Administration of nucleoside-modified mRNA encoding broadly neutralizing antibody protects humanized mice from HIV-1 challenge
Open accessAbstract
Monoclonal antibodies are one of the fastest growing classes of pharmaceutical products, however, their potential is limited by the high cost of development and manufacturing. Here we present a safe and cost-effective platform for in vivo expression of therapeutic antibodies using nucleoside-modified mRNA. To demonstrate feasibility and protective efficacy, nucleoside-modified mRNAs encoding the light and heavy chains of the broadly neutralizing anti-HIV-1 antibody VRC01 are generated and encapsulated into lipid nanoparticles. Systemic administration of 1.4 mg kg−1 of mRNA into mice results in ∼170 μg ml−1 VRC01 antibody concentrations in the plasma 24 h post injection. Weekly injections of 1 mg kg−1 of mRNA into immunodeficient mice maintain trough VRC01 levels above 40 μg ml−1. Most importantly, the translated antibody from a single injection of VRC01 mRNA protects humanized mice from intravenous HIV-1 challenge, demonstrating that nucleoside-modified mRNA represents a viable delivery platform for passive immunotherapy against HIV-1 with expansion to a variety of diseases.
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The feasibility of using mRNA for passive vaccination was independently confirmed in an HIV model (Pardi et al, 2017).
“While the present manuscript was under review, the feasibility of using mRNA for passive vaccination was independently confirmed in an HIV model (Pardi et al, 2017).”
From mRNA mediates passive vaccination against infectious agents, toxins, and tumors (2017) · cites this paper as Pardi et al, 2017
A single dose of mRNA expressing VRC01 protected mice from intravenous challenge with HIV-1.
“Importantly, a single dose protected mice from intravenous challenge with HIV-1.”
From mRNA vaccines for infectious diseases: principles, delivery and clinical translation (2021) · cites this paper as [169]
A single 0.7 mg kg−1 intravenous injection of a lipid nanoparticle-encapsulated, nucleoside-modified mRNA expressing VRC01 produced similar antibody concentrations to those typically achieved by injecting a 10-20 mg kg−1 dose of monoclonal antibody protein.
“In one study, a single 0.7 mg kg−1 intravenous injection of a LNP-encapsulated, nucleoside-modified mRNA expressing VRC01, produced similar antibody concentrations to those typically achieved by injecting a 10–20 mg kg−1 dose of mAb protein169.”
From mRNA vaccines for infectious diseases: principles, delivery and clinical translation (2021) · cites this paper as [169]
Lipid nanoparticle-mRNA formulations have been applied to produce therapeutic proteins or antibodies, to edit virus genomes and to engineer immune cells.
“In addition, lipid nanoparticle–mRNA formulations have been applied to produce therapeutic proteins or antibodies39,75,145,146, to edit virus genomes105 and to engineer immune cells136.”
From Lipid nanoparticles for mRNA delivery (2021) · cites this paper as [145]
Mice administered HPLC-purified and m1ψ modified mRNA with lipid nanoparticle produced protective antibodies, assisting them in overcoming HIV-1 infection.
“The findings revealed that mice administered mRNA-LNP produced protective antibodies, assisting them in overcoming HIV-1 infection (Pardi et al. 2017).”
From Modifications of mRNA vaccine structural elements for improving mRNA stability and translation efficiency (2022) · cites this paper as Pardi et al. 2017
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“While the group of Drew Weissman described successful passive mRNA immunization for prophylaxis of viral infections [267] , Stadler et al.”
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“149 Nevertheless, more efforts are needed in both preclinical and clinical research to combat AIDS using mRNA-LNP technology.”
Engineering nanoparticle toolkits for mRNA delivery
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“The Weissman group was the first to publish on an mRNA-encoded antibody approach [48].”
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- Authors
- Pardi, N., Secreto, A. J., Shan, X., Debonera, F., Glover, J., Yi, Y., Muramatsu, H., Ni, H., Mui, B. L., Tam, Y. K., Shaheen, F., Collman, R. G., Karikó, K., Danet-Desnoyers, G. A., Madden, T. D., Hope, M. J., & Weissman, D.
- Affiliations
- University of Pennsylvania (US)
- Acuitas Therapeutics (Canada) (CA)
- Corresponding author
- Weissman, Drew
- ORCID
- Venue
- Nature Communications
- Published
- 2017-03-02
- Volume
- 8
- Issue
- 1
- Pages
- 14630-14630
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC5337964
- OpenAlex
- W2593990758
- Semantic Scholar
- 8656da6083e114b29e158ff926ed576066e074f8
- Cited by
- 352
- References
- 45
- Citations by year
- 2026: 33 · 2025: 33 · 2024: 34 · 2023: 38 · 2022: 38 · 2021: 58 · 2020: 41 · 2019: 29 · 2018: 34 · 2017: 14
- FWCI
- 13.17
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Nature Communications (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- University of Pennsylvania (P30 AI 045008)
- Vaccine Research Center
- National Institutes of Health (R01-AI084860, AI084860, AI045008)
- Center for AIDS Research, University of Washington (P30-AI-045008)
- National Institute of Allergy and Infectious Diseases (R01-AI084860, R01AI050484, R01AI124429, AI045008, P30AI045008)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Monoclonal and Polyclonal Antibodies Research
- Life Sciences › Immunology and Microbiology › Virology › HIV Research and Treatment
- Keywords
- nucleoside-modified mRNA, mRNA vaccines, broadly neutralizing antibodies, VRC01, HIV-1, passive immunotherapy, lipid nanoparticles, humanized mice, monoclonal antibodies
- MeSH terms
- Broadly Neutralizing Antibodies, Animals, Antibodies, Monoclonal, Drug Administration Schedule, Female, Humans, Immunization, Passive, Lipids, Mice, Inbred BALB C, Mice, Inbred C57BL, Mice, Transgenic, Nucleosides, RNA, Messenger, HIV Antibodies, HIV-1, HIV Infections, Mice, SCID, Mice, Inbred NOD, Mice, Nanoparticles, Antibodies, Neutralizing
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