妻人人看人人澡| 999久久久国产精品视频| 国产欧美日韩精品亚洲av| www.www免费av| 国产97色在线日韩免费| 一区二区三区国产精品乱码| 黄色 视频免费看| 久久国产精品男人的天堂亚洲| 久久中文看片网| 51午夜福利影视在线观看| 成人国语在线视频| 欧美性长视频在线观看| 亚洲国产看品久久| av超薄肉色丝袜交足视频| 亚洲欧洲精品一区二区精品久久久| 久久国产精品影院| 午夜免费观看网址| 后天国语完整版免费观看| 国产在线精品亚洲第一网站| 老汉色∧v一级毛片| 男女下面进入的视频免费午夜 | 国产av又大| 99精品在免费线老司机午夜| 黄网站色视频无遮挡免费观看| 久久久国产欧美日韩av| 黄色视频,在线免费观看| 无人区码免费观看不卡| 精品欧美一区二区三区在线| 亚洲av成人一区二区三| 伊人久久大香线蕉亚洲五| 国产精品九九99| 欧美人与性动交α欧美精品济南到| 欧美久久黑人一区二区| 久久久久久免费高清国产稀缺| 88av欧美| 一本一本综合久久| 欧美乱码精品一区二区三区| av中文乱码字幕在线| 久久久久久大精品| aaaaa片日本免费| 不卡av一区二区三区| 一a级毛片在线观看| 成人午夜高清在线视频 | 国产高清视频在线播放一区| 亚洲精品粉嫩美女一区| 精品熟女少妇八av免费久了| 可以在线观看毛片的网站| 亚洲 国产 在线| 久久久久久大精品| xxxwww97欧美| 国产免费男女视频| 成人三级黄色视频| 日本a在线网址| 亚洲国产精品久久男人天堂| 在线观看www视频免费| 亚洲精品美女久久av网站| 可以在线观看的亚洲视频| 亚洲中文日韩欧美视频| 久久人人精品亚洲av| 欧美成人性av电影在线观看| www.熟女人妻精品国产| 变态另类成人亚洲欧美熟女| 1024香蕉在线观看| 午夜福利视频1000在线观看| 国产精品电影一区二区三区| 国内少妇人妻偷人精品xxx网站 | 国产激情欧美一区二区| 精品人妻1区二区| 91av网站免费观看| 99热这里只有精品一区 | 欧美在线黄色| 国产精品久久视频播放| 国产精品电影一区二区三区| 男人舔奶头视频| 嫩草影院精品99| 精品午夜福利视频在线观看一区| 美女国产高潮福利片在线看| 国内揄拍国产精品人妻在线 | 精品久久蜜臀av无| 日韩国内少妇激情av| 久久精品aⅴ一区二区三区四区| 日韩大码丰满熟妇| 脱女人内裤的视频| 日韩欧美国产一区二区入口| 久久中文字幕人妻熟女| 亚洲第一欧美日韩一区二区三区| 欧美激情久久久久久爽电影| 午夜福利一区二区在线看| 麻豆av在线久日| 国内精品久久久久精免费| 欧美+亚洲+日韩+国产| 中文字幕另类日韩欧美亚洲嫩草| www国产在线视频色| 女同久久另类99精品国产91| 国产一区二区激情短视频| 人人妻人人澡人人看| 超碰成人久久| 国产av一区二区精品久久| 最近在线观看免费完整版| 国产成人精品久久二区二区免费| 午夜福利18| 久久久久国内视频| 热re99久久国产66热| 国产不卡一卡二| 久久香蕉激情| 又黄又爽又免费观看的视频| 久久久水蜜桃国产精品网| 国内精品久久久久久久电影| av免费在线观看网站| 99在线人妻在线中文字幕| av片东京热男人的天堂| 免费无遮挡裸体视频| 在线天堂中文资源库| 免费看日本二区| 亚洲国产高清在线一区二区三 | av视频在线观看入口| 一本精品99久久精品77| 亚洲最大成人中文| 亚洲av成人av| 亚洲第一欧美日韩一区二区三区| 精品不卡国产一区二区三区| 久久久久久国产a免费观看| 久久久久国产一级毛片高清牌| 精品国产超薄肉色丝袜足j| 极品教师在线免费播放| 日本三级黄在线观看| 无遮挡黄片免费观看| 嫁个100分男人电影在线观看| 中文资源天堂在线| 亚洲片人在线观看| 午夜福利视频1000在线观看| 波多野结衣巨乳人妻| 中文字幕人成人乱码亚洲影| 一夜夜www| or卡值多少钱| svipshipincom国产片| 91字幕亚洲| 欧美成人一区二区免费高清观看 | 一边摸一边抽搐一进一小说| 国产1区2区3区精品| 97碰自拍视频| 一本一本综合久久| 亚洲精品在线美女| 18禁美女被吸乳视频| svipshipincom国产片| 麻豆久久精品国产亚洲av| 黄色视频,在线免费观看| 看免费av毛片| 日本 av在线| 香蕉丝袜av| 欧美zozozo另类| 国产人伦9x9x在线观看| www.精华液| 久久久国产成人免费| 国产亚洲精品一区二区www| 亚洲久久久国产精品| 特大巨黑吊av在线直播 | 日本精品一区二区三区蜜桃| 国产区一区二久久| 99久久久亚洲精品蜜臀av| 日本a在线网址| 久久精品国产综合久久久| 国产av一区二区精品久久| 欧美中文日本在线观看视频| 不卡一级毛片| 日韩高清综合在线| 欧美乱色亚洲激情| 亚洲精品色激情综合| 久久亚洲真实| 天堂影院成人在线观看| 亚洲国产毛片av蜜桃av| av福利片在线| 精品国产超薄肉色丝袜足j| 久久中文字幕一级| 国产精品久久电影中文字幕| 亚洲自拍偷在线| 久久久国产成人免费| 色婷婷久久久亚洲欧美| 久久精品影院6| 亚洲第一电影网av| 久久国产精品男人的天堂亚洲| 色av中文字幕| 波多野结衣高清无吗| 亚洲成人久久爱视频| 欧美精品亚洲一区二区| 黄色视频,在线免费观看| 丰满人妻熟妇乱又伦精品不卡| 亚洲国产毛片av蜜桃av| 亚洲人成伊人成综合网2020| 一级黄色大片毛片| 午夜亚洲福利在线播放| 50天的宝宝边吃奶边哭怎么回事| 成人特级黄色片久久久久久久| 在线天堂中文资源库| 中出人妻视频一区二区| 99久久久亚洲精品蜜臀av| 搡老妇女老女人老熟妇| 久久午夜综合久久蜜桃| 欧美av亚洲av综合av国产av| 久久久久九九精品影院| 欧美 亚洲 国产 日韩一| www.999成人在线观看| www.精华液| 91字幕亚洲| 亚洲aⅴ乱码一区二区在线播放 | 老司机午夜福利在线观看视频| 亚洲成人免费电影在线观看| 亚洲国产精品成人综合色| 怎么达到女性高潮| 他把我摸到了高潮在线观看| 无人区码免费观看不卡| 亚洲三区欧美一区| av在线天堂中文字幕| 精品国内亚洲2022精品成人| 一级a爱片免费观看的视频| 男人的好看免费观看在线视频 | 黄色丝袜av网址大全| 韩国精品一区二区三区| 日韩大码丰满熟妇| 韩国av一区二区三区四区| 波多野结衣高清作品| www国产在线视频色| 亚洲最大成人中文| 日韩视频一区二区在线观看| 国产av一区在线观看免费| 久久人人精品亚洲av| 香蕉国产在线看| 精品不卡国产一区二区三区| 成在线人永久免费视频| 啦啦啦韩国在线观看视频| 一a级毛片在线观看| 成人国语在线视频| 99久久久亚洲精品蜜臀av| 一本久久中文字幕| 欧美日本视频| 91成人精品电影| 亚洲色图 男人天堂 中文字幕| 中文字幕精品免费在线观看视频| 成人免费观看视频高清| 精品久久久久久久久久久久久 | 国产免费av片在线观看野外av| 国产麻豆成人av免费视频| 麻豆成人av在线观看| 欧美日韩亚洲综合一区二区三区_| 最新美女视频免费是黄的| 一进一出好大好爽视频| 亚洲男人的天堂狠狠| 2021天堂中文幕一二区在线观 | 久热爱精品视频在线9| 69av精品久久久久久| 日日爽夜夜爽网站| 变态另类丝袜制服| 日日爽夜夜爽网站| 国产一区二区激情短视频| 脱女人内裤的视频| 日韩成人在线观看一区二区三区| 在线看三级毛片| 女人高潮潮喷娇喘18禁视频| 中文字幕精品亚洲无线码一区 | 日本免费一区二区三区高清不卡| 免费在线观看亚洲国产| 久久久久久人人人人人| 麻豆成人午夜福利视频| 国产熟女xx| 91成年电影在线观看| 黄色丝袜av网址大全| 国产精品久久久久久精品电影 | 亚洲专区国产一区二区| 黑丝袜美女国产一区| 中文字幕高清在线视频| 国产精品免费一区二区三区在线| 热99re8久久精品国产| 自线自在国产av| 国产av又大| 国产成人欧美| 18禁裸乳无遮挡免费网站照片 | 一边摸一边做爽爽视频免费| 国产黄色小视频在线观看| 国产免费男女视频| 听说在线观看完整版免费高清| 看片在线看免费视频| 亚洲久久久国产精品| 怎么达到女性高潮| 亚洲成人国产一区在线观看| 日本三级黄在线观看|