Immunogenicity of RNA Replicons Encoding HIV Env Immunogens Designed for Self-Assembly into Nanoparticles

Mariane Melo; Ely Porter; Yuan Zhang; Murillo Silva; Na Li; Brian Dobosh; Alessia Liguori; Pat Skog; Elise Landais; Sergey Menis; Devin Sok; David Nemazee; William R Schief; Ron Weiss; Darrell J Irvine

doi:10.1016/j.ymthe.2019.08.007

Immunogenicity of RNA Replicons Encoding HIV Env Immunogens Designed for Self-Assembly into Nanoparticles

Mol Ther. 2019 Dec 4;27(12):2080-2090. doi: 10.1016/j.ymthe.2019.08.007. Epub 2019 Aug 19.

Authors

Mariane Melo¹, Ely Porter², Yuan Zhang³, Murillo Silva⁴, Na Li⁴, Brian Dobosh², Alessia Liguori⁵, Pat Skog⁵, Elise Landais⁶, Sergey Menis⁶, Devin Sok⁶, David Nemazee⁵, William R Schief⁷, Ron Weiss⁸, Darrell J Irvine⁹

Affiliations

¹ Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA; Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, The Scripps Research Institute, La Jolla, CA, USA; Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA, USA.
² Synthetic Biology Center, Massachusetts Institute of Technology, Cambridge, MA, USA.
³ Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA.
⁴ Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA; Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, The Scripps Research Institute, La Jolla, CA, USA.
⁵ Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, The Scripps Research Institute, La Jolla, CA, USA; Immunology and Microbial Science, TSRI, La Jolla, CA, USA.
⁶ Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, The Scripps Research Institute, La Jolla, CA, USA; International AIDS Vaccine Initiative, The Scripps Research Institute, La Jolla, CA, USA; Immunology and Microbial Science, TSRI, La Jolla, CA, USA.
⁷ Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, The Scripps Research Institute, La Jolla, CA, USA; International AIDS Vaccine Initiative, The Scripps Research Institute, La Jolla, CA, USA; Immunology and Microbial Science, TSRI, La Jolla, CA, USA; Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA, USA.
⁸ Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA; Synthetic Biology Center, Massachusetts Institute of Technology, Cambridge, MA, USA; Department of Biological Engineering, MIT, Cambridge, MA, USA.
⁹ Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA; Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, The Scripps Research Institute, La Jolla, CA, USA; Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA, USA; Department of Biological Engineering, MIT, Cambridge, MA, USA; Materials Science & Engineering, MIT, Cambridge, MA, USA; Howard Hughes Medical Institute, Chevy Chase, MD, USA. Electronic address: djirvine@mit.edu.

Abstract

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

AIDS Vaccines / administration & dosage
AIDS Vaccines / immunology*
Animals
Antibodies, Neutralizing / immunology
B-Lymphocytes / immunology
Encephalitis Virus, Venezuelan Equine / genetics
Female
Gene Knock-In Techniques
HIV Antibodies / immunology*
HIV Antigens / immunology
HIV Infections / immunology
HIV Infections / prevention & control*
HIV Infections / virology
HIV-1 / drug effects
HIV-1 / genetics
HIV-1 / immunology*
Humans
Immunization
Male
Mice
Mice, Inbred BALB C
Mice, Inbred C57BL
Mice, Transgenic
Nanoparticles / administration & dosage
Nanoparticles / chemistry*
Replicon / genetics
Replicon / immunology*
env Gene Products, Human Immunodeficiency Virus / genetics
env Gene Products, Human Immunodeficiency Virus / immunology*

Substances

AIDS Vaccines
Antibodies, Neutralizing
HIV Antibodies
HIV Antigens
env Gene Products, Human Immunodeficiency Virus

Abstract

Publication types

MeSH terms

Substances

Grants and funding