Immunogenicity of RNA Replicons Encoding HIV Env Immunogens Designed for Self-Assembly into Nanoparticles
Open accessAbstract
RNA replicons are a promising platform technology for vaccines. To evaluate the potential of lipid nanoparticle-formulated replicons for delivery of HIV immunogens, we designed and tested an alphavirus replicon expressing a self-assembling protein nanoparticle immunogen, the glycoprotein 120 (gp120) germline-targeting engineered outer domain (eOD-GT8) 60-mer. The eOD-GT8 immunogen is a germline-targeting antigen designed to prime human B cells capable of evolving toward VRC01-class broadly neutralizing antibodies. Replicon RNA was encapsulated with high efficiency in 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP)-based lipid nanoparticles, which provided effective delivery in the muscle and expression of luciferase lasting ∼30 days in normal mice, contrasting with very brief and low levels of expression obtained by delivery of equivalent modified mRNA (modRNA). eOD-GT8 60-mer-encoding replicons elicited high titers of gp120-specific antibodies following a single injection in mice, and increased levels of antigen-specific germinal center B cells compared with protein immunization. Immunization of transgenic mice expressing human inferred-germline VRC01 heavy chain B cell receptors that are the targets of the eOD antigen led to priming of B cells and somatic hypermutation consistent with VRC01-class antibody development. Altogether, these data suggest replicon delivery of Env immunogens may be a promising avenue for HIV vaccine development.
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Administration routes can greatly influence organ distribution, expression kinetics and therapeutic outcomes of lipid nanoparticle-mRNA formulations.
“Administration routes can greatly influence organ distribution, expression kinetics and therapeutic outcomes of lipid nanoparticle–mRNA formulations143,144.”
From Lipid nanoparticles for mRNA delivery (2021) · cites this paper as [144]
Lipid nanoparticle-mRNA vaccines have been tested against other viruses in animal models, including human immunodeficiency virus, Powassan virus, Venezuelan equine encephalitis virus, dengue virus and Ebola virus.
“Furthermore, lipid nanoparticle–mRNA vaccines have been tested against other viruses in animal models, including human immunodeficiency virus28,144,181,190, Powassan virus195, Venezuelan equine encephalitis virus196, dengue virus73 and Ebola virus197.”
From Lipid nanoparticles for mRNA delivery (2021) · cites this paper as [144]
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- Authors
- Melo, M., Porter, E., Zhang, Y., Silva, M., Li, N., Dobosh, B., Liguori, A., Skog, P., Landais, E., Menis, S., Sok, D., Nemazee, D., Schief, W. R., Weiss, R., & Irvine, D. J.
- Affiliations
- Scripps Research Institute (US)
- Massachusetts Institute of Technology (US)
- Koch Institute for Integrative Cancer Research At MIT (US)
- Corresponding author
- Irvine, Darrell J.
- ORCID
- Venue
- Molecular Therapy
- Publisher
- Elsevier BV
- Published
- 2019-12
- Volume
- 27
- Issue
- 12
- Pages
- 2080-2090
- ISSN
- 1525-0016 (ISSN-L)
- PMC
- PMC6904793
- OpenAlex
- W2969694946
- Cited by
- 88
- References
- 68
- Citations by year
- 2026: 6 · 2025: 13 · 2024: 13 · 2023: 16 · 2022: 16 · 2021: 11 · 2020: 13
- FWCI
- 3.31
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Molecular Therapy (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- DSpace@MIT (Massachusetts Institute of Technology) (submittedVersion, cc-by-nc-nd)
- Funders
- International AIDS Vaccine Initiative
- Howard Hughes Medical Institute
- National Institutes of Health
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Life Sciences › Immunology and Microbiology › Virology › HIV Research and Treatment
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Keywords
- RNA replicon, HIV vaccine, envelope glycoprotein, gp120, self-assembling protein nanoparticles, alphavirus replicon, lipid nanoparticles, DOTAP, B cell priming, somatic hypermutation, germinal center B cells, immunogenicity, transgenic mice
- MeSH terms
- Animals, B-Lymphocytes, Encephalitis Virus, Venezuelan Equine, Female, Humans, Immunization, Male, Mice, Inbred BALB C, Mice, Inbred C57BL, Mice, Transgenic, Replicon, HIV Antibodies, HIV Antigens, HIV-1, HIV Infections, AIDS Vaccines, Mice, Nanoparticles, env Gene Products, Human Immunodeficiency Virus, Gene Knock-In Techniques, Antibodies, Neutralizing
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