4.6 Article

Enhanced Immunogenicity of Stabilized Trimeric Soluble Influenza Hemagglutinin

期刊

PLOS ONE
卷 5, 期 9, 页码 -

出版社

PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.pone.0012466

关键词

-

资金

  1. National Institutes of Health [AI074579, EB006369]

向作者/读者索取更多资源

Background: The recent swine-origin H1N1 pandemic illustrates the need to develop improved procedures for rapid production of influenza vaccines. One alternative to the current egg-based manufacture of influenza vaccine is to produce a hemagglutinin (HA) subunit vaccine using a recombinant expression system with the potential for high protein yields, ease of cloning new antigenic variants, and an established safety record in humans. Methodology/Principal Findings: We generated a soluble HA (sHA), derived from the H3N2 virus A/Aichi/2/68, modified at the C-terminus with a GCN4pII trimerization repeat to stabilize the native trimeric structure of HA. When expressed in the baculovirus system, the modified sHA formed native trimers. In contrast, the unmodified sHA was found to present epitopes recognized by a low-pH conformation specific monoclonal antibody. We found that mice primed and boosted with 3 mu g of trimeric sHA in the absence of adjuvants had significantly higher IgG and HAI titers than mice that received the unmodified sHA. This correlated with an increased survival and reduced body weight loss following lethal challenge with mouse-adapted A/Aichi/2/68 virus. In addition, mice receiving a single vaccination of the trimeric sHA in the absence of adjuvants had improved survival and body weight loss compared to mice vaccinated with the unmodified sHA. Conclusions/Significance: Our data indicate that the recombinant trimeric sHA presents native trimeric epitopes while the unmodified sHA presents epitopes not exposed in the native HA molecule. The epitopes presented in the unmodified sHA constitute a silent face'' which may skew the antibody response to epitopes not accessible in live virus at neutral pH. The results demonstrate that the trimeric sHA is a more effective influenza vaccine candidate and emphasize the importance of structure-based antigen design in improving recombinant HA vaccines.

作者

我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。

评论

主要评分

4.6
评分不足

次要评分

新颖性
-
重要性
-
科学严谨性
-
评价这篇论文

推荐

Article Chemistry, Analytical

Silver nanotriangle array based LSPR sensor for rapid coronavirus detection

Yanjun Yang, Jackelyn Murray, James Haverstick, Ralph A. Tripp, Yiping Zhao

Summary: The researchers developed a rapid coronavirus detection method using a functionalized silver nanotriangle array localized surface plasmon resonance sensor. The sensor shows high sensitivity and specificity in detecting SARS-CoV-2 infection, and the detection time is less than 20 minutes.

SENSORS AND ACTUATORS B-CHEMICAL (2022)

Article Multidisciplinary Sciences

ACE2-IgG1 fusions with improved in vitro and in vivo activity against SARS-CoV-2

Naoki Iwanaga, Laura Cooper, Lijun Rong, Nicholas J. Maness, Brandon Beddingfield, Zhongnan Qin, Jackelyn Crabtree, Ralph A. Tripp, Haoran Yang, Robert Blair, Sonia Jangra, Adolfo Garcia-Sastre, Michael Schotsaert, Sruti Chandra, James E. Robinson, Akhilesh Srivastava, Felix Rabito, Xuebin Qin, Jay K. Kolls

Summary: Researchers constructed an ACE2-human IgG1 fusion protein with mutations in the catalytic domain of ACE2, which significantly increased binding to SARS-CoV-2 spike protein and improved lung infection caused by the virus in vivo. This study suggests that MDR504 hACE2-Fc may be a promising candidate for the treatment or prevention of COVID-19 and emerging variants.

ISCIENCE (2022)

Article Biochemical Research Methods

Isothermal amplification using sequence-specific fluorescence detection of SARS coronavirus 2 and variants in nasal swabs

Les Jones, Hemant K. Naikare, Yung-Yi C. Mosley, Ralph A. Tripp

Summary: The study aimed to develop a rapid and sensitive nucleic acid amplification assay for the detection of the novel coronavirus and its variants. The researchers successfully designed a fluorescence-quenched reverse transcription loop-mediated isothermal amplification method, which can detect the virus in clinical samples within a short time and has high sensitivity and specificity.

BIOTECHNIQUES (2022)

Review Virology

Repurposing Probenecid to Inhibit SARS-CoV-2, Influenza Virus, and Respiratory Syncytial Virus (RSV) Replication

Ralph A. Tripp, David E. Martin

Summary: Viral replication and transmissibility are the main causes of endemic and pandemic disease threats. Broad-spectrum antiviral agents are needed. The most common respiratory viruses are coronaviruses, respiratory syncytial viruses, and influenza viruses. Probenecid has been shown to be safe and effective in limiting the replication of influenza A virus and SARS-CoV-2, as well as inhibiting RSV replication in vitro and in vivo.

VIRUSES-BASEL (2022)

Article Virology

Probenecid Inhibits Respiratory Syncytial Virus (RSV) Replication

Jackelyn Murray, Harrison C. Bergeron, Les P. Jones, Zachary Beau Reener, David E. Martin, Fred D. Sancilio, Ralph A. Tripp

Summary: This study investigated the prophylactic and therapeutic efficacy of probenecid, an FDA-approved drug, in inhibiting RSV replication. The results showed that nanomolar concentrations of probenecid prevented RSV replication in vitro and in vivo, suggesting its potential as a prophylactic and chemotherapeutic agent for RSV.

VIRUSES-BASEL (2022)

Article Chemistry, Medicinal

Exploring Noncovalent Protease Inhibitors for the Treatment of Severe Acute Respiratory Syndrome and Severe Acute Respiratory Syndrome-Like Coronaviruses

Brendan T. Freitas, Daniil A. Ahiadorme, Rahul S. Bagul, Ian A. Durie, Samir Ghosh, Jarvis Hill, Naomi E. Kramer, Jackelyn Murray, Brady M. O'Boyle, Emmanuel Onobun, Michael G. Pirrone, Justin D. Shepard, Suzanne Enos, Yagya P. Subedi, Kapil Upadhyaya, Ralph A. Tripp, Brian S. Cummings, David Crich, Scott D. Pegan

Summary: In the past 20 years, both severe acute respiratory syndrome coronavirus-1 and severe acute respiratory syndrome coronavirus-2 have caused zoonotic outbreaks in humans. The PLpro enzyme from a subgroup 2b bat coronavirus has been studied to identify structural features and substrate specificity. Based on this, 30 novel noncovalent inhibitors for subgroup 2b PLpro enzymes were designed, providing new directions for antiviral development against this group of coronaviruses.

ACS INFECTIOUS DISEASES (2022)

Article Chemistry, Multidisciplinary

ISCOMs/MPLA-Adjuvanted SDAD Protein Nanoparticles Induce Improved Mucosal Immune Responses and Cross-Protection in Mice

Wandi Zhu, Jaeyoung Park, Thomas Pho, Lai Wei, Chunhong Dong, Joo Kim, Yao Ma, Julie A. Champion, Bao-Zhong Wang

Summary: This study explores the use of a novel type of core/shell protein nanoparticle as a vaccine for influenza virus, with the addition of appropriate adjuvants and finding effective mucosal vaccines to combat respiratory infection. The immune-stimulating complexes (ISCOMs)/monophosphoryl lipid A (MPLA) adjuvants boost the immune responses induced by the protein nanoparticles when administered intramuscularly. Furthermore, intranasal delivery of ISCOMs/MPLA-adjuvanted nanoparticles results in significantly strengthened immune responses and higher levels of antigen-specific antibodies in both systemic and local mucosa.
Article Virology

Immune Prophylaxis Targeting the Respiratory Syncytial Virus (RSV) G Protein

Harrison C. Bergeron, Jackelyn Murray, Aakash Arora, Ana M. Nunez M. Castrejon, Rebecca M. DuBois, Larry J. Anderson, Lawrence M. Kauvar, Ralph A. Tripp

Summary: Respiratory syncytial virus (RSV) causes respiratory disease in infants and elderly. Current immune prophylaxis is limited to anti-RSV fusion (F) protein monoclonal antibody (mAb). However, mAbs targeting the attachment (G) protein are necessary to prevent aberrant pathogenic responses. Two high-affinity anti-G protein mAbs, 3D3 and 2D10, have been identified as effective in neutralizing RSV and reducing disease. This study compares the neutralization and immune responses of 3D3, 2D10, and palivizumab in a mouse model of RSV infection.

VIRUSES-BASEL (2023)

Review Immunology

Understanding immunity to influenza: implications for future vaccine development

Ralph A. Tripp

Summary: Influenza virus constantly changes, making it difficult to develop immunity through vaccination. Efforts are being made to develop universal vaccines that can protect against various strains of influenza viruses. Understanding the host immune response is crucial for vaccine development.

EXPERT REVIEW OF VACCINES (2023)

Article Virology

Oral Probenecid for Nonhospitalized Adults with Symptomatic Mild-to-Moderate COVID-19

David E. Martin, Neelam Pandey, Purvi Chavda, Gurpreet Singh, Rakesh Sutariya, Frederic Sancilio, Ralph A. Tripp

Summary: This study suggests that treating symptomatic mild-to-moderate COVID-19 patients with probenecid can significantly decrease the time to viral clearance and result in a higher proportion of complete symptom resolution by day 10.

VIRUSES-BASEL (2023)

Article Immunology

Heterologous Prime-Boost Vaccination with Inactivated Influenza Viruses Induces More Effective Cross-Protection than Homologous Repeat Vaccination

Noopur Bhatnagar, Ki-Hye Kim, Jeeva Subbiah, Sakinah Muhammad-Worsham, Bo Ryoung Park, Rong Liu, Phillip Grovenstein, Bao-Zhong Wang, Sang-Moo Kang

Summary: The study suggests that heterologous prime-boost influenza vaccination strategy is more effective in inducing broader protective immunity compared to repeated vaccination with the same antigen, by increasing strain-specific hemagglutination inhibition titers and high levels of IgG antibodies.

VACCINES (2023)

Review Microbiology

Interferons-Implications in the Immune Response to Respiratory Viruses

Harrison C. Bergeron, Matthew R. Hansen, Ralph A. Tripp

Summary: This review examines the roles and functions of type I, II, and III IFN responses to respiratory virus infections, as well as the specific IFN responses underlying immunity and protection from disease.

MICROORGANISMS (2023)

Article Infectious Diseases

Anti-G protein antibodies targeting the RSV G protein CX3C chemokine region improve the interferon response

Harrison C. Bergeron, Lawrence M. Kauvar, Ralph A. Tripp

Summary: This study investigates how monoclonal antibodies against the RSV F and G proteins modify the type I and III IFN responses to RSV infection. The findings reveal that an anti-G protein monoclonal antibody improves the protective early antiviral response, which has important implications for vaccine and therapeutic design. This research provides insights into the role of G protein antibodies in improving IFN responses against RSV disease.

THERAPEUTIC ADVANCES IN INFECTIOUS DISEASE (2023)

Article Virology

Screening Drugs for Broad-Spectrum, Host-Directed Antiviral Activity: Lessons from the Development of Probenecid for COVID-19

Ralph A. Tripp, David E. Martin

Summary: In the early stages of drug discovery, assays are developed to evaluate the effectiveness of new and known molecular entities, primarily targeting specific features within the virus. However, screening efforts often prioritize finding active antiviral drugs against known viral targets, overlooking drugs that inhibit virus replication by targeting host genes or pathways.

VIRUSES-BASEL (2023)

Review Engineering, Biomedical

Engineered Nanoparticulate Vaccines to Combat Recurring and Pandemic Influenza Threats

Chunhong Dong, Bao-Zhong Wang

Summary: This review highlights the importance and characteristics of next-generation influenza vaccines, as well as the contribution of cutting-edge nanoparticle technology. It provides new insights into the rational design of nanoparticle universal vaccines to combat influenza epidemics and pandemics.

ADVANCED NANOBIOMED RESEARCH (2022)

暂无数据