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Author Correction: Development of an anti-tauopathy mucosal vaccine specifically targeting pathologic conformers. 作者更正:开发专门针对病理构象的抗牛头癣粘膜疫苗。
IF 6.9 1区 医学 Q1 IMMUNOLOGY Pub Date : 2024-06-28 DOI: 10.1038/s41541-024-00910-3
Wenzhi Tan, Jayalakshmi Thiruppathi, Seol Hee Hong, Sao Puth, Sophea Pheng, Bo-Ram Mun, Won-Seok Choi, Kyung-Hwa Lee, Hyun-Sun Park, Duc Tien Nguyen, Min-Cheol Lee, Kwangjoon Jeong, Jin Hai Zheng, Young Kim, Shee Eun Lee, Joon Haeng Rhee
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引用次数: 0
A safe and potentiated multi-type HPV L2-E7 nanoparticle vaccine with combined prophylactic and therapeutic activity. 具有预防和治疗双重活性的安全增效多型人乳头瘤病毒 L2-E7 纳米粒子疫苗。
IF 6.9 1区 医学 Q1 IMMUNOLOGY Pub Date : 2024-06-26 DOI: 10.1038/s41541-024-00914-z
Xueer Zhao, Yueru Zhang, Oscar Trejo-Cerro, Ecem Kaplan, Zhe Li, Femke Albertsboer, Neyla El Hammiri, Filipe Colaço Mariz, Lawrence Banks, Simone Ottonello, Martin Müller

Persistent infection with high-risk human papillomavirus (HPV) is widely recognized as the primary cause of cervical and other malignant cancers. There are six licensed prophylactic vaccines available against HPV, but none of them shows any significant therapeutic effect on pre-existing infections or lesions. Thus, a prophylactic vaccine also endowed with therapeutic activity would afford protection regardless of the vaccine recipients HPV-infection status. Here, we describe the refinement and further potentiation of a dual-purpose HPV nanoparticle vaccine (hereafter referred to as cPANHPVAX) relying on eight different HPV L2 peptide epitopes and on the E7 oncoantigens from HPV16 and 18. cPANHPVAX not only induces anti-HPV16 E7 cytotoxic T-cell responses in C57BL/6 mice, but also anti-HPV18 E7 T-cell responses in transgenic mice with the A2.DR1 haplotype. These cytotoxic responses add up to a potent, broad-coverage humoral (HPV-neutralizing) response. cPANHPVAX safety was further improved by deletion of the pRb-binding domains of E7. Our dual-purpose vaccine holds great potential for clinical translation as an immune-treatment capable of targeting active infections as well as established HPV-related malignancies, thus benefiting both uninfected and infected individuals.

高危人乳头瘤病毒(HPV)的持续感染被公认为是宫颈癌和其他恶性癌症的主要病因。目前有六种获得许可的 HPV 预防性疫苗,但没有一种对已有的感染或病变有明显的治疗效果。因此,如果预防性疫苗也具有治疗活性,那么无论疫苗接种者是否感染人乳头瘤病毒,都能起到保护作用。在此,我们介绍了一种两用型 HPV 纳米颗粒疫苗(以下简称 cPANHPVAX)的改进和进一步增效,该疫苗依赖于 8 种不同的 HPV L2 肽表位以及 HPV16 和 18 的 E7 肿瘤抗原。cPANHPVAX 不仅能诱导 C57BL/6 小鼠产生抗 HPV16 E7 细胞毒性 T 细胞反应,还能诱导 A2.DR1 单倍型转基因小鼠产生抗 HPV18 E7 T 细胞反应。通过删除 E7 的 pRb 结合域,cPANHPVAX 的安全性得到了进一步提高。我们的两用疫苗具有巨大的临床应用潜力,它是一种免疫疗法,既能针对活动性感染,也能针对已确诊的人乳头瘤病毒相关恶性肿瘤,从而使未感染者和已感染者都能受益。
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引用次数: 0
The direct effect of SARS-CoV-2 virus vaccination on human ovarian granulosa cells explains menstrual irregularities. 接种 SARS-CoV-2 病毒疫苗对人类卵巢颗粒细胞的直接影响解释了月经不调的原因。
IF 6.9 1区 医学 Q1 IMMUNOLOGY Pub Date : 2024-06-26 DOI: 10.1038/s41541-024-00911-2
Hadas Bar-Joseph, Yael Raz, Anat Eldar-Boock, Nadav Michaan, Yoel Angel, Esther Saiag, Luba Nemerovsky, Ido Ben-Ami, Ruth Shalgi, Dan Grisaru

Following administration of the SARS-CoV-2 vaccine, many women worldwide reported short-term menstrual irregularities. Although menstrual bleeding, "the fifth vital sign", is experienced by more than 300 million people on any given day worldwide, these changes were only partially studied. Irregular periods are important well beyond fertility and the discomfort they impose; they are associated with the risk of cardiovascular morbidity, chronic diseases, and premature mortality. Pre-clinical examination of the vaccine polymeric envelope indicates its accumulation in the ovaries. The somatic endocrine cells of the ovarian follicle - the granulosa cells (GCs)-participate in the strict hypothalamic-pituitary-ovarian (HPO) feedback loop that governs the menstrual cycle via endocrine and paracrine regulators, as AMH and Inhibins. We aimed to unravel the direct effect of the COVID-19 vaccine on GCs and link their post-vaccine activity to changes in menstrual patterns. Human primary GCs exposed in-vitro to the Pfizer COVID-19 vaccine BNT162b2, demonstrated no change in their viability but altered mRNA transcripts, specifically of the regulatory key factors: InhibinB was upregulated, whereas AMH was downregulated. We further examined pre- and post-vaccination blood samples from individual women and found a 2-3 folds change in the post-vaccination FSH/InhibinB protein level ratio, compared to their pre-vaccination values. This altered expression of InhibinB could significantly impact the HPO axis in vaccinated women and may ultimately influence the endometrium cyclicity, manifested clinically by the commonly reported changes in menstrual bleeding patterns.

接种 SARS-CoV-2 疫苗后,全球许多妇女都报告了短期的月经不调。虽然全世界每天有 3 亿多人经历 "第五生命体征"--月经出血,但对这些变化的研究还很有限。月经不调的重要意义远不止生育和带来的不适,它还与心血管疾病、慢性疾病和过早死亡的风险有关。对疫苗聚合包膜的临床前检查显示,它在卵巢中积聚。卵巢滤泡的体细胞内分泌细胞--颗粒细胞(GCs)--参与了严格的下丘脑-垂体-卵巢(HPO)反馈环路,该环路通过内分泌和旁分泌调节因子(如 AMH 和抑制素)控制月经周期。我们的目的是揭示 COVID-19 疫苗对 GC 的直接影响,并将其疫苗后活性与月经模式的变化联系起来。体外暴露于辉瑞 COVID-19 疫苗 BNT162b2 的人类原发性 GCs 的存活率没有变化,但 mRNA 转录本发生了变化,特别是调控关键因子:抑制素 B 上调,而 AMH 下调。我们进一步检查了个别妇女接种疫苗前后的血液样本,发现接种疫苗后的 FSH/InhibinB 蛋白水平比值与接种疫苗前相比变化了 2-3 倍。抑制素B表达的这种变化可能会对接种疫苗妇女的HPO轴产生重大影响,并可能最终影响子宫内膜的周期性,临床表现为通常报告的月经出血模式的变化。
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引用次数: 0
Systemic prime mucosal boost significantly increases protective efficacy of bivalent RSV influenza viral vectored vaccine. 全身原发性粘膜增强可显著提高二价 RSV 流感病毒载体疫苗的保护效力。
IF 6.9 1区 医学 Q1 IMMUNOLOGY Pub Date : 2024-06-26 DOI: 10.1038/s41541-024-00912-1
Cameron Bissett, Sandra Belij-Rammerstorfer, Marta Ulaszewska, Holly Smith, Reshma Kailath, Susan Morris, Claire Powers, Sarah Sebastian, Hannah R Sharpe, Elizabeth R Allen, Ziyin Wang, Robert F Cunliffe, Hadijatou J Sallah, Alexandra J Spencer, Sarah Gilbert, John S Tregoning, Teresa Lambe

Although licensed vaccines against influenza virus have been successful in reducing pathogen-mediated disease, they have been less effective at preventing viral infection of the airways and current seasonal updates to influenza vaccines do not always successfully accommodate viral drift. Most licensed influenza and recently licensed RSV vaccines are administered via the intramuscular route. Alternative immunisation strategies, such as intranasal vaccinations, and "prime-pull" regimens, may deliver a more sterilising form of protection against respiratory viruses. A bivalent ChAdOx1-based vaccine (ChAdOx1-NP + M1-RSVF) encoding conserved nucleoprotein and matrix 1 proteins from influenza A virus and a modified pre-fusion stabilised RSV A F protein, was designed, developed and tested in preclinical animal models. The aim was to induce broad, cross-protective tissue-resident T cells against heterotypic influenza viruses and neutralising antibodies against RSV in the respiratory mucosa and systemically. When administered via an intramuscular prime-intranasal boost (IM-IN) regimen in mice, superior protection was generated against challenge with either RSV A, Influenza A H3N2 or H1N1. These results support further clinical development of a pan influenza & RSV vaccine administered in a prime-pull regimen.

尽管流感病毒特许疫苗在减少病原体介导的疾病方面取得了成功,但它们在预防呼吸道病毒感染方面的效果较差,而且目前流感疫苗的季节性更新并不总是能成功地适应病毒漂移。大多数获得许可的流感疫苗和最近获得许可的 RSV 疫苗都是通过肌肉注射途径接种的。替代性免疫策略,如鼻内接种和 "原位牵引 "疗法,可提供更有效的呼吸道病毒灭菌保护。我们设计、开发并在临床前动物模型中测试了一种基于 ChAdOx1 的双价疫苗(ChAdOx1-NP + M1-RSVF),该疫苗编码了甲型流感病毒的保守核蛋白和基质 1 蛋白以及改良的预融合稳定 RSV A F 蛋白。其目的是在呼吸道粘膜和全身诱导针对异型流感病毒的广泛、交叉保护性组织驻留 T 细胞和针对 RSV 的中和抗体。通过肌肉注射原体-鼻内增强(IM-IN)方案给小鼠注射后,小鼠在面对甲型 RSV、甲型 H3N2 流感或 H1N1 流感挑战时都能获得超强的保护。这些结果为进一步临床开发以原浆-注射方案接种的流感和 RSV 泛型疫苗提供了支持。
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引用次数: 0
A gH/gL-encoding replicon vaccine elicits neutralizing antibodies that protect humanized mice against EBV challenge. gH/gL 编码的复制子疫苗可激发中和抗体,保护人源化小鼠免受 EBV 病毒挑战。
IF 6.9 1区 医学 Q1 IMMUNOLOGY Pub Date : 2024-06-26 DOI: 10.1038/s41541-024-00907-y
Kristina R Edwards, Harman Malhi, Karina Schmidt, Amelia R Davis, Leah J Homad, Nikole L Warner, Crystal B Chhan, Samuel C Scharffenberger, Karen Gaffney, Troy Hinkley, Nicole B Potchen, Jing Yang Wang, Jason Price, M Juliana McElrath, James Olson, Neil P King, Jennifer M Lund, Zoe Moodie, Jesse H Erasmus, Andrew T McGuire

Epstein-Barr virus (EBV) is associated with several malignancies, neurodegenerative disorders and is the causative agent of infectious mononucleosis. A vaccine that prevents EBV-driven morbidity and mortality remains an unmet need. EBV is orally transmitted, infecting both B cells and epithelial cells. Several virally encoded proteins are involved in entry. The gH/gL glycoprotein complex is essential for infectivity irrespective of cell type, while gp42 is essential for infection of B cells. gp350 promotes viral attachment by binding to CD21 or CD35 and is the most abundant glycoprotein on the virion. gH/gL, gp42 and gp350, are known targets of neutralizing antibodies and therefore relevant immunogens for vaccine development. Here, we developed and optimized the delivery of several alphavirus-derived replicon RNA (repRNA) vaccine candidates encoding gH/gL, gH/gL/gp42 or gp350 delivered by a cationic nanocarrier termed LION™. The lead candidate, encoding full-length gH/gL, elicited high titers of neutralizing antibodies that persisted for at least 8 months and a vaccine-specific CD8+ T cell response. Transfer of vaccine-elicited IgG protected humanized mice from EBV-driven tumor formation and death following high-dose viral challenge. These data demonstrate that LION/repRNA-gH/gL is an ideal candidate vaccine for preventing EBV infection and/or related malignancies in humans.

爱泼斯坦-巴氏病毒(EBV)与多种恶性肿瘤和神经退行性疾病有关,也是传染性单核细胞增多症的病原体。目前,预防 EBV 导致的发病率和死亡率的疫苗仍是一个尚未满足的需求。EB 病毒经口传播,可感染 B 细胞和上皮细胞。有几种病毒编码蛋白参与了病毒的进入。gH/gL、gp42和gp350是已知的中和抗体靶标,因此是开发疫苗的相关免疫原。在这里,我们开发并优化了几种源于α病毒的复制子 RNA(repRNA)候选疫苗的递送,这些候选疫苗编码 gH/gL、gH/gL/gp42 或 gp350,由称为 LION™ 的阳离子纳米载体递送。编码全长 gH/gL 的主要候选疫苗可产生高滴度的中和抗体,这种抗体可持续至少 8 个月,并产生疫苗特异性 CD8+ T 细胞应答。疫苗诱导的 IgG 可保护人源化小鼠免受 EBV 驱动的肿瘤形成和高剂量病毒挑战后的死亡。这些数据表明,LION/repRNA-gH/gL 是预防人类 EBV 感染和/或相关恶性肿瘤的理想候选疫苗。
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引用次数: 0
A replication-deficient gammaherpesvirus vaccine protects mice from lytic disease and reduces latency establishment. 复制缺陷型γ疱疹病毒疫苗可保护小鼠免于感染裂解病并减少潜伏期的建立。
IF 6.9 1区 医学 Q1 IMMUNOLOGY Pub Date : 2024-06-24 DOI: 10.1038/s41541-024-00908-x
Wesley A Bland, Dipanwita Mitra, Shana Owens, Kyle McEvoy, Chad H Hogan, Luciarita Boccuzzi, Varvara Kirillov, Thomas J Meyer, Camille Khairallah, Brian S Sheridan, J Craig Forrest, Laurie T Krug

Gammaherpesviruses are oncogenic viruses that establish lifelong infections and are significant causes of morbidity and mortality. Vaccine strategies to limit gammaherpesvirus infection and disease are in development, but there are no FDA-approved vaccines for Epstein-Barr or Kaposi sarcoma herpesvirus. As a new approach to gammaherpesvirus vaccination, we developed and tested a replication-deficient virus (RDV) platform, using murine gammaherpesvirus 68 (MHV68), a well-established mouse model for gammaherpesvirus pathogenesis studies and preclinical therapeutic evaluations. We employed codon-shuffling-based complementation to generate revertant-free RDV lacking expression of the essential replication and transactivator protein encoded by ORF50 to arrest viral gene expression early after de novo infection. Inoculation with RDV-50.stop exposes the host to intact virion particles and leads to limited lytic gene expression in infected cells yet does not produce additional infectious particles. Prime-boost vaccination of mice with RDV-50.stop elicited virus-specific neutralizing antibody and effector T cell responses in the lung and spleen. In contrast to vaccination with heat-inactivated WT MHV68, vaccination with RDV-50.stop resulted in a near complete abolishment of virus replication in the lung 7 days post-challenge and reduction of latency establishment in the spleen 16 days post-challenge with WT MHV68. Ifnar1-/- mice, which lack the type I interferon receptor, exhibit severe disease and high mortality upon infection with WT MHV68. RDV-50.stop vaccination of Ifnar1-/- mice prevented wasting and mortality upon challenge with WT MHV68. These results demonstrate that prime-boost vaccination with a gammaherpesvirus that is unable to undergo lytic replication offers protection against acute replication, impairs the establishment of latency, and prevents severe disease upon the WT virus challenge. Our study also reveals that the ability of a gammaherpesvirus to persist in vivo despite potent pre-existing immunity is an obstacle to obtaining sterilizing immunity.

γ疱疹病毒是致癌病毒,可造成终生感染,是发病和死亡的重要原因。限制γ疱疹病毒感染和疾病的疫苗策略正在开发中,但目前还没有针对 Epstein-Barr 或 Kaposi 肉瘤疱疹病毒的疫苗获得美国食品及药物管理局的批准。作为γ疱疹病毒疫苗接种的一种新方法,我们开发并测试了一种复制缺陷病毒(RDV)平台,该平台使用了小鼠γ疱疹病毒 68 (MHV68),这是一种用于γ疱疹病毒发病机制研究和临床前治疗评估的成熟小鼠模型。我们采用了基于密码子洗码的互补技术,生成了无逆转录病毒的 RDV,这种 RDV 缺乏 ORF50 编码的重要复制和转录激活蛋白的表达,从而在新生感染后早期抑制病毒基因的表达。接种 RDV-50.stop 会使宿主接触到完整的病毒颗粒,并导致感染细胞中有限的溶解基因表达,但不会产生额外的传染性颗粒。小鼠接种 RDV-50.stop 后,肺部和脾脏会产生病毒特异性中和抗体和效应 T 细胞反应。与接种热灭活的 WT MHV68 不同的是,接种 RDV-50.stop 会导致小鼠在接种 WT MHV68 后 7 天内肺部的病毒复制几乎完全消失,并在接种 WT MHV68 后 16 天内降低脾脏的潜伏期。缺乏 I 型干扰素受体的 Ifnar1-/- 小鼠在感染 WT MHV68 后会表现出严重的疾病和很高的死亡率。给 Ifnar1-/- 小鼠接种 RDV-50.stop 疫苗可防止小鼠在感染 WT MHV68 后消瘦和死亡。这些结果表明,接种一种无法进行溶解复制的γ疱疹病毒的原代强化疫苗可防止急性复制,影响潜伏期的建立,并防止在受到 WT 病毒挑战时发生严重疾病。我们的研究还揭示了,γ疱疹病毒在已有强大免疫力的情况下仍能在体内持续存在,这是获得绝育免疫力的一个障碍。
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引用次数: 0
T cell independent antibody responses with class switch and memory using peptides anchored on liposomes. 利用锚定在脂质体上的多肽实现具有类别转换和记忆功能的独立于 T 细胞的抗体反应。
IF 6.9 1区 医学 Q1 IMMUNOLOGY Pub Date : 2024-06-22 DOI: 10.1038/s41541-024-00902-3
Ásdís Hjálmsdóttir, Fabio Hasler, Ying Waeckerle-Men, Agathe Duda, María Pilar López-Deber, Maria Pihlgren, Marija Vukicevic, Thomas M Kündig, Pål Johansen

Vaccines generally require T lymphocytes for B-cell activation and immunoglobulin class switching in response to peptide or protein antigens. In the absence of T cells, limited IgG class switch takes place, germinal centers are short-lived, and the B cells lack memory. Here, immunization of mice with liposomes containing 15mer peptides and monophosphoryl lipid A (MPLA) as adjuvant, induced T-cell independent (TI) IgG class switch within three days, as well as germinal center formation. The antibody responses were long-lived, strictly dependent on Toll-like receptor 4 (TLR4) signaling, partly dependent on Bruton's tyrosine kinase (BTK) signal transmission, and independent of signaling through T-cell receptors, MHC class II and inflammasome. The antibody response showed characteristics of both TI type 1 and TI type 2. All IgG subclasses could be boosted months after primary immunization, and the biological function of the secreted antibodies was demonstrated in murine models of allergic anaphylaxis and of bacterial infection. Moreover, antibody responses after immunization with peptide- and MPLA-loaded liposomes could be triggered in neonatal mice and in mice receiving immune-suppressants. This study demonstrates T-cell independent endogenous B-cell memory and recall responses in vivo using a peptide antigen. The stimulation of these antibody responses required a correct and dense assembly and administration of peptide and adjuvant on the surface of liposomes. In the future, TI vaccines may prove beneficial in pathological conditions in which T-cell immunity is compromised through disease or medicines or when rapid, antibody-mediated immune protection is needed.

疫苗通常需要 T 淋巴细胞来激活 B 细胞,并对肽或蛋白质抗原进行免疫球蛋白类转换。在缺乏 T 细胞的情况下,IgG 类的转换有限,生殖中心寿命短,B 细胞缺乏记忆。在这里,用含有15mer肽的脂质体和单磷脂A(MPLA)作为佐剂对小鼠进行免疫,可在三天内诱导出独立于T细胞(TI)的IgG类别转换以及生殖中心的形成。抗体反应持续时间长,严格依赖于Toll样受体4(TLR4)信号传导,部分依赖于布鲁顿酪氨酸激酶(BTK)信号传导,与T细胞受体、MHC II类和炎症小体的信号传导无关。抗体反应显示出 TI 1 型和 TI 2 型的特征。所有 IgG 亚类都能在初次免疫数月后得到增强,分泌抗体的生物功能在过敏性过敏性休克和细菌感染的小鼠模型中得到了证实。此外,新生小鼠和接受免疫抑制药物的小鼠在免疫多肽和载 MPLA 脂质体后也能触发抗体反应。这项研究利用多肽抗原证明了体内独立于 T 细胞的内源性 B 细胞记忆和回忆反应。这些抗体反应的激发需要在脂质体表面正确、密集地组装和施用多肽和佐剂。未来,TI 疫苗可能会在因疾病或药物导致 T 细胞免疫受损的病理情况下,或在需要快速抗体介导的免疫保护时发挥作用。
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引用次数: 0
Calcifediol boosts efficacy of ChAdOx1 nCoV-19 vaccine by upregulating genes promoting memory T cell responses. 骨化二醇通过上调促进记忆性 T 细胞反应的基因来提高 ChAdOx1 nCoV-19 疫苗的疗效。
IF 6.9 1区 医学 Q1 IMMUNOLOGY Pub Date : 2024-06-20 DOI: 10.1038/s41541-024-00909-w
Himanshu Singh Saroha, Swati Bhat, Liza Das, Pinaki Dutta, Michael F Holick, Naresh Sachdeva, Raman Kumar Marwaha

The ChAdOx1 nCoV-19 (COVISHIELD) vaccine has emerged as a pivotal tool in the global fight against the COVID-19 pandemic. In our previous study eligible subjects were supplemented with calcifediol, a direct precursor to the biologically active form of vitamin D, calcitriol with an objective to enhance the immunogenicity of the COVISHIELD vaccine. Herein we investigated the effects of calcifediol supplementation on gene expression profiles in individuals who received the COVISHIELD vaccine. Peripheral blood mononuclear cells were isolated from vaccinated individuals with and without calcifediol supplementation at baseline, 3rd and 6th month, and the gene expression profiles were analyzed using high-throughput sequencing. The results revealed distinct patterns of gene expression associated with calcifediol supplementation, suggesting potential molecular mechanisms underlying the beneficial effects of calcifediol in improving the efficacy of COVISHIELD vaccine via augmentation of T cell activation, proliferation and T cell memory responses. Additionally, there was upregulation of NOD like receptor, JAK/STAT and TGF beta signaling pathways. Calcifediol supplementation in vaccinated individuals also downregulated the pathways related to the Coronavirus disease. Taken together, our findings provide valuable insights into the interplay between vitamin D receptor (VDR) signaling and vaccine-induced immune responses and offer another approach in improving vaccination induced antiviral responses.

ChAdOx1 nCoV-19(COVISHIELD)疫苗已成为全球抗击 COVID-19 大流行的关键工具。在我们之前的研究中,我们为符合条件的受试者补充了降钙素二醇(一种具有生物活性的维生素 D 的直接前体--降钙三醇),目的是增强 COVISHIELD 疫苗的免疫原性。在此,我们研究了补充降钙二醇对接种 COVISHIELD 疫苗的个体基因表达谱的影响。在基线期、第 3 个月和第 6 个月,从补充和未补充降钙素的疫苗接种者中分离外周血单核细胞,并使用高通量测序技术分析其基因表达谱。结果发现了与补充降钙素相关的不同基因表达模式,提示了降钙素通过增强 T 细胞活化、增殖和 T 细胞记忆反应提高 COVISHIELD 疫苗疗效的潜在分子机制。此外,NOD 类受体、JAK/STAT 和 TGF beta 信号通路也出现了上调。在接种疫苗的个体中补充骨化二醇也会下调与冠状病毒疾病相关的通路。综上所述,我们的研究结果为维生素 D 受体(VDR)信号传导与疫苗诱导的免疫反应之间的相互作用提供了宝贵的见解,并为改善疫苗诱导的抗病毒反应提供了另一种方法。
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引用次数: 0
Analyzing atomic force microscopy images of virus-like particles by expectation-maximization. 通过期望最大化分析类病毒粒子的原子力显微镜图像。
IF 6.9 1区 医学 Q1 IMMUNOLOGY Pub Date : 2024-06-20 DOI: 10.1038/s41541-024-00871-7
Rachel A McCormick, Nicole M Ralbovsky, William Gilbraith, Joseph P Smith, Karl S Booksh

Analysis of virus-like particles (VLPs) is an essential task in optimizing their implementation as vaccine antigens for virus-initiated diseases. Interrogating VLP collections for elasticity by probing with a rigid atomic force microscopy (AFM) tip is a potential method for determining VLP morphological changes. During VLP morphological change, it is not expected that all VLPs would be in the same state. This leads to the open question of whether VLPs may change in a continuous or stepwise fashion. For continuous change, the statistical distribution of observed VLP properties would be expected as a single distribution, while stepwise change would lead to a multimodal distribution of properties. This study presents the application of a Gaussian mixture model (GMM), fit by the Expectation-Maximization (EM) algorithm, to identify different states of VLP morphological change observed by AFM imaging.

分析病毒样颗粒(VLPs)是优化其作为疫苗抗原用于治疗病毒引发疾病的一项重要任务。用刚性原子力显微镜(AFM)针尖探测 VLP 的弹性是确定 VLP 形态变化的一种潜在方法。在 VLP 形态变化过程中,并非所有 VLP 都会处于相同状态。这就引出了一个悬而未决的问题,即 VLP 是以连续还是逐步的方式发生变化。对于连续变化,所观察到的 VLP 特性的统计分布预计将是单一分布,而逐步变化将导致特性的多模式分布。本研究介绍了高斯混合模型(GMM)的应用,该模型通过期望最大化(EM)算法拟合,以识别 AFM 成像观察到的 VLP 形态变化的不同状态。
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引用次数: 0
Distinct dynamics of mRNA LNPs in mice and nonhuman primates revealed by in vivo imaging. 体内成像技术揭示了小鼠和非人灵长类体内 mRNA LNPs 的不同动态。
IF 6.9 1区 医学 Q1 IMMUNOLOGY Pub Date : 2024-06-20 DOI: 10.1038/s41541-024-00900-5
Katia Lemdani, Romain Marlin, Céline Mayet, Vladimir Perkov, Quentin Pascal, Manon Ripoll, Francis Relouzat, Nina Dhooge, Laetitia Bossevot, Nathalie Dereuddre-Bosquet, Gihad Dargazanli, Kevin Thibaut-Duprey, Jean Haensler, Catherine Chapon, Christine Prost, Roger Le Grand

The characterization of vaccine distribution to relevant tissues after in vivo administration is critical to understanding their mechanisms of action. Vaccines based on mRNA lipid nanoparticles (LNPs) are now being widely considered against infectious diseases and cancer. Here, we used in vivo imaging approaches to compare the trafficking of two LNP formulations encapsulating mRNA following intramuscular administration: DLin-MC3-DMA (MC3) and the recently developed DOG-IM4. The mRNA formulated in DOG-IM4 LNPs persisted at the injection site, whereas mRNA formulated in MC3 LNPs rapidly migrated to the draining lymph nodes. Furthermore, MC3 LNPs induced the fastest increase in blood neutrophil counts after injection and greater inflammation, as shown by IL-1RA, IL-15, CCL-1, and IL-6 concentrations in nonhuman primate sera. These observations highlight the influence of the nature of the LNP on mRNA vaccine distribution and early immune responses.

体内给药后疫苗在相关组织分布的特征对于了解其作用机制至关重要。目前,基于 mRNA 脂质纳米颗粒(LNPs)的疫苗正被广泛用于防治传染病和癌症。在这里,我们使用体内成像方法比较了两种包裹 mRNA 的 LNP 制剂在肌肉注射后的运输情况:DLin-MC3-DMA(MC3)和最近开发的 DOG-IM4。在 DOG-IM4 LNPs 中配制的 mRNA 在注射部位持续存在,而在 MC3 LNPs 中配制的 mRNA 则迅速迁移到引流淋巴结。此外,从非人灵长类血清中的 IL-1RA、IL-15、CCL-1 和 IL-6 浓度来看,MC3 LNPs 在注射后可诱导血液中性粒细胞数量的最快增长和更大的炎症。这些观察结果突显了 LNP 的性质对 mRNA 疫苗分布和早期免疫反应的影响。
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NPJ Vaccines
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