Intramuscular Delivery of Replicon RNA Encoding ZIKV-117 Human Monoclonal Antibody Protects against Zika Virus Infection
Open accessAbstract
Monoclonal antibody (mAb) therapeutics are an effective modality for the treatment of infectious, autoimmune, and cancer-related diseases. However, the discovery, development, and manufacturing processes are complex, resource-consuming activities that preclude the rapid deployment of mAbs in outbreaks of emerging infectious diseases. Given recent advances in nucleic acid delivery technology, it is now possible to deliver exogenous mRNA encoding mAbs for in situ expression following intravenous (i.v.) infusion of lipid nanoparticle-encapsulated mRNA. However, the requirement for i.v. administration limits the application to settings where infusion is an option, increasing the cost of treatment. As an alternative strategy, and to enable intramuscular (IM) administration of mRNA-encoded mAbs, we describe a nanostructured lipid carrier for delivery of an alphavirus replicon encoding a previously described highly neutralizing human mAb, ZIKV-117. Using a lethal Zika virus challenge model in mice, our studies show robust protection following alphavirus-driven expression of ZIKV-117 mRNA when given by IM administration as pre-exposure prophylaxis or post-exposure therapy.
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The current understanding of the field is that incorporating modified NTPs into saRNA abrogates downstream efficacy.
“However, the current understanding of the field is that incorporating modified NTPs into saRNA abrogates downstream efficacy, as reported by multiple independent groups5,19–28.”
From Complete substitution with modified nucleotides in self-amplifying RNA suppresses the interferon response and increases potency (2025) · cites this paper as [23]
The Results section (“RepRNA Mediates Higher Expression of Antibody Compared to Non-Replicating mRNA”; page not available in our copy) reports that pseudouridine-modified repRNA was non-functional, with no detectable ZIKV-117 antibody in mouse serum. This supports the claim for that modification and outcome, but not the broader assertion that incorporating modified NTPs into saRNA generally abrogates downstream efficacy. (LLM, conf=0.86)
Experimental — accuracy not yet measuredmRNA therapeutics encoding neutralizing monoclonal antibodies may have both prophylactic and therapeutic activity.
“Interestingly, these results suggest that mRNA therapeutics encoding neutralizing mAbs may have both prophylactic and therapeutic activity.”
From mRNA vaccines for infectious diseases: principles, delivery and clinical translation (2021) · cites this paper as [157]
A single 40 μg dose of mRNA encoding neutralizing ZIKV-117 monoclonal antibodies delivered either a day before or a day after viral inoculation protected immunocompromised mice from the lethal viral challenge.
“A single 40 µg dose delivered either a day before or a day after viral inoculation protected immunocompromised mice from the lethal viral challenge157.”
From mRNA vaccines for infectious diseases: principles, delivery and clinical translation (2021) · cites this paper as [157]
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 [39]
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References 72 · Cited by 118
Research works printed but not linked: 1
- [48]Frolov I. Hoffman T.A. Prágai B.M. Dryga S.A. Huang H.V. Schlesinger S. Rice C.M. Alphavirus-based expression vectors: strategies and applications Proc. Natl. Acad. Sci. USA 93 1996 11371 11377 8876142 PMC38064
- Authors
- Erasmus, J. H., Archer, J., Fuerte-Stone, J., Khandhar, A. P., Voigt, E., Granger, B., Bombardi, R. G., Govero, J., Tan, Q., Durnell, L. A., Coler, R. N., Diamond, M. S., Crowe, J. E., Reed, S. G., Thackray, L. B., Carnahan, R. H., & Van Hoeven, N.
- Affiliations
- Infectious Disease Research Institute (US)
- Vanderbilt University Medical Center (US)
- Washington University in St. Louis (US)
- Corresponding author
- Erasmus, Jesse H.
- ORCID
- Venue
- Molecular Therapy - Methods & Clinical Development
- Publisher
- Elsevier BV
- Published
- 2020-09
- Volume
- 18
- Pages
- 402-414
- ISSN
- 2329-0501 (ISSN-L)
- PMC
- PMC7363633
- OpenAlex
- W3036298160
- Cited by
- 118
- References
- 72
- Citations by year
- 2026: 10 · 2025: 28 · 2024: 21 · 2023: 23 · 2022: 17 · 2021: 15 · 2020: 4
- FWCI
- 4.78
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Molecular Therapy — Methods & Clinical Development (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Digital Commons@Becker (Washington University School of Medicine) (submittedVersion, cc-by-nc-nd)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Foundation for the National Institutes of Health
- Defense Advanced Research Projects Agency
- Washington Research Foundation
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Mosquito-borne diseases and control
- Health Sciences › Medicine › Infectious Diseases › SARS-CoV-2 and COVID-19 Research
- Keywords
- Zika virus, human monoclonal antibodies, alphavirus replicon, nanostructured lipid carriers, intramuscular administration, mRNA therapeutics, pre-exposure prophylaxis, neutralizing antibodies, emerging infectious diseases
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