Nanoparticle Vaccines for Inducing HIV-1 Neutralizing Antibodies

Brinkkemper, Mitch; Sliepen, Kwinten

doi:10.3390/vaccines7030076

Cited by 42 publications

(62 citation statements)

References 95 publications

(154 reference statements)

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“…Because previous work involving icosahedral nanoparticle scaffolds displaying HIV-1 Env trimers has shown that antigen crowding can modulate the accessibility of specific epitopes and thereby influence the humoral immune response 19,36 , we characterized the antigenicity of the BG505 SOSIP fusion nanoparticles in more detail.…”

Section: Geometriesmentioning

confidence: 99%

“…These proteins represent a panel of molecules well-suited to probe not only the adaptive immune response, but also other biological systems across various size scales.The ability to fully customize the structures of nanoparticle scaffolds could be particularly useful for HIV-1 Env-based immunogens. While previous studies of nanoparticle-displayed HIV-1 Env trimers have demonstrated enhanced immunogenicity39 , the effects are often modest compared to those observed for other antigens1,2,18,36 . While there may exist intrinsic peculiarities to HIV-1 Env that limit increases in Ab responses upon multivalent display40,41 , limitations associated with epitope inaccessibility caused by crowding of the trimers on nanoparticle surfaces have also been identified19 .…”

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confidence: 98%

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Tailored Design of Protein Nanoparticle Scaffolds for Multivalent Presentation of Viral Glycoprotein Antigens

Ueda

Antanasijevic

Fallas

et al. 2020

Preprint

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The adaptive immune system is highly sensitive to arrayed antigens, and multivalent display of viral glycoproteins on symmetric scaffolds has been found to substantially increase the elicitation of antigen-specific antibodies. Motivated by the considerable promise of this strategy for next-generation anti-viral vaccines, we set out to design new self-assembling protein nanoparticles with geometries specifically tailored to scaffold ectodomains of different viral glycoproteins. We first designed and characterized homo-trimers from designed repeat proteins with N-terminal helices positioned to match the C termini of several viral glycoprotein trimers. Oligomers found to experimentally adopt the designed configuration were then used to generate nanoparticles with tetrahedral, octahedral, or icosahedral symmetry. Examples of all three target symmetries were experimentally validated by cryo-electron microscopy and several were assessed for their ability to display viral glycoproteins via genetic fusion. Electron microscopy and antibody binding experiments demonstrated that the designed nanoparticles display conformationally intact native-like HIV-1 Env, influenza hemagglutinin, and prefusion RSV F trimers in the predicted geometries. This work demonstrates that novel nanoparticle immunogens can be designed from the bottom up with atomic-level accuracy and provides a general strategy for precisely controlling epitope presentation and accessibility.

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Section: Geometriesmentioning

confidence: 99%

mentioning

confidence: 98%

Tailored Design of Protein Nanoparticle Scaffolds for Multivalent Presentation of Viral Glycoprotein Antigens

Ueda

Antanasijevic

Fallas

et al. 2020

Preprint

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“…Multimerization of Env glycoproteins on viral-resembling particles has also been achieved by their fusion to bacterial self-assembling proteins, like ferritin from Helicobacter pylori, E2 protein from Geobacillus stearothermophilus and lumazine synthase from Aquifex aeolicus [200,201]. BG505.SOSIP antigens presented on ferritin nanoparticles induced stronger neutralizing responses than their soluble trimer counterparts in rabbits [202,203]. The autologous Tier 2 responses were not significantly increased, but the Tier 1A responses were, probably due to the presentation of linear V3 epitopes on nonnative Env forms on ferritin particles [202].…”

Section: Nanoparticle Presentationmentioning

confidence: 99%

Strategies for inducing effective neutralizing antibody responses against HIV-1

Moral-Sánchez

Sliepen

2019

Expert Review of Vaccines

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Introduction: Despite intensive research efforts, there is still no effective prophylactic vaccine available against HIV-1. Currently, substantial efforts are devoted to the development of vaccines aimed at inducing broadly neutralizing antibodies (bNAbs), which are capable of neutralizing most HIV-1 strains. All bNAbs target the HIV-1 envelope glycoprotein (Env), but Env immunizations usually only induce neutralizing antibodies (NAbs) against the sequence-matched virus and not against other strains. Areas covered: We describe the different strategies that have been explored to improve the breadth and potency of anti-HIV-1 NAb responses. The discussed strategies include the application of engineered Env immunogens, optimization of (bNAb) epitopes, different cocktail and sequential vaccination strategies, nanoparticles and nucleic acid-based vaccines. Expert opinion: A combination of the strategies described in this review and future approaches are probably needed to develop an effective HIV-1 vaccine that can induce broad, potent and long-lasting NAb responses.

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“…The inability to control the quality of Env or of nanoparticles can be a drawback of the use of in vivo-assembling protein nanoparticles. However, this can be overcome by using twocomponent platforms where native-like, trimeric Env and nanoparticles are expressed and purified separately and then assembled in vitro (Brinkkemper and Sliepen, 2019).…”

Section: Discussionmentioning

confidence: 99%

Characterization and Immunogenicity of HIV Envelope gp140 Zera® Tagged Antigens

Ximba

Chapman

Meyers

et al. 2020

Front. Bioeng. Biotechnol.

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HIV-1 envelope glycoprotein (Env) remains the most relevant target for the elicitation of functional antibodies to HIV by vaccination. However, soluble Env antigens often do not elicit the desired immune responses. Delivering subunit antigens on particulate nanoparticles is an established approach to improve their immunogenicity. In this study the sequence encoding Zera R , a proline-rich domain derived from the γ -zein storage protein, was fused to either the C-or N-terminus of the superinfecting HIV-1 CAP256 gp140 envelope: Zera R generally induces the formation of protein bodies (PBs), which can significantly improve both the immunogenicity and yields of the partner protein. The expression of gp140-Zera R and Zera R -gp140 (N-and C-terminal fusions respectively) in mammalian cells was confirmed by western blot analysis and immunostaining. However, isopycnic ultracentrifugation showed that neither gp140-Zera R nor Zera R -gp140 accumulated in characteristic electron-dense PBs. gp140-Zera R elicited higher binding antibody titers in rabbits to autologous gp140 and V1V2 scaffold than Zera R -gp140. Rabbit anti-gp140-Zera R sera also had significantly higher Tier 1A neutralizing antibody titers than anti-Zera R -gp140 sera. Neither gp140-Zera R nor Zera R -gp140specific sera neutralized Tier 1B or autologous Tier 2 viruses. These results showed that HIV-1 gp140 tagged with Zera R at either the N-or C-termini elicited high titers of gp140 and V1V2 binding antibodies, and low levels of Tier 1 neutralizing antibodies in rabbits.

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Nanoparticle Vaccines for Inducing HIV-1 Neutralizing Antibodies

Cited by 42 publications

References 95 publications

Tailored Design of Protein Nanoparticle Scaffolds for Multivalent Presentation of Viral Glycoprotein Antigens

Tailored Design of Protein Nanoparticle Scaffolds for Multivalent Presentation of Viral Glycoprotein Antigens

Strategies for inducing effective neutralizing antibody responses against HIV-1

Characterization and Immunogenicity of HIV Envelope gp140 Zera® Tagged Antigens

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