Laboratory And Pre-clinical Studies Of Parainfluenza Viruses

副流感病毒的实验室和临床前研究

• 批准号: 10927726
• 负责人: Ursula Buchholz
• 金额: $ 171.02万
• 依托单位: NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10927726
• 关键词: Active Immunization; Age; Animal Experiments; Antibodies; Antigens; Antiviral Agents; Attenuated; Attenuated Vaccines; Blood group antigen f; Cattle; Cell Culture Techniques; Child; Childhood; Clinical Research; Clinical Trials; Complement; Cooperative Research and Development Agreement; Cytoplasmic Tail; Development; Disease; Engineering; Genes; Glycoproteins; Human; Human Parainfluenza Virus 2; Immunization; In Vitro; Infant; Infection; Intranasal Administration; Laboratory Study; Lead; Life; Lower respiratory tract structure; Membrane; Missense Mutation; Modification; Molecular Biology; Molecular Conformation; Molecular Virology; Mutation; NIH Vaccine Research Center; Para-Influenza Virus Type 1; Para-Influenza Virus Type 3; Phase; Phase I Clinical Trials; Phenotype; Pneumovirus; Preparation; Protein Conformation; Proteins; Protocols documentation; Reporting; Respiratory Syncytial Virus Vaccines; Respiratory Tract Diseases; Respiratory syncytial virus; Respiratory syncytial virus RSV F proteins; Serotyping; Serum; System; Vaccine Clinical Trial; Vaccines; Vertebral column; Viral; Viral Antigens; Virus; Work; attachment protein G; attenuation; disulfide bond; immunogenic; immunogenicity; immunoprophylaxis; lead candidate; manufacture; neutralizing antibody; nonhuman primate; parainfluenza virus; particle; phase 1 study; preclinical study; programs; research clinical testing; respiratory pathogen; reverse genetics; vaccine candidate; vector

In recent years, we have focused on using a PIV3-based vector to express RSV antigen, providing a bivalent vaccine against the two most important pediatric viral respiratory pathogens. The vector is one that we previously developed, called rB/HPIV3, which consists of bovine PIV3 in which the F and HN genes have been replaced by those of HPIV3. This results in a chimeric virus that is attenuated in non-human primates and humans due to the BPIV3 backbone, and which bears the neutralization and major protective F and HN antigens of HPIV3. Both the empty B/HPIV3 vector and B/HPIV3 expressing the unmodified RSV F protein were previously shown to be well-tolerated in infants and young children. Therefore, this vector appears to be in the desired range of attenuation. In work continuing from previous years, we continued to focus on expressing the RSV fusion F glycoprotein because it generally is considered to be the most important RSV neutralization and protective antigen. RSV F also is much more highly conserved among RSV strains than the attachment G protein, which is the other neutralization antigen and the second most important protective antigen. We continued to evaluate a number of strategies to optimize the immunogenicity of rB/HPIV3 expressing RSV F protein. One modification was to increase the stability of the pre-fusion conformation of the F protein - the conformation that is the most effective in inducing RSV-neutralizing antibodies - by introducing mutations that have been reported by colleagues in the NIH Vaccine Research Center and elsewhere. The most successful mutations involved addition of a disulfide bond (called the DS mutation) in combination with two cavity-filling missense mutations (called Cav1). The other modification was to engineer RSV F to be efficiently packaged in the B/HPIV3 vector particle. This was done by replacing the transmembrane and cytoplasmic tail (TMCT) domains of RSV F with those of BPIV3 F. Each of these two modifications, DS-Cav1 and TMCT, resulted in a substantial increase in the induction of serum RSV-neutralizing antibodies, and in particular antibodies that neutralized RSV efficiently in vitro without added complement and thus are highly effective in neutralization. Clinical study material of these lead candidates has been prepared and characterized and will be evaluated in a Phase 1 study in 2024. In the past year, regulatory documents have been prepared, and a clinical study protocol is currently in preparation.

近年来，我们致力于利用基于piv3的载体表达RSV抗原，提供针对两种最重要的儿科呼吸道病毒病原体的二价疫苗。该载体是我们以前开发的一种，称为rB/HPIV3，它由牛PIV3组成，其中F和HN基因已被HPIV3基因所取代。这就产生了一种嵌合病毒，这种病毒在非人灵长类动物和人类中由于BPIV3骨干而被减毒，并且具有HPIV3的中和和主要保护性F和HN抗原。空的B/HPIV3载体和表达未修饰的RSV F蛋白的B/HPIV3在婴儿和幼儿中均表现出良好的耐受性。因此，这个矢量似乎在期望的衰减范围内。

项目成果

Progress in respiratory virus vaccine development.

• DOI: 10.1055/s-0031-1283289
• 发表时间: 2011-08
• 期刊: Seminars in respiratory and critical care medicine
• 影响因子: 3.2
• 作者: Schmidt AC

Recombinant human parainfluenza virus type 2 with mutations in V that permit cellular interferon signaling are not attenuated in non-human primates.

• DOI: 10.1016/j.virol.2010.07.011
• 发表时间: 2010-10-10
• 期刊: Virology
• 影响因子: 3.7
• 作者: Schaap-Nutt A;D'Angelo C;Amaro-Carambot E;Nolan SM;Davis S;Wise SM;Higgins C;Bradley K;Kim O;Mayor R;Skiadopoulos MH;Collins PL;Murphy BR;Schmidt AC
• 通讯作者: Schmidt AC

Identification of human parainfluenza virus type 2 (HPIV-2) V protein amino acid residues that reduce binding of V to MDA5 and attenuate HPIV-2 replication in nonhuman primates.

鉴定人副流感病毒 2 型 (HPIV-2) V 蛋白氨基酸残基，可减少 V 与 MDA5 的结合并减弱非人灵长类动物中 HPIV-2 的复制。

• DOI: 10.1128/jvi.02542-10
• 发表时间: 2011
• 期刊: Journal of virology
• 影响因子: 5.4
• 作者: Schaap-Nutt,Anne;Higgins,Caraline;Amaro-Carambot,Emerito;Nolan,SheilaM;D'Angelo,Christopher;Murphy,BrianR;Collins,PeterL;Schmidt,AlexanderC
• 通讯作者: Schmidt,AlexanderC

The aberrant gene-end transcription signal of the matrix M gene of human parainfluenza virus type 3 downregulates fusion F protein expression and the F-specific antibody response in vivo.

3型人副流感病毒基质M基因的异常基因末端转录信号下调融合F蛋白表达和体内F特异性抗体反应。

• DOI: 10.1128/jvi.03148-14
• 发表时间: 2015
• 期刊: Journal of virology
• 影响因子: 5.4
• 作者: Lingemann,Matthias;Surman,Sonja;Amaro-Carambot,Emérito;Schaap-Nutt,Anne;Collins,PeterL;Munir,Shirin
• 通讯作者: Munir,Shirin

Attenuated Human Parainfluenza Virus Type 1 (HPIV1) Expressing the Fusion Glycoprotein of Human Respiratory Syncytial Virus (RSV) as a Bivalent HPIV1/RSV Vaccine.

表达人呼吸道合胞病毒 (RSV) 融合糖蛋白的减毒人副流感病毒 1 型 (HPIV1)，作为二价 HPIV1/RSV 疫苗。

• DOI: 10.1128/jvi.01380-15
• 发表时间: 2015
• 期刊: Journal of virology
• 影响因子: 5.4
• 作者: Mackow,Natalie;Amaro-Carambot,Emérito;Liang,Bo;Surman,Sonja;Lingemann,Matthias;Yang,Lijuan;Collins,PeterL;Munir,Shirin
• 通讯作者: Munir,Shirin