MERS-CoV Spike Vaccine-induced N-Terminal Domain-specific Antibodies are More Protective than Receptor Binding Domain-specific Antibodies DOI Creative Commons
Olubukola M. Abiona, Nianshuang Wang, Sarah R. Leist

et al.

iScience, Journal Year: 2024, Volume and Issue: 28(2), P. 111632 - 111632

Published: Dec. 18, 2024

The COVID-19 pandemic underscores the need to prepare for future emerging coronavriuses (CoVs) by understanding principles behind effective CoV vaccine design such as protective immunity and antibody responses. To study which epitopes subdomains contribute in vivo protection, we utilized prefusion-stabilized spike protein of MERS-CoV, MERS S-2P, a immunogen. Vaccination with S-2P elicited both receptor-binding domain (RBD)- non-RBD-specific antibodies, including N-terminal (NTD)-specific G2-and CDC2-A2-like antibodies. Intriguingly, immunogen S-2P_ΔRBD, RBDs removed, protects comparably S1 immunogens against MERS-CoV challenge. Moreover, passive transfer studies polyclonal IgG from immunized mice depleted subdomain-specific antibodies demonstrated that non-RBD protected more than non-NTD Altogether, these findings illustrate in-vivo protection is not solely driven RBD-specific highlights importance targeting sites designs.

Language: Английский

Vaccine design via antigen reorientation DOI Creative Commons
Duo Xu, Joshua Carter, Chunfeng Li

et al.

Nature Chemical Biology, Journal Year: 2024, Volume and Issue: 20(8), P. 1012 - 1021

Published: Jan. 15, 2024

Abstract A major challenge in creating universal influenza vaccines is to focus immune responses away from the immunodominant, variable head region of hemagglutinin (HA-head) and toward evolutionarily conserved stem (HA-stem). Here we introduce an approach control antigen orientation via site-specific insertion aspartate residues that facilitates binding alum. We demonstrate generalizability this with antigens Ebola, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viruses observe enhanced neutralizing antibody all cases. then reorient H2 HA ‘upside-down’ configuration increase exposure immunogenicity HA-stem. The reoriented (reoH2HA) on alum induced stem-directed antibodies cross-react both group 1 subtypes. Electron microscopy polyclonal epitope mapping (EMPEM) revealed reoH2HA (group 1) elicits cross-reactive targeting HA-stems. Our results highlight reorientation as a generalizable for designing epitope-focused vaccines.

Language: Английский

Citations

18
RBD-displaying OMV nanovaccine boosts immunity against SARS-CoV-2 DOI Creative Commons

Rang Feng,

Ruo‐Yi Xue,

Chang Liu

et al.

Journal of Nanobiotechnology, Journal Year: 2025, Volume and Issue: 23(1)

Published: Feb. 8, 2025

Since the emergence of SARS-CoV-2, causative agent COVID-19, global health landscape has confronted an unprecedented and formidable challenge. The SARS-CoV-2 receptor-binding domain (RBD) is a key antigen in vaccine design. However, its low immunogenicity been hurdle, resulting production minimal anti-RBD antibodies even when combined with alum adjuvant. Outer membrane vesicles (OMVs), secreted by Gram-negative bacteria, are nanospherical structures that can display or deliver antigens while also providing adjuvant activity through pathogen-associated molecular patterns (PAMPs). In this study, we utilized SpyTag (ST)/SpyCatcher (SC) bioconjugation system to couple OMV RBD vitro. We successfully prepared 'plug-and-display' nanovaccine OMV-RBD, which demonstrated good safety profiles promoted uptake DCs maturation BMDCs activating TLR3 NOD2 signaling pathways. Both intranasal intramuscular immunization OMV-RBD elicited robust antigen-specific humoral cellular immune responses. Importantly, induced effectively inhibited binding human angiotensin-converting enzyme 2 (hACE2) neutralized pseudoviruses. This platform offers alternative strategy for developing recombinant subunit vaccines against potentially enhancing responses improving efficacy.

Language: Английский

Citations

1
Influence of membrane on the antigen presentation of the HIV-1 envelope membrane proximal external region (MPER) DOI
César A. López,

S. Munir Alam,

Cynthia A. Derdeyn

et al.

Current Opinion in Structural Biology, Journal Year: 2024, Volume and Issue: 88, P. 102897 - 102897

Published: Aug. 22, 2024

Language: Английский

Citations

6
Revisiting the dimensions of universal vaccine with special focus on COVID-19: Efficacy versus methods of designing DOI

Puja Jaishwal,

Kisalay Jha,

Satarudra Prakash Singh

et al.

International Journal of Biological Macromolecules, Journal Year: 2024, Volume and Issue: 277, P. 134012 - 134012

Published: July 22, 2024

Language: Английский

Citations

4
Heterologous Prime-Boost with Immunologically Orthogonal Protein Nanoparticles for Peptide Immunofocusing DOI Creative Commons
Sonia Bhattacharya, Matthew C. Jenkins, Parisa Keshavarz-Joud

et al.

ACS Nano, Journal Year: 2024, Volume and Issue: 18(31), P. 20083 - 20100

Published: July 23, 2024

Protein nanoparticles are effective platforms for antigen presentation and targeting effector immune cells in vaccine development. Encapsulins a class of protein-based microbial nanocompartments that self-assemble into icosahedral structures with external diameters ranging from 24 to 42 nm. Myxococcus xanthus were designed package bacterial RNA when produced E. coli shown have immunogenic self-adjuvanting properties enhanced by this RNA. We genetically incorporated 20-mer peptide derived mutant strain the SARS-CoV-2 receptor binding domain (RBD) encapsulin protomeric coat protein on exterior surface particle, inducing formation several nonicosahedral characterized cryogenic electron microscopy. This immunogen elicited conformationally relevant humoral responses RBD. Immunological recognition was same presented heterologous prime/boost vaccination strategy using engineered previously reported variant PP7 virus-like leading development selective antibody response against RBD point mutant. While generating epitope-focused is an interplay between inherent B/T cells, here we demonstrate use orthogonal fine-tune control epitope focusing.

Language: Английский

Citations

4
Rethinking Optimal Immunogens to Face SARS‐CoV‐2 Evolution Through Vaccination DOI Creative Commons
Julià Blanco, Benjamin Trinité, Joan Puig‐Barberà

et al.

Influenza and Other Respiratory Viruses, Journal Year: 2025, Volume and Issue: 19(1)

Published: Jan. 1, 2025

ABSTRACT SARS‐CoV‐2, which originated in China late 2019, quickly fueled the global COVID‐19 pandemic, profoundly impacting health and economy worldwide. A series of vaccines, mostly based on full SARS‐CoV‐2 Spike protein, were rapidly developed, showing excellent humoral cellular responses high efficacy against both symptomatic infection severe disease. However, viral evolution waning neutralizing strongly challenged vaccine long term effectiveness, mainly infection, making necessary a strategy repeated updated booster shots. In this vaccination context, antibody repertoire diversification was evidenced, although immune imprinting after doses or reinfection also demonstrated identified as major determinant immunological to antigen exposures. Considering that small domain receptor binding (RBD), is target antibodies concentrates most mutations, following text aims provide insights into ongoing debate over best strategies for boosters. We address relevance developing new vaccines evolving RBD, thus focusing relevant antigenic sites variants. combination with immunofusing computerized approaches could minimize imprinting, therefore optimizing efficacy.

Language: Английский

Citations

0
Structural characterization of influenza group 1 chimeric hemagglutinins as broad vaccine immunogens DOI Creative Commons
Yen Thi Kim Nguyen, Xueyong Zhu, Julianna Han

et al.

Proceedings of the National Academy of Sciences, Journal Year: 2025, Volume and Issue: 122(7)

Published: Feb. 12, 2025

Chimeric hemagglutinins (cHA) appear to be promising for the design and development of universal influenza vaccines. Influenza A group 1 cHAs, cH5/1, cH8/1, cH11/1, comprising an H1 stem attached either H5, H8, or H11 globular head, have been used sequentially as vaccine immunogens in human clinical trials induced high levels broadly protective antibodies. Using X-ray crystallography negative-stain electron microscopy, we determined structures cH11/1 HAs their apo (unliganded) antibody Fab-bound states. Stem-reactive antibodies 3E1 31.b.09 recognize cognate epitopes HAs. However, with head domains are rotated by 35 45° around threefold axis HA trimer compared native a more splayed-open conformation at base. is structurally native-like but resembles cH5/1 31.b.09, whereas cH8/1 exhibited range closed-to-open configurations some separation domains. Furthermore, all these cHAs effectively bound broad interface other Thus, exhibit structural plasticity without compromising elicitation cross-reactive

Language: Английский

Citations

0
Structure-based design of an immunogenic, conformationally stabilized FimH antigen for a urinary tract infection vaccine DOI Creative Commons
Natalie C. Silmon de Monerri, Ye Che, Joshua A. Lees

et al.

PLoS Pathogens, Journal Year: 2025, Volume and Issue: 21(2), P. e1012325 - e1012325

Published: Feb. 19, 2025

Adhesion of E. coli to the urinary tract epithelium is a critical step in establishing infections. FimH an adhesin positioned on fimbrial tip which binds mannosylated proteins via its lectin domain (FimH LD ). interest as target vaccines prevent infections (UTI). Previously, difficulties obtaining purified recombinant from along with poor inherent immunogenicity have hindered development effective vaccine candidates. To overcome these challenges, we devised novel production method using mammalian cells produce high yields homogeneous protein comparable biochemical and immunogenic properties produced coli. Next, optimize conformational stability FimH, used computational approach design improved mutants evaluated their biophysical properties, murine bacterial adhesion inhibition assay. This identified variant (FimH- d onor- s trand complemented Fim G peptide ‘triple mutant’, FimH-DSG TM) capable blocking that at cells. By x-ray crystallography, confirmed stabilized structure TM similar native tip. Characterization monoclonal antibodies elicited by can block binding surfaces 4 non-overlapping sites whose epitopes were mapped combinatorial cryogenic electron microscopy approach. Novel inhibitory identified, revealing diverse functional mechanisms FimH-directed relevance FimH-targeted UTI vaccines.

Language: Английский

Citations

0
Structure-Guided Loop Grafting Improves Expression and Stability of Influenza Neuraminidase for Vaccine Development DOI Open Access
Pramila Rijal,

Leiyan Wei,

Guido C. Paesen

et al.

Published: March 20, 2025

Influenza neuraminidase is a crucial target for protective antibodies, yet the development of recombinant protein as vaccine has been held back by instability and variable expression. We have taken pragmatic approach to improving expression stability grafting antigenic surface loops from low-expressing proteins onto scaffold high-expressing counterparts. The resulting hybrid retained properties loop donor while benefiting high-yield expression, stability, tetrameric structure recipient. These were recognised broad set human monoclonal antibodies elicited influenza infection or vaccination, with X-ray structures validating accurate structural conformation grafted enzymatic cavity. Immunisation mice hybrids induced inhibitory conferred protected against lethal challenge. This technique offers robust solution development.

Language: Английский

Citations

0
Structure-Guided Loop Grafting Improves Expression and Stability of Influenza Neuraminidase for Vaccine Development DOI Open Access
Pramila Rijal,

Leiyan Wei,

Guido C. Paesen

et al.

Published: March 20, 2025

Influenza neuraminidase is a crucial target for protective antibodies, yet the development of recombinant protein as vaccine has been held back by instability and variable expression. We have taken pragmatic approach to improving expression stability grafting antigenic surface loops from low-expressing proteins onto scaffold high-expressing counterparts. The resulting hybrid retained properties loop donor while benefiting high-yield expression, stability, tetrameric structure recipient. These were recognised broad set human monoclonal antibodies elicited influenza infection or vaccination, with X-ray structures validating accurate structural conformation grafted enzymatic cavity. Immunisation mice hybrids induced inhibitory conferred protected against lethal challenge. This technique offers robust solution development.

Language: Английский

Citations

0