作者: Rosenberg, Aaron ; Kumar, Shaji K. ; Chung, David J. ; Martin, Thomas ; Nooka, Ajay K. ; Torres, Kathleen ; Weiss, Brendan M. ; Richard, Shambavi ; Vij, Ravi ; Pederson, Levi ; Derkach, Andriy ; Geyer, Susan ; Chari, Ajai ; Wood, William A. ; Schroeder, Mark A. ; D’Souza, Anita ; Zonder, Jeffrey ; James, Shandra ; Semmel, Emily A. ; Usmani, Saad Z. ; Anderson, Kenneth C. ; Neuberg, Donna S. ; Rubinstein, Samuel

Abstract:

Patients with multiple myeloma have an elevated risk of severe complications from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2; COVID-19) infection. To demonstrate proof of concept for a pandemic preparedness and response network, the American Society of Hematology Research Collaborative Multiple Myeloma Program developed a prospective, decentralized study within a site-based provider network. In the COVID-19 outcomes in myeloma and the impact of vaccines (COSMIC) study, patients provided consent, permitted electronic health record data collection, completed patient-reported outcomes at baseline, day 30, and day 180 through an electronic study portal, and were compensated for participation. Clinicians at participating sites facilitated study recruitment and shared best practices monthly to accelerate study execution. The COSMIC study rapidly consented 201 patients from 8 participating sites over 4 months (22 January 2024 through 17 May 2024). Consented participants were 30 to 93 years old, with a median age of 67; 46% were female, 69% were non-Hispanic White, 17% were non-Hispanic Black, and 8% were Hispanic/Latino. Patient-reported data completion was 97% at baseline, 81% at 1 month, and 79% at 6 months. At baseline, 55% of patients reported a history of COVID-19 infection and had received a median of 4 SARS-CoV-2 vaccines. For all patients, there were an additional 18 COVID-19 infections and 57 vaccines received during the 6-month observation period. There were no significant differences in health-related quality of life over time or by history of COVID-19 infection. COSMIC demonstrates the feasibility of an innovative evidence generation strategy to drive rapid accrual of patients to address an evolving area of need. This trial was registered at www.clinicaltrials.gov as #NCT05831787.

2026-01-06·Microbiology Spectrum

Development of an RT-qPCR and a Next-Generation Sequencing approach to assess viral shedding of NDV-based SARS-CoV-2 variant vaccines

Article

作者: Lemus, Nicholas ; Slamanig, Stefan ; Abdeljawad, Adam ; Sun, Weina ; Shea, William ; González-Domínguez, Irene ; Boza, Marta ; Palese, Peter ; Lai, Tsoi Ying

ABSTRACT:

Live-attenuated intranasal vaccines offer great promise to generate mucosal immunity and reduce breakthrough infections after vaccination. Previously, we have developed a Newcastle disease virus (NDV)-based vaccine expressing the spike (S) protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), named NDV-HXP-S. This vaccine can be administered intranasally as a live-attenuated vector to provide both systemic and mucosal immunity. With the appearance of new SARS-CoV-2 variants of concern, new NDV-HXP-S variant-based vaccines have been developed. These new NDV-HXP-S variant vaccines can be combined in a multivalent formulation to extend their protection against other SARS-CoV-2 variants of concern. One of the main concerns when administering a live-attenuated vector intranasally is the possible vaccine shedding after vaccination. In the present work, we have developed a reverse transcriptase-quantitative polymerase chain reaction (RT-qPCR) method to evaluate NDV-HXP-S in vitro and in vivo along with an amplicon-based next-generation sequencing technique to quantify the relative percentage of each variant vaccine in the multivalent formulation. Both techniques were validated following the recommendations of the Food and Drug Administration and the European Medicines Agency. Finally, we applied both methods in in vitro cell culture experiments. The quantification of the NDV-based vaccines by RT-qPCR and the relative percentage of each variant vaccine were confirmed using a prototype trivalent formulation expressing the Ancestral (Wuhan), Beta, and Delta SARS-CoV-2 spikes. The present results will help the study of virus shedding in future clinical trials.

IMPORTANCE:

Live-attenuated intranasal vaccines offer great promise to generate mucosal immunity and reduce breakthrough infections after vaccination. In this work, we have developed a combined reverse transcriptase-quantitative polymerase chain reaction and next-generation sequencing-directed approach to assess the viral shedding of multivalent Newcastle disease virus-based severe acute respiratory syndrome coronavirus 2 vaccines. This new formulation will be evaluated as a mucosal booster in phase I clinical trials next year.

2025-10-23·JOURNAL OF VIROLOGY

Adjuvant-dependent protection of SARS-CoV-2 spike vaccines: comparative immunogenicity of human-applicable formulations

Article

作者: Liu, Yangang ; Qi, Zhongtian ; Chen, Yingying ; Xu, Jianqing ; Pan, Zhendong ; Wang, Ying ; Zhang, Xiaoyan ; Peng, Haoran ; Jiang, Liangliang ; Zhao, Ping ; Ding, Cuiling ; Zheng, Xu ; Liu, Yan ; He, Yanhua

ABSTRACT:

Although recombinant vaccines with various adjuvant systems are widely deployed in global coronavirus disease 2019 immunization, their distinct immune profiles have not been fully elucidated. In this study, we evaluated immune responses induced by four clinically validated adjuvants—aluminum hydroxide (Al), two water-in-oil emulsions (Montanide ISA720 and ISA51), and an oil-in-water emulsion (Sepivac SWE)—formulated with the prefusion-stabilized ancestral severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike trimer (S-2P) in mouse models. Both S-2P:ISA720 and S-2P:ISA51 elicited potent humoral immunity, including cross-neutralizing antibodies against Omicron variants, along with robust interferon gamma-producing T-cell responses in the spleen and lung. Immunization with S-2P:ISA720 conferred complete protection against lethal challenge with the ancestral virus as well as Omicron subvariants BA.5 and BF.7. In contrast, S-2P:Al and S-2P:SWE elicited substantially weaker antibody responses, undetectable T-cell immunity, and markedly reduced protective efficacy. Prime-boost immunization with S-2P:ISA720 induced sustained peak antibody titers against both homologous SARS-CoV-2 and the Omicron BA.2 subvariant, affording complete protection for up to 17 weeks post-vaccination. While a third dose of S-2P:Al following a prime-boost regimen triggered a robust increase in antibody levels, titers declined rapidly thereafter, recapitulating the decay kinetics observed after the second dose. Both ISA720 and Al formulations exhibited age-dependent declines in antibody responses and protective efficacy. Notably, aged mice displayed markedly attenuated neuroinflammatory responses following SARS-CoV-2 challenge and significantly compromised protection after adoptive transfer of immune serum. These results underscore adjuvant-specific determinants of broad and durable immunity and reveal novel age-related constraints in vaccine-induced protection against SARS-CoV-2.

IMPORTANCE:

Persistent viral evolution, rapid waning of vaccine-induced immunity, and the heightened vulnerability of elderly populations remain major challenges for COVID-19 vaccination strategies. In this study, we systematically assessed immune responses elicited by the ancestral spike protein formulated with four distinct adjuvants in mouse models. We demonstrate that an optimized adjuvant formulation markedly enhances the magnitude and breadth of antibody responses, potentiates T-cell immunity, and rapidly induces sustained peak antibody titers against both homologous virus and Omicron variants. Vaccine-induced antibody responses were significantly attenuated in aged mice, and furthermore, both the protective efficacy of antibodies and inflammatory cytokine responses upon viral challenge were impaired in aged animals. These results provide compelling evidence that rational adjuvant selection is critical for enabling recombinant vaccines to achieve rapid-onset, broad, and durable immune protection. Furthermore, our study offers new mechanistic insights into the reduced vaccine efficacy observed in the elderly.

项与新型冠状病毒多肽疫苗 (成大生物) 相关的新闻（医药）

2023-12-12

·生物谷

Nature子刊 | 清华大学程功/喻国灿/向烨与合作者发现人源中和单抗mRNA的肺部靶向递送可预防并治疗新冠病毒感染

2023年12月5日，清华大学医学院程功团队、化学系喻国灿团队、医学院向烨团队联合深圳湾实验室及长春兽医研究所团队在Nature Communications（自然.通讯) 期刊发表题为A lung-selective delivery of mRNA encoding broadly neutralizing antibody against SARS-CoV-2 infection（肺部靶向递送广谱中和抗体抵御新冠感染）的研究性论文。该研究制备了用于递送编码SARS-CoV-2广谱中和抗体的mRNA肺靶向脂质纳米颗粒（LNPs），在肺部原位产生高滴度的抗体，在预防和治疗SARS-CoV-2突变株感染方面取得了显著效果。COVID-19大流行已导致全球数百万人感染和死亡，呼吸系统，尤其是肺部感染是介导重症和死亡的关键因素之一，肺部保护性抗体水平与COVID-19的预防和感染具有显著影响。本项研究中，研究人员从临床患者中鉴定出一株人源单克隆抗体8-9D，可以高效阻断新冠病毒受体结合区RBD与细胞受体ACE2结合，对多数SARS-CoV-2流行突变株，包括Omicron BA.3、BA.4和BA.5等均显示广谱中和活性。鉴于静脉给药将抗体针对性地送入肺部的效率低，以及通过雾化免疫方式递送的抗体在肺部的半衰期短等问题，该研究在系统评估了8-9D中和抗体的效力基础上，通过肺靶向LNP新型递送系统将编码8-9D的mRNA精准递送至肺部，mRNA在肺部产生高滴度的中和抗体，从而有效阻断新冠病毒感染，利用hACE2转基因鼠开展的攻毒保护实验显示，可有效预防或治疗新冠病毒重要流行突变株的感染。图1：高效人源中和单抗mRNA的肺靶向递送可有效预防并治疗新冠病毒感染该研究强调了肺部靶向性mRNA递送技术在由SARS-CoV-2突变株引起的感染中的潜在预防和治疗作用，缩短了目前SARS-CoV-2疫苗接种后的免疫缺陷期。研究结果显示，在给药后第二天提供快速而强效的抗病毒保护，且在给药后两小时内即可监测到抗体。该研究的策略经济有效，为其他呼吸系统传染病的防控提供了一个可行的参考方案。清华大学医学院程功教授、化学系喻国灿助理教授、医学院向烨副教授、长春兽医研究所田明尧副研究员为本论文共同通讯作者。深圳湾实验室传染病研究所太万博博士、清华大学化学系杨凯博士、清华大学医学院刘玉斌博士、博士生李若凡、冯胜勇博士、柴本杰博士及长春兽医研究所庄忻雨博士为并列第一作者。该研究获科技部国家重点研发计划、国家自然科学基金基础科学中心、国家自然科学基金委杰出青年基金、重点项目、面上项目和青年项目资助、云南省专家工作站、佛山-清华产学研合作协同创新专项(佛山创新专项)、万科基金、深圳市三名工程，新基石研究员项目及科学探索奖资助。原文链接：https://doi.org/10.1038/s41467-023-43798-8本文仅用于学术分享，转载请注明出处。若有侵权，请联系微信：bioonSir 删除或修改！

信使RNA疫苗

2022-07-02

·生物制品圈

清华大学祁海/张林琦系统总结和展望新冠病毒感染的体液和抗体反应及通用型疫苗研发

2022年6月27日，清华大学医学院祁海教授和张林琦教授受邀在 Nature Immunology 期刊发表了题为：The humoral response and antibodies against SARS-CoV-2 infection（新型冠状病毒感染的体液免疫应答和抗体）的综述论文。该综述全面系统总结了新型冠状病毒感染者的体液免疫过程，以及病毒感染或疫苗诱导机体产生的中和抗体的关键特征，并展望了诱导新冠变异株广谱中和抗体的疫苗设计策略。2019年底以来，新型冠状病毒（SARS-CoV-2）在世界各地广泛传播，造成了新型冠状病毒肺炎（COVID-19）大流行。据世界卫生组织报道，截止6月26日全世界 SARS-CoV-2 感染数字超过5.4亿人次，超过600万人死于 COVID-19。从疫情暴发初期，为高效遏制新冠病毒的广泛传播，科学家们对 SARS-CoV-2 的致病机理及机体的抵御机制进行了大量研究。不仅对先天性免疫和获得性免疫过程有了更清晰的认识，也为治疗 COVID-19 和开发疫苗提供了潜在的靶点和策略。其中，诱导产生保护性抗体阻断病毒感染、复制和传播，既是机体抵御 SARS-CoV-2 的关键机制，也是疫苗发挥功能的重要方式。该综述对 SARS-CoV-2 感染和疫苗接种后机体的体液免疫（humoral response）过程及产生的中和抗体（antibody）特征进行了全面的分析和总结。大量研究表明，与其它呼吸道冠状病毒引起的体液免疫应答相似，机体感染 SARS-CoV-2 后1周左右，在血清中开始出现特异性识别 SARS-CoV-2 的 IgM、IgA 和 IgG 等多种类型的抗体反应，并展示一定程度的中和能力；3～4周后，抗 SARS-CoV-2 的中和抗体量达到峰值；之后 IgG 抗体水平在峰值维持几个月，而 IgM 和 IgA 水平逐渐下降。如图1所示，抗原特异性B细胞被激活后，一部分在滤泡区外（extrafollicular, EF）分化成为短寿命浆细胞（short-lived plasma cell），快速分泌具一定中和能力的抗体，抑制 SARS-CoV-2 在体内扩散；另一部分则回到滤泡区分化成为生发中心（germinal center）B细胞，经过筛选和克隆增殖后最终分化成为长寿命浆细胞（long-lived plasma cells）。这些长寿命浆细胞多数定居在骨髓中，能够分泌具有较强中和能力的抗体，并维持适当的水平，协助机体有效控制 SARS-CoV-2 的复制。虽然这两个过程均会产生记忆B细胞（memory B cell），但生发中心反应来源的记忆B细胞存活时间更长，并且表达的B细胞受体（B cell receptor，BCR）结合和中和病毒能力更强，与长寿命浆细胞一起建立体液免疫记忆，有效抵御 SARS-CoV-2 的再次感染。除血清外，IgA 型中和抗体还会分布在包括鼻黏膜等病毒侵入途经的呼吸道黏膜组织中，对抵御再次感染或减轻感染症状有重要意义。此外，尽管 SARS-CoV-2 和其它人源冠状病毒序列相似度不高，但感染产生的抗体仍会发生相互的交叉反应（cross-reactivity），一定程度上识别并中和 SARS-CoV-2，抵御感染。图1. 针对SARS-CoV-2感染的B细胞和抗体免疫应答随后，文章进一步总结了识别 SARS-CoV-2 表面刺突蛋白（spike glycoprotein，S蛋白）抗体的中和能力和广谱能力。包被在病毒表面的 S 蛋白是中和抗体的主要识别位点。如图2，S 蛋白有 S1 和 S2 两个功能区，S1 由 N 端结构域（N-amino-terminal domain，NTD）和受体结合域（Receptor-Binding Domain，RBD）等四种结构域构成，与宿主细胞受体 ACE2 结合；而 S2 则介导病毒和细胞膜的融合，完成病毒遗传物质向胞内释放。中和抗体主要通过竞争性结合 RBD 来抑制 SARS-CoV-2 的感染和扩散。目前流行的 SARS-CoV-2 变异株的大部分突变都集中在包含 RBD 和 NTD 的 S1 功能区，增强了新冠病毒对抗体药物和疫苗的逃逸能力。能够结合 RBD 的中和抗体主要分为7类（RBD-1～RBD-7），主要识别顶部面（top face）、外表面（outer face）和内表面（inner face）。其中识别顶部面的主要是RBD-1～RBD-3。这三类中和抗体的结合位点高度重合，但各自有特定的结合方式，保证了高特异性和强结合力。但正是由于高强度识别和结合，导致多种变异株的出现，从而逃逸这几类抗体的中和作用。RBD-4 和 RBD-5 两类主要识别 RBD 的外表面，也是目前最广谱、结合能力最强的中和抗体。但它们也存在和 RBD-1～3 一样的问题，即变异发生在 S 蛋白与抗体结合的表位区域时，直接导致活性降低和病毒逃避。RBD-6 和 RBD-7 两类主要是结合 RBD 内表面的抗体，通常情况下在 RBD 是向上构象时才能结合其内部的表位，中和能力相对较弱。而奥密克戎（Omicron）变异株 BA.1 和 BA.2 在这两类抗体结合的位点都发生了突变，导致大部分 RBD-6 和 RBD-7 丢失中和能力。除了识别 RBD 的中和抗体之外，结合 NTD 的抗体也具有一定的中和能力。根据结合的位置不同，NTD 抗体大概分为三类，即 NTD-1、NTD-2 和 NTD-3，其中 NTD-1 类抗体结合在 NTD 的顶部（top side），NTD-2 类抗体结合在 NTD 的前侧（front side），NTD-3 类抗体则结合在靠近 RBD 的左侧（left side）。与 RBD 抗体比较， NTD 抗体中和能力较弱，大多数识别病毒蛋白三维空间构象，在突变株的 NTD 区域，有大量的氨基酸缺失和插入，以及众多的点突变，其中大部分都可以逃逸 NTD 抗体的识别和中和。图2. SARS-CoV-2 S蛋白中和抗体特征综合目前对于 SARS-CoV-2 抗体反应的认识，祁海教授和张林琦教授指出，目前大多数 SARS-CoV-2 的疫苗设计开发仅是针对原始毒株，但病毒不断的变异，导致目前疫苗策略对新发变异株的保护能力显著降低，亟需能够诱导广谱中和抗体的通用型疫苗的研发和上市。一方面，补打加强针能够在一定程度上增强和维持机体的抗突变株的广谱中和能力，尤其是序贯异源疫苗接种，能够显著地提高机体内中和抗体的中和能力和广谱能力。另一方面，来自不同变异株的多种抗原集合研究，开发通用型 SARS-CoV-2 疫苗更能够有助于广谱中和抗体的产生和维持，为构建更强、更广谱和更持久的免疫屏障提供新的策略和思路。清华大学医学院祁海教授和张林琦教授是本文的共同通讯作者，清华大学医学院博士后刘波和生命科学学院王新泉教授做出了重要贡献。相关研究受到了科技部、卫健委、国家自然科学基金委、清华—北大生命科学联合中心、北京市科学技术委员会、北京生物结构前沿研究中心、腾讯基金会和清华大学春风基金等机构的资助支持。论文链接：https://www.nature.com/articles/s41590-022-01248-5识别微信二维码，添加生物制品圈小编，符合条件者即可加入微信群！请注明：姓名+研究方向！版权声明本公众号所有转载文章系出于传递更多信息之目的，且明确注明来源和作者，不希望被转载的媒体或个人可与我们联系(cbplib@163.com)，我们将立即进行删除处理。所有文章仅代表作者观点，不代表本站立场。

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100 项与新型冠状病毒多肽疫苗 (成大生物) 相关的药物交易

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