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

Ivan V. Kuzmin; Ruben Soto Acosta; Layne Pruitt; Perry T. Wasdin; Kritika Kedarinath; Keziah R. Hernandez; Kristyn A. Gonzales; Kharighan Hill; Nicole G. Weidner; Chad Mire; Taylor B. Engdahl; Woohyun J. Moon; Vsevolod Popov; James E. Crowe; Ivelin S. Georgiev; Mariano A. Garcia-Blanco; Robert K. Abbott; Alexander Bukreyev

doi:10.1038/s41467-024-50774-3

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

Ivan V. Kuzmin, Ruben Soto Acosta, Layne Pruitt, Perry T. Wasdin, Kritika Kedarinath, Keziah R. Hernandez, Kristyn A. Gonzales, Kharighan Hill, Nicole G. Weidner, Chad Mire, Taylor B. Engdahl, Woohyun J. Moon, Vsevolod Popov, James E. Crowe, Ivelin S. Georgiev, Mariano A. Garcia-Blanco, Robert K. Abbott, Alexander Bukreyev

Pathology

Research output: Contribution to journal › Article › peer-review

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.

Original language	English (US)
Article number	6421
Journal	Nature communications
Volume	15
Issue number	1
DOIs	https://doi.org/10.1038/s41467-024-50774-3
State	Published - Dec 2024

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy

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Kuzmin, I. V., Soto Acosta, R., Pruitt, L., Wasdin, P. T., Kedarinath, K., Hernandez, K. R., Gonzales, K. A., Hill, K., Weidner, N. G., Mire, C., Engdahl, T. B., Moon, W. J., Popov, V., Crowe, J. E., Georgiev, I. S., Garcia-Blanco, M. A., Abbott, R. K., & Bukreyev, A. (2024). Comparison of uridine and N1-methylpseudouridine mRNA platforms in development of an Andes virus vaccine. Nature communications, 15(1), Article 6421. https://doi.org/10.1038/s41467-024-50774-3

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, Georgiev, IS, Garcia-Blanco, MA, Abbott, RK & Bukreyev, A 2024, 'Comparison of uridine and N1-methylpseudouridine mRNA platforms in development of an Andes virus vaccine', Nature communications, vol. 15, no. 1, 6421. https://doi.org/10.1038/s41467-024-50774-3

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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 na{\"i}ve 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.",

author = "Kuzmin, {Ivan V.} and {Soto Acosta}, Ruben and Layne Pruitt and Wasdin, {Perry T.} and Kritika Kedarinath and Hernandez, {Keziah R.} and Gonzales, {Kristyn A.} and Kharighan Hill and Weidner, {Nicole G.} and Chad Mire and Engdahl, {Taylor B.} and Moon, {Woohyun J.} and Vsevolod Popov and Crowe, {James E.} and Georgiev, {Ivelin S.} and Garcia-Blanco, {Mariano A.} and Abbott, {Robert K.} and Alexander Bukreyev",

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AU - Kuzmin, Ivan V.

AU - Soto Acosta, Ruben

AU - Pruitt, Layne

AU - Wasdin, Perry T.

AU - Kedarinath, Kritika

AU - Hernandez, Keziah R.

AU - Gonzales, Kristyn A.

AU - Hill, Kharighan

AU - Weidner, Nicole G.

AU - Mire, Chad

AU - Engdahl, Taylor B.

AU - Moon, Woohyun J.

AU - Popov, Vsevolod

AU - Crowe, James E.

AU - Georgiev, Ivelin S.

AU - Garcia-Blanco, Mariano A.

AU - Abbott, Robert K.

AU - Bukreyev, Alexander

PY - 2024/12

Y1 - 2024/12

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

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