A Trans-amplifying RNA Vaccine Strategy for Induction of Potent Protective Immunity.
Animals
Antibodies, Neutralizing
/ immunology
Antibodies, Viral
/ immunology
Cricetinae
Dogs
Female
Genetic Vectors
HEK293 Cells
Hemagglutinin Glycoproteins, Influenza Virus
/ immunology
Humans
Immunogenicity, Vaccine
Influenza A Virus, H1N1 Subtype
/ immunology
Influenza Vaccines
/ administration & dosage
Influenza, Human
/ metabolism
Madin Darby Canine Kidney Cells
Mice
Mice, Inbred BALB C
Orthomyxoviridae Infections
/ prevention & control
RNA, Viral
/ genetics
Semliki forest virus
/ genetics
Vaccination
Viral Replicase Complex Proteins
/ genetics
RNA vaccine
alphavirus
influenza vaccine
replicon
saRNA
taRNA
trans-replication
vaccine
Journal
Molecular therapy : the journal of the American Society of Gene Therapy
ISSN: 1525-0024
Titre abrégé: Mol Ther
Pays: United States
ID NLM: 100890581
Informations de publication
Date de publication:
08 01 2020
08 01 2020
Historique:
received:
16
04
2019
revised:
03
09
2019
accepted:
06
09
2019
pubmed:
19
10
2019
medline:
22
12
2020
entrez:
19
10
2019
Statut:
ppublish
Résumé
Here, we present a potent RNA vaccine approach based on a novel bipartite vector system using trans-amplifying RNA (taRNA). The vector cassette encoding the vaccine antigen originates from an alphaviral self-amplifying RNA (saRNA), from which the replicase was deleted to form a transreplicon. Replicase activity is provided in trans by a second molecule, either by a standard saRNA or an optimized non-replicating mRNA (nrRNA). The latter delivered 10- to 100-fold higher transreplicon expression than the former. Moreover, expression driven by the nrRNA-encoded replicase in the taRNA system was as efficient as in a conventional monopartite saRNA system. We show that the superiority of nrRNA- over saRNA-encoded replicase to drive expression of the transreplicon is most likely attributable to its higher translational efficiency and lack of interference with cellular translation. Testing the novel taRNA system in mice, we observed that doses of influenza hemagglutinin antigen-encoding RNA as low as 50 ng were sufficient to induce neutralizing antibodies and mount a protective immune response against live virus challenge. These findings, together with a favorable safety profile, a simpler production process, and the universal applicability associated with this bipartite vector system, warrant further exploration of taRNA.
Identifiants
pubmed: 31624015
pii: S1525-0016(19)30412-5
doi: 10.1016/j.ymthe.2019.09.009
pmc: PMC6953774
pii:
doi:
Substances chimiques
Antibodies, Neutralizing
0
Antibodies, Viral
0
Hemagglutinin Glycoproteins, Influenza Virus
0
Influenza Vaccines
0
RNA, Viral
0
Viral Replicase Complex Proteins
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
119-128Informations de copyright
Copyright © 2019. Published by Elsevier Inc.
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