scholarly journals Single-component multilayered self-assembling nanoparticles presenting rationally designed glycoprotein trimers as Ebola virus vaccines

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Linling He ◽  
Anshul Chaudhary ◽  
Xiaohe Lin ◽  
Cindy Sou ◽  
Tanwee Alkutkar ◽  
...  
Keyword(s):  
Neutralizing Antibodies ◽  
Ebola Virus ◽  
Heptad Repeat ◽  
T Cell Epitopes ◽  
Vaccine Strategy ◽  
Cell Responses ◽  
Self Assembling ◽  
Protein Nanoparticles ◽  
Main Target ◽  
Repertoire Sequencing

AbstractEbola virus (EBOV) glycoprotein (GP) can be recognized by neutralizing antibodies (NAbs) and is the main target for vaccine design. Here, we first investigate the contribution of the stalk and heptad repeat 1-C (HR1C) regions to GP metastability. Specific stalk and HR1C modifications in a mucin-deleted form (GPΔmuc) increase trimer yield, whereas alterations of HR1C exert a more complex effect on thermostability. Crystal structures are determined to validate two rationally designed GPΔmuc trimers in their unliganded state. We then display a modified GPΔmuc trimer on reengineered protein nanoparticles that encapsulate a layer of locking domains (LD) and a cluster of helper T-cell epitopes. In mice and rabbits, GP trimers and nanoparticles elicit cross-ebolavirus NAbs, as well as non-NAbs that enhance pseudovirus infection. Repertoire sequencing reveals quantitative profiles of vaccine-induced B-cell responses. This study demonstrates a promising vaccine strategy for filoviruses, such as EBOV, based on GP stabilization and nanoparticle display.

scholarly journals Single-component multilayered self-assembling nanoparticles presenting rationally designed glycoprotein trimers as Ebola virus vaccines

2020 ◽  
Author(s):  
Linling He ◽  
Anshul Chaudhary ◽  
Xiaohe Lin ◽  
Cindy Sou ◽  
Sonu Kumar ◽  
...  
Keyword(s):  
Neutralizing Antibodies ◽  
Ebola Virus ◽  
Single Component ◽  
Engineered Nanoparticles ◽  
Heptad Repeat ◽  
T Cell Epitopes ◽  
Self Assembling ◽  
Next Generation Sequencing Ngs ◽  
Insight Into

ABSTRACTThe Ebola virus (EBOV) glycoprotein (GP) can be recognized by neutralizing antibodies (NAbs) and is the main target for vaccine design. We first investigated the contribution of the stalk and the heptad repeat 1-C (HR1C) region to GP metastability. Specific stalk and HR1C modifications in a mucin-deleted form (GPΔmuc) increased trimer yield, while alteration of HR1C exerted a more complex effect on thermostability. Crystal structures were determined to validate these rationally designed GPΔmuc trimers in their unliganded state. We then displayed a modified GPΔmuc trimer on engineered nanoparticles with encapsulated locking domains (LD) and a cluster of helper T-cell epitopes. In mice and rabbits, GP trimers and nanoparticles elicited cross-ebolavirus NAbs as well as non-NAbs that enhance in-vitro infection. Next-generation sequencing (NGS) revealed B-cell profiles that are specific to vaccine platforms. This study provides insight into GP metastability and paves the way for development of an effective, pan-ebolavirus nanoparticle vaccine.TEASERWe rationally redesigned the EBOV glycoprotein and engineered single-component multilayered nanoparticles as vaccine candidates

scholarly journals Design, immunogenicity, and efficacy of a pan-sarbecovirus dendritic-cell targeting vaccine

2021 ◽  
Author(s):  
Séverin Coléon ◽  
Aurélie Wiedemann ◽  
Mathieu Surénaud ◽  
Christine Lacabaratz ◽  
Sophie Hue ◽  
...  
Keyword(s):  
T Cell ◽  
Neutralizing Antibodies ◽  
T Cell Responses ◽  
T Cell Epitopes ◽  
Viral Control ◽  
Cell Responses ◽  
Alignment Analysis ◽  
Antigen Presenting ◽  
New Generation

AbstractThe emergence of SARS-CoV-2 variants of concern (VOCs) that escape pre-existing antibody neutralizing responses increases the need for vaccines that target conserved epitopes and induce cross-reactive B- and T-cell responses. We used a computational approach and sequence alignment analysis to design a new-generation subunit vaccine targeting conserved sarbecovirus B- and T-cell epitopes from Spike (S) and Nucleocapsid (N) to antigen-presenting cells expressing CD40 (CD40.CoV2). We demonstrate the potency of CD40.CoV2 to elicit high levels of cross-neutralizing antibodies against SARS-CoV-2, VOCs, and SARS-CoV-1 in K18-hACE2 transgenic mice, associated with improved viral control and survival after challenge. In addition, we demonstrate the potency of CD40.CoV2 in vitro to recall human multi-epitope, functional, and cytotoxic SARS-CoV-2 S- and N-specific T-cell responses that are unaffected by VOC mutations and cross-reactive with SARS-CoV-1 and, to a lesser extent, MERS epitopes. Overall, these findings provide a framework for a pan-sarbecovirus vaccine.

scholarly journals Neutralizing Antibodies Induced by First-Generation gp41-Stabilized HIV-1 Envelope Trimers and Nanoparticles

mBio ◽  
2021 ◽  
Author(s):  
Sonu Kumar ◽  
Xiaohe Lin ◽  
Timothy Ngo ◽  
Benjamin Shapero ◽  
Cindy Sou ◽  
...  
Keyword(s):  
Neutralizing Antibodies ◽  
First Generation ◽  
Neutralizing Antibody ◽  
Tier 2 ◽  
Self Assembling ◽  
Protein Nanoparticles ◽  
Functional Analyses ◽  
Hiv 1

Self-assembling protein nanoparticles (NPs) presenting BG505 envelope (Env) trimers can elicit tier 2 HIV-1-neutralizing antibody (NAb) responses more effectively than soluble trimers. In the present study, monoclonal NAbs were isolated from previously immunized mice and rabbits for structural and functional analyses, which revealed that potent mouse NAbs recognize the C3/V4 region and small NP-elicited rabbit NAbs primarily target known glycan holes on BG505 Env.

scholarly journals Nonneutralizing Antibodies Induced by the HIV-1 gp41 NHR Domain Gain Neutralizing Activity in the Presence of the HIV Fusion Inhibitor Enfuvirtide: a Potential Therapeutic Vaccine Strategy

2015 ◽  
Vol 89 (13) ◽  
pp. 6960-6964 ◽  
Author(s):  
Qian Wang ◽  
Wenwen Bi ◽  
Xiaojie Zhu ◽  
Haoyang Li ◽  
Qianqian Qi ◽  
...  
Keyword(s):  
Neutralizing Antibodies ◽  
Therapeutic Vaccine ◽  
Viral Envelope ◽  
Heptad Repeat ◽  
Fusion Inhibitor ◽  
Vaccine Strategy ◽  
Therapeutic Vaccines ◽  
Neutralizing Activity ◽  
Key Barrier ◽  
Hiv 1

A key barrier against developing preventive and therapeutic human immunodeficiency virus (HIV) vaccines is the inability of viral envelope glycoproteins to elicit broad and potent neutralizing antibodies. However, in the presence of fusion inhibitor enfuvirtide, we show that the nonneutralizing antibodies induced by the HIV type 1 (HIV-1) gp41 N-terminal heptad repeat (NHR) domain (N63) exhibit potent and broad neutralizing activity against laboratory-adapted HIV-1 strains, including the drug-resistant variants, and primary HIV-1 isolates with different subtypes, suggesting the potential of developing gp41-targeted HIV therapeutic vaccines.

scholarly journals “Monozygotic twins discordant for severe clinical recurrence of COVID-19 show drastically distinct T cell responses to SARS-Cov-2”

2021 ◽  
Author(s):  
Mateus V. de Castro ◽  
Keity S. Santos ◽  
Juliana S. Apostolico ◽  
Edgar R. Fernandes ◽  
Rafael R. Almeida ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cell ◽  
Neutralizing Antibodies ◽  
Twin Pair ◽  
T Cell Responses ◽  
Monozygotic Twin ◽  
Type I ◽  
T Cell Epitopes ◽  
Clinical Recurrence ◽  
Cell Responses

ABSTRACTBackgroundClinical recurrence of COVID-19 in convalescent patients has been reported, which immune mechanisms have not been thoroughly investigated. Presence of neutralizing antibodies suggests other types of immune response are involved.MethodsWe assessed the innate type I/III IFN response, T cell responses to SARS-CoV-2 with IFNγ ELISPOT, binding and neutralizing antibody assays, in two monozygotic twin pairs with one COVID-19 recurrence case.ResultsIn pair 1, four months after a first mild episode of infection for both siblings, one displayed severe clinical recurrence of COVID-19. Twin pair 2 of siblings underwent non-recurring asymptomatic infection. All fours individuals presented similar overall responses, except for remarkably difference found in specific cellular responses. Recurring sibling presented a reduced number of recognized T cell epitopes as compared to the other three including her non-recurring sibling.ConclusionsOur results suggest that an effective SARS-CoV-2-specific T cell immune response is key for complete viral control and avoidance of clinical recurrence of COVID-19. Besides, adaptive immunity can be distinct in MZ twins. Given the rising concern about SARS-CoV-2 variants that evade neutralizing antibodies elicited by vaccination or infection, our study stresses the importance of T cell responses in protection against recurrence/reinfection.Key pointsImmune parameters leading to COVID-19 recurrence/reinfection are incompletely understood. A COVID-19 recurrence case in a monozygotic twin pair is described with an intact antibody and innate type I/III Interferon response and drastically reduced number of recognized SARS-CoV-2 T cell epitopes.

scholarly journals Self-assembling nanoparticles presenting receptor binding domain and stabilized spike as next-generation COVID-19 vaccines

2020 ◽  
Author(s):  
Linling He ◽  
Xiaohe Lin ◽  
Ying Wang ◽  
Ciril Abraham ◽  
Cindy Sou ◽  
...  
Keyword(s):  
Receptor Binding ◽  
Neutralizing Antibody ◽  
Binding Domain ◽  
Heptad Repeat ◽  
High Yield ◽  
Receptor Binding Domain ◽  
Next Generation ◽  
Vaccine Strategy ◽  
Self Assembling ◽  
Cell Immunity

ABSTRACTWe present a comprehensive vaccine strategy for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) by combining antigen optimization and nanoparticle display. We first developed a receptor binding domain (RBD)-specific antibody column for purification and displayed the RBD on self-assembling protein nanoparticles (SApNPs) using the SpyTag/SpyCatcher system. We then identified the heptad repeat 2 (HR2) stalk as a major cause of spike metastability, designed an HR2-deleted glycine-capped spike (S2GΔHR2), and displayed S2GΔHR2 on three SApNPs with high yield, purity, and antigenicity. Compared to the RBD, the RBD-ferritin SApNP elicited a more potent murine neutralizing antibody (NAb) response on par with the spike. S2GΔHR2 elicited two-fold-higher NAb titers than the proline-capped spike (S2P), while S2GΔHR2 SApNPs derived from multilayered E2p and I3-01v9 60-mers elicited up to 10-fold higher NAb titers. The S2GΔHR2-presenting I3-01v9 SApNP also induced critically needed T-cell immunity, thereby providing a next-generation vaccine candidate to battle the COVID-19 pandemic.ONE-SENTENCE SUMMARYThe receptor binding domain and stabilized SARS-CoV-2 spike were displayed on nanoparticles as vaccine antigens and elicited potent immune responses.

scholarly journals Human T-Cell Responses to Vaccinia Virus Envelope Proteins

2006 ◽  
Vol 80 (20) ◽  
pp. 10010-10020 ◽  
Author(s):  
Jie Tang ◽  
Mariam Murtadha ◽  
Matthias Schnell ◽  
Laurence C. Eisenlohr ◽  
Jay Hooper ◽  
...  
Keyword(s):  
T Cell ◽  
Vaccinia Virus ◽  
Neutralizing Antibodies ◽  
Mononuclear Cells ◽  
T Cell Responses ◽  
Envelope Proteins ◽  
T Cell Epitopes ◽  
Virus Envelope ◽  
Cell Responses ◽  
Human T Cell

ABSTRACT One approach for a safer smallpox vaccine is to utilize recombinant subunits rather than live vaccinia virus (VACV). The products of the VACV envelope genes A27L, L1R, B5R, and A33R induce protective antibodies in animal models. We propose that proteins that elicit T-cell responses, as well as neutralizing antibodies, will be important to include in a molecular vaccine. To evaluate VACV-specific memory T-cell responses, peripheral blood mononuclear cells (PBMC) from four VACV vaccinees were tested against whole VACV and the individual envelope proteins A27, B5, L1, and A33, using gamma interferon enzyme-linked immunospot and cytokine flow cytometry assays. PBMC were stimulated with autologous dendritic cells infected with VACV or electroporated with individual VACV protein mRNAs. T-cell lines from all donors, vaccinated from 1 month to over 20 years ago, recognized all four VACV envelope proteins. Both CD4+ and CD8+ T-cell responses to each protein were detected. Further analysis focused on representative proteins B5 and A27. PBMC from a recent vaccinee exhibited high frequencies of CD4+ and CD8+ T-cell precursors to both B5 (19.8 and 20%, respectively) and A27 (6.8 and 3.7%). In comparison, B5- and A27-specific T-cell frequencies ranged from 0.4 to 1.3% in a donor vaccinated 3 years ago. Multiple CD4+ and CD8+ T-cell epitopes were identified from both A27 and B5, using overlapping 15-mer peptides. These data suggest that all four VACV envelope proteins may contribute to protective immunity, not only by inducing antibody responses, but also by eliciting T-cell responses.

scholarly journals Comparison of Immunogenicity in Rhesus Macaques of Transmitted-Founder, HIV-1 Group M Consensus, and Trivalent Mosaic Envelope Vaccines Formulated as a DNA Prime, NYVAC, and Envelope Protein Boost

2015 ◽  
Vol 89 (12) ◽  
pp. 6462-6480 ◽  
Author(s):  
Sandrine L. Hulot ◽  
Bette Korber ◽  
Elena E. Giorgi ◽  
Nathan Vandergrift ◽  
Kevin O. Saunders ◽  
...  
Keyword(s):  
T Cell ◽  
In Silico ◽  
Neutralizing Antibodies ◽  
Rhesus Macaques ◽  
Antibody Responses ◽  
T Cell Epitopes ◽  
Cell Responses ◽  
Protein Boost ◽  
Env Protein ◽  
Hiv 1

ABSTRACTAn effective human immunodeficiency virus type 1 (HIV-1) vaccine must induce protective antibody responses, as well as CD4+and CD8+T cell responses, that can be effective despite extraordinary diversity of HIV-1. The consensus and mosaic immunogens are complete but artificial proteins, computationally designed to elicit immune responses with improved cross-reactive breadth, to attempt to overcome the challenge of global HIV diversity. In this study, we have compared the immunogenicity of a transmitted-founder (T/F) B clade Env (B.1059), a global group M consensus Env (Con-S), and a global trivalent mosaic Env protein in rhesus macaques. These antigens were delivered using a DNA prime-recombinant NYVAC (rNYVAC) vector and Env protein boost vaccination strategy. While Con-S Env was a single sequence, mosaic immunogens were a set of three Envs optimized to include the most common forms of potential T cell epitopes. Both Con-S and mosaic sequences retained common amino acids encompassed by both antibody and T cell epitopes and were central to globally circulating strains. Mosaics and Con-S Envs expressed as full-length proteins bound well to a number of neutralizing antibodies with discontinuous epitopes. Also, both consensus and mosaic immunogens induced significantly higher gamma interferon (IFN-γ) enzyme-linked immunosorbent spot assay (ELISpot) responses than B.1059 immunogen. Immunization with these proteins, particularly Con-S, also induced significantly higher neutralizing antibodies to viruses than B.1059 Env, primarily to tier 1 viruses. Both Con-S and mosaics stimulated more potent CD8-T cell responses against heterologous Envs than did B.1059. Both antibody and cellular data from this study strengthen the concept of usingin silico-designed centralized immunogens for global HIV-1 vaccine development strategies.IMPORTANCEThere is an increasing appreciation for the importance of vaccine-induced anti-Env antibody responses for preventing HIV-1 acquisition. This nonhuman primate study demonstrates thatin silico-designed global HIV-1 immunogens, designed for a human clinical trial, are capable of eliciting not only T lymphocyte responses but also potent anti-Env antibody responses.

scholarly journals Characterisation of the T-cell response to Ebola virus glycoprotein amongst survivors of the 2013–16 West Africa epidemic

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
T. R. W. Tipton ◽  
Y. Hall ◽  
J. A. Bore ◽  
A. White ◽  
L. S. Sibley ◽  
...  
Keyword(s):  
T Cell ◽  
West Africa ◽  
Cell Response ◽  
Ebola Virus ◽  
Medical Condition ◽  
Virus Disease ◽  
T Cell Response ◽  
Ebola Virus Disease ◽  
Cell Phenotype ◽  
T Cell Epitopes

AbstractZaireebolavirus (EBOV) is a highly pathogenic filovirus which can result in Ebola virus disease (EVD); a serious medical condition that presents as flu like symptoms but then often leads to more serious or fatal outcomes. The 2013–16 West Africa epidemic saw an unparalleled number of cases. Here we show characterisation and identification of T cell epitopes in surviving patients from Guinea to the EBOV glycoprotein. We perform interferon gamma (IFNγ) ELISpot using a glycoprotein peptide library to identify T cell epitopes and determine the CD4+ or CD8+ T cell component response. Additionally, we generate data on the T cell phenotype and measure polyfunctional cytokine secretion by these antigen specific cells. We show candidate peptides able to elicit a T cell response in EBOV survivors and provide inferred human leukocyte antigen (HLA) allele restriction. This data informs on the long-term T cell response to Ebola virus disease and highlights potentially important immunodominant peptides.

scholarly journals HIV mRNA Vaccines—Progress and Future Paths

Vaccines ◽  
2021 ◽  
Vol 9 (2) ◽  
pp. 134
Author(s):  
Zekun Mu ◽  
Barton F. Haynes ◽  
Derek W. Cain
Keyword(s):  
T Cell ◽  
Neutralizing Antibodies ◽  
Vaccination Strategy ◽  
T Cell Responses ◽  
Neutralizing Antibody ◽  
Cytotoxic T Cell ◽  
Therapeutic Vaccines ◽  
Cell Responses ◽  
Broadly Neutralizing Antibody ◽  
Cytotoxic T Cell Responses

The SARS-CoV-2 pandemic introduced the world to a new type of vaccine based on mRNA encapsulated in lipid nanoparticles (LNPs). Instead of delivering antigenic proteins directly, an mRNA-based vaccine relies on the host’s cells to manufacture protein immunogens which, in turn, are targets for antibody and cytotoxic T cell responses. mRNA-based vaccines have been the subject of research for over three decades as a platform to protect against or treat a variety of cancers, amyloidosis and infectious diseases. In this review, we discuss mRNA-based approaches for the generation of prophylactic and therapeutic vaccines to HIV. We examine the special immunological hurdles for a vaccine to elicit broadly neutralizing antibodies and effective T cell responses to HIV. Lastly, we outline an mRNA-based HIV vaccination strategy based on the immunobiology of broadly neutralizing antibody development.

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