Pub Date : 2024-06-22DOI: 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。
{"title":"T cell independent antibody responses with class switch and memory using peptides anchored on liposomes.","authors":"Ásdís Hjálmsdóttir, Fabio Hasler, Ying Waeckerle-Men, Agathe Duda, María Pilar López-Deber, Maria Pihlgren, Marija Vukicevic, Thomas M Kündig, Pål Johansen","doi":"10.1038/s41541-024-00902-3","DOIUrl":"10.1038/s41541-024-00902-3","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":19335,"journal":{"name":"NPJ Vaccines","volume":null,"pages":null},"PeriodicalIF":6.9,"publicationDate":"2024-06-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11193769/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141440768","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-06-20DOI: 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。
{"title":"Calcifediol boosts efficacy of ChAdOx1 nCoV-19 vaccine by upregulating genes promoting memory T cell responses.","authors":"Himanshu Singh Saroha, Swati Bhat, Liza Das, Pinaki Dutta, Michael F Holick, Naresh Sachdeva, Raman Kumar Marwaha","doi":"10.1038/s41541-024-00909-w","DOIUrl":"10.1038/s41541-024-00909-w","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":19335,"journal":{"name":"NPJ Vaccines","volume":null,"pages":null},"PeriodicalIF":6.9,"publicationDate":"2024-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11190216/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141432444","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-06-20DOI: 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.
{"title":"Analyzing atomic force microscopy images of virus-like particles by expectation-maximization.","authors":"Rachel A McCormick, Nicole M Ralbovsky, William Gilbraith, Joseph P Smith, Karl S Booksh","doi":"10.1038/s41541-024-00871-7","DOIUrl":"10.1038/s41541-024-00871-7","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":19335,"journal":{"name":"NPJ Vaccines","volume":null,"pages":null},"PeriodicalIF":6.9,"publicationDate":"2024-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11190231/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141432443","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-06-20DOI: 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.
{"title":"Distinct dynamics of mRNA LNPs in mice and nonhuman primates revealed by in vivo imaging.","authors":"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","doi":"10.1038/s41541-024-00900-5","DOIUrl":"10.1038/s41541-024-00900-5","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":19335,"journal":{"name":"NPJ Vaccines","volume":null,"pages":null},"PeriodicalIF":6.9,"publicationDate":"2024-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11189915/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141432445","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-06-19DOI: 10.1038/s41541-024-00899-9
Daniela Ogonczyk-Makowska, Pauline Brun, Clémence Vacher, Caroline Chupin, Clément Droillard, Julie Carbonneau, Emilie Laurent, Victoria Dulière, Aurélien Traversier, Olivier Terrier, Thomas Julien, Marie Galloux, Stéphane Paul, Jean-François Eléouët, Julien Fouret, Marie-Eve Hamelin, Andrés Pizzorno, Guy Boivin, Manuel Rosa-Calatrava, Julia Dubois
Live-Attenuated Vaccines (LAVs) stimulate robust mucosal and cellular responses and have the potential to protect against Respiratory Syncytial Virus (RSV) and Human Metapneumovirus (HMPV), the main etiologic agents of viral bronchiolitis and pneumonia in children. We inserted the RSV-F gene into an HMPV-based LAV (Metavac®) we previously validated for the protection of mice against HMPV challenge, and rescued a replicative recombinant virus (Metavac®-RSV), exposing both RSV- and HMPV-F proteins at the virion surface and expressing them in reconstructed human airway epithelium models. When administered to BALB/c mice by the intranasal route, bivalent Metavac®-RSV demonstrated its capacity to replicate with reduced lung inflammatory score and to protect against both RSV and lethal HMPV challenges in vaccinated mice while inducing strong IgG and broad RSV and HMPV neutralizing antibody responses. Altogether, our results showed the versatility of the Metavac® platform and suggested that Metavac®-RSV is a promising mucosal bivalent LAV candidate to prevent pneumovirus-induced diseases.
{"title":"Mucosal bivalent live attenuated vaccine protects against human metapneumovirus and respiratory syncytial virus in mice.","authors":"Daniela Ogonczyk-Makowska, Pauline Brun, Clémence Vacher, Caroline Chupin, Clément Droillard, Julie Carbonneau, Emilie Laurent, Victoria Dulière, Aurélien Traversier, Olivier Terrier, Thomas Julien, Marie Galloux, Stéphane Paul, Jean-François Eléouët, Julien Fouret, Marie-Eve Hamelin, Andrés Pizzorno, Guy Boivin, Manuel Rosa-Calatrava, Julia Dubois","doi":"10.1038/s41541-024-00899-9","DOIUrl":"10.1038/s41541-024-00899-9","url":null,"abstract":"<p><p>Live-Attenuated Vaccines (LAVs) stimulate robust mucosal and cellular responses and have the potential to protect against Respiratory Syncytial Virus (RSV) and Human Metapneumovirus (HMPV), the main etiologic agents of viral bronchiolitis and pneumonia in children. We inserted the RSV-F gene into an HMPV-based LAV (Metavac®) we previously validated for the protection of mice against HMPV challenge, and rescued a replicative recombinant virus (Metavac®-RSV), exposing both RSV- and HMPV-F proteins at the virion surface and expressing them in reconstructed human airway epithelium models. When administered to BALB/c mice by the intranasal route, bivalent Metavac®-RSV demonstrated its capacity to replicate with reduced lung inflammatory score and to protect against both RSV and lethal HMPV challenges in vaccinated mice while inducing strong IgG and broad RSV and HMPV neutralizing antibody responses. Altogether, our results showed the versatility of the Metavac® platform and suggested that Metavac®-RSV is a promising mucosal bivalent LAV candidate to prevent pneumovirus-induced diseases.</p>","PeriodicalId":19335,"journal":{"name":"NPJ Vaccines","volume":null,"pages":null},"PeriodicalIF":6.9,"publicationDate":"2024-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11187144/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141427355","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-06-18DOI: 10.1038/s41541-024-00901-4
Ross N England, Elizabeth M Drapeau, Mohamad-Gabriel Alameh, Reihaneh Hosseinzadeh, Drew Weissman, Scott E Hensley
Maternal antibodies (matAbs) protect against a myriad of pathogens early in life; however, these antibodies can also inhibit de novo immune responses against some vaccine platforms. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) matAbs are efficiently transferred during pregnancy and protect infants against subsequent SARS-CoV-2 infections. It is unknown if matAbs inhibit immune responses elicited by different types of SARS-CoV-2 vaccines. Here, we established a mouse model to determine if SARS-CoV-2 spike-specific matAbs inhibit immune responses elicited by recombinant protein and nucleoside-modified mRNA-lipid nanoparticle (mRNA-LNP) vaccines. We found that SARS-CoV-2 mRNA-LNP vaccines elicited robust de novo antibody responses in mouse pups in the presence of matAbs. Recombinant protein vaccines were also able to circumvent the inhibitory effects of matAbs when adjuvants were co-administered. While additional studies need to be completed in humans, our studies raise the possibility that mRNA-LNP-based and adjuvanted protein-based SARS-CoV-2 vaccines have the potential to be effective when delivered very early in life.
{"title":"Evaluation of mRNA-LNP and adjuvanted protein SARS-CoV-2 vaccines in a maternal antibody mouse model.","authors":"Ross N England, Elizabeth M Drapeau, Mohamad-Gabriel Alameh, Reihaneh Hosseinzadeh, Drew Weissman, Scott E Hensley","doi":"10.1038/s41541-024-00901-4","DOIUrl":"10.1038/s41541-024-00901-4","url":null,"abstract":"<p><p>Maternal antibodies (matAbs) protect against a myriad of pathogens early in life; however, these antibodies can also inhibit de novo immune responses against some vaccine platforms. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) matAbs are efficiently transferred during pregnancy and protect infants against subsequent SARS-CoV-2 infections. It is unknown if matAbs inhibit immune responses elicited by different types of SARS-CoV-2 vaccines. Here, we established a mouse model to determine if SARS-CoV-2 spike-specific matAbs inhibit immune responses elicited by recombinant protein and nucleoside-modified mRNA-lipid nanoparticle (mRNA-LNP) vaccines. We found that SARS-CoV-2 mRNA-LNP vaccines elicited robust de novo antibody responses in mouse pups in the presence of matAbs. Recombinant protein vaccines were also able to circumvent the inhibitory effects of matAbs when adjuvants were co-administered. While additional studies need to be completed in humans, our studies raise the possibility that mRNA-LNP-based and adjuvanted protein-based SARS-CoV-2 vaccines have the potential to be effective when delivered very early in life.</p>","PeriodicalId":19335,"journal":{"name":"NPJ Vaccines","volume":null,"pages":null},"PeriodicalIF":6.9,"publicationDate":"2024-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11189435/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141420035","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-06-15DOI: 10.1038/s41541-024-00905-0
Zhi-Jian Zhu, Man Teng, Yu Liu, Fu-Jia Chen, Yongxiu Yao, En-Zhong Li, Jun Luo
Marek's disease virus (MDV) is a highly pathogenic and oncogenic alpha herpesvirus that causes Marek's disease (MD), which is one of the most important immunosuppressive and rapid-onset neoplastic diseases in poultry. The onset of MD lymphomas and other clinical diseases can be efficiently prevented by vaccination; these vaccines are heralded as the first demonstration of a successful vaccination strategy against a cancer. However, the persistent evolution of epidemic MDV strains towards greater virulence has recently resulted in frequent outbreaks of MD in vaccinated chicken flocks worldwide. Herein, we provide an overall review focusing on the discovery and identification of the strategies by which MDV evades host immunity and attacks the immune system. We have also highlighted the decrease in the immune efficacy of current MD vaccines. The prospects, strategies and new techniques for the development of efficient MD vaccines, together with the possibilities of antiviral therapy in MD, are also discussed.
{"title":"Immune escape of avian oncogenic Marek's disease herpesvirus and antagonistic host immune responses.","authors":"Zhi-Jian Zhu, Man Teng, Yu Liu, Fu-Jia Chen, Yongxiu Yao, En-Zhong Li, Jun Luo","doi":"10.1038/s41541-024-00905-0","DOIUrl":"10.1038/s41541-024-00905-0","url":null,"abstract":"<p><p>Marek's disease virus (MDV) is a highly pathogenic and oncogenic alpha herpesvirus that causes Marek's disease (MD), which is one of the most important immunosuppressive and rapid-onset neoplastic diseases in poultry. The onset of MD lymphomas and other clinical diseases can be efficiently prevented by vaccination; these vaccines are heralded as the first demonstration of a successful vaccination strategy against a cancer. However, the persistent evolution of epidemic MDV strains towards greater virulence has recently resulted in frequent outbreaks of MD in vaccinated chicken flocks worldwide. Herein, we provide an overall review focusing on the discovery and identification of the strategies by which MDV evades host immunity and attacks the immune system. We have also highlighted the decrease in the immune efficacy of current MD vaccines. The prospects, strategies and new techniques for the development of efficient MD vaccines, together with the possibilities of antiviral therapy in MD, are also discussed.</p>","PeriodicalId":19335,"journal":{"name":"NPJ Vaccines","volume":null,"pages":null},"PeriodicalIF":9.2,"publicationDate":"2024-06-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11180173/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141327635","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-06-15DOI: 10.1038/s41541-024-00904-1
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
Alzheimer's disease (AD) and related tauopathies are associated with pathological tau protein aggregation, which plays an important role in neurofibrillary degeneration and dementia. Targeted immunotherapy to eliminate pathological tau aggregates is known to improve cognitive deficits in AD animal models. The tau repeat domain (TauRD) plays a pivotal role in tau-microtubule interactions and is critically involved in the aggregation of hyperphosphorylated tau proteins. Because TauRD forms the structural core of tau aggregates, the development of immunotherapies that selectively target TauRD-induced pathological aggregates holds great promise for the modulation of tauopathies. In this study, we generated recombinant TauRD polypeptide that form neurofibrillary tangle-like structures and evaluated TauRD-specific immune responses following intranasal immunization in combination with the mucosal adjuvant FlaB. In BALB/C mice, repeated immunizations at one-week intervals induced robust TauRD-specific antibody responses in a TLR5-dependent manner. Notably, the resulting antiserum recognized only the aggregated form of TauRD, while ignoring monomeric TauRD. The antiserum effectively inhibited TauRD filament formation and promoted the phagocytic degradation of TauRD aggregate fragments by microglia. The antiserum also specifically recognized pathological tau conformers in the human AD brain. Based on these results, we engineered a built-in flagellin-adjuvanted TauRD (FlaB-TauRD) vaccine and tested its efficacy in a P301S transgenic mouse model. Mucosal immunization with FlaB-TauRD improved quality of life, as indicated by the amelioration of memory deficits, and alleviated tauopathy progression. Notably, the survival of the vaccinated mice was dramatically extended. In conclusion, we developed a mucosal vaccine that exclusively targets pathological tau conformers and prevents disease progression.
阿尔茨海默病(AD)和相关的tau病与病理性tau蛋白聚集有关,而tau蛋白聚集在神经纤维变性和痴呆症中扮演着重要角色。众所周知,消除病理性 tau 蛋白聚集的靶向免疫疗法可改善 AD 动物模型的认知障碍。tau重复结构域(TauRD)在tau与微管的相互作用中起着关键作用,并在高磷酸化tau蛋白的聚集过程中起着至关重要的作用。由于 TauRD 构成了 tau 蛋白聚集体的结构核心,因此开发选择性靶向 TauRD 诱导的病理聚集体的免疫疗法在调节 tau 病症方面大有可为。在这项研究中,我们生成了能形成神经纤维缠结样结构的重组 TauRD 多肽,并评估了鼻内免疫结合粘膜佐剂 FlaB 后 TauRD 的特异性免疫反应。在 BALB/C 小鼠中,间隔一周的重复免疫以 TLR5 依赖性方式诱导了强大的 TauRD 特异性抗体反应。值得注意的是,由此产生的抗血清只识别 TauRD 的聚集形式,而忽略了单体 TauRD。这种抗血清能有效抑制 TauRD 长丝的形成,并促进小胶质细胞对 TauRD 聚集片段的吞噬降解。该抗血清还能特异性识别人类AD大脑中的病理tau构象。基于这些结果,我们设计了一种内置的鞭毛蛋白佐剂 TauRD(FlaB-TauRD)疫苗,并在 P301S 转基因小鼠模型中测试了其疗效。FlaB-TauRD的粘膜免疫改善了记忆缺陷,从而提高了生活质量,并缓解了tauopathy的进展。值得注意的是,接种疫苗的小鼠存活期显著延长。总之,我们开发出了一种专门针对病理 tau 构象并能预防疾病进展的粘膜疫苗。
{"title":"Development of an anti-tauopathy mucosal vaccine specifically targeting pathologic conformers.","authors":"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","doi":"10.1038/s41541-024-00904-1","DOIUrl":"10.1038/s41541-024-00904-1","url":null,"abstract":"<p><p>Alzheimer's disease (AD) and related tauopathies are associated with pathological tau protein aggregation, which plays an important role in neurofibrillary degeneration and dementia. Targeted immunotherapy to eliminate pathological tau aggregates is known to improve cognitive deficits in AD animal models. The tau repeat domain (TauRD) plays a pivotal role in tau-microtubule interactions and is critically involved in the aggregation of hyperphosphorylated tau proteins. Because TauRD forms the structural core of tau aggregates, the development of immunotherapies that selectively target TauRD-induced pathological aggregates holds great promise for the modulation of tauopathies. In this study, we generated recombinant TauRD polypeptide that form neurofibrillary tangle-like structures and evaluated TauRD-specific immune responses following intranasal immunization in combination with the mucosal adjuvant FlaB. In BALB/C mice, repeated immunizations at one-week intervals induced robust TauRD-specific antibody responses in a TLR5-dependent manner. Notably, the resulting antiserum recognized only the aggregated form of TauRD, while ignoring monomeric TauRD. The antiserum effectively inhibited TauRD filament formation and promoted the phagocytic degradation of TauRD aggregate fragments by microglia. The antiserum also specifically recognized pathological tau conformers in the human AD brain. Based on these results, we engineered a built-in flagellin-adjuvanted TauRD (FlaB-TauRD) vaccine and tested its efficacy in a P301S transgenic mouse model. Mucosal immunization with FlaB-TauRD improved quality of life, as indicated by the amelioration of memory deficits, and alleviated tauopathy progression. Notably, the survival of the vaccinated mice was dramatically extended. In conclusion, we developed a mucosal vaccine that exclusively targets pathological tau conformers and prevents disease progression.</p>","PeriodicalId":19335,"journal":{"name":"NPJ Vaccines","volume":null,"pages":null},"PeriodicalIF":6.9,"publicationDate":"2024-06-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11180213/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141327634","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-06-14DOI: 10.1038/s41541-024-00898-w
Calum Macdonald, Norah Palmateer, Andrew McAuley, Laura Lindsay, Taimoor Hasan, Safraj Shahul Hameed, Elliot Hall, Karen Jeffrey, Zoë Grange, Petros Gousias, Sally Mavin, Lisa Jarvis, J Claire Cameron, Luke Daines, Holly Tibble, Colin R Simpson, Colin McCowan, Srinivasa Vittal Katikireddi, Igor Rudan, Adeniyi Francis Fagbamigbe, Lewis Ritchie, Ben Swallow, Paul Moss, Chris Robertson, Aziz Sheikh, Josie Murray
Several population-level studies have described individual clinical risk factors associated with suboptimal antibody responses following COVID-19 vaccination, but none have examined multimorbidity. Others have shown that suboptimal post-vaccination responses offer reduced protection to subsequent SARS-CoV-2 infection; however, the level of protection from COVID-19 hospitalisation/death remains unconfirmed. We use national Scottish datasets to investigate the association between multimorbidity and testing antibody-negative, examining the correlation between antibody levels and subsequent COVID-19 hospitalisation/death among double-vaccinated individuals. We found that individuals with multimorbidity ( ≥ five conditions) were more likely to test antibody-negative post-vaccination and 13.37 [6.05-29.53] times more likely to be hospitalised/die from COVID-19 than individuals without conditions. We also show a dose-dependent association between post-vaccination antibody levels and COVID-19 hospitalisation or death, with those with undetectable antibody levels at a significantly higher risk (HR 9.21 [95% CI 4.63-18.29]) of these serious outcomes compared to those with high antibody levels.
{"title":"Association between antibody responses post-vaccination and severe COVID-19 outcomes in Scotland.","authors":"Calum Macdonald, Norah Palmateer, Andrew McAuley, Laura Lindsay, Taimoor Hasan, Safraj Shahul Hameed, Elliot Hall, Karen Jeffrey, Zoë Grange, Petros Gousias, Sally Mavin, Lisa Jarvis, J Claire Cameron, Luke Daines, Holly Tibble, Colin R Simpson, Colin McCowan, Srinivasa Vittal Katikireddi, Igor Rudan, Adeniyi Francis Fagbamigbe, Lewis Ritchie, Ben Swallow, Paul Moss, Chris Robertson, Aziz Sheikh, Josie Murray","doi":"10.1038/s41541-024-00898-w","DOIUrl":"10.1038/s41541-024-00898-w","url":null,"abstract":"<p><p>Several population-level studies have described individual clinical risk factors associated with suboptimal antibody responses following COVID-19 vaccination, but none have examined multimorbidity. Others have shown that suboptimal post-vaccination responses offer reduced protection to subsequent SARS-CoV-2 infection; however, the level of protection from COVID-19 hospitalisation/death remains unconfirmed. We use national Scottish datasets to investigate the association between multimorbidity and testing antibody-negative, examining the correlation between antibody levels and subsequent COVID-19 hospitalisation/death among double-vaccinated individuals. We found that individuals with multimorbidity ( ≥ five conditions) were more likely to test antibody-negative post-vaccination and 13.37 [6.05-29.53] times more likely to be hospitalised/die from COVID-19 than individuals without conditions. We also show a dose-dependent association between post-vaccination antibody levels and COVID-19 hospitalisation or death, with those with undetectable antibody levels at a significantly higher risk (HR 9.21 [95% CI 4.63-18.29]) of these serious outcomes compared to those with high antibody levels.</p>","PeriodicalId":19335,"journal":{"name":"NPJ Vaccines","volume":null,"pages":null},"PeriodicalIF":9.2,"publicationDate":"2024-06-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11178861/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141321322","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-06-14DOI: 10.1038/s41541-024-00885-1
Carlos A Fierro, Michal Sarnecki, Bart Spiessens, Oscar Go, Tracey A Day, Todd A Davies, Germie van den Dobbelsteen, Jan Poolman, Darren Abbanat, Wouter Haazen
The safety, reactogenicity, and immunogenicity of 3 doses of ExPEC10V (VAC52416), a vaccine candidate to prevent invasive Escherichia coli disease, were assessed in a phase 1/2a study (NCT03819049). In Cohort 1, ExPEC10V was well tolerated; the high dose was selected as optimal and further characterized in Cohort 2. Cohort 2 comprised a maximum 28-day screening, vaccination (Day 1), double-blind 181-day follow-up, and open-label long-term follow-up until Year 1. Healthy participants (≥60 years) with a history of urinary tract infection (UTI) within 5 years were randomized to receive ExPEC10V or placebo. The primary endpoint evaluated the safety and reactogenicity of ExPEC10V (solicited local and systemic AEs [until Day 15]; unsolicited AEs [until Day 30], SAEs [until Day 181], and immunogenicity [Day 30]) via multiplex electrochemiluminescent (ECL) and multiplex opsonophagocytic assay (MOPA). 416 participants (ExPEC10V, n = 278; placebo, n = 138) were included (mean age [SD], 68.8 [6.52] years; female, 79.6%; White, 96.1%). The incidence of solicited AEs was higher with ExPEC10V (local, 50.0% [n = 139]; systemic, 50.0% [n = 139]) than placebo (15.9% [n = 22]; 38.4% [n = 53]); rates of unsolicited AEs were comparable (ExPEC10V, 28.4% [n = 79]; placebo, 26.1% [n = 36]). No vaccine-related SAEs or deaths were reported. ExPEC10V elicited a robust antibody-mediated immunogenic response across all serotypes with ECL (Day 30 geometric mean fold increase, 2.33-8.18) and demonstrated functional opsonophagocytic killing activity across all measured serotypes (Day 30 geometric mean fold increase, 1.81-9.68). ExPEC10V exhibited an acceptable safety profile and a robust vaccine-induced functional immunogenic response in participants with a history of UTI. Clinical trial registration details: https://clinicaltrials.gov/study/NCT03819049 .
{"title":"A randomized phase 1/2a trial of ExPEC10V vaccine in adults with a history of UTI.","authors":"Carlos A Fierro, Michal Sarnecki, Bart Spiessens, Oscar Go, Tracey A Day, Todd A Davies, Germie van den Dobbelsteen, Jan Poolman, Darren Abbanat, Wouter Haazen","doi":"10.1038/s41541-024-00885-1","DOIUrl":"10.1038/s41541-024-00885-1","url":null,"abstract":"<p><p>The safety, reactogenicity, and immunogenicity of 3 doses of ExPEC10V (VAC52416), a vaccine candidate to prevent invasive Escherichia coli disease, were assessed in a phase 1/2a study (NCT03819049). In Cohort 1, ExPEC10V was well tolerated; the high dose was selected as optimal and further characterized in Cohort 2. Cohort 2 comprised a maximum 28-day screening, vaccination (Day 1), double-blind 181-day follow-up, and open-label long-term follow-up until Year 1. Healthy participants (≥60 years) with a history of urinary tract infection (UTI) within 5 years were randomized to receive ExPEC10V or placebo. The primary endpoint evaluated the safety and reactogenicity of ExPEC10V (solicited local and systemic AEs [until Day 15]; unsolicited AEs [until Day 30], SAEs [until Day 181], and immunogenicity [Day 30]) via multiplex electrochemiluminescent (ECL) and multiplex opsonophagocytic assay (MOPA). 416 participants (ExPEC10V, n = 278; placebo, n = 138) were included (mean age [SD], 68.8 [6.52] years; female, 79.6%; White, 96.1%). The incidence of solicited AEs was higher with ExPEC10V (local, 50.0% [n = 139]; systemic, 50.0% [n = 139]) than placebo (15.9% [n = 22]; 38.4% [n = 53]); rates of unsolicited AEs were comparable (ExPEC10V, 28.4% [n = 79]; placebo, 26.1% [n = 36]). No vaccine-related SAEs or deaths were reported. ExPEC10V elicited a robust antibody-mediated immunogenic response across all serotypes with ECL (Day 30 geometric mean fold increase, 2.33-8.18) and demonstrated functional opsonophagocytic killing activity across all measured serotypes (Day 30 geometric mean fold increase, 1.81-9.68). ExPEC10V exhibited an acceptable safety profile and a robust vaccine-induced functional immunogenic response in participants with a history of UTI. Clinical trial registration details: https://clinicaltrials.gov/study/NCT03819049 .</p>","PeriodicalId":19335,"journal":{"name":"NPJ Vaccines","volume":null,"pages":null},"PeriodicalIF":9.2,"publicationDate":"2024-06-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11178786/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141321321","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}