NPJ Vaccines最新文献

{"title":"Cellular immune signatures and differences of four porcine circovirus type 2 vaccines to heterologous PCV2d infection.","authors":"Shuai Li, Jiawei Liu, Lingbo Meng, Susu Yin, Hua Wu, Jianwen Zou, Dongbo Yuan, Hairong He, Guanghao Yin, Xianfeng Jia, Xiaoli Hao, Shaobin Shang","doi":"10.1038/s41541-025-01138-5","DOIUrl":"https://doi.org/10.1038/s41541-025-01138-5","url":null,"abstract":"<p><p>Multiple PCV2 vaccines originating from different antigens and formula are commercially available and have shown great effectiveness in protecting pigs from clinical disease. However, our understanding of the immune mechanisms underlying these vaccine-induced protection is fairly limited, except for antibody responses. Head-to-head comparisons of T-cell responses induced by these vaccines in pigs would provide valuable insights into the mechanisms of protective immunity against PCV2. Here, T-cell responses in peripheral blood of pigs after vaccination with four representative PCV2 vaccines, as well as local and systemic recall responses following challenge with a PCV2d strain were examined. All four PCV2 vaccines induce a rapid cellular immune response that could be detected as early as 7 days post-vaccination. Some vaccine-primed CD4 T cells exhibit multifunctionality, being capable of secreting double (IFNγ/TNFα) and even triple cytokines (IFNγ/TNFα/IL-2) simultaneously. In contrast, a weak CD8 T cell response was also detected in the vaccinated pigs but just IFNγ/TNFα double producer and lack of cytotoxicity. These vaccine-activated CD4 and CD8 T cells displayed phenotypes of effector memory or terminally-differentiated effector memory T cells, which rapidly expand to subsequent PCV2d challenges. Prior-vaccinated pigs exhibited a stronger T cell cytokine response post-challenge, being most evident in the spleen. Notably, the cellular immune response induced by different types of PCV2 vaccines exhibited high similarity in phenotypic and functional properties, while showing significant differences in kinetics and magnitude. These results advance our understanding of cell-mediated immune protection afforded by different PCV2 vaccines and unravel fundamental differences in cellular immune response induced by PCV2 vaccines utilizing diverse technologies.</p>","PeriodicalId":19335,"journal":{"name":"NPJ Vaccines","volume":"10 1","pages":"92"},"PeriodicalIF":6.9,"publicationDate":"2025-05-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12065864/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143983713","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}

{"title":"Global socioeconomic inequalities in vaccination coverage, supply, and confidence.","authors":"Qiang Wang, Kathy Leung, Mark Jit, Joseph T Wu, Leesa Lin","doi":"10.1038/s41541-025-01143-8","DOIUrl":"https://doi.org/10.1038/s41541-025-01143-8","url":null,"abstract":"<p><p>Sustainable Development Goal (SDG) adopted in 2015 aim to reduce inequalities and achieve universal health coverage, including access to essential vaccines for all. Using data from WHO, the Vaccine Confidence Project™, World Bank, and UNDP, we analyzed between-country inequalities in coverage of four vaccines (DTP1, DTP3, MCV1, and POL3), vaccine stock-outs, and vaccine confidence. Economic- and education-related inequalities in coverage (measured by the concentration index) declined from 2015 to 2019, increased in 2020, peaked in 2021, and have declined again since 2022. Inequalities increased continuously in the Region of the Americas. Over 2015-2022, 94 countries/territories reported at least one national level DTP-containing vaccine stock-out. Countries/territories with higher income or education attainment showed lower vaccine confidence. Our study underscores the decrease of inequalities in vaccination coverage following the SDG adoption in most regions, and emphasizes the need to address vaccine stock-outs and strength the vaccine confidence.</p>","PeriodicalId":19335,"journal":{"name":"NPJ Vaccines","volume":"10 1","pages":"91"},"PeriodicalIF":6.9,"publicationDate":"2025-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12064651/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143974855","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}

{"title":"Cancer type and gene signatures associated with breakthrough infections following COVID-19 mRNA vaccination.","authors":"Youjia Zhong, Jiaqi Li, Ainsley Ryan Yan Bin Lee, Janice Yu Jin Tan, Carina Jing Xuan Tay, Clara Wt Koh, Ethan Yong Tzi Seow, Wee Chee Yap, Shi Yin Wong, Chun En Yau, Chen Ee Low, Kelvin Bryan Tan, Barnaby Edward Young, Yan Su, Arun George Devasia, Perumal Dharuman, Alexander Lezhava, Rahul Pandey, Panneer Selvi Govindaraju, Sidney Yee, Ruifen Weng, Candy Khoo, Shaun Shi Yan Tan, Matilda Lee, Joline Lim, Esther Chan, Carol Lf Ho, Louis Yi Ann Chai, Chee Wah Tan, Soo Chin Lee, Kuan Rong Chan, Raghav Sundar","doi":"10.1038/s41541-025-01141-w","DOIUrl":"https://doi.org/10.1038/s41541-025-01141-w","url":null,"abstract":"<p><p>We used epidemiological data from 21195 patients with cancer and 180407 matched controls, including in-depth analyses in 216 cancer patients, to discover clinical and molecular determinants that predispose cancer patients to breakthrough infections. Patients with B cell malignancies, with differential expression of CD24, CDK14 and PLEKHG1, were most susceptible to breakthrough infections, suggesting that these patients may require more booster immunisations to ameliorate cellular responses and immune protection against COVID-19.</p>","PeriodicalId":19335,"journal":{"name":"NPJ Vaccines","volume":"10 1","pages":"90"},"PeriodicalIF":6.9,"publicationDate":"2025-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12062431/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143991330","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}

{"title":"An adjuvanted chimeric spike antigen boosts lung-resident memory T-cells and induces pan-sarbecovirus protective immunity.","authors":"Claudio Counoupas, Elizabeth Chan, Paco Pino, Joshua Armitano, Matt D Johansen, Lachlan J Smith, Caroline L Ashley, Eva Estapé, Jean Troyon, Sibel Alca, Stefan Miemczyk, Nicole G Hansbro, Gabriella Scandurra, Warwick J Britton, Thomas Courant, Patrice M Dubois, Nicolas Collin, V Krishna Mohan, Philip M Hansbro, Maria J Wurm, Florian M Wurm, Megan Steain, James A Triccas","doi":"10.1038/s41541-025-01144-7","DOIUrl":"https://doi.org/10.1038/s41541-025-01144-7","url":null,"abstract":"<p><p>Next-generation vaccines are essential to address the evolving nature of SARS-CoV-2 and to protect against emerging pandemic threats from other coronaviruses. These vaccines should elicit broad protection, provide long-lasting immunity and ensure equitable access for all populations. In this study, we developed a panel of chimeric, full-length spike antigens incorporating mutations from previous, circulating and predicted SARS-CoV-2 variants. The lead candidate (CoVEXS5) was produced through a high-yield production process in stable CHO cells achieving >95% purity, demonstrated long-term stability and elicited broadly cross-reactive neutralising antibodies when delivered to mice in a squalene emulsion adjuvant (Sepivac SWE™). In both mice and hamsters, CoVEXS5 immunisation reduced clinical disease signs, lung inflammation and organ viral titres after SARS-CoV-2 infection, including following challenge with the highly immunoevasive Omicron XBB.1.5 subvariant. In mice previously primed with a licenced mRNA vaccine (Comirnaty XBB.1.5, termed mRNA-XBB), CoVEXS5 boosting significantly increased neutralising antibody (nAb) levels against viruses from three sarbecoviruses clades. Boosting with CoVEXS5 via systemic delivery elicited CD4+ lung-resident memory T cells, typically associated with mucosal immunisation strategies, which were not detected following mRNA-XBB boosting. Vaccination of hamsters with CoVEXS5 conferred significant protection against weight loss after SARS-CoV-1 challenge, compared to mRNA-XBB immunisation, that correlated with anti-SARS-CoV-1 nAbs in the sera of vaccinated animals. These findings highlight the potential of a chimeric spike antigen, formulated in an open-access adjuvant, as a next-generation vaccine candidate to enhance cross-protection against emerging sarbecoviruses in vaccinated populations globally.</p>","PeriodicalId":19335,"journal":{"name":"NPJ Vaccines","volume":"10 1","pages":"89"},"PeriodicalIF":6.9,"publicationDate":"2025-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12062434/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144006345","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}

{"title":"Genome-wide association study of myocarditis and pericarditis following COVID-19 vaccination.","authors":"Marco Cavalli, Niclas Eriksson, Tomasz Baron, Ahmet Yalcinkaya, Nils Landegren, Petter Brodin, Pär Hallberg, Mia Wadelius","doi":"10.1038/s41541-025-01139-4","DOIUrl":"https://doi.org/10.1038/s41541-025-01139-4","url":null,"abstract":"<p><p>This genome-wide association study (GWAS) explores the genetic components of severe adverse events following COVID-19 vaccination, with focus on myocarditis and pericarditis. Three SNPs (rs536572545, rs146289966 and rs142297026) near the SCAF11 gene were linked to pericarditis, while rs570375365 in the LRRC4C gene was associated with myocarditis. These findings suggest that genetic variants may influence inflammation pathways, providing a basis for further investigation into the immunological responses triggered by vaccines.</p>","PeriodicalId":19335,"journal":{"name":"NPJ Vaccines","volume":"10 1","pages":"88"},"PeriodicalIF":6.9,"publicationDate":"2025-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12062381/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144023675","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}

{"title":"Elicitation of liver-stage immunity by nanoparticle immunogens displaying P. falciparum CSP-derived antigens.","authors":"Mark D Langowski, Joseph R Francica, Alex L Roederer, Nicholas K Hurlburt, Justas V Rodarte, Lais Da Silva Pereira, Barbara J Flynn, Brian Bonilla, Marlon Dillon, Patience Kiyuka, Rashmi Ravichandran, Connor Weidle, Lauren Carter, Mangala Rao, Gary R Matyas, Marion Pepper, Azza H Idris, Robert A Seder, Marie Pancera, Neil P King","doi":"10.1038/s41541-025-01140-x","DOIUrl":"10.1038/s41541-025-01140-x","url":null,"abstract":"<p><p>A vaccine that provides robust, durable protection against malaria remains a global health priority. Although a breakthrough in the fight against malaria has recently been achieved by the licensure of two vaccines based on the circumsporozoite protein (CSP), the effectiveness and durability of protection can still be improved. Both vaccines contain a portion of CSP that does not include epitopes targeted by recently identified, potently protective monoclonal antibodies, suggesting that newer immunogens can expand the breadth of immunity and potentially increase protection. Here we explored >100 alternative CSP-based immunogens and evaluated the immunogenicity and protection of a large number of candidates, comparing several to the licensed R21 vaccine. The data highlight several general features that improve the stability and immunogenicity of CSP-based vaccines, such as inclusion of the C-terminal domain and high-density display on protein nanoparticle scaffolds. We also identify antigen design strategies that do not warrant further exploration, such as synthetic repeat regions that include non-native repeat cadences. The benchmark R21 vaccine outperformed our best immunogen for immunogenicity and protection. Overall, our data provide valuable insights on the inclusion of junctional region epitopes that will guide the development of potent and durable vaccines against malaria.</p>","PeriodicalId":19335,"journal":{"name":"NPJ Vaccines","volume":"10 1","pages":"87"},"PeriodicalIF":6.9,"publicationDate":"2025-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12053698/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144046579","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}

{"title":"An mRNA vaccine provides effective protection against Duck Tembusu Virus infection.","authors":"Shi Xu, Lijiao Zhang, Caiyi Fei, Guilai Liu, Mengwei Xu, Rui Liu, Jing Li, Aili Wang, Qing He, Ke Cai, Qingtao Liu, Tiyun Han","doi":"10.1038/s41541-025-01146-5","DOIUrl":"https://doi.org/10.1038/s41541-025-01146-5","url":null,"abstract":"<p><p>As an emerging flavivirus, Duck Tembusu virus (DTMUV) causes severe neurological disorder and acute egg drop syndrome in poultry. Herein, we report the development of a highly effective mRNA vaccine against DTMUV using lipid nanoparticle (LNP) delivery technology. We engineered an mRNA construct encoding the pre-membrane (prM) and envelope (E) proteins of DTMUV, with an upstream signal peptide to enhance secretion. Two doses of our mRNA vaccine elicited robust neutralizing antibody titers and conferred 100% protection against challenge with a prevalent virulent DTMUV strain. Notably, in a head-to-head comparison, the neutralizing antibody titers induced by our mRNA vaccine were approximately 40-fold of a commercial live-attenuated vaccine (FX2010-180P). Importantly, our mRNA vaccine demonstrated efficient maternal antibody transfer via egg yolk deposition, indicating the potential for protecting offspring through maternal immunity. These findings demonstrate the superiority of our mRNA vaccine platform, as well as the feasibility of applying mRNA vaccines in poultry.</p>","PeriodicalId":19335,"journal":{"name":"NPJ Vaccines","volume":"10 1","pages":"86"},"PeriodicalIF":6.9,"publicationDate":"2025-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12052822/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144028989","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}

{"title":"Controlling reactogenicity while preserving immunogenicity from a self-amplifying RNA vaccine by modulating nucleocytoplasmic transport.","authors":"Jason A Wojcechowskyj, Robyn M Jong, Imre Mäger, Britta Flach, Paul V Munson, Progya P Mukherjee, Barbara Mertins, Katherine R Barcay, Thomas Folliard","doi":"10.1038/s41541-025-01135-8","DOIUrl":"10.1038/s41541-025-01135-8","url":null,"abstract":"<p><p>Self-amplifying RNA (saRNA)-based vaccines have emerged as a potent and durable RNA vaccine platform relative to first generation mRNA vaccines. However, RNA vaccine platforms trigger undesirable side effects at protective doses, underscoring the need for improved tolerability. To address this, we leveraged the Cardiovirus leader protein, which is well-characterized to dampen host innate signaling by modulating nucleocytoplasmic transport (NCT). Co-administration of a leader-protein-encoding mRNA (which we have named \"RNAx\") delivered alongside vaccine cargo saRNA reduced interferon production while enhancing Influenza hemagglutinin (HA) expression in human primary cells and murine models. RNAx potently decreased serum biomarkers of reactogenicity after immunizations with an HA-expressing saRNA-LNP vaccine while maintaining the magnitude of the antibody and cellular response. RNAx also consistently enhanced binding antibody titers after a single injection and in some conditions enhanced binding antibody and neutralization titers post-boost. These findings support RNAx as a promising platform approach for improving tolerability of saRNA-LNP vaccines while preserving or enhancing immunogenicity.</p>","PeriodicalId":19335,"journal":{"name":"NPJ Vaccines","volume":"10 1","pages":"85"},"PeriodicalIF":6.9,"publicationDate":"2025-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12041602/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144005899","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}

{"title":"Development and in vivo evaluation of a SARS-CoV-2 inactivated vaccine using high hydrostatic pressure.","authors":"Martina Brandolini, Pietro Rocculi, Michele Morbarigazzi, Alessandra Mistral De Pascali, Giorgio Dirani, Silvia Zannoli, Davide Lelli, Antonio Lavazza, Francesca Battioni, Laura Grumiro, Simona Semprini, Massimiliano Guerra, Giulia Gatti, Laura Dionisi, Ludovica Ingletto, Claudia Colosimo, Anna Marzucco, Maria Sofia Montanari, Monica Cricca, Alessandra Scagliarini, Vittorio Sambri","doi":"10.1038/s41541-025-01136-7","DOIUrl":"https://doi.org/10.1038/s41541-025-01136-7","url":null,"abstract":"<p><p>Developing low-cost vaccine production strategies is crucial to achieving global health equity and mitigating the spread and impact of disease outbreaks. High hydrostatic pressure (HHP) technology is a widely used technology employed in the food industry for long-term preservation. This project aims at validating HHP as a cost-effective method for the production of highly immunogenic thermal stable whole-virus SARS-CoV-2 vaccines. Structural studies on HHP-inactivated viruses demonstrated pressure-dependent effects, with higher pressures (500-600 MPa) destabilizing viral morphology. Immunogenicity assessments, in animal models, revealed that 500 MPa treatment elicited the most robust humoral and cellular immune responses, outperforming heat inactivation. Additionally, HHP-inactivated viral preparation retained thermostability for 30 days at 4 °C, reducing cold-chain dependencies and enabling vaccine distribution also in low-resource settings. With its rapid, cost-effective, and scalable production process, HHP presents a transformative, equitable solution for global vaccine development, particularly for emerging pathogens.</p>","PeriodicalId":19335,"journal":{"name":"NPJ Vaccines","volume":"10 1","pages":"83"},"PeriodicalIF":6.9,"publicationDate":"2025-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12032236/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143991796","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}

{"title":"Repurposing anti-viral subunit and mRNA vaccines T cell immunity for intratumoral immunotherapy against solid tumors.","authors":"Shiv K Sethi, Claire E Bradley, Lukas Bialkowski, Yuk Ying Pang, Cynthia D Thompson, John T Schiller, Nicolas Çuburu","doi":"10.1038/s41541-025-01131-y","DOIUrl":"https://doi.org/10.1038/s41541-025-01131-y","url":null,"abstract":"<p><p>Intratumoral (IT) immunotherapy can stimulate the tumor microenvironment and enhance anti-tumor immunity. We investigated IT delivery of three licensed viral vaccines-Shingrix (VZV shingles), Gardasil-9 (HPV), and Spikevax (SARS-CoV-2)-in prevaccinated mice using the murine tumor model TC-1, which expresses HPV16 oncogenes E6 and E7. Shingrix IT injection often induced tumor regression and resistance to secondary challenge. Injecting a VZV glycoprotein E (gE)-derived MHC-II-restricted peptide with polyI:C also led to durable remission, highlighting the role of gE-specific CD4⁺ T cells. While Gardasil-9 IT injection alone was ineffective, combining a HPV L1-derived MHC-I-restricted peptide with polyI:C or Shingrix enhanced tumor regression. Both approaches elicited CD8⁺ T cells against the E7 tumor viral oncoprotein. Tumor microenvironment analysis revealed remodeling of the myeloid compartment, significant induction of IFN-γ, TNF-α, and CXCL9 and broad gene expression reprograming. In a dual-flank model, IT injection of Shingrix with an MHC-I-restricted E7 tumor-specific peptide eliminated primary and non-injected tumors. Finally, Spikevax IT injection showed modest tumor growth delay, while improved control was observed with a SARS-CoV-2 spike-derived MHC-I-restricted peptide and polyI:C. These results demonstrate the potential of licensed vaccines as promising platforms for IT immunotherapy, either alone or combined with vaccine- or tumor-derived MHC-I-restricted peptide epitopes.</p>","PeriodicalId":19335,"journal":{"name":"NPJ Vaccines","volume":"10 1","pages":"84"},"PeriodicalIF":6.9,"publicationDate":"2025-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12032097/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144046580","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}