title: Self-amplifying mRNA vaccines.
abstract: This chapter provides a brief introduction to nucleic acid-based vaccines and recent research in developing self-amplifying mRNA vaccines. These vaccines promise the flexibility of plasmid DNA vaccines with enhanced immunogenicity and safety. The key to realizing the full potential of these vaccines is efficient delivery of nucleic acid to the cytoplasm of a cell, where it can amplify and express the encoded antigenic protein. The hydrophilicity and strong net negative charge of RNA impedes cellular uptake. To overcome this limitation, electrostatic complexation with cationic lipids or polymers and physical delivery using electroporation or ballistic particles to improve cellular uptake has been evaluated. This chapter highlights the rapid progress made in using nonviral delivery systems for RNA-based vaccines. Initial preclinical testing of self-amplifying mRNA vaccines has shown nonviral delivery to be capable of producing potent and robust innate and adaptive immune responses in small animals and nonhuman primates. Historically, the prospect of developing mRNA vaccines was uncertain due to concerns of mRNA instability and the feasibility of large-scale manufacturing. Today, these issues are no longer perceived as barriers in the widespread implementation of the technology. Currently, nonamplifying mRNA vaccines are under investigation in human clinical trials and can be produced at a sufficient quantity and quality to meet regulatory requirements. If the encouraging preclinical data with self-amplifying mRNA vaccines are matched by equivalently positive immunogenicity, potency, and tolerability in human trials, this platform could establish nucleic acid vaccines as a versatile new tool for human immunization.
authors.affiliation: Novartis Vaccines, Inc., Cambridge, MA, USA.
authors.forename: Luis A
authors.initials: LA
authors.lastname: Brito
authors.affiliation: Novartis Vaccines, Inc., Cambridge, MA, USA.
authors.forename: Sushma
authors.initials: S
authors.lastname: Kommareddy
authors.affiliation: Novartis Vaccines, Inc., Siena, Italy.
authors.forename: Domenico
authors.initials: D
authors.lastname: Maione
authors.affiliation: Novartis Vaccines, Inc., Siena, Italy.
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Uematsu
authors.affiliation: Novartis Vaccines, Inc., Siena, Italy.
authors.forename: Cinzia
authors.initials: C
authors.lastname: Giovani
authors.affiliation: Novartis Vaccines, Inc., Holly Springs, NC, USA.
authors.forename: Francesco
authors.initials: F
authors.lastname: Berlanda Scorza
authors.affiliation: Novartis Vaccines, Inc., Cambridge, MA, USA.
authors.forename: Gillis R
authors.initials: GR
authors.lastname: Otten
authors.affiliation: Novartis Vaccines, Inc., Cambridge, MA, USA.
authors.forename: Dong
authors.initials: D
authors.lastname: Yu
authors.affiliation: Novartis Vaccines, Inc., Cambridge, MA, USA.
authors.forename: Christian W
authors.initials: CW
authors.lastname: Mandl
authors.affiliation: Regeneron Pharmaceuticals, Inc., Tarrytown, NY, USA.
authors.forename: Peter W
authors.initials: PW
authors.lastname: Mason
authors.affiliation: Novartis Vaccines, Inc., Cambridge, MA, USA.
authors.forename: Philip R
authors.initials: PR
authors.lastname: Dormitzer
authors.affiliation: Novartis Vaccines, Inc., Cambridge, MA, USA.
authors.forename: Jeffrey B
authors.initials: JB
authors.lastname: Ulmer
authors.affiliation: Novartis Vaccines, Inc., Cambridge, MA, USA.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Geall
mesh_terms: D000818:Animals; D000941:Antigens / Q000235:genetics; D018274:Electroporation; D006801:Humans; D053758:Nanoparticles / Q000008:administration & dosage / Q000737:chemistry; D012333:RNA, Messenger / Q000008:administration & dosage* / Q000009:adverse effects / Q000235:genetics; D014612:Vaccines / Q000008:administration & dosage* / Q000009:adverse effects; D014765:Viral Vaccines
chemical_list: D000941:Antigens; D012333:RNA, Messenger; D014612:Vaccines; D014765:Viral Vaccines
keywords: Cationic nanoemulsion; Lipid nanoparticle; Nonviral delivery; Nucleic acid vaccine; Self-amplifying mRNA vaccine; mRNA vaccine