• <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 ?

    Next Steps for Efficacy Evaluation in Clinical Trials of COVID-19 Vaccines

    2021-12-25 10:06:42HuDhunJingLiZhngJingXinLiFengCiZhu
    Engineering 2021年7期

    Hu-Dhun Jing, Li Zhng, Jing-Xin Li, Feng-Ci Zhu,b,

    a School of Public Health, Southeast University, Nanjing 210009, China

    b NHC Key Laboratory of Enteric Pathogenic Microbiology, Jiangsu Provincial Center for Disease Control and Prevention, Nanjing 210009, China

    c Center for Global Health, Nanjing Medical University, Nanjing 211166, China

    d Department of Vaccine Clinical Evaluation, Jiangsu Provincial Center for Disease Control and Prevention, Nanjing 210009, China

    1. Introduction

    A vaccine clinical trial examines the effects of a vaccine on human volunteers in terms of safety,immunogenicity,and clinical efficacy through three distinct stages[1].In general,phase 1 studies focus on safety and reactogenicity, while phase 2 studies attempt to establish an immunogenicity proof of dose range,dosage, and immunization procedure (sometimes even efficacy data). Large phase 3 studies are designed to evaluate whether the dosing and vaccination schedule can deliver the desired protection efficacy with an acceptable safety profile [2]. A phase 3 vaccine clinical trial provides indispensable efficacy data to support a vaccine that has been issued with licensure.

    To date,April 30,2021,27 coronavirus disease 2019(COVID-19)vaccines are being evaluated in phase 3 clinical trials, all of which are designed as individually randomized,placebo-controlled studies with 30 000–40 000 participants in each trial. The preliminary efficacies from the phase 3 trials of the ‘‘first wave” of ten COVID-19 vaccines were recently announced (Table 1): two mRNA vaccines (BNT162b2 developed by BioNTech/Pfizer, with a vaccine efficacy(VE)of 95.0%;and mRNA-1273 developed by Moderna,with a VE of 94.1%); four non-replicating viral-vectored vaccines(AZD1222 developed by the University of Oxford/AstraZeneca,with a VE of 70.0%; Sputnik V developed by Gamaleya, with a VE of 91.4%; Ad26.COV2.S developed by Janssen, with a VE of 66.9%;and Ad5-nCoV developed by CanSino Biologics and the Beijing Institute of Biotechnology, with a VE of 68.8%); a protein subunit vaccine (NVX-CoV237 developed by Novavax, with a VE of 89.3%); and three inactivated vaccines (BBIBP-CorV developed by the Beijing Institute of Biological Products, with a VE of 78.1%;the inactivated whole-virus nCov-19 vaccine developed by the Wuhan Institute of Biological Products, with a VE of 72.8%; and CoronaVac developed by Sinovac, with a VE of 91.3% in Turkey and 50.4% in Brazil) [3–8]. Based on these results, nine of the ten COVID-19 vaccines have been granted emergency-use authorization or conditional licensure in some regions or countries.Another protein subunit vaccine (ZF2001) has also received approval for emergency use.

    As the COVID-19 pandemic continues to rage around the world,the demand for effective vaccines is an unprecedented huge. It is clear that the production amount of the first ten vaccines is unlikely to meet the world’s needs. Thus, research is still needed on other COVID-19 vaccine candidates, and will hopefully determine more effective vaccines against COVID-19 in phase 3 clinical trials.However, conducting individually randomized placebo-controlled clinical trials during a viral pandemic with such a high burden of disease and implementing an immunization campaign while previous approved vaccines are available have never been done before.The approval of the ‘‘first wave” of COVID-19 vaccines raises concerns about the administration of a placebo during the ongoing and future phase 3 trials of other COVID-19 vaccine candidates.

    Here, we discuss the issues that may affect clinical trials of COVID-19 vaccines aiming to evaluate VE in the near future and examine the possibility of alternative trial designs, while taking ethical concerns,the circumstances of the epidemic,and statistical considerations into account.

    2. Challenges for future COVID-19 vaccine clinical studies

    2.1. Hundreds of COVID-19 vaccines under evaluation

    As of April 30, 2021, 277 candidate vaccines against severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)are under development worldwide, according to a survey by the World Health Organization (WHO) [9]. Among them, at least 93 vaccines have been approved for clinical trials. These approved vaccines mainly comprise protein subunit vaccines (n = 29, 31% of the 93 approved vaccines),viral vector vaccines(n=18,19%),inactivated vaccines(n=13,14%),DNA or RNA vaccines(n=23,25%),and viral particle vaccines (n = 5, 5%).

    Aside from the ‘‘first wave” of COVID-19 vaccines, many of the vaccine candidates under development have as-yet undetermined efficacies;this is particularly true for the vaccines based on protein subunit technology platforms, which accounts for more than a third of the total. Such recombinant protein-based subunit vaccines are generally safe to administer to a wider variety of people,including children, seniors, and immune-compromised individuals;they are also easy to deal with in terms of storage and logistics.If all these vaccine candidates enter clinical trials at the same time,there may be insufficient resources to complete effective clinicaltrials, as was the case during the epidemic in the mainland of China, in the early part of the global pandemic, when trials for the development of COVID-19 therapeutic drugs lacked the ability to obtain solid evidence.

    Table 1 Efficacy results of published COVID-19 vaccine candidates.

    An efficacy trial should normally be carried out in a high-risk population that cannot access effective approved vaccines at that time, in areas experiencing an epidemic. However, conducting a clinical trial during an emergency situation posing huge challenges[10], especially if a vaccination campaign for emergency use has already been implemented that will reduce the pool of eligible study populations for subsequent COVID-19 vaccine trials. Therefore, the implementation of future phase 3 efficacy trials for COVID-19 vaccines may be concentrated in developing countries or regions with inadequate healthcare resources, which could impose a further burden on local healthcare systems and exacerbate the uneven accessibility of efficacious vaccines.

    2.2. Limitations of ongoing COVID-19 vaccine clinical studies

    The interim analysis results of the efficacy data from the phase 3 clinical trials of the ‘‘first wave” of COVID-19 vaccines have demonstrated their safety and efficacy against COVID-19,but over a fairly short term. The average observation periods for COVID-19 cases surveillance in the trials of BNT162b2, mRNA-1273, and AZD1222 were 2–3 months [3–5], so the durability of the protection and the long-term safety of these vaccines still remain to be determined. Due to the limited observation period, only a few or several severe COVID-19 cases were captured during the trials, leading to a lack of robust efficacy data on severe cases for these vaccines. In addition, although a similar VE was observed across subgroups defined by age in the open results of the phase 3 efficacy trials of BNT162b2, mRNA-1273, Sputnik V and Ad26.COV2.S [3,4,8,11], this data is not solid, as the small number of seniors enrolled in the trial and the protective efficacy of other candidate vaccines in seniors were not estimated. Therefore, the evidence on the protective effect of these vaccines in seniors is still insufficient. However, due to the good immunogenicity of the candidate vaccines in seniors, and to seniors’ high risk of being attacked by SARS-CoV-2, people aged 60 years and over are also eligible for vaccine administration in China.

    As a result of all these knowledge gaps,scientists have called for the continuation of clinical trials with placebos,in order to avoid a loss of valuable research data and a decrease in health equity if participants do not belong to the identified priority groups [12].

    3. Study design for VE evaluation

    3.1. When placebo use is acceptable

    According to the recommendations of a WHO expert panel,placebo use in vaccine trials is clearly acceptable when no efficacious and safe vaccine exists and when the vaccine under consideration is intended to benefit the population among which the vaccine is to be tested [13]. Although some COVID-19 vaccines have been approved for emergency use or conditional marketing, they are not considered to have the same level of known efficacy and safety as non-emergency vaccines for other diseases,since their approval was only based on short-term efficacy and safety data. Therefore,their emergency-use approval is not a marketing license,and many experts still advocate a placebo-use control in vaccine trials(Table 2).

    3.1.1. Cross-over design

    In a traditional (2 × 2) cross-over design, each participant receives two different treatments, which are labeled as A and B.Half of the participants receive A first;then,after a suitably chosen period of time, they cross over to receive B. The remaining participants receive B first, and then cross over to receive A. The aim of such a study is to compare the effects of A and B [14,15].This cross-over design could be an alternative method to evaluate the efficacy of COVID-19 vaccines in phase 3 trials, instead of placebo-controlled randomized trials (Fig. 1). During the first period of time, the participants would be individually randomized into a vaccine or placebo arm of the study; they would respectively receive shots of the vaccine or placebo, and then be followed up with to surveil for COVID-19 cases. After that, the participants in the vaccine group would cross over to receive the placebo, while the participants in the placebo group would receive the vaccine.Both the investigators and the participants would be masked to the group allocation. This design can maintain the benefits of placebo control and randomization without demanding an exceptional degree of altruism from the participants; in this way, it can help preserve the public’s trust that the scientists and regulators are prioritizing both the science and the participants [16].However, this design cannot be used to evaluate the long-term safety and efficacy of a vaccine compared with a placebo. Another concern is that offering the vaccine to the participants in the placebo arm would decrease health equity, because the participants in the placebo arm might not be prioritized for vaccination outside of the trial under conditions of vaccine scarcity.

    Table 2 Elements of the proposed study designs.

    3.1.2. Human challenge trial

    Human challenge trials involve the intentional infection of healthy, adult, consenting volunteers with an infectious agent(e.g.,a virus,parasite,bacteria,or fungus).The participants are randomly allocated to the vaccine or placebo arm of the study. After receiving intervention, the participants are intentionally exposed to the infectious agent in a controlled setting with adequate medication. The challenge strain should be well characterized,frequently attenuated, and manufactured under current good manufacturing practice (cGMP) or GMP-like conditions [17,18].Human challenge trials can move faster than traditional human trials and can quickly obtain VE data;furthermore,they need a much smaller sample size than a traditional randomized controlled trial.However, this design cannot evaluate VE against serious disease and death, because the challenge dose of the virus is carefully designed and the volunteers are treated early if they get sick.Nevertheless, in a human challenge trial for a COVID-19 vaccine, the volunteers in the placebo group may still face risks because there are no reliable treatments for severe COVID-19 [19]. Furthermore,the results obtained from young volunteers might not be reasonably extrapolated to seniors.In addition,the infectious agent used to challenge the volunteers may differ from a natural agent in terms of the dose or genes[19].

    Fig. 1. Individual-randomized, double-blinded, and cross-over design for the efficacy evaluation of COVID-19 vaccines.

    3.2. When placebo use is unacceptable

    Placebo use in vaccine trials is clearly unacceptable when ①a highly efficacious and safe vaccine exists and is currently accessible in the public health system of the country in which the trial is planned,and ②the risks to the participants of delaying or foregoing the available vaccine cannot be adequately minimized or mitigated(e.g.,by providing counselling and education on behavioral diseaseprevention strategies, or by ensuring adequate treatment for the condition under study to prevent serious harm)[13].The data that accumulates as time goes by would support the vaccines that have already been approved for emergency use and have been demonstrated to be safe and effective.Thus,once the authorized vaccines become available in sufficient quantities to begin immunizing broader groups, it may no longer be feasible or ethical to include individuals in placebo-controlled trials [12]. Therefore, it is necessary to discuss alternative study designs without a placebo arm.

    3.2.1. Head-to-head non-inferiority trial

    A head-to-head non-inferiority randomized controlled trial aims to demonstrate that a new vaccine is no worse than an active comparator that has already shown its efficacy over a placebo within a prespecified margin that might be adopted when placebo use is not acceptable[20].Non-inferiority designs are useful in situations in which the efficacy of a new vaccine is deemed to be the same as that of the active comparator, but the new vaccine has additional benefits,such as fewer adverse events or reduced costs.A new vaccine is called‘‘non-inferior”to the comparator if the difference between the active comparator and the new vaccine is greater than the predefined margin (i.e., the boundary of the confidence interval exceeds the margin [20,21]). If the non-inferiority hypothesis is well established,it is even possible to perform a further superiority test on the active comparator, particularly for an active vaccine with only a moderate efficacy against clinical endpoints. However, compared with a placebo-controlled trial, a non-inferiority trial requires a larger sample size and a longer time to obtain clinical endpoints, since both arms of the study receive the vaccines, and the incidence of cases would be significantly reduced. Although the calculated sample size for a non-inferiority trial may vary from 20 000 to 50 000 people per year according to the different efficacies of the active comparator and the margin, it is still feasible.Moreover,a non-inferiority trial could also facilitate direct safety comparisons between the new vaccine and its established comparator [22].

    3.2.2. Test-negative design

    The test-negative design, which is a modified case-control study, has been introduced to assess vaccine effectiveness, especially against influenza vaccines[23].Under a test-negative design for vaccine effectiveness, the study subjects are all persons who seek medical care for suspected symptomatic illness. To evaluate COVID-19 vaccines,all subjects would first be tested using a highly specific assay(e.g.,polymerase chain reaction(PCR))for the detection of COVID-19; they would then be grouped according to their test results as either cases (those that test positive) or controls(those that test negative). Vaccine effectiveness would be estimated from the ratio of the odds of vaccination among the cases to the odds of vaccination among the controls [24]. From a practical standpoint, the test-negative design is easier to conduct than other study designs and makes it possible to minimize confounding due to health-care-seeking behavior [25]. However,a test-negative design is an observational study, so its validity depends on a careful assessment of potential biases and adjustment for them—particularly in terms of differences in disease severity among cases and non-cases.

    3.2.3. Stepped-wedge design

    A stepped-wedge cluster randomized controlled trial is commonly used for the evaluation of service delivery or policy interventions delivered at the level of the clusters. Examples of clusters may include schools, communities, factories, or families,although there are many other possible choices.In order to capture the population-level effects of an intervention, such as a vaccine designed to reduce the transmission of an infectious agent, a cluster randomized design can be adopted [26]. The design includes an initial period in which no clusters are exposed to the candidate vaccine. Subsequently, at regular intervals (the‘‘steps”),one cluster(or a group of clusters)is randomized to cross from the control to the vaccination under evaluation.This process continues until all clusters are exposed to the vaccination. Data collection continues throughout the study, so that each cluster contributes observations under both pre- and post-vaccination periods [27].The intervention effect is determined by comparing the data points in the post-vaccination section of the wedge with those in the control section. The stepped-wedge design is considered to be advantageous compared with a traditional parallel design, as long as there is a prior belief that the vaccination will do more good than harm,and when the vaccination can only be implemented in stages due to logistical,practical,or financial constraints[28].The biggest potential problem in using a stepped-wedge design to evaluate COVID-19 VE is the variation in COVID-19 incidence over time and space. In addition, the sample size of the design may be 100 times greater than that of an individually randomized trial.Therefore,the stepped-wedge design is usually used to estimate vaccine effectiveness after a vaccine license has been obtained.

    4. Perspective

    Traditionallarge-scaleindividual-randomized,placebocontrolled trials are the basis of modern clinical decision-making and remain the most efficient way to obtain reliable results for novel vaccines [29], as long as the trial’s risk–benefit profile remains acceptable [30]. Since emergency-use authorization and conditional licensure are not full licensures, the WHO has suggested that it is ethically acceptable to continue the blinded follow-up of placebo recipients in existing studies and to continue to perform placebo-controlled trials in order to yield unbiased evidence for the next vaccine candidates[29].However,as an increasing amount of evidence on the safety and efficacy of the COVID-19 vaccines is obtained and as authorized vaccines become more widely available, the risk-benefit profile of a normal placebocontrolled trial will become unacceptable, and the compliance of the trial may be impacted by drop-outs or‘‘contamination.”Therefore, alternative strategies to evaluate those vaccines are needed.

    A placebo-controlled cross-over design could be used as an alternative to replace common placebo-controlled trials by reducing the ethical concern regarding long-term risks in the participants receiving a placebo; however, the long-term efficacy of the vaccine compared with that of a placebo would not be obtainable.Human challenge trials can also be used to accelerate the placebocontrolled efficacy estimation of a vaccine, when the use of a placebo in a large population is no longer recommended. However,the human challenge model can only be performed in a small number of participants, which may not be adequate for vaccine authorization, as an extended safety cohort and an extended head-to-head immunogenicity cohort are demanded in order to ensure a vaccine’s safety, immunogenicity, and persistency.

    Head-to-head non-inferiority randomized controlled trials are an alternative design for the evaluation of new candidate COVID-19 vaccines.A head-to-head comparative design targeting efficacy requires a relatively large sample size and longer surveillance period for COVID-19 cases, to ensure that sufficient evidence on the vaccine’s relative efficacy can be obtained in order for the vaccine to be authorized[31].In general,a VE evaluation based on clinical endpoints is costly and time consuming.This will be especially true for trials using an active vaccine as a comparator.

    In contrast, an efficacy evaluation of a vaccine based on the immunological correlates of protection is much easier to operate;it also saves time by measuring the proportion of vaccinees who generate a particular immune response, without capturing the clinical events [32]. A serological study strategy using an immunological correlate combined with an extended safety cohort has been successfully applied to assess other vaccines, such as influenza vaccines. However, the immunological correlate of protection for COVID-19 might not be available within a short period of time, since no standard serum immunological tests have been established as yet [33].

    In order to evaluate vaccine effectiveness in the real world,nonrandomized observational studies, such as a test-negative design,are suggested.However,observational studies could yield misleading answers about safety and effectiveness, mainly due to the different risk exposures between vaccinated people and unvaccinated people during an epidemic[34,35].A potential strategy for assessing the population-level vaccine effectiveness against COVID-19 is to design cluster randomized trials that could reveal indirect effectiveness [36]; for example, a stepped-wedge approach has been recommended for use in evaluating vaccines in outbreak settings[37].

    Nevertheless, post-licensure studies on vaccine effectiveness and safety in a large population are extremely important, particularly in order to screen for all rare severe adverse reactions. Some adverse events that have been reported in phase 3 studies,such as acute hypersensitive reaction, Bell facial paralysis, transverse myelitis,and abnormal plasma glucose,but whose association with COVID-19 vaccines has not been confirmed, will continue to be monitored and evaluated in post-marketing studies [38].

    In conclusion, there remains a need to further evaluate the COVID-19 vaccines that were first authorized for use in order to fill in the knowledge gaps, and to develop additional vaccines that may be preferable for reasons of safety, efficacy, subgroup advantages, or logistics. Placebo-controlled trials are critical for efficacy and safety evaluation, and therefore should not be immediately eliminated.However,alternative trial designs must also be considered when the use of a placebo becomes ethically unacceptable and difficult to implement. With mass vaccination coverage anticipated, the findings from post-marketing data on COVID-19 vaccines can guide regulatory decisions and public health practices to maintain a positive benefit-risk balance.

    av网站免费在线观看视频| 99re在线观看精品视频| 高清黄色对白视频在线免费看| 国产真人三级小视频在线观看| 久久久久久久国产电影| 日韩一区二区三区影片| 亚洲国产欧美日韩在线播放| 欧美 日韩 精品 国产| 美女视频免费永久观看网站| 亚洲第一欧美日韩一区二区三区 | 亚洲国产中文字幕在线视频| 丰满迷人的少妇在线观看| 丰满少妇做爰视频| 九色亚洲精品在线播放| 国产精品99久久99久久久不卡| 男人舔女人的私密视频| 国产一区二区三区综合在线观看| 久久午夜亚洲精品久久| 两个人看的免费小视频| 美女视频免费永久观看网站| 老汉色av国产亚洲站长工具| 视频区图区小说| 国产人伦9x9x在线观看| 欧美亚洲日本最大视频资源| 亚洲熟妇熟女久久| 三级毛片av免费| 窝窝影院91人妻| 黄色 视频免费看| 人人妻人人爽人人添夜夜欢视频| 满18在线观看网站| 日韩大片免费观看网站| 超碰成人久久| 色在线成人网| cao死你这个sao货| 夫妻午夜视频| 老熟妇乱子伦视频在线观看| 精品视频人人做人人爽| 男女免费视频国产| 高清毛片免费观看视频网站 | 日本黄色日本黄色录像| 欧美精品一区二区免费开放| 黄色怎么调成土黄色| 黑人巨大精品欧美一区二区mp4| 巨乳人妻的诱惑在线观看| 成人亚洲精品一区在线观看| 桃花免费在线播放| 亚洲午夜精品一区,二区,三区| 男人舔女人的私密视频| 国产亚洲精品久久久久5区| e午夜精品久久久久久久| 99久久99久久久精品蜜桃| 黑人巨大精品欧美一区二区蜜桃| 一本一本久久a久久精品综合妖精| 男女下面插进去视频免费观看| 成人国产av品久久久| 日本黄色日本黄色录像| 日本一区二区免费在线视频| 啦啦啦视频在线资源免费观看| 国产av又大| 久久这里只有精品19| 成人18禁高潮啪啪吃奶动态图| 精品国产乱子伦一区二区三区| 国产精品久久久久久精品电影小说| 涩涩av久久男人的天堂| 亚洲av第一区精品v没综合| 久久久国产成人免费| 黄色怎么调成土黄色| 午夜两性在线视频| 亚洲中文av在线| 高清毛片免费观看视频网站 | 亚洲国产欧美一区二区综合| 两个人看的免费小视频| 欧美亚洲日本最大视频资源| av有码第一页| 久久久久国产一级毛片高清牌| 国产成+人综合+亚洲专区| 99久久人妻综合| 视频区欧美日本亚洲| 黄色片一级片一级黄色片| 精品高清国产在线一区| 国产xxxxx性猛交| 亚洲黑人精品在线| 我的亚洲天堂| 男女午夜视频在线观看| 久久久久久久精品吃奶| 色尼玛亚洲综合影院| 老司机在亚洲福利影院| 亚洲成av片中文字幕在线观看| 欧美亚洲 丝袜 人妻 在线| 一级片'在线观看视频| 不卡av一区二区三区| 日韩视频在线欧美| 91国产中文字幕| 午夜免费鲁丝| 精品国产超薄肉色丝袜足j| 精品少妇黑人巨大在线播放| 视频区图区小说| 午夜福利视频精品| 91成人精品电影| 国产免费福利视频在线观看| 丰满人妻熟妇乱又伦精品不卡| 国产精品99久久99久久久不卡| avwww免费| a级毛片在线看网站| 久久久久精品国产欧美久久久| 亚洲自偷自拍图片 自拍| 久久久国产欧美日韩av| 久久精品成人免费网站| 亚洲精品久久午夜乱码| 老熟妇仑乱视频hdxx| 露出奶头的视频| 国产成人欧美在线观看 | 丁香六月天网| 视频在线观看一区二区三区| 黄色丝袜av网址大全| 中文亚洲av片在线观看爽 | 国产又色又爽无遮挡免费看| 国产欧美日韩精品亚洲av| 国产成人欧美| a级片在线免费高清观看视频| 午夜福利在线免费观看网站| 香蕉国产在线看| 精品第一国产精品| 脱女人内裤的视频| 悠悠久久av| 亚洲成人国产一区在线观看| av网站免费在线观看视频| 人人妻人人添人人爽欧美一区卜| 亚洲av成人一区二区三| 悠悠久久av| 国产精品香港三级国产av潘金莲| 深夜精品福利| 日韩人妻精品一区2区三区| 国产国语露脸激情在线看| 免费久久久久久久精品成人欧美视频| 91精品国产国语对白视频| 亚洲午夜精品一区,二区,三区| 日韩制服丝袜自拍偷拍| 久久中文看片网| 69av精品久久久久久 | 我要看黄色一级片免费的| 免费日韩欧美在线观看| 欧美日韩亚洲高清精品| 精品一品国产午夜福利视频| 国产在线免费精品| 欧美日韩成人在线一区二区| 国产精品久久电影中文字幕 | 国产男女内射视频| av电影中文网址| 亚洲专区中文字幕在线| 视频区欧美日本亚洲| aaaaa片日本免费| 国产老妇伦熟女老妇高清| 国产不卡av网站在线观看| 免费观看a级毛片全部| 亚洲午夜理论影院| 久久久精品免费免费高清| 51午夜福利影视在线观看| 国产极品粉嫩免费观看在线| 曰老女人黄片| 国产精品一区二区在线观看99| 久久久久久亚洲精品国产蜜桃av| 国产精品亚洲一级av第二区| 精品国产乱码久久久久久男人| 婷婷丁香在线五月| 午夜精品国产一区二区电影| 69av精品久久久久久 | 国产亚洲欧美在线一区二区| 成人国产av品久久久| 精品免费久久久久久久清纯 | 不卡av一区二区三区| 日韩欧美一区视频在线观看| bbb黄色大片| 欧美精品啪啪一区二区三区| 啦啦啦 在线观看视频| 久久久久视频综合| 久热爱精品视频在线9| 在线天堂中文资源库| 成人国语在线视频| 国产亚洲一区二区精品| 肉色欧美久久久久久久蜜桃| 国产精品欧美亚洲77777| 国产视频一区二区在线看| 国产不卡av网站在线观看| 精品人妻熟女毛片av久久网站| 国产精品99久久99久久久不卡| 不卡av一区二区三区| 午夜精品国产一区二区电影| 天天影视国产精品| 精品免费久久久久久久清纯 | 久久精品国产亚洲av高清一级| a在线观看视频网站| av网站在线播放免费| 无限看片的www在线观看| 99国产极品粉嫩在线观看| 岛国毛片在线播放| 亚洲色图 男人天堂 中文字幕| 夫妻午夜视频| av不卡在线播放| 在线观看人妻少妇| videosex国产| 国产精品偷伦视频观看了| 久久久久久亚洲精品国产蜜桃av| 国产97色在线日韩免费| 免费一级毛片在线播放高清视频 | 欧美成人午夜精品| 无遮挡黄片免费观看| 国产av精品麻豆| 亚洲人成电影免费在线| 丁香六月欧美| 999久久久国产精品视频| 19禁男女啪啪无遮挡网站| 久9热在线精品视频| 色视频在线一区二区三区| 精品福利观看| 国产av一区二区精品久久| 一区二区三区精品91| 久久影院123| 久久人人97超碰香蕉20202| 欧美精品人与动牲交sv欧美| 午夜日韩欧美国产| 男女床上黄色一级片免费看| 法律面前人人平等表现在哪些方面| 亚洲精品一卡2卡三卡4卡5卡| 精品少妇黑人巨大在线播放| www.精华液| 日韩欧美国产一区二区入口| 欧美成狂野欧美在线观看| 国产精品久久久久成人av| 欧美午夜高清在线| 欧美成人免费av一区二区三区 | 国产亚洲精品第一综合不卡| 亚洲熟女精品中文字幕| 五月天丁香电影| 99re在线观看精品视频| 夜夜夜夜夜久久久久| 999精品在线视频| 日本a在线网址| 亚洲 欧美一区二区三区| h视频一区二区三区| 欧美日韩一级在线毛片| 少妇 在线观看| 国产免费现黄频在线看| 国产aⅴ精品一区二区三区波| 亚洲av成人不卡在线观看播放网| 99riav亚洲国产免费| 一本综合久久免费| 美女高潮到喷水免费观看| 国产成人免费观看mmmm| 中文字幕高清在线视频| 午夜免费成人在线视频| 成人免费观看视频高清| av福利片在线| 在线观看免费高清a一片| 建设人人有责人人尽责人人享有的| 丁香六月天网| 免费观看人在逋| 亚洲免费av在线视频| 黄色毛片三级朝国网站| 日韩免费av在线播放| 精品国产一区二区三区久久久樱花| 免费在线观看黄色视频的| 亚洲 欧美一区二区三区| 久久久久久人人人人人| 国产欧美亚洲国产| 欧美乱妇无乱码| 黄色怎么调成土黄色| 超碰97精品在线观看| 天堂动漫精品| 一区二区av电影网| 国产免费视频播放在线视频| 国产深夜福利视频在线观看| 亚洲精品粉嫩美女一区| 亚洲国产av影院在线观看| 在线 av 中文字幕| 欧美在线黄色| 久久免费观看电影| 我的亚洲天堂| 亚洲伊人色综图| 国产色视频综合| 精品福利观看| 交换朋友夫妻互换小说| 夜夜骑夜夜射夜夜干| 亚洲男人天堂网一区| 十分钟在线观看高清视频www| 妹子高潮喷水视频| 久久天躁狠狠躁夜夜2o2o| 日韩免费高清中文字幕av| 99国产精品免费福利视频| 色综合欧美亚洲国产小说| av线在线观看网站| 欧美人与性动交α欧美精品济南到| www日本在线高清视频| 精品久久久久久久毛片微露脸| 国产男女内射视频| 天天躁狠狠躁夜夜躁狠狠躁| 两人在一起打扑克的视频| 每晚都被弄得嗷嗷叫到高潮| 后天国语完整版免费观看| 麻豆成人av在线观看| 亚洲一码二码三码区别大吗| 老司机深夜福利视频在线观看| 久久久水蜜桃国产精品网| 搡老乐熟女国产| 国产成人系列免费观看| 热99re8久久精品国产| 久久久久久免费高清国产稀缺| 男女下面插进去视频免费观看| 99国产精品99久久久久| 成人免费观看视频高清| 国产99久久九九免费精品| 国产欧美日韩一区二区三| 99热网站在线观看| 黑人巨大精品欧美一区二区mp4| 9热在线视频观看99| 欧美国产精品va在线观看不卡| 亚洲国产毛片av蜜桃av| 日本a在线网址| av天堂久久9| 老熟妇仑乱视频hdxx| 天堂中文最新版在线下载| 亚洲成国产人片在线观看| 人人澡人人妻人| 黑人巨大精品欧美一区二区蜜桃| 美女高潮到喷水免费观看| 一本色道久久久久久精品综合| 黄色视频在线播放观看不卡| 精品人妻在线不人妻| 一区二区三区精品91| 黄色毛片三级朝国网站| 99re在线观看精品视频| 日本av免费视频播放| 成人精品一区二区免费| 国产不卡一卡二| 别揉我奶头~嗯~啊~动态视频| 丰满少妇做爰视频| 人妻 亚洲 视频| 男人操女人黄网站| 少妇 在线观看| 最近最新中文字幕大全免费视频| 老司机深夜福利视频在线观看| 午夜福利免费观看在线| 色综合婷婷激情| 视频区欧美日本亚洲| 中文字幕av电影在线播放| 人人妻人人爽人人添夜夜欢视频| 久久人妻av系列| 欧美午夜高清在线| 久久人妻av系列| 宅男免费午夜| 久久影院123| 国产主播在线观看一区二区| 黄色丝袜av网址大全| 国产精品久久久人人做人人爽| 色综合欧美亚洲国产小说| 搡老岳熟女国产| 亚洲成国产人片在线观看| 在线观看人妻少妇| 成人国语在线视频| 日韩 欧美 亚洲 中文字幕| 老司机午夜福利在线观看视频 | 久久人妻熟女aⅴ| 亚洲午夜理论影院| 肉色欧美久久久久久久蜜桃| 无限看片的www在线观看| 久久人妻福利社区极品人妻图片| netflix在线观看网站| videosex国产| 一本久久精品| 肉色欧美久久久久久久蜜桃| 欧美人与性动交α欧美软件| 亚洲一码二码三码区别大吗| 亚洲欧美精品综合一区二区三区| 夜夜爽天天搞| 女性被躁到高潮视频| 日韩欧美免费精品| 精品久久久精品久久久| 精品国产一区二区三区久久久樱花| 在线观看免费高清a一片| 啦啦啦 在线观看视频| 啦啦啦视频在线资源免费观看| 十八禁网站网址无遮挡| 日日摸夜夜添夜夜添小说| 大香蕉久久网| 丰满少妇做爰视频| 欧美激情高清一区二区三区| 老司机亚洲免费影院| 99国产精品一区二区蜜桃av | 亚洲欧美色中文字幕在线| 91麻豆av在线| 80岁老熟妇乱子伦牲交| 国产片内射在线| 在线永久观看黄色视频| 91大片在线观看| 亚洲av美国av| 久久国产亚洲av麻豆专区| 欧美激情极品国产一区二区三区| 日日摸夜夜添夜夜添小说| 久久久国产精品麻豆| 亚洲av片天天在线观看| 91av网站免费观看| 午夜日韩欧美国产| 捣出白浆h1v1| 狠狠狠狠99中文字幕| 国产精品成人在线| 无人区码免费观看不卡 | 黄色视频在线播放观看不卡| 飞空精品影院首页| 精品福利永久在线观看| 亚洲精品av麻豆狂野| 国产成人系列免费观看| 久久久久久久久免费视频了| 999久久久精品免费观看国产| 亚洲性夜色夜夜综合| 精品第一国产精品| 免费黄频网站在线观看国产| 亚洲av日韩在线播放| 欧美久久黑人一区二区| 国产精品一区二区精品视频观看| 国产在线视频一区二区| 亚洲色图 男人天堂 中文字幕| 我要看黄色一级片免费的| 国产av精品麻豆| av电影中文网址| 在线看a的网站| 精品久久久精品久久久| 一二三四社区在线视频社区8| 成年女人毛片免费观看观看9 | 俄罗斯特黄特色一大片| 国产精品免费大片| 午夜视频精品福利| 电影成人av| 亚洲精品av麻豆狂野| 国产主播在线观看一区二区| 欧美日韩福利视频一区二区| xxxhd国产人妻xxx| 日本欧美视频一区| 老鸭窝网址在线观看| av电影中文网址| 亚洲黑人精品在线| 热re99久久精品国产66热6| 在线观看免费日韩欧美大片| 好男人电影高清在线观看| a在线观看视频网站| 在线观看66精品国产| 纵有疾风起免费观看全集完整版| 欧美国产精品一级二级三级| 丝瓜视频免费看黄片| 极品教师在线免费播放| 亚洲欧洲日产国产| 丝瓜视频免费看黄片| 夜夜爽天天搞| 热re99久久国产66热| 99re6热这里在线精品视频| 精品久久蜜臀av无| 757午夜福利合集在线观看| 性高湖久久久久久久久免费观看| 99国产综合亚洲精品| 成人18禁在线播放| 午夜免费成人在线视频| 亚洲av第一区精品v没综合| 国产99久久九九免费精品| 国产男靠女视频免费网站| 大香蕉久久成人网| 女人爽到高潮嗷嗷叫在线视频| 国产日韩欧美在线精品| 香蕉国产在线看| 下体分泌物呈黄色| 欧美日韩中文字幕国产精品一区二区三区 | 99久久国产精品久久久| 国产xxxxx性猛交| 91大片在线观看| 国产精品.久久久| 日日爽夜夜爽网站| 精品少妇黑人巨大在线播放| 亚洲国产中文字幕在线视频| 欧美日韩亚洲高清精品| 免费观看人在逋| 一级毛片女人18水好多| 欧美av亚洲av综合av国产av| 成年人黄色毛片网站| 下体分泌物呈黄色| 国产三级黄色录像| 天堂8中文在线网| 色在线成人网| 午夜精品久久久久久毛片777| a级毛片黄视频| 狠狠狠狠99中文字幕| 中文亚洲av片在线观看爽 | 一级毛片电影观看| 99国产精品免费福利视频| 午夜福利视频精品| 天堂中文最新版在线下载| 国产精品免费视频内射| 亚洲人成电影免费在线| 精品人妻1区二区| 热99re8久久精品国产| 日韩制服丝袜自拍偷拍| tocl精华| 少妇 在线观看| 99国产精品免费福利视频| 精品一区二区三区四区五区乱码| 久热爱精品视频在线9| 黄频高清免费视频| 亚洲精品av麻豆狂野| a级片在线免费高清观看视频| av片东京热男人的天堂| 三上悠亚av全集在线观看| 午夜老司机福利片| 久久精品国产亚洲av香蕉五月 | 国产成人精品久久二区二区免费| 久久久水蜜桃国产精品网| 欧美久久黑人一区二区| 日韩欧美一区二区三区在线观看 | 国产精品久久久人人做人人爽| 99久久国产精品久久久| 亚洲精品在线美女| 久久天躁狠狠躁夜夜2o2o| 国产精品国产高清国产av | 丝袜美腿诱惑在线| a级毛片黄视频| 午夜精品久久久久久毛片777| 男女午夜视频在线观看| 老司机福利观看| 日韩精品免费视频一区二区三区| 中文字幕另类日韩欧美亚洲嫩草| 久久午夜亚洲精品久久| 成年版毛片免费区| 免费高清在线观看日韩| www.熟女人妻精品国产| 美女午夜性视频免费| 99久久精品国产亚洲精品| 午夜免费成人在线视频| 极品人妻少妇av视频| 国产男靠女视频免费网站| 91国产中文字幕| 97人妻天天添夜夜摸| 精品福利永久在线观看| 9热在线视频观看99| 人成视频在线观看免费观看| 亚洲一区中文字幕在线| 亚洲av日韩在线播放| 久久影院123| videosex国产| 女同久久另类99精品国产91| aaaaa片日本免费| 1024香蕉在线观看| 一本大道久久a久久精品| 成年人黄色毛片网站| 免费少妇av软件| 国产精品一区二区免费欧美| 肉色欧美久久久久久久蜜桃| 黄网站色视频无遮挡免费观看| 国产麻豆69| 日韩欧美一区二区三区在线观看 | 怎么达到女性高潮| 纵有疾风起免费观看全集完整版| 蜜桃国产av成人99| 欧美日韩亚洲国产一区二区在线观看 | 一个人免费看片子| 最新美女视频免费是黄的| 91av网站免费观看| 50天的宝宝边吃奶边哭怎么回事| 18禁国产床啪视频网站| 日日夜夜操网爽| 丝袜美腿诱惑在线| 精品福利观看| 一区在线观看完整版| 黑人巨大精品欧美一区二区蜜桃| 国产成人一区二区三区免费视频网站| 9热在线视频观看99| 久久免费观看电影| 亚洲成人免费电影在线观看| 国产精品一区二区在线观看99| 国产成人av激情在线播放| 美女高潮喷水抽搐中文字幕| 国产在线精品亚洲第一网站| 日韩三级视频一区二区三区| 男男h啪啪无遮挡| 午夜福利免费观看在线| 超碰成人久久| 视频在线观看一区二区三区| 国产精品久久久久久精品古装| 高清毛片免费观看视频网站 | 18在线观看网站| 国产野战对白在线观看| xxxhd国产人妻xxx| 一级,二级,三级黄色视频| 精品亚洲成国产av| 黄片播放在线免费| 欧美精品一区二区大全| 亚洲精品在线观看二区| 淫妇啪啪啪对白视频| 天天操日日干夜夜撸| 老熟女久久久| 黄色丝袜av网址大全| 精品国产乱码久久久久久男人| 动漫黄色视频在线观看| 亚洲精品国产一区二区精华液| 国产午夜精品久久久久久| 欧美激情久久久久久爽电影 | 欧美av亚洲av综合av国产av| 国精品久久久久久国模美| cao死你这个sao货| 中文字幕制服av| 国产精品一区二区在线不卡| 日韩欧美免费精品| 国产欧美日韩一区二区三区在线| √禁漫天堂资源中文www| 国内毛片毛片毛片毛片毛片| 久久久久久久大尺度免费视频| 国产亚洲午夜精品一区二区久久| 大香蕉久久网| 亚洲成人免费电影在线观看| 色综合欧美亚洲国产小说|