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no. with each individual construct administered alone. These data are among the first demonstrating the feasibility of starting multiple antibodies using mRNA constructs in a large, nonrodent species. Based on empirically derived target serum level and the observed decay rate, the antibody levels attained were unlikely to provide protection. Keywords: MT: Delivery strategies, RNA, monoclonal antibodies, nucleic acid, neutralizing antibody, rabbits, poxvirus, lipid nanoparticle Graphical abstract Open in a separate windows Hooper and colleagues demonstrate the feasibility of simultaneously delivering three monoclonal antibodies (mAbs) via intramuscular administration of mRNA to relatively large animals (rabbits). The unmodified mRNAs were LNP formulated and delivered via needle-free jet injection. All three anti-poxvirus mAbs were detected in sera within 1?day of mRNA injection and were biologically active. Introduction Poxviruses are known to cause disease in humans and animals. From your perspective of human disease, the most notable users are variola computer virus and monkeypox computer virus. Smallpox, the disease manifested by variola computer virus, was responsible for the death and maiming of hundreds of thousands until its eradication from nature in the latter part PH-797804 of the 20th century. It has been over 40 years since the general populace received vaccination, and the protective benefit of the vaccine to smallpox and other orthopoxviruses wanes over time. Therefore, there are numerous at risk for zoonotic poxvirus infections, MYLK such as monkeypox computer virus, or reintroduction of variola computer virus, prompting the need for vaccines and therapeutics. The US Food and Drug Administration has licensed four countermeasures for smallpox. ACAM2000 comprises a less virulent clone PH-797804 of Dryvax, the progenitor to ACAM2000, which was selected in an effort to reduce adverse events associated with the progenitor vaccine. Regrettably, the ACAM2000 vaccine still has the same issues and contraindications as Dryvax. MVA (JYNNEOS), a licensed third-generation vaccine, is usually a highly attenuated nonreplicating vaccine. 1 Although seemingly safer, there are issues about the protective capability of these vaccines. Unlike Dryvax, ACAM2000 and MVA have not been battle tested against smallpox in humans. Two antivirals, TEMBEXA (brincidofovir) and TPOXX (tecovirimat or ST-246), have been approved for treatment of smallpox. These small-molecule inhibitors work via independent mechanisms, one interfering with poxvirus DNA synthesis and the other morphogenesis, respectively. Neither TEMBEXA nor TPOXX has been approved for prophylactic treatment to prevent smallpox. Vaccinia immunoglobin (VIG) has been licensed for complications associated with the smallpox vaccine. VIG was shown to have efficacy against certain vaccine complications.2,3 Among other things, the potency of VIG has been questioned, and potential replacements have been postulated.4 For instance, polyclonal antibodies that were generated from single5,6 or multiple antigens,5 as well as monoclonal antibodies/cocktails,6, 7, 8 have been shown to be more effective in animal models. Whether developing a new vaccine or other countermeasures, it is generally agreed that targeting both the intracellular and the extracellular form of the computer virus is necessary. Morphogenesis of poxviruses produces two general forms of the computer virus, referred to as extracellular enveloped virions (EV) and mature virions (MV). The EVs have an additional envelope in which the extracellular surface is antigenically unique from that of the MV. It has been shown that vaccines lacking PH-797804 or unable to produce viral proteins (antigens) unique to EV, as well as antibodies to these antigens, provide PH-797804 less protection than those including both.5,6,9, 10, 11 More recent improvements in nucleic acid technology and delivery have created the potential for utilizing gene transfer as a therapeutic tool against viral diseases.12, 13, 14, 15, 16, 17 In this study, we attempted to develop nucleic acid-based monoclonal antibodies capable of producing therapeutic levels of circulating anti-poxvirus antibody in a relatively large laboratory animal (>3?kg rabbits). We.