Comparison of uridine and N1-methylpseudouridine mRNA platforms in development of an Andes virus vaccine

The rodent-borne Andes virus (ANDV) causes a severe disease in humans. We developed an ANDV mRNA vaccine based on the M segment of the viral genome, either with regular uridine (U-mRNA) or N1-methylpseudouridine (m1Ψ-mRNA). Female mice immunized by m1Ψ-mRNA developed slightly greater germinal center...

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Published in:	Nature communications Vol. 15; no. 1; pp. 6421 - 18
Main Authors:	Kuzmin, Ivan V., Soto Acosta, Ruben, Pruitt, Layne, Wasdin, Perry T., Kedarinath, Kritika, Hernandez, Keziah R., Gonzales, Kristyn A., Hill, Kharighan, Weidner, Nicole G., Mire, Chad, Engdahl, Taylor B., Moon, Woohyun J., Popov, Vsevolod, Crowe, James E., Georgiev, Ivelin S., Garcia-Blanco, Mariano A., Abbott, Robert K., Bukreyev, Alexander
Format:	Journal Article
Language:	English
Published:	London Nature Publishing Group UK 30-07-2024 Nature Publishing Group Nature Portfolio
Subjects:	13 13/1 13/106 13/109 13/21 13/31 13/51 13/62 38 38/23 631/250/2152/2153/1982 631/326/590/2293 631/326/596 Animals Antibodies Antibodies, Neutralizing - immunology Antibodies, Viral - immunology B-Lymphocytes - immunology Cell activation Cricetinae Female Females Gene expression Gene sequencing Germinal Center - immunology Germinal centers Glycoproteins Hamsters Hemorrhagic Fever, American - immunology Hemorrhagic Fever, American - prevention & control Hemorrhagic Fever, American - virology Humanities and Social Sciences Humans Immune response Immune system Immunization Immunogenicity Lethal dose Lymphocytes B Mesocricetus Mice mRNA mRNA Vaccines multidisciplinary Orthohantavirus - genetics Orthohantavirus - immunology Pseudouridine - immunology RNA modification RNA, Messenger - genetics RNA, Messenger - immunology RNA, Messenger - metabolism RNA, Viral - genetics RNA, Viral - immunology Rodents Science Science (multidisciplinary) Segments Uridine Vaccine Development Vaccines Viral Vaccines - administration & dosage Viral Vaccines - immunology Viruses
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Summary:	The rodent-borne Andes virus (ANDV) causes a severe disease in humans. We developed an ANDV mRNA vaccine based on the M segment of the viral genome, either with regular uridine (U-mRNA) or N1-methylpseudouridine (m1Ψ-mRNA). Female mice immunized by m1Ψ-mRNA developed slightly greater germinal center (GC) responses than U-mRNA-immunized mice. Single cell RNA and BCR sequencing of the GC B cells revealed similar levels of activation, except an additional cluster of cells exhibiting interferon response in animals vaccinated with U-mRNA but not m1Ψ-mRNA. Similar immunoglobulin class-switching and somatic hypermutations were observed in response to the vaccines. Female Syrian hamsters were immunized via a prime–boost regimen with two doses of each vaccine. The titers of glycoprotein-binding antibodies were greater for U-mRNA construct than for m1Ψ-mRNA construct; however, the titers of ANDV-neutralizing antibodies were similar. Vaccinated animals were challenged with a lethal dose of ANDV, along with a naïve control group. All control animals and two animals vaccinated with a lower dose of m1Ψ-mRNA succumbed to infection whereas other vaccinated animals survived without evidence of virus replication. The data demonstrate the development of a protective vaccine against ANDV and the lack of a substantial effect of m1Ψ modification on immunogenicity and protection in rodents. Modified nucleosides are often used in mRNA vaccines and can affect protein expression and immunogenicity. Here, the authors compare M segment based Andes virus mRNA vaccines, either with regular uridine or N1-methylpseudouridine, and characterize immune response and protection in rodents.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	2041-1723 2041-1723
DOI:	10.1038/s41467-024-50774-3