History of vaccination

Plotkin, Stanley А.

doi:10.1073/pnas.1400472111

Cited by 486 publications

(394 citation statements)

References 68 publications

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“…HIV-1 envelope | neutralizing antibodies | antigenic diversity | clade C trimers | HIV immunogens V accines have successfully stopped or limited infections by preventing pathogen transmission and have thereby contributed toward eradication of deadly diseases (1). Nonetheless, successful vaccination against highly variable pathogens, such as enveloped RNA viruses, remains a daunting task.…”

mentioning

confidence: 99%

Design and structure of two HIV-1 clade C SOSIP.664 trimers that increase the arsenal of native-like Env immunogens

Julien

Lee

Ozorowski

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

116

120

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A key challenge in the quest toward an HIV-1 vaccine is design of immunogens that can generate a broadly neutralizing antibody (bnAb) response against the enormous sequence diversity of the HIV-1 envelope glycoprotein (Env). We previously demonstrated that a recombinant, soluble, fully cleaved SOSIP.664 trimer based on the clade A BG505 sequence is a faithful antigenic and structural mimic of the native trimer in its prefusion conformation. Here, we sought clade C native-like trimers with comparable properties. We identified DU422 and ZM197M SOSIP.664 trimers as being appropriately thermostable (Tm of 63.4°C and 62.7°C, respectively) and predominantly native-like, as determined by negative-stain electron microscopy (EM). Size exclusion chromatography, ELISA, and surface plasmon resonance further showed that these trimers properly display epitopes for all of the major bnAb classes, including quaternary-dependent, trimer-apex (e.g., PGT145) and gp120/gp41 interface (e.g., PGT151) epitopes. A cryo-EM reconstruction of the ZM197M SOSIP.664 trimer complexed with VRC01 Fab against the CD4 binding site at subnanometer resolution revealed a striking overall similarity to its BG505 counterpart with expected local conformational differences in the gp120 V1, V2, and V4 loops. These stable clade C trimers contribute additional diversity to the pool of native-like Env immunogens as key components of strategies to induce bnAbs to HIV-1.HIV-1 envelope | neutralizing antibodies | antigenic diversity | clade C trimers | HIV immunogens

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mentioning

confidence: 99%

Design and structure of two HIV-1 clade C SOSIP.664 trimers that increase the arsenal of native-like Env immunogens

Julien

Lee

Ozorowski

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

116

120

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“…VLPs mimic the capsid structure of real viruses, but lack infectious genetic material. Selected VLPs derived from pathogens have already provided major advances in the development of vaccines that have known and relatively homogeneous structures as well as enhanced immunogenicity (2). Such nanoparticles provide comparable cellular uptake and intracellular trafficking compared with natural viruses (3), and also have repetitive surfaces for the high-density display of vaccine antigens (4).…”

mentioning

confidence: 99%

Assessing sequence plasticity of a virus-like nanoparticle by evolution toward a versatile scaffold for vaccines and drug delivery

Chan

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

117

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Virus-like particles (VLPs) have been extensively explored as nanoparticle vehicles for many applications in biotechnology (e.g., vaccines, drug delivery, imaging agents, biocatalysts). However, amino acid sequence plasticity relative to subunit expression and nanoparticle assembly has not been explored. Whereas the hepatitis B core protein (HBc) VLP appears to be the most promising model for fundamental and applied studies; particle instability, antigen fusion limitations, and intrinsic immunogenicity have limited its development. Here, we apply Escherichia coli-based cell-free protein synthesis (CFPS) to rapidly produce and screen HBc protein variants that still self-assemble into VLPs. To improve nanoparticle stability, artificial covalent disulfide bridges were introduced throughout the VLP. Negative charges on the HBc VLP surface were then reduced to improve surface conjugation. However, removal of surface negative charges caused low subunit solubility and poor VLP assembly. Solubility and assembly as well as surface conjugation were greatly improved by transplanting a rare spike region onto the common shell structure. The newly stabilized and extensively modified HBc VLP had almost no immunogenicity in mice, demonstrating great promise for medical applications. This study introduces a general paradigm for functional improvement of complex protein assemblies such as VLPs. This is the first study, to our knowledge, to systematically explore the sequence plasticity of viral capsids as an approach to defining structure function relationships for viral capsid proteins. Our observations on the unexpected importance of the HBc spike tip charged state may also suggest new mechanistic routes toward viral therapeutics that block capsid assembly.virus-like particle | engineered nanoparticles | disulfide stabilization | hepatitis core protein | cell-free protein synthesis V irus-like particles (VLPs) are probably the most precisely defined and, therefore, potentially the most useful complex nanometer-scale scaffolds (1). VLPs mimic the capsid structure of real viruses, but lack infectious genetic material. Selected VLPs derived from pathogens have already provided major advances in the development of vaccines that have known and relatively homogeneous structures as well as enhanced immunogenicity (2). Such nanoparticles provide comparable cellular uptake and intracellular trafficking compared with natural viruses (3), and also have repetitive surfaces for the high-density display of vaccine antigens (4). In addition, VLPs offer favorable trafficking from the injection site to lymph nodes (5). Since the first reported use of a hepatitis B core protein (HBc) VLP as an antigen carrier in 1987 (6), at least 110 VLP vaccine candidates have been constructed by using capsid proteins from 35 different viral families (7).Among different types of VLPs, the HBc VLP is the most flexible and promising model for fundamental and applied immunological studies (8). One advantage of the HBc VLP platform is that the capsids can be produ...

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“…Lehenengo taldean, badaude txerto inaktibatuak (hilda dauden organismoak) eta indargabetuak (hainbat tratamenduren bitartez birulentzia galdu duten baina bizirik dauden organismoez osaturikoak). Bigarren taldean aldiz, errekonbinazio bidez ekoiztutako organismoaren antigeno jakin batzuk; hauek besteak beste, proteina, DNA edo birusak imitatzen dituzten partikulak (VLP, ingelesetik, Viral Like Particles) izan daitezke [21]. Bigarren taldeko txertoen abantailak bi dira; alde batetik, sistema immunearen erantzuna pizten duten patogenoaren molekulak normalean gutxi direnez, errazagoa da estrategia «minimalista» honen bitartez autoimmunitate-erreakzioak ekiditea.…”

Section: Txerto Motakunclassified

GIBaren aurkako txertoaren bila

Torralba¹,

Goikoetxea²,

Apellániz

2017

EKAIA

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Laburpena: GIB birusa, giza historian zehar gertatu den pandemiarik hilgarrienetariko baten eragilea da, HIESa alegia. Nahiz eta azken urteetan HAART terapia antirretrobiralari esker heriotza tasa asko murriztu den, infekzio berrien kopurua etengabe emendatzen ari da. Hori dela eta, badirudi pandemiari azkenik amaiera eman ahal izateko txerto prebentibo baten garapena izan daitekeela jokaera eraginkorrena. Hala ere, birusak garatu dituen estrategia natural desberdinek eta immunizazioz sortu nahi diren antigorputz neutralizatzaileen ezaugarri bereziek oso zaila egiten dute infekziotik babestuko lukeen txertoaren garapena. RV144 entsegu klinikoaren eraginkortasun apalek eta espektro zabaleko antigorputz neutralizatzaileekin immunizazio pasiboz lorturiko emaitzek iradokitzen dute hurbilago gaudela txerto eraginkor baten garapena lortzetik. Orain arte hainbat txerto mota erabili diren arren, emaitza onik ez da lortu. Hala ere, sakon aztertzen ari da bai immunogeno naturalen egitura, bai immunogenoak ezagutzen dituzten antigorputzen egitura, eta badirudi, besteak beste, ikerketa horiek bide berriak irekiko dituztela txerto berrien diseinuan. Hitz gakoak: GIB, txertoa, antigorputz neutralizatzaileak, Env fusio-glukoproteina.Abstract: HIV is the causative agent of one of the most lethal pandemics in human history, AIDS. Although in recent years HAART therapy has considerably reduced death rate, new infections keep arising. Therefore, a preventive vaccine remains the most promising tool to end the pandemic. However, the virus has developed many natural strategies to evade the immune system and, moreover, the special characteristics of the neutralizing antibodies that a vaccine aims to elicit, makes vaccine design extremely challenging. The efficiency of the RV144 clinical trial and the promising results obtained by passive immunization with broadly neutralizing antibodies suggest that the objective of obtaining an effective vaccine is closer. Until now, a myriad of vaccine strategies have been attempted but the expected results have not been yet ob-EKAIA 32.indd 7 EKAIA 32.indd 7

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History of vaccination

Cited by 486 publications

References 68 publications

Design and structure of two HIV-1 clade C SOSIP.664 trimers that increase the arsenal of native-like Env immunogens

Design and structure of two HIV-1 clade C SOSIP.664 trimers that increase the arsenal of native-like Env immunogens

Assessing sequence plasticity of a virus-like nanoparticle by evolution toward a versatile scaffold for vaccines and drug delivery

GIBaren aurkako txertoaren bila

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