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Long term T cell response and safety of a tetravalent dengue vaccine in healthy children. 健康儿童对四价登革热疫苗的长期 T 细胞反应和安全性。
IF 6.9 1区 医学 Q1 IMMUNOLOGY Pub Date : 2024-10-17 DOI: 10.1038/s41541-024-00967-0
Sanja Mandaric, Heather Friberg, Xavier Saez-Llorens, Charissa Borja-Tabora, Shibadas Biswal, Ian Escudero, Alice Faccin, Raphael Gottardo, Manja Brose, Nicholas Roubinis, Darlene Fladager, Rodrigo DeAntonio, Julie Anne L Dimero, Nathali Montenegro, Nicolas Folschweiller, Jeffrey R Currier, Mayuri Sharma, Vianney Tricou

As robust cellular responses are important for protection against dengue, this phase 2 study evaluated the kinetics and phenotype of T cell responses induced by TAK-003, a live-attenuated tetravalent dengue vaccine, in 4-16-year-old living in dengue-endemic countries (NCT02948829). Two hundred participants received TAK-003 on Days 1 and 90. Interferon-gamma (IFN-γ) enzyme-linked immunospot assay [ELISPOT] and intracellular cytokine staining were used to analyze T cell response and functionality, using peptide pools representing non-structural (NS) proteins NS3 and NS5 matching DENV-1, -2, -3, and -4 and DENV-2 NS1. One month after the second TAK-003 dose (Day 120), IFN-γ ELISPOT T cell response rates against any peptide pool were 97.1% (95% CI: 93.4% to 99.1%), and similar for baseline dengue seropositive (96.0%) and seronegative (98.6%) participants. IFN-γ ELISPOT T cell response rates at Day 120 were 79.8%, 90.2%, 77.3%, and 74.0%, against DENV-1, -2, -3, and -4, respectively, and remained elevated through 3 years post-vaccination. Multifunctional CD4 and CD8 T cell responses against DENV-2 NS peptides were observed, independent of baseline serostatus: CD8 T cells typically secreted IFN-γ and TNF-α whereas CD4 T cells secreted ≥ 2 of IFN-γ, IL-2 and TNF-α cytokines. NAb titers and seropositivity rates remained substantially elevated through 3 years post-vaccination. Overall, TAK-003 was well tolerated and elicited durable T cell responses against all four DENV serotypes irrespective of baseline serostatus in children and adolescents aged 4-16 years living in dengue-endemic countries. TAK-003-elicited CD4 and CD8 T cells were multifunctional and persisted up to 3 years post-vaccination.

由于强健的细胞应答对于预防登革热非常重要,这项2期研究评估了TAK-003(一种减毒的四价登革热活疫苗)诱导的T细胞应答的动力学和表型,研究对象是生活在登革热流行国家的4-16岁儿童(NCT02948829)。200名参与者在第1天和第90天接种了TAK-003。γ干扰素(IFN-γ)酶联免疫吸附试验[ELISPOT]和细胞内细胞因子染色用于分析T细胞的反应和功能,使用的肽池代表与DENV-1、-2、-3和-4以及DENV-2 NS1相匹配的非结构(NS)蛋白NS3和NS5。在服用第二剂TAK-003一个月后(第120天),针对任何肽池的IFN-γ ELISPOT T细胞应答率为97.1%(95% CI:93.4%至99.1%),登革热血清基线阳性者(96.0%)和血清阴性者(98.6%)的应答率相似。接种第120天时,针对DENV-1、-2、-3和-4的IFN-γ ELISPOT T细胞应答率分别为79.8%、90.2%、77.3%和74.0%,并且在接种后3年中一直保持较高水平。针对DENV-2 NS肽的多功能CD4和CD8 T细胞反应与基线血清状态无关:CD8 T细胞通常分泌IFN-γ和TNF-α,而CD4 T细胞则分泌≥2种IFN-γ、IL-2和TNF-α细胞因子。NAb滴度和血清阳性率在接种后3年仍大幅升高。总体而言,TAK-003在登革热流行国家的4-16岁儿童和青少年中具有良好的耐受性,并能引起针对所有四种登革热病毒血清型的持久T细胞应答,而与基线血清状态无关。TAK-003激发的CD4和CD8 T细胞具有多功能性,在接种后可持续3年。
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引用次数: 0
A novel outer membrane vesicle adjuvant improves vaccine protection against Bordetella pertussis. 一种新型外膜囊泡佐剂可提高百日咳博德特氏菌疫苗的保护效果。
IF 6.9 1区 医学 Q1 IMMUNOLOGY Pub Date : 2024-10-16 DOI: 10.1038/s41541-024-00990-1
Michelle Galeas-Pena, Allyson Hirsch, Erin Kuang, Joseph Hoffmann, Patrick Gellings, Jasmine B Brown, Vanessa M Limbert, Claire L Callahan, James B McLachlan, Lisa A Morici

Pertussis is a vaccine-preventable respiratory disease caused by the Gram negative coccobacillus Bordetella pertussis. The licensed acellular pertussis (aP) vaccines protect against disease but do not prevent bacterial colonization and transmission. Here, we developed and tested an intranasal vaccine composed of aP antigens combined with T-vant, a novel adjuvant derived from bacterial outer membrane vesicles, that elicits both mucosal and systemic immune responses. We hypothesized that immunization of mice with aP-T-vant would enhance mucosal immunity and eliminate B. pertussis in the respiratory tract. In contrast to mice immunized intramuscularly with the licensed aP vaccine, intranasal immunization with aP-T-vant eliminated bacteria in both the lung and nasopharynx. Protection was associated with IFN-gamma and IL-17-producing, non-circulating CD4 + T cells in the lung and nasopharynx, and sterilizing immunity in the nasopharynx was dependent on IL-17. Novel mucosal adjuvants, such as T-vant, warrant further investigation to enhance the efficacy of next generation pertussis vaccines.

百日咳是由革兰氏阴性球菌百日咳杆菌引起的一种可通过疫苗预防的呼吸道疾病。已获许可的无细胞百日咳(aP)疫苗可预防疾病,但不能防止细菌定植和传播。在这里,我们开发并测试了一种由 aP 抗原和 T-vant(一种从细菌外膜囊泡中提取的新型佐剂)组成的鼻内疫苗,它能引起粘膜和全身免疫反应。我们假设用 aP-T-vant 对小鼠进行免疫可增强粘膜免疫并消灭呼吸道中的百日咳杆菌。与肌肉注射 aP 疫苗的小鼠相比,aP-T-vant 的鼻内免疫可消灭肺部和鼻咽部的细菌。保护作用与肺部和鼻咽部产生 IFN-gamma 和 IL-17 的非循环 CD4 + T 细胞有关,鼻咽部的杀菌免疫依赖于 IL-17。新型粘膜佐剂(如 T-vant)值得进一步研究,以提高下一代百日咳疫苗的功效。
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引用次数: 0
A multiantigenic Orf virus-based vaccine efficiently protects hamsters and nonhuman primates against SARS-CoV-2. 基于多抗原 Orf 病毒的疫苗可有效保护仓鼠和非人灵长类动物免受 SARS-CoV-2 的感染。
IF 6.9 1区 医学 Q1 IMMUNOLOGY Pub Date : 2024-10-16 DOI: 10.1038/s41541-024-00981-2
Alena Reguzova, Melanie Müller, Felix Pagallies, Dominique Burri, Ferdinand Salomon, Hanns-Joachim Rziha, Zsofia Bittner-Schrader, Babs E Verstrepen, Kinga P Böszörményi, Ernst J Verschoor, Ingo Gerhauser, Knut Elbers, Meral Esen, Alessandro Manenti, Martina Monti, Hans-Georg Rammensee, Madiha Derouazi, Markus W Löffler, Ralf Amann

Among the common strategies to design next-generation COVID-19 vaccines is broadening the antigenic repertoire thereby aiming to increase efficacy against emerging variants of concern (VoC). This study describes a new Orf virus-based vector (ORFV) platform to design a multiantigenic vaccine targeting SARS-CoV-2 spike and nucleocapsid antigens. Vaccine candidates were engineered, either expressing spike protein (ORFV-S) alone or co-expressing nucleocapsid protein (ORFV-S/N). Mono- and multiantigenic vaccines elicited comparable levels of spike-specific antibodies and virus neutralization in mice. Results from a SARS-CoV-2 challenge model in hamsters suggest cross-protective properties of the multiantigenic vaccine against VoC, indicating improved viral clearance with ORFV-S/N, as compared to equal doses of ORFV-S. In a nonhuman primate challenge model, vaccination with the ORFV-S/N vaccine resulted in long-term protection against SARS-CoV-2 infection. These results demonstrate the potential of the ORFV platform for prophylactic vaccination and represent a preclinical development program supporting first-in-man studies with the multiantigenic ORFV vaccine.

设计下一代 COVID-19 疫苗的常用策略之一是扩大抗原库,从而提高对新出现的相关变异株 (VoC) 的效力。本研究介绍了一种新的基于 Orf 病毒的载体(ORFV)平台,用于设计针对 SARS-CoV-2 穗状抗原和核壳抗原的多抗原疫苗。候选疫苗既可单独表达尖头蛋白(ORFV-S),也可同时表达核壳蛋白(ORFV-S/N)。单抗原疫苗和多抗原疫苗在小鼠体内激发的尖峰特异性抗体和病毒中和水平相当。SARS-CoV-2仓鼠挑战模型的结果表明,多抗原疫苗对VoC具有交叉保护特性,与相同剂量的ORFV-S相比,ORFV-S/N的病毒清除率更高。在非人灵长类动物挑战模型中,接种 ORFV-S/N 疫苗可对 SARS-CoV-2 感染产生长期保护作用。这些结果证明了 ORFV 平台在预防性疫苗接种方面的潜力,并代表了一个支持多抗原 ORFV 疫苗首次人体接种研究的临床前开发计划。
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引用次数: 0
An mRNA vaccine candidate encoding H5HA clade 2.3.4.4b protects mice from clade 2.3.2.1a virus infection. 编码 H5HA 2.3.4.4b 支系的 mRNA 候选疫苗可保护小鼠免受 2.3.2.1a 支系病毒感染。
IF 6.9 1区 医学 Q1 IMMUNOLOGY Pub Date : 2024-10-14 DOI: 10.1038/s41541-024-00988-9
Shiho Chiba, Maki Kiso, Shinya Yamada, Kazuhiko Someya, Yoshikuni Onodera, Aya Yamaguchi, Satoko Matsunaga, Ryuta Uraki, Kiyoko Iwatsuki-Horimoto, Seiya Yamayoshi, Fumihiko Takeshita, Yoshihiro Kawaoka

Highly pathogenic avian influenza (HPAI) H5 viruses from different clades have been circulating globally, threatening wild/domestic birds and mammals. Given frequent spillovers and high mortality among mammals, coupled with our inability to predict which clade of H5 virus has pandemic potential, cross-clade protective HPAI H5 vaccines are urgently needed. Here, we demonstrate the applicability of a lipid nanoparticle-based mRNA vaccine modality to induce cross-protective immunity against lethal HPAI virus infection.

来自不同支系的高致病性禽流感 H5 病毒一直在全球流行,威胁着野生/家养鸟类和哺乳动物。鉴于哺乳动物间的频繁传播和高死亡率,再加上我们无法预测哪个支系的 H5 病毒具有大流行的潜力,因此迫切需要跨支系的高致病性禽流感 H5 保护性疫苗。在这里,我们展示了基于脂质纳米粒子的 mRNA 疫苗模式在诱导对致命性高致病性禽流感病毒感染的交叉保护性免疫方面的适用性。
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引用次数: 0
Aerosol immunization with influenza matrix, nucleoprotein, or both prevents lung disease in pig. 用流感基质、核蛋白或两者进行气溶胶免疫可预防猪肺部疾病。
IF 6.9 1区 医学 Q1 IMMUNOLOGY Pub Date : 2024-10-13 DOI: 10.1038/s41541-024-00989-8
Eleni Vatzia, Basudev Paudyal, Barbara Dema, Brigid Veronica Carr, Ehsan Sedaghat-Rostami, Simon Gubbins, Bhawna Sharma, Elliot Moorhouse, Susan Morris, Marta Ulaszewska, Ronan MacLoughlin, Francisco J Salguero, Sarah C Gilbert, Elma Tchilian

Current influenza vaccines are strain-specific and require frequent updates to combat new strains, making a broadly protective influenza vaccine (BPIV) highly desirable. A promising strategy is to induce T-cell responses against internal proteins conserved across influenza strains. In this study, pH1N1 pre-exposed pigs were immunized by aerosol using viral vectored vaccines (ChAdOx2 and MVA) expressing matrix (M1) and nucleoprotein (NP). Following H3N2 challenge, all immunizations (M1, NP or NPM1) reduced lung pathology, but M1 alone offered the greatest protection. NP or NPM1 immunization induced both T-cell and antibody responses. M1 immunization generated no detectable antibodies but elicited M1-specific T-cell responses, suggesting T cell-mediated protection. Additionally, a single aerosol immunization with the ChAdOx vaccine encoding M1, NP and neuraminidase reduced lung pathology. These findings provide insights into BPIV development using a relevant large natural host, the pig.

目前的流感疫苗都是针对特定菌株的,需要经常更新以对付新菌株,因此一种具有广泛保护作用的流感疫苗(BPIV)就变得非常理想。一种很有前景的策略是诱导针对不同流感病毒株之间共有的内部蛋白的 T 细胞反应。在这项研究中,使用表达基质(M1)和核蛋白(NP)的病毒载体疫苗(ChAdOx2 和 MVA)对预先暴露于 pH1N1 的猪进行气溶胶免疫。在接受 H3N2 病毒挑战后,所有免疫接种(M1、NP 或 NPM1)均可减少肺部病变,但单用 M1 可提供最大的保护。NP或NPM1免疫可诱导T细胞和抗体反应。免疫 M1 不会产生可检测到的抗体,但会引起 M1 特异性 T 细胞反应,这表明 T 细胞介导的保护作用。此外,用编码 M1、NP 和神经氨酸酶的 ChAdOx 疫苗进行单次气溶胶免疫可减少肺部病变。这些发现为利用猪这一相关的大型天然宿主开发 BPIV 提供了新的视角。
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引用次数: 0
Recombinant RSV G protein vaccine induces enhanced respiratory disease via IL-13 and mucin overproduction. 重组 RSV G 蛋白疫苗通过 IL-13 和粘蛋白过量产生诱发呼吸道疾病。
IF 6.9 1区 医学 Q1 IMMUNOLOGY Pub Date : 2024-10-12 DOI: 10.1038/s41541-024-00987-w
Eigo Kawahara, Kota Senpuku, Yoshino Kawaguchi, Shinya Yamamoto, Koubun Yasuda, Etsushi Kuroda, Noriko Ouji-Sageshima, Toshihiro Ito, Toshiro Hirai, Takehiko Shibata, Yasuo Yoshioka

The G protein expressed on the surface of respiratory syncytial virus (RSV) is important for adhesion to host cells and as a vaccine target antigen. The corresponding vaccines can effectively eliminate RSV. However, they exacerbate pulmonary immunopathology including eosinophilic infiltration in the lungs after an RSV challenge in animal models, raising concerns about enhanced respiratory disease (ERD); thus, approaches that mitigate these effects are urgently needed. Herein, we aimed to examine the mechanisms of G protein vaccine-induced ERD in mice, using recombinant G protein as a vaccine antigen. After the RSV challenge, G protein-vaccinated mice exhibited lung weight gain, lung tissue damage, and increased infiltration of eosinophils, neutrophils, and CD4+ T cells into the lungs. We set lung weight gain as the endpoint for ERD and examined the impact of each infiltrating cell on lung weight gain. We observed that CD4+ T cells, but not eosinophils or neutrophils, that infiltrate the lungs are responsible for lung weight gain. In addition, T helper 2 cell-mediated IL-13 induced mucin hypersecretion and lung weight gain. Mucin hypersecretion may contribute to weight gain in the lungs. In conclusion, our results indicate a novel mechanism of G protein vaccine-induced ERD via IL-13 and mucin hypersecretion, which could lead to the development of safe G protein vaccines and the elucidation of the causes of ERD associated with other vaccines.

呼吸道合胞病毒(RSV)表面表达的 G 蛋白对于粘附宿主细胞和作为疫苗靶抗原非常重要。相应的疫苗可以有效消灭 RSV。然而,在动物模型中,它们会加剧肺部免疫病理学,包括 RSV 挑战后肺部的嗜酸性粒细胞浸润,引起人们对呼吸道疾病(ERD)增强的担忧;因此,迫切需要减轻这些影响的方法。在此,我们以重组 G 蛋白作为疫苗抗原,旨在研究 G 蛋白疫苗诱导小鼠 ERD 的机制。在 RSV 挑战后,接种 G 蛋白疫苗的小鼠表现出肺重量增加、肺组织损伤以及肺内嗜酸性粒细胞、中性粒细胞和 CD4+ T 细胞浸润增加。我们将肺重量增加作为 ERD 的终点,并研究了每种浸润细胞对肺重量增加的影响。我们观察到,浸润肺部的 CD4+ T 细胞(而非嗜酸性粒细胞或中性粒细胞)是肺重量增加的原因。此外,T辅助细胞2介导的IL-13诱导粘蛋白分泌过多和肺增重。粘蛋白分泌过多可能会导致肺部增重。总之,我们的研究结果表明了G蛋白疫苗通过IL-13和粘蛋白高分泌诱导ERD的新机制,这将有助于开发安全的G蛋白疫苗,并阐明与其他疫苗相关的ERD的原因。
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引用次数: 0
Filovirus vaccines as a response paradigm for emerging infectious diseases. 丝状病毒疫苗作为应对新发传染病的范例。
IF 6.9 1区 医学 Q1 IMMUNOLOGY Pub Date : 2024-10-11 DOI: 10.1038/s41541-024-00985-y
Andrea Marzi, Heinz Feldmann

Nowadays, filovirus vaccine development may be seen as a paradigm for our response capabilities to emerging and re-emerging infectious diseases. Specifically, the West African Ebola virus disease (EVD) epidemic accelerated countermeasure licensure for several vaccine and therapeutic products. Those products have been successfully used to control EVD outbreaks in Central Africa over the past years. This positive development, however, has not yet reached beyond EVD. Therefore, it is pertinent to increase our efforts in the development of countermeasures for other human pathogenic members of the family Filoviridae as they continue to threaten public health in Sub-Saharan Africa. This review article summarizes the current filovirus vaccines in preclinical macaque studies and human clinical trials and discusses the most promising recent advancements.

如今,丝状病毒疫苗的开发可被视为我们应对新发和再发传染病能力的典范。具体来说,西非埃博拉病毒病(EVD)疫情加速了几种疫苗和治疗产品的对策许可。在过去几年中,这些产品已成功用于控制埃博拉病毒病在中非的爆发。然而,这一积极进展尚未超出 EVD 的范围。因此,由于丝状病毒科的其他人类致病成员继续威胁着撒哈拉以南非洲地区的公共健康,我们有必要加大力度开发针对它们的对策。这篇综述文章总结了目前在临床前猕猴研究和人体临床试验中使用的丝状病毒疫苗,并讨论了最有希望的最新进展。
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引用次数: 0
Vaccine responses and hybrid immunity in people living with HIV after SARS-CoV-2 breakthrough infections. SARS-CoV-2 突发性感染后艾滋病病毒感染者的疫苗反应和混合免疫。
IF 6.9 1区 医学 Q1 IMMUNOLOGY Pub Date : 2024-10-09 DOI: 10.1038/s41541-024-00972-3
Amin Alirezaylavasani, Linda Gail Skeie, Ingrid Marie Egner, Adity Chopra, Tuva Børresdatter Dahl, Christian Prebensen, John Torgils Vaage, Bente Halvorsen, Fridtjof Lund-Johansen, Kristian Tonby, Dag Henrik Reikvam, Birgitte Stiksrud, Jan Cato Holter, Anne Ma Dyrhol-Riise, Ludvig A Munthe, Hassen Kared

The COVID-19 pandemic posed a challenge for people living with HIV (PLWH), particularly immune non-responders (INR) with compromised CD4 T-cell reconstitution following antiretroviral therapy (CD4 count <350 cells per mm3). Their diminished vaccine responses raised concerns about their vulnerability to SARS-CoV-2 breakthrough infections (BTI). Our in-depth study here revealed chronic inflammation in PLWH and a limited anti-Spike IgG response after vaccination in INR. Nevertheless, the imprinting of Spike-specific B cells by vaccination significantly enhanced the humoral responses after BTI. Notably, the magnitude of cellular CD4 response in all PLWH was comparable to that in healthy donors (HD). However, the polyfunctionality and phenotype of Spike-specific CD8 T cells in INR differed from controls. The findings highlight the need for additional boosters with variant vaccines, and for monitoring ART adherence and the durability of both humoral and cellular anti-SARS-CoV-2 immunity in INR.

COVID-19 大流行给艾滋病病毒感染者(PLWH)带来了挑战,尤其是抗逆转录病毒治疗后 CD4 T 细胞重建受损(CD4 细胞数为 3)的免疫无反应者(INR)。他们对疫苗反应的减弱引起了人们对他们容易感染 SARS-CoV-2 突发性感染 (BTI) 的担忧。我们在此进行的深入研究显示,PLWH 存在慢性炎症,而 INR 接种疫苗后的抗 Spike IgG 反应有限。然而,接种疫苗后,斯派克特异性 B 细胞的印记显著增强了 BTI 后的体液反应。值得注意的是,所有 PLWH 的细胞 CD4 反应程度与健康供体(HD)相当。但是,INR 中尖峰特异性 CD8 T 细胞的多功能性和表型与对照组不同。研究结果突出表明,有必要使用变异疫苗进行额外的强化治疗,并监测抗逆转录病毒疗法的依从性以及 INR 中体液和细胞抗 SARS-CoV-2 免疫的持久性。
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引用次数: 0
Potent neutralization of SARS-CoV-2 variants by RBD nanoparticle and prefusion-stabilized spike immunogens. RBD 纳米粒子和预灌注稳定尖峰免疫原对 SARS-CoV-2 变体的强效中和作用。
IF 6.9 1区 医学 Q1 IMMUNOLOGY Pub Date : 2024-10-08 DOI: 10.1038/s41541-024-00982-1
Marcos C Miranda, Elizabeth Kepl, Mary Jane Navarro, Chengbo Chen, Max Johnson, Kaitlin R Sprouse, Cameron Stewart, Anne Palser, Adian Valdez, Deleah Pettie, Claire Sydeman, Cassandra Ogohara, John C Kraft, Minh Pham, Michael Murphy, Sam Wrenn, Brooke Fiala, Rashmi Ravichandran, Daniel Ellis, Lauren Carter, Davide Corti, Paul Kellam, Kelly Lee, Alexandra C Walls, David Veesler, Neil P King

We previously described a two-component protein nanoparticle vaccine platform that displays 60 copies of the SARS-CoV-2 spike protein RBD (RBD-NP). The vaccine, when adjuvanted with AS03, was shown to elicit robust neutralizing antibody and CD4 T cell responses in Phase I/II clinical trials, met its primary co-endpoints in a Phase III trial, and has been licensed by multiple regulatory authorities under the brand name SKYCovioneTM. Here we characterize the biophysical properties, stability, antigenicity, and immunogenicity of RBD-NP immunogens incorporating mutations from the B.1.351 (β) and P.1 (γ) variants of concern (VOCs) that emerged in 2020. We also show that the RBD-NP platform can be adapted to the Omicron strains BA.5 and XBB.1.5. We compare β and γ variant and E484K point mutant nanoparticle immunogens to the nanoparticle displaying the Wu-1 RBD, as well as to soluble prefusion-stabilized (HexaPro) spike trimers harboring VOC-derived mutations. We find the properties of immunogens based on different SARS-CoV-2 variants can differ substantially, which could affect the viability of variant vaccine development. Introducing stabilizing mutations in the linoleic acid binding site of the RBD-NPs resulted in increased physical stability compared to versions lacking the stabilizing mutations without deleteriously affecting immunogenicity. The RBD-NP immunogens and HexaPro trimers, as well as combinations of VOC-based immunogens, elicited comparable levels of neutralizing antibodies against distinct VOCs. Our results demonstrate that RBD-NP-based vaccines can elicit neutralizing antibody responses against SARS-CoV-2 variants and can be rapidly designed and stabilized, demonstrating the potential of two-component RBD-NPs as a platform for the development of broadly protective coronavirus vaccines.

我们以前曾描述过一种双组分蛋白纳米粒子疫苗平台,它能显示 60 个拷贝的 SARS-CoV-2 尖峰蛋白 RBD(RBD-NP)。该疫苗在添加 AS03 佐剂后,在 I/II 期临床试验中被证明能引起强大的中和抗体和 CD4 T 细胞应答,在 III 期试验中达到了主要共同终点,并以 SKYCovioneTM 品牌获得了多个监管机构的许可。在这里,我们描述了含有 2020 年出现的 B.1.351 (β) 和 P.1 (γ) 变异的 RBD-NP 免疫原的生物物理特性、稳定性、抗原性和免疫原性。我们还表明,RBD-NP 平台可适用于 Omicron 菌株 BA.5 和 XBB.1.5。我们将β和γ变体及E484K点突变纳米粒子免疫原与显示Wu-1 RBD的纳米粒子进行了比较,同时还将其与携带VOC衍生突变的可溶性预融合稳定(HexaPro)尖峰三聚体进行了比较。我们发现基于不同SARS-CoV-2变体的免疫原的特性会有很大不同,这可能会影响变体疫苗开发的可行性。在 RBD-NPs 的亚油酸结合位点引入稳定突变,与缺乏稳定突变的 RBD-NPs 相比,物理稳定性得到了提高,但不会对免疫原性产生有害影响。RBD-NP 免疫原和 HexaPro 三聚体以及基于挥发性有机化合物的免疫原组合能激发出针对不同挥发性有机化合物的相当水平的中和抗体。我们的研究结果表明,基于 RBD-NP 的疫苗可以引起针对 SARS-CoV-2 变体的中和抗体反应,并且可以快速设计和稳定,这证明了双组分 RBD-NP 作为开发广泛保护性冠状病毒疫苗平台的潜力。
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引用次数: 0
Preclinical immunogenicity and safety of hemagglutinin-encoding modRNA influenza vaccines. 血凝素编码 modRNA 流感疫苗的临床前免疫原性和安全性。
IF 6.9 1区 医学 Q1 IMMUNOLOGY Pub Date : 2024-10-07 DOI: 10.1038/s41541-024-00980-3
Teresa Hauguel, Amy Sharma, Emily Mastrocola, Susan Lowry, Mohan S Maddur, Cheng Hui Hu, Swati Rajput, Allison Vitsky, Shambhunath Choudhary, Balasubramanian Manickam, Ivna De Souza, Yana Chervona, Raquel Munoz Moreno, Charisse Abdon, Larissa Falcao, Kristin Tompkins, Deanne Illenberger, Rachel Smith, Fanyu Meng, Shuai Shi, Kari Sweeney Efferen, Victoria Markiewicz, Cinthia Umemoto, Jianfang Hu, Wei Chen, Ingrid Scully, Cynthia M Rohde, Annaliesa S Anderson, Pirada Suphaphiphat Allen

Seasonal epidemics of influenza viruses are responsible for a significant global public health burden. Vaccination remains the most effective way to prevent infection; however, due to the persistence of antigenic drift, vaccines must be updated annually. The selection of vaccine strains occurs months in advance of the influenza season to allow adequate time for production in eggs. RNA vaccines offer the potential to accelerate production and improve efficacy of influenza vaccines. We leveraged the nucleoside-modified RNA (modRNA) platform technology and lipid nanoparticle formulation process of the COVID-19 mRNA vaccine (BNT162b2; Comirnaty®) to create modRNA vaccines encoding hemagglutinin (HA) (modRNA-HA) for seasonal human influenza strains and evaluated their preclinical immunogenicity and toxicity. In mice, a monovalent modRNA vaccine encoding an H1 HA demonstrated robust antibody responses, HA-specific Th1-type CD4+ T cell responses, and HA-specific CD8+ T cell responses. In rhesus and cynomolgus macaques, the vaccine exhibited durable functional antibody responses and HA-specific IFN-γ+ CD4+ T cell responses. Immunization of mice with monovalent, trivalent, and quadrivalent modRNA-HA vaccines generated functional antibody responses targeting the seasonal influenza virus(es) encoded in the vaccines that were greater than, or similar to, those of a licensed quadrivalent influenza vaccine. Monovalent and quadrivalent modRNA-HA vaccines were well-tolerated by Wistar Han rats, with no evidence of systemic toxicity. These nonclinical immunogenicity and safety data support further evaluation of the modRNA-HA vaccines in clinical studies.

流感病毒的季节性流行给全球公共卫生造成了巨大负担。接种疫苗仍然是预防感染的最有效方法;然而,由于抗原漂移的持续存在,疫苗必须每年更新。疫苗菌株的选择要在流感季节到来前几个月进行,以便有足够的时间在鸡蛋中生产。RNA 疫苗有可能加速流感疫苗的生产并提高其效力。我们利用 COVID-19 mRNA 疫苗 (BNT162b2; Comirnaty®)的核苷修饰 RNA (modRNA) 平台技术和脂质纳米颗粒配方工艺,为季节性人类流感病毒株开发了编码血凝素 (HA) 的 modRNA 疫苗(modRNA-HA),并对其临床前免疫原性和毒性进行了评估。在小鼠体内,编码 H1 HA 的单价 modRNA 疫苗表现出强大的抗体反应、HA 特异性 Th1 型 CD4+ T 细胞反应和 HA 特异性 CD8+ T 细胞反应。在恒河猴和猕猴中,疫苗表现出持久的功能性抗体反应和 HA 特异性 IFN-γ+ CD4+ T 细胞反应。用单价、三价和四价 modRNA-HA 疫苗对小鼠进行免疫,可产生针对疫苗中编码的季节性流感病毒的功能性抗体反应,这种反应高于或类似于获得许可的四价流感疫苗。Wistar Han 大鼠对单价和四价 modRNA-HA 疫苗的耐受性良好,无全身毒性证据。这些非临床免疫原性和安全性数据支持在临床研究中进一步评估 modRNA-HA 疫苗。
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NPJ Vaccines
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