动力模型在评价流感疫苗控制大流行疫情效果中的研究

[目的]模拟流感大流行对人类的影响,了解流感疫苗对控制流感大流行的作用,并预测为使疫苗物有所值,疫苗计划的滞后时间(TL)和完成时间(DV)。[方法]基于传染病的自然规律,在传统SEIR模型的基础上建立对人群免疫的传染病模型,采用感染率(AR)作为判断指标。[结果]对于R0在2左右的流感大流行,感染者均表现临床症状的情况下,疫苗计划滞后时间对感染率的影响大于疫苗计划完成时间,当感染率控制在50%以下则被认为疫苗计划有价值时,最大的TL和DV组合为30和80或40和30d。[结论]为最大程度地减少大流行期间的损失,防病重点应放在尽早地开发和使用疫苗上。     

加替沙星Ⅰ期临床试验中不良事件的研究

目的对甲磺酸加替沙星临床耐受性试验中不良事件进行综合性的分析和评价. 方法通过甲磺酸加替沙星Ⅰ期临床试验观察分析其不良反应. 结果在本次试验中共发现6例不良反应,这些不良反应均为轻度一过性、可耐受,未见其他有临床意义的症状、体征及实验室检查改变,这部分受试者未作任何特殊治疗和处理,停药后1周内全部自行恢复正常. 结论甲磺酸加替沙星是安全性较高的新型广谱氟喹诺酮类抗菌药物,但也要关注其不良反应,如轻度肝功能改变和过敏反应等.     

基于全过程管理的Ⅰ期临床试验管理系统设计与实现

目的 实现Ⅰ期临床试验全过程管理,畅通研究各方的沟通交流,提高项目管理规范性,形成唯一、留痕、可溯源的数据记录.方法 从不同环节对Ⅰ期临床试验管理业务进行梳理,运用全过程管理理念进行多角色的流程优化和管理闭环.结果 设计了包含项目配置、项目计划执行、受试者管理、生物样本管理、药品管理、质量控制等功能的Ⅰ期临床试验系统....     

国产流感病毒裂解疫苗的免疫原性及安全性效果评价

目的观察国产流感病毒裂解疫苗的免疫原性及安全性。方法通过对疫苗接种者的随访调查和血清学检测,分析国产疫苗和进口疫苗间的免疫差异,从而对国产疫苗进行效果评价。结果接种国产疫苗和进口疫苗后,除个别有发热现象外,未发现其他异常反应,且两组的发热比率经检验差异无统计学意义;国产疫苗H1N1亚型、H3N2亚型和B型HI抗体阳转率、GMT增长倍数以及易感人群下降率,与进口疫苗相比差异均无统计学意义。结论国产疫苗具有很好的安全性和免疫原性。     

国产流感病毒裂解疫苗的免疫原性及安全性效果评价

目的观察国产流感病毒裂解疫苗的免疫原性及安全性。方法通过对疫苗接种者的随访调查和血清学检测,分析国产疫苗和进口疫苗间的免疫差异,从而对国产疫苗进行效果评价。结果接种国产疫苗和进口疫苗后,除个别有发热现象外,未发现其他异常反应,且两组的发热比率经检验差异无统计学意义;国产疫苗H1N1亚型、H3N2亚型和B型HI抗体阳转率、GMT增长倍数以及易感人群下降率,与进口疫苗相比差异均无统计学意义。结论国产疫苗具有很好的安全性和免疫原性。     

人用大流行流感疫苗佐剂的研究进展

1997年5月9日,香港一名3岁男童体内分离出一株A型流感病毒,同年8月确诊为全球首例由A型禽流感病毒(H5N1)引起的人间病例.据世界卫生组织(WHO)报道,截止到2008年4月3日,14个国家报告378例A型禽流感(H5N1)确诊病人,其中7238人死亡,病死率为62.96%.根据2005年WHO对流感大流行预警期的划分,当前全球正处在预警期的第三阶段,即以散发病例和有限的人传人疫情为特征[1].     

对接受药物Ⅰ期临床试验的受试者进行病房管理和优质护理的效果研究

目的：分析优质护理联合病房管理在药物Ⅰ期临床试验中的临床效果。方法：经我院医学伦理委员会审批,回顾分析我院于2021年4月至2021年12月参与药物Ⅰ期临床试验的受试者142例为研究对象,随机数字分为对照组71例,观察组71例。对照组采用常规护理,观察组采用优质护理配合病房管理。统计护理质量、受试者焦虑、抑郁评分及依从性情况,并统计不良事件发生情况与试验完成情况。结果：观察组护理质量评分均超过90分,高于对照组;观察组护理后焦虑、抑郁评分均低于30分,显著低于对照组;观察组受试者依从性评分超过的90分,高于对照组;观察组不良事件发生率低于3%,低于对照组;且所有受试者均完成了试验,完成比率显著高于对照组,上述差异具有统计学意义（P<0.05）。结论：在药物Ⅰ期临床试验中适用病房管理配合优质护理能实现较好的临床效果,建议在临床护理中推广使用。     

我国甲型H1N1流感疫苗临床试验进展顺利——卫生部长甘当首批受试者

我国甲型H1N1流感疫苗临床试验工作进展顺利。在完成对受试者接种第一针甲型H1N1流感疫苗的初步安全性分析报告后，从8月12日开始，甲型H1N1流感疫苗临床试验受试者开始接种第二针，而整个临床试验预计将在9月中旬完成。     

实施创新药Ⅰ期临床试验中的问题与对策

创新药的Ⅰ期临床试验是整个临床研究过程的关键环节.本研究重点阐述了南京医科大学第一附属医院在实施创新药Ⅰ期临床研究中的体会与经验.     

Stopped hearts,amputated toes and NASA: contemporary legends among healthy volunteers in US phase I clinical trials

The first stage of testing new pharmaceuticals in humans is referred to as a phase I clinical trial. The purpose of these studies is to test the safety of the drugs and to establish appropriate doses that can later be given to patients. Most of these studies are conducted under controlled, in‐patient conditions using healthy volunteers who are paid for their participation. To explore healthy volunteers’ experiences in clinical trials, an ethnographic study was conducted at six in‐patient phase I clinics in the USA. In addition to the observation of clinic activities (from informed consent procedures to dosing to blood draws), 268 semi‐structured interviews were conducted, 33 with clinic staff and 235 with healthy volunteers. Drawing on this dataset, this article explores healthy volunteers’ exchange of contemporary legends about phase I clinical trials. In addition to potentially scaring the listener and communicating distrust in the medical community, these incredible stories help participants cope with perceived stigma and establish a gradient of risk of trial participation, creating potential boundaries to their participation in medical research. The article argues that contemporary legends play a productive role in society, shaping how people view themselves and others and influencing their decisions about risky activities.     

Non-clinical and phase I clinical trials of a Vero cell-derived inactivated Japanese encephalitis vaccine

The safety and effectiveness of a Vero cell-derived inactivated Japanese encephalitis (JE) vaccine were compared with those of a current JE vaccine in non-clinical studies and a phase I clinical trial. The single-dose toxicity study showed no toxicity of either the current JE vaccine or the investigational Vero cell-derived JE vaccine. In a local irritation study, the degree of irritation caused by both vaccines was determined to be the same as that induced by normal saline. To investigate genotoxicity, a chromosomal aberration test was conducted and the results were negative. Both JE vaccines were administered to a group of 30 subjects who were seronegative (neutralizing antibody titer <10(1)) for JEV virus (Beijing-1 Strain). Each subject was subcutaneously inoculated twice at an interval of 1-4 weeks, followed by an additional booster inoculation 4-8 weeks later, and clinical reactions and serological responses were subsequently investigated. Adverse drug reactions of local reaction, headache and malaise were mild, occurring at a rate of 6.7 and 20.0% after administration of the Vero cell-derived JE vaccine and the current JE vaccine, respectively. The seroconversion rate after three doses of both JE vaccines was 100%, while the geometric mean titer for the Vero cell-derived and current JE vaccines was 10(2.35) and 10(2.03), respectively. These results suggest that the safety and effectiveness of the Vero cell-derived inactivated JE vaccine are equal to those of the currently available conventional vaccine in humans, and that the Vero cell-derived vaccine could be a useful second-generation JE vaccine.     

Predictors of influenza vaccine acceptance among healthy adults.

BACKGROUND: Previous studies investigating predictors of influenza vaccine acceptance have focused on high-risk patients or health care workers. Few studies have examined flu shot acceptance among healthy adults in workplace settings, even though influenza vaccine is recommended for this group as well. METHODS: Two studies investigated predictors of flu vaccine acceptance in workplace samples of healthy adults. In the first study, 79 university employees were interviewed, while in the second, 435 corporate employees completed a questionnaire. RESULTS: In the first study, flu shot acceptance was predicted by perceived effectiveness of the vaccine (r = 0.36), perceived likelihood of vaccine side effects (r = -0.32), and having received the shot in the previous year (r = 0.25). In the second study, flu shot acceptance was again predicted by perceived effectiveness (r = 0.49), likelihood of side effects (r = -0.31), and previous flu shot (r = 0.66) and was also related to older age (r = 0.10) and to predicted percentage of co-workers who also received the shot (r = 0.24). CONCLUSIONS: The current studies indicate that predictors of vaccine acceptance among healthy adults are similar to those identified in studies of high-risk patient populations and health care workers.     

Randomized,single-blind,active-controlled phase I clinical trial to evaluate the immunogenicity and safety of GC3114 (high-dose,quadrivalent influenza vaccine) in healthy adults

Influenza is a major medically attended respiratory illness. The impact of influenza on morbidity and mortality is particularly high in the elderly. Immunosenescence attenuates the immune response of influenza vaccine in the elderly. High-dose influenza vaccine contains 60 μg of hemagglutinin per strain, four times more compared with standard-dose (SD) influenza vaccine. This study is a phase I clinical trial investigating the immunogenicity and safety of the GC3114, high-dose, quadrivalent inactivated influenza vaccine (HD-QIV) in healthy adults aged 19–64 years during the 2017–2018 season. Seroprotection rates of HD-QIV were 100.0% for A/H1N1, 96.67% for A/H3N2, 83.33% for B/Yamagata, and 96.67% for B/Victoria. Seroconversion rate for A/H1N1, A/H3N2, B/Yamagata, and B/Victoria strains were 86.67%, 90.0%, 53.33%, and 53.33%, respectively, in the HD-QIV group. The post-/pre-vaccination geometric mean titer ratio (GMTR) was 15.28 for A/H1N1, 8.19 for A/H3N2, 3.56 for B/Yamagata, and 3.03 for B/Victoria in the HD-QIV group. Seroconversion rate and post-/pre-vaccination GMTR for A/H3N2 were significantly higher in the HD-QIV group than in the SD-QIV group (control). No serious adverse events were reported. In conclusion, GC3114 was safe, well-tolerated, and immunogenic in healthy adults. Clinical Trials Identifier: NCT03357263.     

Influenza vaccine in healthy preschool children

BACKGROUND: Studies of influenza vaccination in healthy children have not definitely answered the question of their efficacy. METHODS: We have carried out a randomized trial in a well selected population of healthy preschool children in Sardinia, Italy. During October 1995, 344 children aged 1 to 6 years, were randomly assigned to receive influenza vaccine (n=177) or no treatment (n=167). Two doses of a trivalent subvirion vaccine, containing 15mg of highly purified surface antigens from the component strains A/Johannesburg/33/94-like, A/Singapore/6/86-like and B/ Beijing/184/ 93-like were administered. Follow-up data were collected from December 1, 1995 through April 30, 1996. RESULTS: Seroconversion was documented in 17 out of 17 children. No specific systemic symptoms or severe local reactions were observed after vaccination. Influenza-like episodes, defined by the presence of fever and cough or sore throat that lasted at least 72 hours, occurred in 63 (37.7%) of unvaccinated children and in 22 (12.4%) of vaccinated ones. The corresponding reduction in disease incidence was 67% (95% CI: 0.59-0.74). Three episodes of otitis were observed among children in the control group versus zero among vaccinated children (p=0.07). Mean duration of day care center absenteism was significantly reduced by vaccination (2.3 days in unvaccinated and 0.5 day in vaccinated children, p<0.001) CONCLUSIONS: Influenza vaccine is safe and effective in healthy preschool children. However the favourable implications of vaccination on disease rate in subsequent years have to be evaluated.     

A phase 2 open-label safety and immunogenicity study of a meningococcal B bivalent rLP2086 vaccine in healthy adults

Background

Neisseria meningitidis serogroup B (MnB) is a leading cause of bacterial meningitis and septicemia in adolescents and young adults. No currently licensed and available vaccine has been shown to provide broad protection against endemic MnB disease. A bivalent rLP2086 vaccine based on two factor H-binding proteins (fHBPs) has been developed to provide broad protection against MnB disease-causing strains.

Methods

This study assessed the safety and immunogenicity of the final formulation of a bivalent rLP2086 vaccine in 60 healthy adults (18–40 years of age) receiving 120 μg doses at 0, 1, and 6 months. Safety was assessed by collecting solicited reactogenicity data and participant-reporting of adverse events. Immunogenicity was evaluated by human serum bactericidal assay (hSBA) against 5 MnB strains expressing distinct fHBP variants and fHBP-specific immunoglobulin G titre.

Results

After each immunisation, local reactions such as pain at the injection site and erythema were generally mild or moderate. The most common vaccine-related adverse event was upper respiratory tract infection, which was reported by two participants. Seroprotection (hSBA titres ≥ 1:4) was achieved in 94.3% of participants against a MnB strain expressing the vaccine-homologous fHBP variant A05 and 70.0%–94.7% against MnB strains expressing the heterologous fHBP variants B02, A22, B44, and B24. Seroconversion rates (≥4-fold rise in hSBA titres) ranged from 70.0% to 94.7% across the five MnB test strains following the 3-dose vaccination regimen. Immunogenicity responses tended to increase upon subsequent vaccine doses.

Conclusions

Bivalent rLP2086 is a promising vaccine candidate for broad protection against MnB disease-causing strains.     

A Bayesian design for phase I cancer therapeutic vaccine trials

Phase I clinical trials are the first step in drug development to test a new drug or drug combination on humans. Typical designs of Phase I trials use toxicity as the primary endpoint and aim to find the maximum tolerable dosage. However, these designs are poorly applicable for the development of cancer therapeutic vaccines because the expected safety concerns for these vaccines are not as much as cytotoxic agents. The primary objectives of a cancer therapeutic vaccine phase I trial thus often include determining whether the vaccine shows biologic activity and the minimum dose necessary to achieve a full immune or even clinical response. In this paper, we propose a new Bayesian phase I trial design that allows simultaneous evaluation of safety and immunogenicity outcomes. We demonstrate the proposed clinical trial design by both a numeric study and a therapeutic human papillomavirus vaccine trial.     

Adaptive dose modification for phase I clinical trials

Most phase I dose‐finding methods in oncology aim to find the maximum‐tolerated dose from a set of prespecified doses. However, in practice, because of a lack of understanding of the true dose–toxicity relationship, it is likely that none of these prespecified doses are equal or reasonably close to the true maximum‐tolerated dose. To handle this issue, we propose an adaptive dose modification (ADM) method that can be coupled with any existing dose‐finding method to adaptively modify the dose, when it is needed, during the course of dose finding. To reflect clinical practice, we divide the toxicity probability into three regions: underdosing, acceptable, and overdosing regions. We adaptively add a new dose whenever the observed data suggest that none of the investigational doses are likely to be located in the acceptable region. The new dose is estimated via a nonparametric dose–toxicity model based on local polynomial regression. The simulation study shows that ADM substantially outperforms the similar existing method. We applied ADM to a phase I cancer trial. Copyright © 2016 John Wiley & Sons, Ltd.     

Bayesian methods for phase I clinical trials.

Phase I clinical trials are conducted to determine the dose-response curve of a new drug with respect to toxic side effects and, in particular, to estimate the maximum tolerated dose (MTD). In this paper we take a Bayesian approach to the problem of making inferences about the MTD. Working with broad classes of priors, we obtain the posterior distribution of the MTD and study its properties. We also address the question of providing updated assessments of the risk of toxicity for new patients entering the study at a specific dose level. These assessments would be useful in deciding issues of study management and ethics. Our analysis pays particular attention to the sensitivity of the inferences and risk assessments to the choice of prior and the choice of model for the dose-response relationship.