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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Veröffentlicht in:Nature communications Jg. 15; H. 1; S. 6421 - 18
Hauptverfasser: 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
Sprache:Englisch
Veröffentlicht: London Nature Publishing Group UK 30.07.2024
Nature Publishing Group
Nature Portfolio
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13/1
13/106
13/109
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13/31
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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
ISSN:2041-1723, 2041-1723
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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 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.
AbstractList 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.
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.
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.
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.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.
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.
ArticleNumber 6421
Author Weidner, Nicole G.
Kuzmin, Ivan V.
Hernandez, Keziah R.
Wasdin, Perry T.
Garcia-Blanco, Mariano A.
Popov, Vsevolod
Engdahl, Taylor B.
Hill, Kharighan
Crowe, James E.
Pruitt, Layne
Mire, Chad
Moon, Woohyun J.
Soto Acosta, Ruben
Bukreyev, Alexander
Gonzales, Kristyn A.
Abbott, Robert K.
Georgiev, Ivelin S.
Kedarinath, Kritika
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  surname: Kuzmin
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  organization: Department of Pathology, University of Texas Medical Branch, Galveston National Laboratory
– sequence: 2
  givenname: Ruben
  surname: Soto Acosta
  fullname: Soto Acosta, Ruben
  organization: Department of Pathology, University of Texas Medical Branch, Galveston National Laboratory
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  givenname: Layne
  surname: Pruitt
  fullname: Pruitt, Layne
  organization: Department of Pathology, University of Texas Medical Branch
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  givenname: Perry T.
  orcidid: 0000-0001-7351-2048
  surname: Wasdin
  fullname: Wasdin, Perry T.
  organization: Vanderbilt University Medical Center, Vanderbilt Vaccine Center
– sequence: 5
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  surname: Kedarinath
  fullname: Kedarinath, Kritika
  organization: Department of Pathology, University of Texas Medical Branch, Galveston National Laboratory
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  givenname: Keziah R.
  surname: Hernandez
  fullname: Hernandez, Keziah R.
  organization: Department of Pathology, University of Texas Medical Branch, Galveston National Laboratory
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  givenname: Kristyn A.
  surname: Gonzales
  fullname: Gonzales, Kristyn A.
  organization: Department of Pathology, University of Texas Medical Branch
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  givenname: Kharighan
  surname: Hill
  fullname: Hill, Kharighan
  organization: Department of Pathology, University of Texas Medical Branch
– sequence: 9
  givenname: Nicole G.
  surname: Weidner
  fullname: Weidner, Nicole G.
  organization: Department of Pathology, University of Texas Medical Branch
– sequence: 10
  givenname: Chad
  orcidid: 0000-0001-7596-1808
  surname: Mire
  fullname: Mire, Chad
  organization: Department of Pathology, University of Texas Medical Branch, Galveston National Laboratory
– sequence: 11
  givenname: Taylor B.
  orcidid: 0000-0002-6280-4405
  surname: Engdahl
  fullname: Engdahl, Taylor B.
  organization: Vanderbilt University Medical Center, Vanderbilt Vaccine Center
– sequence: 12
  givenname: Woohyun J.
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  organization: Acuitas Therapeutics
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  givenname: Vsevolod
  surname: Popov
  fullname: Popov, Vsevolod
  organization: Department of Pathology, University of Texas Medical Branch
– sequence: 14
  givenname: James E.
  orcidid: 0000-0002-0049-1079
  surname: Crowe
  fullname: Crowe, James E.
  organization: Vanderbilt University Medical Center, Vanderbilt Vaccine Center
– sequence: 15
  givenname: Ivelin S.
  orcidid: 0000-0002-6312-7696
  surname: Georgiev
  fullname: Georgiev, Ivelin S.
  organization: Vanderbilt University Medical Center, Vanderbilt Vaccine Center
– sequence: 16
  givenname: Mariano A.
  surname: Garcia-Blanco
  fullname: Garcia-Blanco, Mariano A.
  organization: Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Department of Microbiology, Immunology and Cancer Biology, University of Virginia
– sequence: 17
  givenname: Robert K.
  orcidid: 0000-0003-0335-1175
  surname: Abbott
  fullname: Abbott, Robert K.
  email: rkabbott@utmb.edu
  organization: Department of Pathology, University of Texas Medical Branch
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  givenname: Alexander
  orcidid: 0000-0002-0342-4824
  surname: Bukreyev
  fullname: Bukreyev, Alexander
  email: alexander.bukreyev@UTMB.EDU
  organization: Department of Pathology, University of Texas Medical Branch, Galveston National Laboratory, Department of Microbiology and Immunology, University of Texas Medical Branch
BackLink https://www.ncbi.nlm.nih.gov/pubmed/39080316$$D View this record in MEDLINE/PubMed
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Snippet 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...
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,...
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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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Title Comparison of uridine and N1-methylpseudouridine mRNA platforms in development of an Andes virus vaccine
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