This post-marketing study is a multicenter cohort study in pregnant women vaccinated with Abrysvo (RSV vaccine）designed to confirm the safety in pregnant women and their infants under actual clinical practice in Japan.

开始日期2024-09-30

申办/合作机构

Pfizer Inc.

NCT06551506 / Not yet recruiting临床4期IIT

A Prospective, Randomized, Open-label Phase 4 Study of the Immunology and Safety of Maternal RSV Vaccination (ABRYSVO (TM)), Infant Nirsevimab (BEYFORTUS (TM)) Immunization, or Both Products During the First Year of Life

Respiratory Syncytial Virus (RSV) is the leading cause of lower respiratory tract infections (LRTIs) in infants and young children. It is also a leading cause of mortality in children <5 years of age worldwide. Until recently, no Food and Drug Administration (FDA)-approved vaccines were available to prevent RSV infection. The only prophylactic product for RSV prevention recommended for infants was the monoclonal antibody palivizumab, but administration was limited to those with extreme prematurity, chronic lung disease, or hemodynamically significant congenital heart disease. However, in 2023, the FDA approved two products designed to prevent RSV lower respiratory tract disease (LRTD) in all infants: an active RSV vaccine based on the prefusion F protein (RSVpreF, ABRYSVO, Pfizer) administered during pregnancy, and a passive, long-acting monoclonal antibody (nirsevimab-alip [henceforth referred to as nirsevimab], BEYFORTUS, AstraZeneca) administered to infants at birth or at the start of their first RSV season. Both products were evaluated in Phase 3 pivotal clinical trials and have high efficacy in preventing LRTD caused by RSV in infants. Although there is no established correlate of protection against RSV, antibodies have been associated with protection across multiple studies. The clinical development plan for the products did not include comprehensive evaluations of the magnitude and durability of the immune response, nor were the two products tested in a single trial. This study is a prospective, randomized, open-label Phase 4 study with the primary objective of evaluating the magnitude and durability of RSV-specific neutralizing antibodies in infants through 12 months of life following either maternal RSV vaccination, infant nirsevimab administration, or both products combined.

开始日期2024-09-15

申办/合作机构

National Institute of Allergy & Infectious Diseases

NCT06546800 / Not yet recruitingN/A

SPECIAL INVESTIGATION FOR ABRYSVO INTRAMUSCULAR INJECTION -INVESTIGATION IN INDIVIDUALS AGED 60 YEARS OR OLDER-

This post-marketing study is a multicenter cohort study in individuals aged 60 years or older vaccinated with Abrysvo (RSV vaccine）designed to confirm the safety in individuals aged 60 years or older under actual clinical practice in Japan.

开始日期2024-08-31

申办/合作机构

Pfizer Inc.

100 项与呼吸道合胞病毒疫苗（辉瑞大药厂）相关的临床结果

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项与呼吸道合胞病毒疫苗（辉瑞大药厂）相关的文献（医药）

2024-05-15·Clinical infectious diseases : an official publication of the Infectious Diseases Society of America

Safety and Immunogenicity of Bivalent RSVpreF Vaccine Coadministered With Seasonal Inactivated Influenza Vaccine in Older Adults

Article

作者: Li, Wen ; Morbey, Claire ; Cooper, David ; Jiang, Qin ; Deshmukh, Sachin ; Colquhoun, David ; Bird, Paul ; Eizenberg, Peter ; McGirr, Anthony ; Mohan, Rahul ; Wark, Peter ; Leelasena, Indika ; Ryan, Philip ; Tai, Sze ; Hiew, Valerie ; Gurtman, Alejandra ; Rook, Christopher ; Athan, Eugene ; Lickliter, Jason ; Nelson, Mark ; Arya, Mark ; Argent, Christopher ; Scott, Robert J ; Cutler, Mark W ; Quan, Karen ; Swanson, Kena A ; De Silva, Gustinna ; Scott, Robert ; Bull, Sheetal ; Schmoele-Thoma, Beate ; Russo, Marc ; Bloch, Mark ; Baber, James ; Gunner, Elizabeth ; Tiong, Florence ; Neville, A Munro ; Voloshyna, Olga ; Gilfillan, Christopher ; Gruber, William C ; Jaques, Anna ; Kalinina, Elena V ; Leah, Amber ; Murdoch, Louise ; O'Sullivan, Matthew ; Anderson, Annaliesa S

Abstract:

Background:

Respiratory syncytial virus (RSV) and influenza are both typically seasonal diseases, with winter peaks in temperate climates. Coadministration of an RSV vaccine and influenza vaccine could be a benefit, requiring 1 rather than 2 visits to a healthcare provider for individuals receiving both vaccines.

Methods:

The primary immunogenicity objective of this phase 3, 1:1 randomized, double-blind, placebo-controlled study in healthy adults aged ≥65 years in Australia was to demonstrate noninferiority of immune responses with coadministration of the stabilized RSV prefusion F protein–based vaccine (RSVpreF) and seasonal inactivated influenza vaccine (SIIV) versus SIIV or RSVpreF administered alone, using a 1.5-fold noninferiority margin (lower bound 95% confidence interval >.667). Safety and tolerability were evaluated by collecting reactogenicity and adverse event data.

Results:

Of 1403 participants randomized, 1399 received vaccinations (median age, 70; range, 65‒91 years). Local reactions and systemic events were mostly mild or moderate when RSVpreF was coadministered with SIIV or administered alone. No vaccine-related serious adverse events were reported. Geometric mean ratios were 0.86 for RSV-A and 0.85 for RSV-B neutralizing titers at 1 month after RSVpreF administration and 0.77 to 0.90 for strain-specific hemagglutination inhibition assay titers at 1 month after SIIV. All comparisons achieved the prespecified 1.5-fold noninferiority margin.

Conclusions:

The primary study objectives were met, demonstrating noninferiority of RSVpreF and SIIV immune responses when RSVpreF was coadministered with SIIV and that RSVpreF had an acceptable safety and tolerability profile when coadministered with SIIV. The results of this study support coadministration of RSVpreF and SIIV in an older-adult population.

Clinical Trials Registration:

https://clinicaltrials.gov/study/NCT05301322.

2024-03-01·Obstetrics and gynecology

What U.S. Obstetricians Need to Know About Respiratory Syncytial Virus

Review

作者: Jones, Jefferson M ; Meaney-Delman, Dana ; Debessai, Haben ; Rasmussen, Sonja A

Respiratory syncytial virus (RSV) is the leading cause of acute lower respiratory tract infections in neonates, infants, and children worldwide. The virus is estimated to infect 97% of this population in the United States by the age of 2 years, leading to hospitalization for severe lower respiratory tract disease in 2–3% of infants younger than age 6 months. Two preventive options, prenatal administration of a maternal vaccine and administration of a long-acting monoclonal antibody to the infant, are now available for the prevention of RSV-associated lower respiratory tract infection in infants in the United States. The U.S. Food and Drug Administration (FDA) has approved and the Centers for Disease Control and Prevention (CDC) has recommended a new maternal vaccination, RSVPreF, to be administered between 32 0/7 and 36 6/7 weeks of gestation to reduce the risk of RSV-associated lower respiratory tract infection in infants in the first 6 months of life. The monoclonal antibody nirsevimab was approved by the FDA and recommended by the CDC for prevention of RSV-associated lower respiratory tract infection in infants younger than age 8 months who are born during or entering their first RSV season and for infants and children aged 8–19 months who are at high risk for RSV-associated lower respiratory tract infection and entering their second RSV season. Either maternal vaccination during pregnancy or monoclonal antibody administration to the infant is recommended to prevent RSV-associated lower respiratory tract infection among infants, but both are not needed for most infants. Given that the availability of these products may vary as these recommendations are implemented, it is important that obstetricians and other prenatal practitioners have the information they need to counsel their pregnant patients about both options. We review the safety and efficacy of these products, current recommendations for their use, and relative advantages and disadvantages of both newly approved options for the prevention of RSV-associated lower respiratory tract infection in infants to assist obstetricians and other prenatal practitioners in their counseling of pregnant patients.

2023-12-01·Lancet regional health. Americas

Cost-effectiveness analysis of nirsevimab and maternal RSVpreF vaccine strategies for prevention of Respiratory Syncytial Virus disease among infants in Canada: a simulation study

Article

作者: Moghadas, Seyed M ; Halperin, Scott A ; Shoukat, Affan ; Langley, Joanne M ; Galvani, Alison P ; Abdollahi, Elaheh

Background:

The cost-effectiveness of immunisation strategies with a long-acting monoclonal antibody (nirsevimab) and/or a protein-based maternal vaccine (RSVpreF) for protecting infants from Respiratory Syncytial Virus (RSV)-associated illness has not been previously determined for Canada. We estimated the health benefits and cost-effectiveness of nirsevimab for immunising the entire birth cohort, regardless of gestational age or other risk factors. Additionally, we evaluated the health benefits and cost-effectiveness of a combined strategy of year-round vaccination of pregnant women with RSVpreF and immunisation of infants at high risk, including those born preterm or with chronic conditions, with nirsevimab during the RSV season.

Methods:

We developed a discrete-event simulation model, parameterized with the data on medically-attended RSV infections among infants under one year of age from 2010 to 2019, including outpatient care, hospitalisations, and deaths. Intervention scenarios targeting twelve monthly birth cohorts and pregnant women, reflecting the 2021 census data for Ontario, Canada were evaluated over a follow-up time horizon of one year from birth. Taking into account the costs (in 2023 Canadian dollars) associated with RSV-related outcomes, we calculated the net monetary benefit using the quality-adjusted life-year (QALY) gained. Further, we determined the range of price-per-dose (PPD) for nirsevimab and RSVpreF within which the program was cost-effective. Cost-effectiveness analyses were conducted from both healthcare and societal perspectives.

Findings:

Using a willingness-to-pay of CAD$50,000 per QALY gained, we found that immunising the entire birth cohort with nirsevimab would be cost-effective from a societal perspective for a PPD of up to $290, with an annual budget impact of $83,978 for 1113 infants per 100,000 population. An alternative, combined strategy of vaccinating pregnant women and immunising only infants at high risk of severe disease would lead to a lower budget impact of $49,473 per 100,000 population with a PPD of $290 and $195 for nirsevimab and RSVpreF vaccine, respectively. This combined strategy would reduce infant mortality by 76%-85%, comparable to a 78% reduction achieved through a nirsevimab-only program of the entire birth cohort. The PPD for cost-effective programs with nirsevimab was sensitive to the target population among infants.

Interpretation:

Passive immunisation of infants under 6 months of age with nirsevimab and vaccination of pregnant women with RSVpreF could be a cost-effective strategy for protecting infants during their first RSV season.

Funding:

This study was supported by the Canadian Immunisation Research Network (CIRN) and the Canadian Institutes of Health Research (CIHR). Seyed M. Moghadas acknowledges support from the Natural Sciences and Engineering Research Council of Canada (MfPH and Discovery grants). Alison P. Galvani acknowledges support from the The Notsew Orm Sands Foundation.

420

项与呼吸道合胞病毒疫苗（辉瑞大药厂）相关的新闻（医药）

2024-09-17

·BioSpace

Sanofi, AstraZeneca Get FDA Approval of New Manufacturing Line to Bolster US Supply of RSV Antibody

iStock, graphixchon The newly approved filling line will be able to provide both 50-mg and 100-mg doses of the respiratory syncytial virus antibody Beyfortus to help meet demand ahead of the 2024/2025 RSV season. The FDA has given the green light to Sanofi and AstraZeneca ’s new filling line for their respiratory syncytial virus antibody Beyfortus for newborns and infants (nirsevimab-alip), which will enable the companies to expand manufacturing capacity and meet demand in the U.S. for the coming season, according to Sanofi’s announcement on Monday. The approval of the filling lines will allow the partners to deliver both 50-mg and 100-mg Beyfortus doses to private healthcare providers and to the Centers for Disease Control and Prevention for its Vaccines for Children program. Supplies of Beyfortus in the U.S. should be enough such that “every eligible baby” born off-season can receive immunization at a regular checkup, while all of those born during the season will be able to receive the antibody at birth. Through AstraZeneca, which is responsible for Beyfortus development and manufacturing, several doses of the immunizing antibody have already been produced and packaged, according to Sanofi’s announcement. With Monday’s approval of the filling line, the companies are now “ready to ship” these doses and boost the supply in the Northern Hemisphere ahead of the 2024/2025 respiratory syncytial virus (RSV) season. “This accomplishment aimed at equitable access was made possible through close partnership with the White House, Centers for Disease Control and Prevention, the U.S. Food and Drug Administration, and healthcare providers,” Thomas Grenier, head of vaccines, North America at Sanofi, said in a statement, noting that the newly approved filling line will help both the partners and health authorities make Beyfortus “widely available” to patients who need it. Sanofi and AstraZeneca have another filling line that is also set to provide additional doses for the coming 2024/2025 season, according to the announcement. Beyfortus is a long-acting antibody that facilitates passive immunity to RSV by targeting and binding to the part of the virus that it uses to enter host cells. Through this mechanism of action, Beyfortus can block RSV infection at a cellular level. In July 2023, the FDA signed off on the use of Beyfortus in infants entering their first RSV season and in children up to 24 months old who are at severe risk of infection in their second RSV season. In March 2024, a CDC analysis showed that Beyfortus was highly effective in infants, demonstrating 90% efficacy at preventing RSV hospitalization . At the time, the agency noted that these data support its recommendation that “all infants should be protected by maternal RSV vaccination or infant receipt of nirsevimab.” RSV vaccines are helping to prevent infection in adults. In May 2023, GSK’s Arexvy became the first FDA-approved RSV shot , indicated for adults aged 60 and above. The pharma expanded the label to cover younger seniors aged 50 to 59 in June 2024. Pfizer is also competing in the RSV vaccine space with Abrysvo, which was first approved in June 2023 . Abrysvo has since been expanded to allow pediatric immunization through maternal injection at 32 weeks to 36 weeks of gestation.

上市批准疫苗

2024-09-16

·BioPharmaDive

Sanofi readies to meet US demand for RSV antibody

Sanofi said its ready to meet demand for its RSV shot Beyfortus this year, announcing Monday the clearance by the Food and Drug Administration of a new manufacturing line.The French pharmaceutical company and partner AstraZeneca are shipping 50 milligram and 100 milligram doses of the antibody drug to private healthcare providers and the U.S. government, ahead of the start of this years season for respiratory syncytial virus infections in the Northern Hemisphere.The companies also expect another production line to provide doses of Beyfortus this year, and are continuing to build inventory.Beyfortus gained U.S. approval last July to prevent RSV in newborns during or entering their first RSV season, as well as in children up to 24 months who are at risk of severe disease.When the RSV season began, though, the companies struggled to maintain supply. Demand for the shot was higher than expected, leading to a shortage, particularly of the 100 milligram dose recommended for infants weighing 11 pounds or more. Due to the shortage, the Centers for Disease Control and Prevention recommended doses be prioritized for infants who were at higher risk for disease.RSV affects almost every infant at some point and, while most of the time it causes only mild illness, infections are the leading cause of hospitalizations in newborns. Up until last year, the only preventive drug was another antibody called Synagis, but its use was limited to certain high-risk newborns.Pfizers RSV vaccine Abrysvo is approved for maternal use, which passes on passive immunity to the child after birth. The CDC encouraged pregnant women to receive Abrysvo to protect their newborns while Beyfortus was in short supply.Sanofi said it is shipping doses to the CDC for the agencys Vaccines for Children program. The French pharma also launched a reservation system to help it gauge demand from private healthcare providers.The US market is anticipated to have enough supply so that every eligible baby born outside of the season will have access to immunization at a regular checkup and those born during the season will have access at birth, Sanofi said in its statement. '

上市批准疫苗

2024-09-06

·生物制品圈

RSV预防在儿童和孕妇中的临床研究

摘要：呼吸道合胞病毒（RSV）是婴儿和儿童支气管炎和肺炎的重要致病因子。RSV表面融合糖蛋白的鉴定和结构分析是RSV预防发展的关键进展。本综述全面总结了ClinicalTrials.gov上注册的RSV单克隆抗体（mAb）和疫苗临床试验，重点介绍了新生儿、婴儿和儿童RSV疫苗的分类、名称、靶标、阶段、临床结果和安全性数据。我们还讨论了用于母体免疫的RSV疫苗类型的特点，并总结了目前孕妇RSV疫苗的临床研究进展及其在婴儿中的保护效果。本综述将为未来儿童RSV预防的发展提供新的思路。 1.引言呼吸道合胞病毒（RSV）是婴儿支气管炎和肺炎的主要病原体，也是6个月以下婴儿严重下呼吸道感染（LRTIs）的最常见原因，几乎所有儿童在2岁之前都感染过RSV，并且再次感染是常见的。根据2005年的一份报告，RSV感染或相关并发症导致的死亡人数估计在5岁以下儿童中为66,000至160,000人。尽管RSV发病率高，但目前尚无明确的治疗方法。 RSV基因组跨度为15.2 kb（如图1所示），包含10个基因，编码11种蛋白质。值得注意的是，M2基因包含两个重叠的ORF，产生M2-1和M2-2两种蛋白质。M2-1对病毒转录至关重要，而M2-2控制从转录到基因组复制的转变。RSV基因组的初始转录产生非结构蛋白NS1和NS2，它们共同作用以抑制凋亡和干扰素反应。此外，RSV病毒颗粒的特征是单链、负义RNA基因组，被脂质双层包裹，展示融合（F）、附着（G）和小疏水（SH）蛋白（图1）。病毒表面主要由G和F糖蛋白组成，它们在进入过程中发挥关键作用。F蛋白的前融合构象是人类血清中RSV中和活性的主要靶标，许多强效抗体对此构象具有特异性。因此，在开发含F蛋白的疫苗候选物时，优先考虑基于结构的工程策略，以稳定F蛋白在其前融合构象。图1展示了RSV基因组的组织和蛋白质结构。(A) RSV基因组组织；(B) RSV蛋白质结构。近年来，在理解RSV糖蛋白的构型和运作以及它们与宿主细胞因子的相互作用方面取得了显著进展，这些相互作用促进了宿主细胞的进入，从而为阻止RSV提供了新的途径。迄今为止，RSV预防干预策略包括mAbs和六种类型的疫苗，包括基于颗粒的疫苗、基于载体的疫苗、减毒或嵌合疫苗、亚单位疫苗、mRNA疫苗。本文全面概述了目前针对新生儿、婴儿和儿童的RSV疫苗和mAbs的临床研究进展。考虑到母婴免疫的重要性，我们还包括了针对孕妇的RSV疫苗的临床研究。讨论包括各种疫苗的作用机制、应用范围、有效性和可能的不良反应，引用了Clinical Trials.gov和PubMed的数据。本综述旨在为政府政策制定者、学术机构和制药企业提供值得注意的见解和创新视角。 2.材料和方法使用关键词“respiratory syncytial virus” AND “Early Phase 1, Phase 1, Phase 2, Phase 3, and Phase 4”在ClinicalTrials.gov网站的“Additional Criteria”字段中进行搜索，研究开始时间限制在2025年5月20日之前。试验排除标准如下：（1）状态为暂停、终止、撤回或未知，（2）研究条件不是RSV，以及（3）主要目的是治疗、基础科学或其他。共筛选了254项临床试验，根据其状态排除了28项试验，根据其研究条件排除了19项试验，根据其主要目的排除了86项试验。最终，121项临床试验被纳入分析。数据检索过程如图2所示。图2展示了数据检索的过程。收集以下信息进行分析：NCT编号、干预措施、药物、分类、给药方式、状态、赞助者/合作者、性别、年龄、阶段、资金、首次发布日期和地点。描述性分析使用数值和百分比表示分类变量，数据处理和分析使用Microsoft Office Excel 365进行。由于研究仅使用公开数据且不包含个人信息，因此免于伦理委员会审查。 3.结果 3.1.基本特征共纳入121项试验，其基本特征如表1所述。大多数RSV疫苗试验已完成，占67.77%，14.05%的试验正在招募中，17.36%的试验正在进行但未招募。这些试验的详细信息如表2所示。考察的RSV疫苗类型包括47种亚单位疫苗（38.84%）、26种减毒疫苗（21.49%）、23种基于载体的疫苗（19.01%）、19种mAbs疫苗（15.70%）、5种mRNA疫苗（4.13%）和1种基于颗粒的疫苗（0.83%）。大多数试验（85.12%）在两性中进行，13.22%的试验仅在女性中进行。有42项试验仅在儿童中进行（34.71%），74项试验在成人中进行（61.16%），5项试验在儿童和成人中进行（4.13%）。RSV临床研究的概览如图3所示。图3提供了RSV疫苗试验的概览。(A) 从2005年到2023年每年各阶段试验的数量；(B) 各种疫苗类型中各阶段试验的数量。从受试者人群的角度来看，47项试验关注儿童，13项关注孕妇。发现孕妇使用的RSV疫苗是亚单位疫苗和基于颗粒的疫苗，而儿童使用的包括亚单位疫苗、减毒疫苗、基于载体的疫苗、mRNA疫苗和mAbs。图4A、B显示了每种疫苗和mAbs的药物详细信息。 3.2.儿童RSV单克隆抗体 3.2.1.mAbs 单克隆抗体（mAbs）因其对病原体的显著特异性和提供被动免疫反应的能力，成为解决病毒感染的有力替代方案。主要目标是针对RSV前F蛋白上的一个高度中和、敏感的表位。此外，最新一代的RSV抗体经过Fc突变修饰，可以延长其半衰期。有5种针对RSV活性的mAbs，包括帕利珠单抗、莫他珠单抗、尼西瑞单抗、克雷索瑞单抗和TM001。（1）帕利珠单抗。帕利珠单抗（Synagis）是FDA批准的首个用于预防高风险婴儿因细支气管炎住院的人源化mAb。帕利珠单抗在首个RSV季节的五个月里，每月以15 mg/kg的剂量通过肌肉注射给药，以预防儿童严重的RSV LRTI。帕利珠单抗结合RSV融合（F）蛋白上的抗原位点A，这是一个高度保守的区域，能够通过结合病毒表面的RSV融合蛋白阻止膜融合过程，也可以防止感染RSV的细胞之间的融合过程。这种干预仅限于儿科人群中的一小部分，即胎龄低于35周的婴儿和RSV季节开始时年龄在6个月以下的婴儿。这使得每年有数百万婴儿面临严重或潜在致命疾病的风险，没有RSV的保护。目前正在进行两项临床试验，研究帕利珠单抗对两岁以下儿童预防RSV的有效性（NCT01006629/2/3期；NCT01466062/3期）。鉴于新型长效mAbs的出现，有必要进一步实验以验证其对6个月以上儿童的保护效果。 3.2.2.莫他珠单抗莫他珠单抗，也称为MEDI-524或Numax，是通过亲和力成熟技术从帕利珠单抗开发出的第二代mAb。研究发现，它能有效减轻高风险婴儿的RSV疾病负担。这种mAb已经进行了五项临床试验。一项随机、双盲、安慰剂对照试验（NCT00121108/3期）表明，与安慰剂组相比，莫他珠单抗使因RSV住院的婴儿比例相对减少了87%。此外，接受莫他珠单抗治疗的受试者不良事件（AEs）的发生率低于接受安慰剂的受试者，并且没有报告与莫他珠单抗相关的死亡。两组之间严重不良事件（SAEs）或超敏反应事件的发生没有统计学上显著差异。比较单独使用莫他珠单抗与莫他珠单抗和帕利珠单抗联合方案的给药，观察到高风险儿童连续联合方案给药相关的不良事件和抗药物抗体（ADAs）的发生率在两组之间相似。 3.2.3.尼西瑞单抗尼西瑞单抗是一种针对F蛋白的Ø位点设计的人源mAb，其Fc部分具有YTE突变，以延长其血清半衰期，作为单一剂量给药，在整个RSV季节提供全面保护。2022年11月，EMA和欧盟批准了Beyfortus（尼西瑞单抗）在新生儿和婴儿中的使用，以帮助预防他们最初的RSV大流行季节期间的RSV LRTIs。 MEDI8897的平均半衰期在不同剂量队列中为85至117天，随后在给予300毫克肌肉注射剂量后，生物利用度为77%（NCT02114268/1期）。干预组中ADA和AEs的发生率与安慰剂组观察到的相似。随后的2期（NCT02878330）和3期试验（NCT03979313）表明，尼西瑞单抗在治疗药物处理患者中的LRTIs方面的有效性分别为70.1%（95% CI，52.3至81.2）和74.5%（95% CI，49.6至87.1）。此外，尼西瑞单抗在预防早产儿因RSV住院方面的有效性分别发现为78.4%（95% CI，51.9至90.3）和62.1%（95% CI，-8.6至86.8）。两组之间的SAEs相似。此外，尼西瑞单抗在被诊断为先天性心脏病（CHD）或慢性肺病（CLD）的婴儿中的安全性与接受帕利珠单抗治疗的早产儿观察到的相似（NCT03959488/2/3期）。 3.2.4.Clesrovimab (MK-1654) Clesrovimab是一种半衰期延长的单克隆抗体，具有与尼西瑞单抗相同的YTE突变，旨在靶向RSV F蛋白的位点IV，尽管它部分靶向位点V，并且优先结合前F。在日本成人中进行了两项1期临床试验，以测试MK-1654。单次肌肉注射MK-1654使RSV血清中和抗体（SNA）滴度呈剂量依赖性增加。该抗体的半衰期在73至88天之间，估计在300毫克肌肉注射剂量下的生物利用度为69%。MK1654组和安慰剂组之间的安全性事件没有显著差异。Orito等人证明，健康成人中MK-1654的生物利用度分别为100毫克肌肉注射和300毫克肌肉注射的86%和77%。在clinicaltrials.gov中未找到注册号。目前，这种单克隆抗体正在7项婴儿试验中进行测试。 3.3.儿童RSV疫苗 3.3.1.减毒活疫苗（LAVs）由于其鼻内给药、能够诱导局部粘膜和系统反应以及在存在母体抗体时的免疫原性，LAVs是幼儿的有希望的选择，从而使高风险重症婴儿能够免疫。对RSV基因组和反向遗传学的增强理解，促进了通过消除或改变对RNA生物合成控制或阻碍宿主免疫反应有显著影响的蛋白质（如NS2、M2-2、SH、L和G蛋白）的LAV候选物的合理发展，从而限制了病毒复制。LAVs为可能无法从母体疫苗或单克隆抗体获得充分保护的较大婴儿提供了宝贵的无针主动鼻内免疫选择。 3.3.2.RSV DNS2/D1313/I1314L 通过删除NS2基因和L聚合酶蛋白的氨基酸S1313，开发了RSV DNS2/D1313/I1314L。因此，获得了在生理条件下显示温度敏感性的表型稳定变体。在RSV血清阴性的儿童中，给予106个斑块形成单位（PFU）剂量的RSV/DNS2/D1313/I1314L被发现耐受性良好，并且能够诱导免疫反应。在RSV季节之后，观察到接种疫苗的个体与安慰剂接受者相比，RSV滴度显著增加（1:955对比1:69），表明疫苗的有效性（NCT01893554）。RSV/DNS2/D1313/I1314L和RSV/276疫苗接种者（NCT03227029）在接种疫苗后都经历了上呼吸道感染和/或发热，症状通常较轻。值得注意的是，接受RSV/276的受试者咳嗽的发生率显著高于接受RSV/DNS2/D1313/I1314L的受试者（48%对比12%）。未观察到下呼吸道感染和SAEs。两组均在血清RSV中和滴度和抗RSV F IgG滴度方面分别有60%和92%的提升。 3.3.3.MV-012-968 MV-012-968是一种无佐剂的减毒活疫苗。该疫苗对其NS1和NS2蛋白以及G蛋白进行了修改，删除了SH并去除了分泌型G蛋白。目前正在对MV-012-968的安全性和免疫原性进行1期和2期临床试验，但结果尚未公布。 3.3.4.RSV LID DM2-2 RSV LID DM2-2是一种涉及删除RSV M2-2的候选疫苗。LIDDM2-2的减毒导致病毒基因转录和抗原表达增加，RNA复制减少。发现95%接受LIDDM2-2（105 PFU）疫苗的个体脱落疫苗病毒（中位峰值滴度，3.8 log10 PFU/mL；6.3 log10拷贝/mL）（NCT02237209）。此外，90%的疫苗接种者血清中和抗体（SNA）增加了至少四倍。值得注意的是，疫苗和安慰剂组都经历了高比例的呼吸道症状和发热。值得注意的是，一名疫苗接种者在疫苗脱落、鼻病毒和肠病毒的同时，出现了2级喘息。 3.3.5.LID/DM2-2/1030s 通过消除RSV M2-2蛋白并在RSV聚合酶蛋白中引入遗传稳定的温度敏感突变（称为1030s），生产了LID/DM2-2/1030s疫苗。LID/DM2-2/1030s疫苗（105 PFU）显示85%的疫苗脱落和血清中和抗体至少四倍增加。疫苗接种者（60%）和安慰剂接种者（27%）通常报告呼吸道症状和发热。值得注意的是，一名疫苗接种者因鼻病毒而出现2级喘息，但并未同时脱落LID DM2-2/1030s。 3.3.6.D46/NS2/N/DM2-2-HindIII D46/NS2/N/DM2-2-HindIII是一种具有M2-2缺失的重组减毒活疫苗，源自早期候选疫苗LID/DM2-2。所有21名接受D46/NS2/N/DM2-2-HindIII（105 PFUs）（NCT03102034, NCT03099291）的个体均被发现感染了疫苗，其中20人（95%）显示出疫苗脱落。值得注意的是，95%和100%的疫苗接种者分别经历了血清RSV中和抗体和抗RSV融合免疫球蛋白G的至少四倍增加。此外，疫苗接种者（76%）和安慰剂接种者（18%）报告了轻度上呼吸道感染和/或发热。 3.3.7.rA2cp248/404/1030 D SH突变和rA2cp248/104/1030 Delta SH突变这两种疫苗是针对幼儿RSV免疫的初始减毒候选疫苗。两种疫苗在成人和RSV血清阳性儿童中均显示出高度减毒，同时在RSV血清阴性儿童中也表现出良好的耐受性和免疫原性。值得注意的是，rA2cp248/404/1030 Delta SH在RSV血清阴性儿童中的复制受到限制，平均峰值滴度为10（2.5）PFUs/mL，而rA2cp248/404 Delta SH为10（4.3）PFUs/mL。尽管rA2cp248/404/1030 Delta SH在婴儿中耐受性良好，但只有44%接受两个10（5.3）PFU剂量疫苗的接种者显示出明显的抗体反应。 3.3.8.MEDI-559和RSV冷通道/稳定2 MEDI-559是从RSV rA2cp248/404/1030 D SH突变而来，目前正在进行1/2期临床试验（NCT00767416）。RSVcps2是一种新开发的疫苗，通过引入五个核苷酸变化和一个氨基酸变化从MEDI-559修改而来。这种修改导致两个重要衰变突变的稳定，从而防止它们的降解。通过鼻内给药RSVcps2，显著比例的疫苗接种者（85%）获得了RSVcps2感染，其中77%脱落疫苗病毒，59%的RSV SNA滴度增加了至少四倍（NCT01852266, NCT01968083）。疫苗组和安慰剂组之间呼吸道和/或发热疾病的发生率相似。图4展示了儿童和孕妇中试验的RSV疫苗类型和药物。(A) 儿童；(B) 孕妇。 3.4.基于载体的疫苗在重组载体疫苗中，使用基因改造的复制缺陷病毒来传递编码RSV抗原的基因，以引发体液和细胞免疫。目前，有3种疫苗候选物正在进行儿科人群的临床试验，分别是源自黑猩猩腺病毒载体的ChAd155-RSV（GSK3389245A）、Ad26.RSV.preF，以及PIV5载体RSV疫苗（BLB-201）。 3.4.1.ChAd155-RSV 目前正在研究的ChAd155-RSV疫苗是一种基于黑猩猩腺病毒的疫苗，表达三种不同的蛋白，即融合蛋白、核蛋白和M2-1蛋白（55）。在给予GSK3389245A（NCT02927873；1/2期试验）的第一剂后，所有组（0.5 × 1010、1.5 × 1010和5 × 1010病毒颗粒）均显示出RSV-A Nab滴度的剂量依赖性增加，第二剂后未观察到明显的增强效应。一年后，RSV-A Nab滴度仍高于接种前水平。不良事件（AEs）的发生率在所有组中相似，高剂量组发热更为普遍。大多数发热症状轻微。未报告与疫苗相关的SAEs和住院治疗。 3.4.2.Ad26.RSV.preF 编码预融合F（preF）蛋白的腺病毒血清型26 RSV载体（Ad26.RSV.preF），结合RSV preF蛋白。先前的研究已经证明Ad26.RSV.preF在减轻老年人群RSV引起的下呼吸道感染方面的有效性。接受Ad26.RSV.preF的12-24个月龄儿童（NCT03606512；1/2期试验）的RSV A2中和几何平均滴度从121（第0天）显著增加至1608（第29天），并进一步增加至2235（第57天），在7个月以上的时间内保持在较高水平。与接受安慰剂的儿童（5, 41.7%）相比，接受Ad26.RSV.preF的儿童（1, 4.2%）RSV感染的发生率较低。未报告与疫苗接种相关的SAEs。 3.4.3.PIV5载体RSV疫苗（BLB-201）副流感病毒5（PIV5）是一种被用作基于载体的疫苗开发平台的副黏液病毒。已经开发了两种不同的重组PIV5病毒，一种表达融合（F）蛋白，另一种表达附着糖蛋白（G）。目前正在进行1期临床试验，以评估BLB-201疫苗在儿童中的安全性、耐受性和免疫原性（NCT05655182）。 4.其他目前，mRNA疫苗（mRNA-1345, NCT04528719）和亚单位疫苗（NCT02296463）的安全性正在1期临床试验中进行评估。 4.1.孕妇RSV疫苗孕妇免疫被认为是通过转移母体免疫力来保护婴儿免受生命最初阶段多种危险感染的可行方法。这些疫苗类型包括亚单位和基于颗粒的疫苗。RSV preF3、RSV preF和RSV F疫苗是值得注意的例子，它们已经进入3期临床试验，并且根据已发布的数据，显示出良好的安全性、免疫原性和母婴传输率。下面部分将详细介绍这些发现。 4.1.1.RSVPreF3 RSVPreF3是一种无佐剂疫苗。有关RSVPreF3的七项临床研究。在一组健康的非孕妇女中，RSVPreF3（GSK3888550A）（30/60/120 µg）组比安慰剂组（0% ~ 15.9%）显示出更高诱导局部不良事件（AEs）的发生率（4%~53.2%）。然而，大多数上述事件被归类为轻度至中度。此外，RSVPreF3和安慰剂之间的非预期AE报告频率相似，并且没有记录与药物相关的SAEs（NCT03674177, 1期）。Bebia等人建议，RSVPreF3（RSV MAT 009）（60/120 µg）耐受性良好，因为在孕妇及其后代中均未观察到与疫苗相关的AEs。此外，即使在分娩后43天，母亲对RSV的nAbs水平也增加了10倍以上，范围为8.9-10.0倍。新生儿的nAbs水平在出生时达到峰值，逐渐下降，直到产后第181天（NCT04126213/2期）。 4.1.2.RSV稳定预融合F亚单位疫苗在一组孕妇中，随机分配接受双价RSVpreF疫苗（120/240 mg），无论是否含有氢氧化铝，或安慰剂（NCT04032093/2b期）。研究表明，与安慰剂组相比，接种组的50% nAb滴度显著增加。此外，通过胎盘转移的中和抗体比例在1.41和2.10之间。此外，疫苗组中观察到的妇女和婴儿的AEs发生率与安慰剂组相似。RSVpreF在单独或与吸附无细胞百日咳疫苗（Tdap）联合给药时均表现出良好的耐受性和安全性（NCT04071158/2b期）。在妊娠24至36周的孕妇中给予单次肌肉注射RSVpreF疫苗或安慰剂（NCT04424316/3期）。在出生后的前90天内，疫苗在预防由药物治疗引起的严重下呼吸道感染方面的有效率为81.8%（99.5% CI, 40.6至96.3），在预防与呼吸道合胞病毒相关的下呼吸道感染方面的有效率为57.1%（99.5% CI, 14.7至79.8）。此外，在出生后的前180天内，预防严重下呼吸道感染的预防治疗有效率为69.4%（97.58% CI, 44.3至84.1）。在母亲参与者或婴儿和幼儿中未检测到明显的安全信号，直到24个月大。注射或出生1个月内报告的AEs频率在两组之间相似。通过单次肌肉注射在健康非孕妇女中评估GSK3003891A（30/60/120 mg）的免疫原性和安全性（NCT02956837/2期）。结果显示，几何平均滴度（GMT）和PCA浓度以剂量依赖性方式增加。另一项比较分析旨在评估RSV F-020/GSK3003895A（NCT02360475/2期）和RSV F-024/GSK3003891A疫苗（NCT02753413/2期）的安全性和免疫原性。在RSV F-020临床试验中，参与者随机接受单剂量RSV PreF疫苗（30/60 mg无佐剂或60 mg含铝佐剂）或Tdap。在RSV F-024试验（NCT02753413/2期）中，参与者随机分配接受单剂量RSV PreF（60 mg无佐剂）或Tdap。两项研究显示RSV-PreF和Tdap疫苗之间的反应原性概况相似。没有与疫苗注射相关的SAEs。 4.1.3.RSV F疫苗（RSV融合（F）蛋白纳米颗粒）接受RSV F疫苗的孕妇显示出RSV特异性抗体水平的显著提高，表现出与针对多种RSV中和表位的mAbs相当的反应性。（NCT02247726/2期）。通过胎盘传递给免疫女性所生新生儿的抗体转移率在不同检测中发现在90%到120%之间。接受疫苗接种的母亲所生的后代表现出大约40天半衰期的RSV特异性抗体，并且这些新生儿中未检测到严重的RSV疾病。孕妇通过肌肉注射接受了RSV F疫苗，以评估其效果及其为活产婴儿提供保护的潜力。（NCT02624947/3期）。在生命的最初90天内，疫苗对与RSV相关的临床显著下呼吸道感染的有效性为39.4%，对伴有严重低氧血症的与RSV相关的下呼吸道感染的疫苗效力为48.3%。此外，疫苗在预防因与RSV相关的下呼吸道感染而住院方面的有效性被确定为44.4%。观察到疫苗接种的女性中局部注射部位反应的发生频率更高（40.7%对比9.9%）。在这些mAbs和疫苗中，可以在PubMed检索到的效力和安全性数据列在表3中。基于与临床试验阶段相关的属性，合理地优先传播来自大样本量的临床研究结果。例如，Nirsevimab已成功完成3期临床试验，因此只提供了3期效力和安全性数据。 5.展望本文全面回顾了儿童和孕妇RSV疫苗研究的当前进展。本综述的发现为RSV疫苗的未来发展提供了宝贵的见解和新思路。尽管RSV疫苗最近取得了进展，但四个值得注意的问题仍然存在：首先，RSV疫苗的保护效果持续时间，已有报道称像MK1654这样的疫苗可持续长达一年，但需要进一步研究以确定它们的长期效力；其次，尽管已观察到老年人、孕产妇免疫和婴儿单克隆抗体治疗的RSV疫苗取得了成功的结果，但6个月至5岁的儿童仍需要保护；第三，RSV和多种流感病毒流行季节的同时出现导致婴儿经常经历多种病毒感染。同时给予RSV和流感疫苗的效力和安全性需要通过更多数据进一步证实。第四，尽管母婴免疫是保护新生儿的有效方法，但产前疫苗接种对胎儿发育的潜在影响需要进一步审查。

疫苗信使RNA临床研究

100 项与呼吸道合胞病毒疫苗（辉瑞大药厂）相关的药物交易

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研发状态

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适应症	国家/地区	公司	日期
呼吸道合胞病毒肺炎	欧盟	Pfizer Europe MA EEIG	2023-08-23
呼吸道合胞病毒肺炎	冰岛	Pfizer Europe MA EEIG	2023-08-23
呼吸道合胞病毒肺炎	列支敦士登	Pfizer Europe MA EEIG	2023-08-23
呼吸道合胞病毒肺炎	挪威	Pfizer Europe MA EEIG	2023-08-23
呼吸道合胞体病毒感染	美国	Pfizer Inc.	2023-05-31
下呼吸道感染	加拿大	Pfizer Canada ULC	2023-01-04

未上市

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适应症	最高研发状态	国家/地区	公司	日期
流感病毒感染	临床3期	澳大利亚	Pfizer Inc.	2022-04-13
呼吸道感染	临床3期	美国	Pfizer Inc.	2020-06-17
呼吸道感染	临床3期	日本	Pfizer Inc.	2020-06-17
呼吸道感染	临床3期	阿根廷	Pfizer Inc.	2020-06-17
呼吸道感染	临床3期	澳大利亚	Pfizer Inc.	2020-06-17
呼吸道感染	临床3期	巴西	Pfizer Inc.	2020-06-17
呼吸道感染	临床3期	加拿大	Pfizer Inc.	2020-06-17
呼吸道感染	临床3期	智利	Pfizer Inc.	2020-06-17
呼吸道感染	临床3期	丹麦	Pfizer Inc.	2020-06-17
呼吸道感染	临床3期	芬兰	Pfizer Inc.	2020-06-17

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临床结果

适应症

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研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


NCT05842967 (MONeT, PipelineReview) 人工标引	临床3期	呼吸道合胞体病毒感染	203	ABRYSVO	築觸襯窪蓋餘膚築艱醖(淵鹹觸構齋觸遞觸淵繭) = ABRYSVO was well-tolerated during the trial, showing a safety profile consistent with findings from other studies of the vaccine. 積簾鏇廠糧製餘憲廠蓋 (鹽窪獵遞築簾糧壓築餘 ) 更多	积极	2024-08-12
NCT04785612 (CTgov)	临床2期	呼吸道合胞体病毒感染	70	RSVPreF (RSVPreF)	繭壓鹽餘廠構鹹衊繭醖(窪憲願構齋觸簾廠簾範) = 鑰窪繭膚繭糧醖構遞顧憲築鏇鏇醖夢膚艱遞淵 (蓋獵製鹹觸構艱憲獵鏇, 廠廠觸膚構齋顧糧艱壓 ~ 醖觸範獵鏇蓋製淵夢壓) 更多	-	2024-08-07
				Placebo (Placebo)	繭壓鹽餘廠構鹹衊繭醖(窪憲願構齋觸簾廠簾範) = 顧選積蓋襯醖窪餘觸願憲築鏇鏇醖夢膚艱遞淵 (蓋獵製鹹觸構艱憲獵鏇, 繭網蓋襯鑰窪觸壓顧構 ~ 選憲壓簾構鬱獵襯積醖) 更多
NCT05842967 (MONeT, Corporate Publications) 人工标引	临床3期	慢性阻塞性肺疾病 \| 哮喘 \| 糖尿病 ... 更多	-	ABRYSVO	鑰窪餘窪窪觸繭鹹夢襯(衊顧願鏇餘遞鏇鹹繭鹽) = Participants demonstrated RSV-A and RSV-B subgroup neutralizing responses non-inferior to the response seen in the Phase 3 (NCT05035212) RENOIR study of ABRYSVO in more than 34,000 adults aged 60 or older where vaccine efficacy was previously demonstrated. 選蓋廠構壓願觸齋構獵 (膚廠廠壓蓋網餘淵糧範 ) 达到更多	积极	2024-04-09
NCT05035212 (RENOIR, Biospace) 人工标引	临床3期	呼吸道合胞体病毒感染	-	ABRYSVO (three or more symptoms)	構齋願願鹽構醖廠醖顧(窪鏇鹹積鹽積鹽鹹齋壓) = 夢餘膚鑰壓鬱壓蓋鏇積網衊餘醖衊遞簾鹽壓淵 (廠遞膚選壓選觸獵繭範, 51.4 ~ 91.1) 更多	积极	2024-03-29
				ABRYSVO (two or more symptoms)	構齋願願鹽構醖廠醖顧(窪鏇鹹積鹽積鹽鹹齋壓) = 蓋鏇築選衊壓築鹹鏇觸網衊餘醖衊遞簾鹽壓淵 (廠遞膚選壓選觸獵繭範, 34.7 ~ 70.4) 更多
RENOIR (NEWS) 人工标引	N/A	呼吸道合胞体病毒感染	-	Abrysvo (older adults with two or more symptoms of RSV)	醖壓淵遞膚選壓積積夢(鹹鹽廠築製餘艱鹽願簾) = 獵艱淵醖範窪選膚淵襯膚醖齋願襯齋製壓糧顧 (襯鑰齋鏇鬱糧艱鏇獵積 )	积极	2023-11-29
				Abrysvo (older adults with two or more symptoms)	醖壓淵遞膚選壓積積夢(鹹鹽廠築製餘艱鹽願簾) = 繭衊憲憲範醖艱淵繭糧膚醖齋願襯齋製壓糧顧 (襯鑰齋鏇鬱糧艱鏇獵積 )
MATISSE (NEWS) 人工标引	N/A	呼吸道合胞体病毒感染	-	Abrysvo (first 90 days after birth)	網壓觸遞繭憲鑰蓋繭製(壓醖構蓋醖壓簾艱顧餘) = 鬱艱夢襯選糧鹹淵繭窪積鬱獵遞衊鏇簾廠繭築 (鏇構夢構蓋積艱鬱觸網 )	积极	2023-11-29
				Abrysvo (within 180 days)	網壓觸遞繭憲鑰蓋繭製(壓醖構蓋醖壓簾艱顧餘) = 觸窪淵襯鹽鬱衊醖鬱獵積鬱獵遞衊鏇簾廠繭築 (鏇構夢構蓋積艱鬱觸網 )
NCT05301322 (CTgov)	临床3期	呼吸道合胞体病毒感染 \| 流感病毒感染	1,471	SIIV+RSVpreF (RSVpreF + SIIV: Coadministration Group)	齋齋鏇艱鹽網淵醖製淵(餘餘觸夢鏇觸夢網範糧) = 窪餘築醖網獵築鑰構構網夢積糧蓋觸窪壓鏇齋 (範齋廠齋壓齋襯糧窪蓋, 鏇鏇構鑰範遞範簾築鹽 ~ 範糧積觸構簾鬱蓋築鏇) 更多	-	2023-10-27
				Placebo (Placebo: Coadministration Group)	齋齋鏇艱鹽網淵醖製淵(餘餘觸夢鏇觸夢網範糧) = 蓋壓鬱顧餘齋獵糧齋蓋網夢積糧蓋觸窪壓鏇齋 (範齋廠齋壓齋襯糧窪蓋, 艱鬱夢壓願夢鹽廠鹽築 ~ 膚製顧繭衊窪鏇鑰構鹽) 更多
NCT04424316 (FDA) 人工标引	临床3期	呼吸道合胞体病毒感染	7,392	Abrysvo	鹽淵築繭壓選蓋廠醖鬱(觸艱構範網窪鑰鬱蓋窪) = 衊鬱繭淵鹹壓鹽構鏇鏇築衊鹹觸鬱築鏇窪艱醖 (鑰艱餘衊構製憲築築遞, 31.2 ~ 73.5) 更多	积极	2023-08-23
				Placebo	-
NCT05035212 (FDA) 人工标引	临床3期	呼吸道合胞体病毒感染	34,383	ABRYSVO	醖齋壓淵範築網簾膚夢(鏇窪蓋鹽顧簾淵淵網淵) = 範夢鹹窪醖廠網繭鹽積夢鏇壓觸鹽餘顧範衊選 (淵構廠範積製網網壓願 ) 更多	积极	2023-05-31
				Placebo	醖齋壓淵範築網簾膚夢(鏇窪蓋鹽顧簾淵淵網淵) = 選鏇蓋範鬱簾製鬱廠鹽夢鏇壓觸鹽餘顧範衊選 (淵構廠範積製網網壓願 ) 更多
NCT04424316 (MATISSE, Corporate Publications) 人工标引	临床3期	呼吸道合胞体病毒感染	-	RSVpreF	築繭觸膚願網獵製醖繭(繭鹹鬱鏇簾蓋獵淵蓋築) = 範簾構構醖鬱蓋衊繭憲繭醖糧鬱遞艱網衊鹽膚 (衊憲齋鹽鬱鬱願構鑰壓 ) 更多	积极	2022-11-01
				Placebo	-