帕利珠单抗用于治疗 RSV 感染
已经研究将帕利珠单抗与吸入性利巴韦林联合用于治疗 RSV 疾病的患者。虽然几项无对照的病例系列研究指出，使用帕利珠单抗的耐受性良好，并且能改善结局，但其他病例系列研究则未发现有所改善。一项 meta 分析报道，与仅接受吸入性利巴韦林治疗的患者相比，接受二联治疗的患者（使用利巴韦林加静脉注射免疫球蛋白 [IVIG] 或利巴韦林加帕利珠单抗）进展至发生下呼吸道感染的可能性较小。[103]von Lilienfeld-Toal M, Berger A, Christopeit M, et al. Community acquired respiratory virus infections in cancer patients: guideline on diagnosis and management by the Infectious Diseases Working Party of the German Society for Haematology and Medical Oncology. Eur J Cancer. 2016 Nov;67:200-12.http://www.ejcancer.com/article/S0959-8049(16)32388-7/fulltexthttp://www.ncbi.nlm.nih.gov/pubmed/27681877?tool=bestpractice.com 关于帕利珠单抗是否优于 IVIG 尚无定论，帕利珠单抗仅被批准在经筛选的高风险儿童中用于预防 RSV 疾病。IVIG 更常用于几种严重的病毒性疾病。需要进一步的研究来确定最有益的方案。
疫苗
尚未批准任何疫苗用于预防呼吸合胞病毒 (RSV) 感染。在 RSV 疫苗开发中遇到的困难包括：1) 由自然感染引起的保护性免疫无效，2) 难以建立用于评估疫苗反应的终点指标，以及 3) 与福尔马林灭活 RSV 疫苗相关疾病的严重程度增加，提高了对严格安全性分析的需求。[126]Acosta PL, Caballero MT, Polack FP. Brief history and characterization of enhanced respiratory syncytial virus disease. Clin Vaccine Immunol. 2015 Dec 16;23(3):189-95.https://cvi.asm.org/content/23/3/189.fullhttp://www.ncbi.nlm.nih.gov/pubmed/26677198?tool=bestpractice.com 然而，一些针对婴儿、老年人和孕妇的具有前景的疫苗正处于临床发展阶段，几篇报告提供了关于各种候选疫苗的全面总结。[127]PATH. RSV vaccine and mAb snapshot. Oct 2018 [internet publication].https://vaccineresources.org/files/RSV-snapshot-2018Oct_High%20Resolution%20V3.pdf[128]Modjarrad K, Giersing B, Kaslow DC, et al; WHO RSV Vaccine Consultation Expert Group. WHO consultation on respiratory syncytial virus vaccine development report from a World Health Organization meeting held on 23-24 March 2015. Vaccine. 2016 Jan 4;34(2):190-7.https://www.sciencedirect.com/science/article/pii/S0264410X15007677?via%3Dihubhttp://www.ncbi.nlm.nih.gov/pubmed/26100926?tool=bestpractice.com[129]Mazur NI, Higgins D, Nunes MC, et al. The respiratory syncytial virus vaccine landscape: lessons from the graveyard and promising candidates. Lancet Infect Dis. 2018 Oct;18(10):e295-311.http://www.ncbi.nlm.nih.gov/pubmed/29914800?tool=bestpractice.com许多亚单位、减毒、基于颗粒和载体的活疫苗处于临床发展的不同阶段，大多数都针对 RSV 融合糖蛋白 (F)。其中，源自昆虫细胞的 RSV F 纳米颗粒候选疫苗显示出最大潜力。[130]Glenn GM, Smith G, Fries L, et al. Safety and immunogenicity of a Sf9 insect cell-derived respiratory syncytial virus fusion protein nanoparticle vaccine. Vaccine. 2013 Jan 7;31(3):524-32.http://www.ncbi.nlm.nih.gov/pubmed/23153449?tool=bestpractice.com[131]Glenn GM, Fries LF, Thomas DN, et al. A randomized, blinded, controlled, dose-ranging study of a respiratory syncytial virus recombinant fusion (F) nanoparticle vaccine in healthy women of childbearing age. J Infect Dis. 2016 Feb 1;213(3):411-22.http://www.ncbi.nlm.nih.gov/pubmed/26259809?tool=bestpractice.com[132]Falloon J, Ji F, Curtis C, et al. A phase 1a, first-in-human, randomized study of a respiratory syncytial virus F protein vaccine with and without a toll-like receptor-4 agonist and stable emulsion adjuvant. Vaccine. 2016 May 27;34(25):2847-54.https://www.sciencedirect.com/science/article/pii/S0264410X16301220http://www.ncbi.nlm.nih.gov/pubmed/27102821?tool=bestpractice.com 该疫苗已进入第三阶段临床试验，可用于孕妇，预期能够为胎儿带来免疫力。[131]Glenn GM, Fries LF, Thomas DN, et al. A randomized, blinded, controlled, dose-ranging study of a respiratory syncytial virus recombinant fusion (F) nanoparticle vaccine in healthy women of childbearing age. J Infect Dis. 2016 Feb 1;213(3):411-22.http://www.ncbi.nlm.nih.gov/pubmed/26259809?tool=bestpractice.com[133]ClinicalTrials.gov. A study to determine the safety and efficacy of the RSV F vaccine to protect infants via maternal immunization. Nov 2018 [internet publication].https://clinicaltrials.gov/ct2/show/NCT02624947[134]August A, Glenn GM, Kpamegan E, et al. A phase 2 randomized, observer-blind, placebo-controlled, dose-ranging trial of aluminum-adjuvanted respiratory syncytial virus F particle vaccine formulations in healthy women of childbearing age. Vaccine. 2017 Jun 27;35(30):3749-59.https://www.sciencedirect.com/science/article/pii/S0264410X17306813http://www.ncbi.nlm.nih.gov/pubmed/28579233?tool=bestpractice.com美国食品药品监督管理局已授予该候选疫苗快速通道审批资格，用于为婴儿和>60 岁的成人提供保护。[128]Modjarrad K, Giersing B, Kaslow DC, et al; WHO RSV Vaccine Consultation Expert Group. WHO consultation on respiratory syncytial virus vaccine development report from a World Health Organization meeting held on 23-24 March 2015. Vaccine. 2016 Jan 4;34(2):190-7.https://www.sciencedirect.com/science/article/pii/S0264410X15007677?via%3Dihubhttp://www.ncbi.nlm.nih.gov/pubmed/26100926?tool=bestpractice.com[135]ClinicalTrials.gov. A study to evaluate the efficacy of an RSV F vaccine in older adults. Sep 2017 [internet publication].https://clinicaltrials.gov/ct2/show/NCT02608502[136]Langley JM, Aggarwal N, Toma A, et al. A randomized, controlled, observer-blinded phase 1 study of the safety and immunogenicity of a respiratory syncytial virus vaccine with or without alum adjuvant. J Infect Dis. 2017 Jan 1;215(1):24-33.https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5225248/http://www.ncbi.nlm.nih.gov/pubmed/27694633?tool=bestpractice.com其他疫苗（包括添加佐剂的呼吸合胞病毒 F 蛋白）处于临床开发的早期阶段。[137]Falloon J, Talbot HK, Curtis C, et al. Dose selection for an adjuvanted respiratory syncytial virus F protein vaccine for older adults based on humoral and cellular immune responses. Clin Vaccine Immunol. 2017 Sep 5;24(9):e00157-17.https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5585697/http://www.ncbi.nlm.nih.gov/pubmed/28679495?tool=bestpractice.com 迄今为止，RSV 疫苗耐受性良好，没有关于重大不良事件的报告。[129]Mazur NI, Higgins D, Nunes MC, et al. The respiratory syncytial virus vaccine landscape: lessons from the graveyard and promising candidates. Lancet Infect Dis. 2018 Oct;18(10):e295-311.http://www.ncbi.nlm.nih.gov/pubmed/29914800?tool=bestpractice.com[138]Griffin MP, Khan AA, Esser MT, et al. Safety, tolerability, and pharmacokinetics of MEDI8897, the respiratory syncytial virus prefusion F-targeting monoclonal antibody with an extended half-life, in healthy adults. Antimicrob Agents Chemother. 2017 Feb 23;61(3):e01714-16.https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5328523/http://www.ncbi.nlm.nih.gov/pubmed/27956428?tool=bestpractice.com然而，有几种疫苗未能达到预防临床疾病的主要终点。[139]Falloon J, Yu J, Esser MT, et al. An adjuvanted, postfusion F protein-based vaccine did not prevent respiratory syncytial virus illness in older adults. J Infect Dis. 2017 Dec 12;216(11):1362-70.https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5853767/http://www.ncbi.nlm.nih.gov/pubmed/29029260?tool=bestpractice.com
Medi8897
一种靶向 RSV F 蛋白的新型长效重组单克隆抗体正处于临床研究阶段，用于预防婴儿 RSV 相关的下呼吸道感染。Medi8897 在体外的药效比帕利珠单抗强。经设计，在其 Fc 区内采用了 [YTE] 替代品 (M252Y/S254T/T256E)，以防止降解，并增加再循环。[140]Robbie GJ, Criste R, Dall'acqua WF, et al. A novel investigational Fc-modified humanized monoclonal antibody, motavizumab-YTE, has an extended half-life in healthy adults. Antimicrob Agents Chemother. 2013 Dec;57(12):6147-53.https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3837853/http://www.ncbi.nlm.nih.gov/pubmed/24080653?tool=bestpractice.com[141]Kwakkenbos MJ, Diehl SA, Yasuda E, et al. Generation of stable monoclonal antibody-producing B cell receptor-positive human memory B cells by genetic programming. Nat Med. 2010 Jan;16(1):123-8.https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2861345/http://www.ncbi.nlm.nih.gov/pubmed/20023635?tool=bestpractice.com 这将允许单次给药，在 RSV 季节期间提供保护。1/2 期研究表明，Medi8897 的半衰期长达 117 天，其安全性与安慰剂类似。[138]Griffin MP, Khan AA, Esser MT, et al. Safety, tolerability, and pharmacokinetics of MEDI8897, the respiratory syncytial virus prefusion F-targeting monoclonal antibody with an extended half-life, in healthy adults. Antimicrob Agents Chemother. 2017 Feb 23;61(3):e01714-16.https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5328523/http://www.ncbi.nlm.nih.gov/pubmed/27956428?tool=bestpractice.com
新型抗病毒药物
几种抗病毒药物仍处于早期临床发展阶段。[142]Huntjens DRH, Ouwerkerk-Mahadevan S, Brochot A, et al. Population pharmacokinetic modeling of JNJ-53718678, a novel fusion inhibitor for the treatment of respiratory syncytial virus: results from a phase I, double-blind, randomized, placebo-controlled first-in-human study in healthy adult subjects. Clin Pharmacokinet. 2017 Nov;56(11):1331-42.http://www.ncbi.nlm.nih.gov/pubmed/28238203?tool=bestpractice.com
