1. Comparison of uridine and N1-methylpseudouridine mRNA platforms in development of an Andes virus vaccine.
- Author
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Kuzmin IV, Soto Acosta R, Pruitt L, Wasdin PT, Kedarinath K, Hernandez KR, Gonzales KA, Hill K, Weidner NG, Mire C, Engdahl TB, Moon WJ, Popov V, Crowe JE Jr, Georgiev IS, Garcia-Blanco MA, Abbott RK, and Bukreyev A
- Subjects
- Animals, Female, Mice, RNA, Messenger genetics, RNA, Messenger metabolism, RNA, Messenger immunology, Antibodies, Viral immunology, Orthohantavirus immunology, Orthohantavirus genetics, Antibodies, Neutralizing immunology, Germinal Center immunology, Pseudouridine immunology, Cricetinae, mRNA Vaccines, Hemorrhagic Fever, American prevention & control, Hemorrhagic Fever, American immunology, Hemorrhagic Fever, American virology, RNA, Viral genetics, RNA, Viral immunology, B-Lymphocytes immunology, Humans, Vaccine Development, Mesocricetus, Uridine, Viral Vaccines immunology, Viral Vaccines administration & dosage
- Abstract
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., (© 2024. The Author(s).)
- Published
- 2024
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