Enhancing Humoral Responses Against HIV Envelope Trimers via Nanoparticle Delivery with Stabilized Synthetic Liposomes View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2018-11-08

AUTHORS

Talar Tokatlian, Daniel W. Kulp, Andrew A. Mutafyan, Christopher A. Jones, Sergey Menis, Erik Georgeson, Mike Kubitz, Michael H. Zhang, Mariane B. Melo, Murillo Silva, Dong Soo Yun, William R. Schief, Darrell J. Irvine

ABSTRACT

An HIV vaccine capable of eliciting durable neutralizing antibody responses continues to be an important unmet need. Multivalent nanoparticles displaying a high density of envelope trimers may be promising immunogen forms to elicit strong and durable humoral responses to HIV, but critical particle design criteria remain to be fully defined. To this end, we developed strategies to covalently anchor a stabilized gp140 trimer, BG505 MD39, on the surfaces of synthetic liposomes to study the effects of trimer density and vesicle stability on vaccine-elicited humoral responses in mice. CryoEM imaging revealed homogeneously distributed and oriented MD39 on the surface of liposomes irrespective of particle size, lipid composition, and conjugation strategy. Immunization with covalent MD39-coupled liposomes led to increased germinal center and antigen-specific T follicular helper cell responses and significantly higher avidity serum MD39-specific IgG responses compared to immunization with soluble MD39 trimers. A priming immunization with liposomal-MD39 was important for elicitation of high avidity antibody responses, regardless of whether booster immunizations were administered with either soluble or particulate trimers. The stability of trimer anchoring to liposomes was critical for these effects, as germinal center and output antibody responses were further increased by liposome compositions incorporating sphingomyelin that exhibited high in vitro stability in the presence of serum. Together these data highlight key liposome design features for optimizing humoral immunity to lipid nanoparticle immunogens. More... »

PAGES

16527

Identifiers

URI

http://scigraph.springernature.com/pub.10.1038/s41598-018-34853-2

DOI

http://dx.doi.org/10.1038/s41598-018-34853-2

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1107991068

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/30410003


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30 schema:description An HIV vaccine capable of eliciting durable neutralizing antibody responses continues to be an important unmet need. Multivalent nanoparticles displaying a high density of envelope trimers may be promising immunogen forms to elicit strong and durable humoral responses to HIV, but critical particle design criteria remain to be fully defined. To this end, we developed strategies to covalently anchor a stabilized gp140 trimer, BG505 MD39, on the surfaces of synthetic liposomes to study the effects of trimer density and vesicle stability on vaccine-elicited humoral responses in mice. CryoEM imaging revealed homogeneously distributed and oriented MD39 on the surface of liposomes irrespective of particle size, lipid composition, and conjugation strategy. Immunization with covalent MD39-coupled liposomes led to increased germinal center and antigen-specific T follicular helper cell responses and significantly higher avidity serum MD39-specific IgG responses compared to immunization with soluble MD39 trimers. A priming immunization with liposomal-MD39 was important for elicitation of high avidity antibody responses, regardless of whether booster immunizations were administered with either soluble or particulate trimers. The stability of trimer anchoring to liposomes was critical for these effects, as germinal center and output antibody responses were further increased by liposome compositions incorporating sphingomyelin that exhibited high in vitro stability in the presence of serum. Together these data highlight key liposome design features for optimizing humoral immunity to lipid nanoparticle immunogens.
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38 HIV
39 HIV envelope trimer
40 HIV vaccine
41 IgG responses
42 MD39
43 MD39 trimers
44 MD39-specific IgG responses
45 antibodies
46 antibody response
47 avidity antibodies
48 avidity serum MD39-specific IgG responses
49 booster immunization
50 cell responses
51 center
52 composition
53 conjugation strategies
54 covalent MD39
55 criteria
56 critical particle design criteria
57 data highlight key liposome design features
58 delivery
59 density
60 design criteria
61 design features
62 durable humoral responses
63 effect
64 elicitation
65 end
66 envelope trimer
67 features
68 follicular helper cell responses
69 form
70 germinal centers
71 gp140 trimers
72 helper cell responses
73 high density
74 high-avidity antibodies
75 higher avidity serum MD39-specific IgG responses
76 highlight key liposome design features
77 humoral immunity
78 humoral response
79 imaging
80 immunity
81 immunization
82 immunogen
83 immunogen forms
84 important unmet need
85 key liposome design features
86 lipid composition
87 liposome composition
88 liposome design features
89 liposomes
90 mice
91 multivalent nanoparticles
92 nanoparticle delivery
93 nanoparticle immunogens
94 nanoparticles
95 need
96 output antibody responses
97 particle design criteria
98 particle size
99 presence
100 presence of serum
101 priming immunization
102 response
103 serum
104 serum MD39-specific IgG responses
105 size
106 soluble MD39 trimers
107 sphingomyelin
108 stability
109 stability of trimers
110 strategies
111 surface
112 surface of liposomes
113 synthetic liposomes
114 trimer
115 trimer density
116 unmet need
117 vaccine
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119 vesicle stability
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