Application of the Probability Model for Starting Period to Initiate to Take Palivizumab by Prefecture Using National Official Sentinel Surveillance in Japan

Background: Palivizumab were used for the premature infant or a high-risk infant with congenital heart disease. However, recently outbreak pattern of respiratory syncytial (RS) virus infection has been varying year by year. Moreover, it also has some regional difference. Therefore, the object of the present study was to develop early detection of the timing of that outbreak had started in each prefecture. Method: We used data in National Official Sentinel Surveillance for Infectious Diseases (NOSSID). Study period was March 16th, 2011 to December 30th, 2018. We defined stating period to initiate to take palivizumab as 8 - 12 weeks before from the peak of outbreak. We estimated whether the week is included in starting period or not from April 1st to the peak of outbreak by the past number of patients of RS virus infection on week and its squared. Additionally, we have to take delay in NOSSID into consideration. Results: In nationwide, the last two seasons, the model predicted precisely the starting period. At prefectural level, the model predicted the starting period precisely in 16.6% of all year and prefectures pairs. When we consider the delay in NOSSID into consideration, the patients can start to take in 14.9% of all year and prefectures pairs. Discussion and Conclusion: The result of the probability model was not good, and thus we have to develop more sophisticated model for prediction at prefecture level.

Effects of Palivizumab Guideline Changes on RSV Admissions in Patients with Congenital Heart Disease and Prematurity

Background: Respiratory syncytial virus (RSV) causes significant morbidity and mortality in patients with a history of prematurity and congenital heart disease (CHD). In 2014, the guidelines for Palivizumab became more restrictive for this population. We hypothesized the percentage of RSV+ admissions would increase overall and in this target group (TG) specifically. Methods: We conducted a retrospective review of patients under age 2 years admitted with bronchiolitis two seasons prior to the change (Pre) and two seasons after (Post). Our TG included patients who were eligible prior to the 2014 changes but currently no longer eligible. We used chi-square analysis to answer the two main hypotheses: 1) Percent RSV+/total bronchiolitis Pre vs Post and 2) Percent of TG/RSV+ Pre vs Post. Results: 1283 patients (546 pre, 737 post) were admitted with the diagnosis of RSV between 2012-2016, 866 actually tested positive for RSV (367 Pre, 499 Post). There was no significant difference in the number of total patients admitted with RSV (Pre = 67.2%, Post = 67.7%) or in our TG (Pre 7.1% vs Post 8.2%). TG overall had a more complicated course: longer length of stay, median 5 days, IQR 2 - 12 vs 3 days, IQR 1 - 5, (p < 0.001), intensive care unit admissions (36% vs 22.8%, p = 0.02), positive pressure ventilation (25.4% vs 15.4%, p = 0.03) and intubation (16.4% vs 6.8%, p = 0.004), but there was no difference Pre vs Post. Conclusion: The TG had an overall higher acuity, but there was no increase in the number of patients hospitalized with RSV or severity as a result of the Palivizumab guideline changes.

RSV变异时不出现Palivizumab耐药

据medscape．com9月3日报道(原载J Infect Dis 2004；190：975-978)，经常给早产儿应用palivizumab单克隆抗体以预防呼吸道合胞病毒(RSV)。

毛细支气管炎的诊治和预防进展

毛细支气管炎是婴幼儿急诊住院的常见病因,呼吸道合胞病毒(RSV)是最常见的病原体。近年发现,鼻病毒是其第二位病因。毛细支气管炎好发于冬季,发病高峰年龄在2～8个月。RSV通过呼吸道传播,对RSV感染的免疫反应包括体液免疫和细胞免疫。至今对毛细支气管炎仍无特效治疗。利巴韦林雾化、支气管扩张剂、糖皮质激素、heliox等都曾应用,但疗效仍有争议。静脉内免疫球蛋白和palivizumab可用于预防性治疗,但药费昂贵,仅限用于高危患儿。目前,RSV减毒活疫苗和以蛋白质亚单位为基础的疫苗均在研制中。本文综述了近年来对毛细支气管炎的病因、流行病学、病毒免疫学、治疗、预防以及疫苗研究的进展,希望对毛细支气管炎的临床诊治和预防有所帮助。

Burden of respiratory syncytial virus infection in young children

Respiratory syncytial virus(RSV) is the most frequent and important cause of lower respiratory tract infection in infants and children. It is a seasonal virus, with peak rates of infection occurring annually in the cold season in temperate climates, and in the rainy season, as temperatures fall, in tropical climates. High risk groups for severe RSV disease include infants below six mo of age, premature infants with or without chronic lung disease, infants with hemodynamically significant congenital heart disease, infants with immunodeficiency or cystic fibrosis, and infants with neuromuscular diseases. Mortality rates associated with RSV infection are generally low in previous healthy infants(below 1%), but increase significantly in children with underlying chronic conditions and comorbidities. Following early RSV lower respiratory tract infection, some patients experience recurrent episodes of wheezing mimicking early childhood asthma with persistence of lung function abnormalities until adolescence. There is currently no RSV vaccine available, but promising candidate vaccines are in development. Palivizumab, a monoclonal RSV antibody that is the only tool for immunoprophylaxis in high-riskinfants, lowers the burden of RSV infection in certain carefully selected patient groups.

A protective human antibody against respiratory syncytial virus by targeting a prefusion epitope across sites IV and V of the viral fusion glycoprotein

Respiratory syncytial virus(RSV)is one of the leading pathogens that cause lower respiratory tract infections in infants and the elderly.Passive immunoprophylaxis with monoclonal antibody(mAb)has been approved to prevent morbidity and mortality from RSV infection in infants.Here we report the isolation of two neutralizing mAbs against RSV from convalescent children by prefusion form of fusion(F)glycoprotein as bait.One mAb RV11 exhibited good potency in neutralization of RSV strains from both A and B subtypes in cell-based assay,and protected mice from RSV infection in vivo.An RV11 escape mutant was identified,which contains an S443P mutation in F protein.Crystal structure showed the RV11 bound to a conserved prefusion epitope across the antigenic sites IV and V of the F glycoprotein.RV11 showed a strong synergistic effect when combined with two RSV antivirals,an F-targeting small molecular inhibitor ziresovir and a siteØneutralizing mAb D25(the parental mAb for nirsevimab).The study extended our knowledge to the neutralizing and protective epitopes of RSV,and the mAb RV11 deserves further development for clinical translation.

帕利珠单抗生物类似药的细胞培养工艺优化及纯化工艺考察

帕利珠单抗(Synagis)是用于预防呼吸道合胞病毒的经典药物,但由于价格昂贵,限制了其应用范围。该研究采用中国仓鼠卵巢细胞(CHO细胞)表达帕利珠单抗类似药,并以响应面设计法对培养关键参数进行优化,筛选培养基组合以提高产量。研究结果显示,优化工艺参数为以AM01-AF02为基础-补料培养基,每1 mL含5.0×10^(6)个细胞的密度接种,37℃培养7d后,降温至33.0℃,培养至d16。该工艺条件下,可将帕利珠单抗类似药的产量在摇瓶和3L生物反应器中分别提升69.3%和30.0%。随后,对生物反应器上发酵生产的抗体进行了纯化工艺研究,为帕利珠单抗类似药的后续工艺开发提供了参考。

呼吸道合胞病毒逃逸株对单克隆抗体预防的抗性比较

目的Palivizumab(PZ)是目前临床使用的惟一一个预防人类感染性疾病的单克隆抗体,本研究评估不同逃逸株在棉鼠体内对PZ预防的抗性。方法在细胞培养系统中筛选获得PZ逃逸株,测定其全长F基因序列,用微量中和法评估逃逸株对PZ的抗性,在棉鼠模型体内观察逃逸株对PZ预防的抗性差异。结果筛选获得的PZ逃逸株于F蛋白内第268位氨基酸(F212)和272位氨基酸(MP4、MS312、MS412和MS512)发生替换。用Westernblot检测发现所有逃逸株PZ识别位点抗原性改变。F212复制能力受损,而其他逃逸株复制能力与A2母株接近。与A2原型株比较,MP4和MS412在体内外对PZ的中和活性具完全抗性。F212体外对PZ中和活性显示不完全抗性,但大剂量PZ在棉鼠体内仍能有效预防F212感染。结论不同PZ逃逸株体内对PZ的预防效应可能具有不同程度的抗性,某些逃逸株即使在PZ筛选压力下产生,亦不一定导致临床后果。

呼吸道合胞病毒感染的预防和治疗研究进展

由于呼吸道合胞病毒（respiratory syncytial virus，RSV）感染所导致的沉重负担及高危儿童的病死率，对RSV感染的预防和治疗一直受到高度的重视。尽管如此，迄今尚无安全有效的疫苗问世，抗RSV单克隆抗体Palivizumab是目前经证实惟一有效的预防药物，可用于高危儿童的预防。

呼吸道合胞病毒F基因及蛋白的相关研究进展

呼吸道合胞病毒(Respiratory syncytial virus,RSV)属副粘病毒科肺炎病毒属,是婴幼儿呼吸道感染重要的病毒病原。F基因序列保守,变异性小,国内外对F基因变异研究并不多。F蛋白(Fusion glycoprotein)为RSV跨膜糖蛋白,介导病毒与细胞膜的融合和穿入,诱导的中和抗体可以同时抑制A、B两个亚型的病毒感染,故F蛋白是单克隆抗体药物及疫苗研制的主要对象。在无有效疫苗的情况下,目前抗F蛋白单克隆抗体是降低高危患儿RSV感染入院率和疾病严重程度的最重要方法,但单克隆抗体的使用可造成进化压力,产生抗体耐药株。本文对近10年来有关RSV的F基因变异、抗F蛋白单克隆抗体药物及F蛋白相关疫苗的研究进展进行综述。

北京地区急性呼吸道感染儿童RSV F蛋白抗原位点变异分析

目的 为了解我国北京地区呼吸道合胞病毒（Respiratory Syncytial Virus RSV）融合蛋白F基因特征及抗原位点变异情况,本研究对61株RSV分离毒株F蛋白主要抗原位点区进行了基因序列分析.方法 应用RT-PCR方法分段扩增获得F蛋白主要抗原位点区基因,并对产物进行序列测定及拼接.序列比对分析,构建系统发育树,进行亲缘关系分析.结果 61株RSV分离株中,A亚型为43株,B亚型为18株.A、B亚型内核苷酸（氨基酸）同源性较高,分别为95.9％ - 100％（98.3％ - 100％）及97.5％ - 100％ （98.7％ - 100％）,亚型间为83.2％ -84.9％（93.1％ -95.1％）.基于F蛋白主要抗原位点区基因亲缘进化分析,所有分离株可分为两个主要亚群,分别对应A/B亚型;两个亚群又可分别分成6个及3个不同的进化分支.两个亚群中分别存在7个及4个氨基酸位点突变,其中抗原位点（Φ）存在209位从Q到K及211位从S到N的变异,帕利珠单抗作用的抗原位点Ⅱ存在276位从N到S的位点突变,其余突变均位于非抗原位点决定区.结论 北京地区RSV流行株与原型株相比,F蛋白存在一定的变异,但仍具有较高的核苷酸及氨基酸同源性;各抗原位点区氨基酸保守,为疫苗及相关药物研究的重要候选蛋白.

婴幼儿呼吸道合胞病毒感染的治疗

呼吸道合胞病毒(respiratory syncytial virus RSV)是引起婴幼儿毛细支气管炎最重要的病原体。其主要临床表现为喘息。部分患儿可出现反复喘息发作而发展为哮喘。对RSV感染尚无特效治疗药物,仍然以支持对症治疗为主,目前的研究热点是中西医结合治疗,反义基因治疗,高渗盐水雾化吸入治疗等。

呼吸道合胞病毒的治疗药物研发进展

呼吸道合胞病毒(RSV)是婴幼儿、老年人和免疫功能低下者诱发下呼吸道感染的主要原因。RSV引起严重的呼吸系统疾病,与长期喘息和后期哮喘风险增加有关。虽然RSV疫苗的开发已经有50多年,仍然没有批准上市的疫苗,对于预防和治疗RSV感染的疫苗和有效治疗药物尚未满足临床需求。帕利珠单抗和利巴韦林目前可用于RSV感染的预防和治疗,但不完全有效。因此需要针对RSV的预防和治疗提出新的疗法,用于满足临床医疗需求。近10年来,新抗病毒药物和单克隆抗体的研发,已经显示出对RSV治疗的临床应用前景,并且可能在未来几年陆续上市。尽管RSV融合蛋白(F蛋白)已成为小分子抑制剂和单克隆抗体最受欢迎的靶点,但靶向病毒其他蛋白质的新方法也得到了发展。同时针对逃逸株,可能会采用联合用药,用于RSV病毒的治疗。对处于不同临床研发阶段的抗RSV病毒药物和单克隆抗体进行了综述。

2002～2005年期间萨斯喀彻温省儿科三级医疗中心因呼吸道合胞病毒感染住院的儿童病例分析(英文)

中文概呼吸道合胞病毒（RSV）是2岁以下儿童呼吸道感染最常见的病原体，也是引起婴儿病毒感染所致死亡的主要原因。到目前为止，尚未见加拿大萨斯喀彻温省RSV流行病学的研究报道。本研究的目的是描述2002年7月至2005年6月期间在萨斯喀彻温省的两个儿科三级医疗中心，即皇家大学医院（RUH）和萨斯卡通和里贾纳总医院（RGH），因RSV感染住院的儿童的流行病学特点及疾病严重程度，其中部分患儿有帕利珠单抗（palivizumab）预防史。 在上述2个医疗中心住院时间≥24h的儿童（年龄：从出生到16岁11个月）经实验室病毒鉴定确诊为RSV感染的儿童纳入本研究。在RUH中心，患儿鼻咽部分泌物经直接荧光抗体（DFA）检测阳性者确诊为RSV感染。如果DFA为阴性，则对该标本进行病毒培养。在RGH中心，所有患儿鼻咽部分泌物标本均进行DFA检测和病毒培养。确诊后对患儿的健康记录进行回顾性分析，内容包括患儿的人口统计信息、转诊模式、帕利珠单抗预防史、感染严重程度及转归。目前尚无统一的感染严重程度的判断标准，本研究根据住院时间、是否需要小儿重症监护及持续时间、是否机械通气等进行评估。在研究期间，萨斯喀彻温省的帕利珠单抗预防的标准与加拿大儿科学会（CPS）的建议一致。 2002年7月至2005年6月3年期间，总共有590名RSV儿童（包括324名男童）住院治疗，共602次住院记录，其中12名儿童住院1次以上。入院时患儿中位实足年龄为5.3个月，平均住院时间为4.0d（范围：〈1d至121.2个月）。82.4％的患儿出生时胎龄≥36周，7.5％为33-35周，9.5％≤32周。RSV感染住院情况呈现季节性模式，其中大部分发生在三月和六月。患儿最常见的临床表现为细支气管炎（70.2％），38.1％表现为肺炎，17.3％为上呼吸道感染，0.5％表现为哮吼（患儿可能同时有1个以上的临床表现）。478例（81.0％）为RSV轻度至中度感染，110例（18.6％）为重度感染。25.1%的患儿有继发性细菌感染。共有39例（6.7％）需要入住儿科重症监护病房（PICU），中位入住时间为5.0d。其中，22例重症患儿（56％）需要机械通气（通气时间中位数6.0d），14例重症患儿（36％）有继发性细菌感染。与入住普通病房的患儿比较，PICU患儿大多有如下情况：入院时年龄较小（P〈0.01），有潜在的肺部疾病（P〈0.01）或先天性心脏疾病（P=0.01），有两个或更多潜在的疾病（P〈0.01），与其他儿童共同居住（P=0.02）。在本研究过程中，2例儿童死亡，但均与RSV感染无关。 本研究有22例患儿在入院前接受过帕利珠单抗预防RSV感染，其中18例已完成至少2个月的剂量，17例（77％）有1个或以上的慢性疾病，14例（64%）出生时胎龄不超过32周。入院时中位实足年龄为5.6个月（范围0-27.5个月），中位住院时间为9.5d（范围2-271d）。大多数儿童（17/22）为轻度至中度RSV感染。 小结：RSV在萨斯喀彻温省保持较高的发病率，男性、实足年龄小于1岁的足月儿或晚期早产儿发病率较高。细支气管炎是最常见的临床表现。大多数患儿呈轻度至中度感染，但约7％的患儿需要重症监护。较小的实足年龄、潜在的肺部或心脏疾病或多个潜在疾病等因素均有可能导致患儿需要重症监护。此外，与其他孩子同住也有可能是导致患儿需要重症监护的一个因素。需要重症监护的患儿往往胎龄大于35周。虽然部分接受过帕利珠单抗预防的患儿也感染了RSV，但是其大部分患儿的病情为轻度至中度。这些曾接受过帕利珠单抗预防的患儿更可能有潜在疾病，并且出生时胎龄往往小于32周。在本研究中，无一例因RSV感染而引起的死亡病例。本研究尚浅，需要开展更深入的研究，以进一步确定RSV患儿，特别是PICU患儿以及曾接受过帕利珠单抗预防却仍然受到RSV感染的患儿的特征。