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Article ; Online: Multidimensional sample analysis to determine pandemic viral evolution.

O'Donnell, Kyle L / Marzi, Andrea

2023 Volume 92, Page(s) 104606

MeSH term(s)	Humans ; Pandemics ; Evolution, Molecular ; Phylogeny
Language	English
Publishing date	2023-05-06
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	2851331-9
ISSN	2352-3964
ISSN (online)	2352-3964
DOI	10.1016/j.ebiom.2023.104606
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Article ; Online: Single-Dose Treatment With Vesicular Stomatitis Virus-Based Ebola Virus Vaccine Expressing Ebola Virus-Specific Artificial Micro-RNA Does Not Protect Mice From Lethal Disease.

O'Donnell, Kyle L / Callison, Julie / Feldmann, Heinz / Hoenen, Thomas / Marzi, Andrea

The Journal of infectious diseases

2023 Volume 228, Issue Suppl 7, Page(s) S677–S681

Abstract: Although significant progress has been made in the development of therapeutics against Ebola virus (EBOV), we sought to expand upon existing strategies and combine an RNA interference-based intervention with the approved vesicular stomatitis virus-based ... ...

Abstract	Although significant progress has been made in the development of therapeutics against Ebola virus (EBOV), we sought to expand upon existing strategies and combine an RNA interference-based intervention with the approved vesicular stomatitis virus-based Ebola virus (VSV-EBOV) vaccine to conjointly treat and vaccinate patients during an outbreak. We constructed VSV-EBOV vectors expressing artificial micro-RNAs (amiRNAs) targeting sequences of EBOV proteins. In vitro experiments demonstrated a robust decrease in EBOV replication using a minigenome system and infectious virus. For in vivo evaluation, mouse-adapted EBOV-infected CD-1 mice were treated 24 hours after infection with a single dose of the VSV-EBOV amiRNA constructs. We observed no difference in disease progression or survival compared to the control-treated mice. In summary, while amiRNAs decrease viral replication in vitro, the effect is not sufficient to protect mice from lethal disease, and this therapeutic approach requires further optimization.
MeSH term(s)	Humans ; Animals ; Mice ; Ebolavirus/genetics ; Hemorrhagic Fever, Ebola ; Ebola Vaccines ; Vesicular Stomatitis ; RNA
Chemical Substances	Ebola Vaccines ; RNA (63231-63-0)
Language	English
Publishing date	2023-04-26
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Intramural
ZDB-ID	3019-3
ISSN	1537-6613 ; 0022-1899
ISSN (online)	1537-6613
ISSN	0022-1899
DOI	10.1093/infdis/jiad121
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Article ; Online: Preexisting Immunity Does Not Prevent Efficacy of Vesicular Stomatitis Virus-Based Filovirus Vaccines in Nonhuman Primates.

Marzi, Andrea / Feldmann, Friederike / O'Donnell, Kyle L / Hanley, Patrick W / Messaoudi, Ilhem / Feldmann, Heinz

The Journal of infectious diseases

2023 Volume 228, Issue Suppl 7, Page(s) S671–S676

Abstract: Ebola virus (EBOV) and Marburg virus (MARV) made headlines in the past decade, causing outbreaks of human disease in previously nonendemic yet overlapping areas. While EBOV outbreaks can be mitigated with licensed vaccines and treatments, there is not ... ...

Abstract	Ebola virus (EBOV) and Marburg virus (MARV) made headlines in the past decade, causing outbreaks of human disease in previously nonendemic yet overlapping areas. While EBOV outbreaks can be mitigated with licensed vaccines and treatments, there is not yet a licensed countermeasure for MARV. Here, we used nonhuman primates (NHPs) previously vaccinated with vesicular stomatitis virus (VSV)-MARV and protected against lethal MARV challenge. After a resting period of 9 months, these NHPs were revaccinated with VSV-EBOV and challenged with EBOV, resulting in 75% survival. Surviving NHPs developed EBOV glycoprotein (GP)-specific antibody titers and no viremia or clinical signs of disease. The single vaccinated NHP succumbing to challenge showed the lowest EBOV GP-specific antibody response after challenge, supporting previous findings with VSV-EBOV that antigen-specific antibodies are critical in mediating protection. This study again demonstrates that VSVΔG-based filovirus vaccine can be successfully used in individuals with preexisting VSV vector immunity, highlighting the platform's applicability for consecutive outbreak response.
MeSH term(s)	Animals ; Humans ; Hemorrhagic Fever, Ebola/prevention & control ; Vesicular Stomatitis/prevention & control ; Ebola Vaccines ; Ebolavirus ; Vesiculovirus ; Vesicular stomatitis Indiana virus ; Marburgvirus ; Antibodies, Viral ; Glycoproteins ; Primates
Chemical Substances	Ebola Vaccines ; Antibodies, Viral ; Glycoproteins
Language	English
Publishing date	2023-06-08
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Intramural
ZDB-ID	3019-3
ISSN	1537-6613 ; 0022-1899
ISSN (online)	1537-6613
ISSN	0022-1899
DOI	10.1093/infdis/jiad208
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Article: Immunotherapeutics for Ebola Virus Disease: Hope on the Horizon.

O'Donnell, Kyle L / Marzi, Andrea

Biologics : targets & therapy

2021 Volume 15, Page(s) 79–86

Abstract: Ebola virus disease (EVD) remains among the biggest public health threats in Africa, even though recently a vaccine was approved for human use. However, in outbreak situations treatment strategies are needed in combination with vaccination campaigns to ... ...

Abstract	Ebola virus disease (EVD) remains among the biggest public health threats in Africa, even though recently a vaccine was approved for human use. However, in outbreak situations treatment strategies are needed in combination with vaccination campaigns to impact and stop the spread of the disease. Here, we discuss the development of the immunotherapeutics against EDV both targeting the virus itself and bolstering the immunological environment of the host at both the pre-clinical and clinical level. The early development of antibody therapy in preclinical settings and the early pitfalls in the implementation of this therapeutic strategy are discussed. We also consider the advancement of the production, modulation, and specificity of the antibody treatment that garnered increased success in preclinical studies to the point that it was warranted to test them in a clinical setting. Initial clinical trials in an outbreak scenario proved difficult to definitively confirm the efficacy of the implemented treatment. Upon further modification and with the experiences from the challenging outbreak conditions in mind, the PALM clinical trial demonstrated efficacy of an antibody cocktail which recently received approval for human use.
Language	English
Publishing date	2021-03-18
Publishing country	New Zealand
Document type	Journal Article ; Review
ISSN	1177-5475
ISSN	1177-5475
DOI	10.2147/BTT.S259069
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Article ; Online: Establishing a Mouse Model for Sexual Transmission and Male Reproductive Tract Persistence of Ebola Virus.

Clancy, Chad S / Smart, Gabrielle / Rhoderick, J Fred / O'Donnell, Kyle L / Rosenke, Rebecca / Schäfer, Alexandra / Marzi, Andrea

The Journal of infectious diseases

2023 Volume 228, Issue Suppl 7, Page(s) S554–S558

Abstract: Ebola virus disease (EVD) has resulted in the death of over 15 000 people since its discovery in 1976. At least 1 incident of re-emergence of EVD has been associated with persistent male reproductive tract infection in a patient surviving EVD greater ... ...

Abstract	Ebola virus disease (EVD) has resulted in the death of over 15 000 people since its discovery in 1976. At least 1 incident of re-emergence of EVD has been associated with persistent male reproductive tract infection in a patient surviving EVD greater than 500 days prior. To date, animal models of Ebola virus (EBOV) infection have failed to fully characterize the pathogenesis of reproductive tract infection. Furthermore, no animal model of sexual transmission of EBOV exists. In this study, we describe a roadmap to modeling sexual transmission of EBOV using a mouse-adapted EBOV isolate in immunocompetent male mice and female Ifnar-/- mice.
MeSH term(s)	Animals ; Humans ; Male ; Female ; Ebolavirus ; Hemorrhagic Fever, Ebola ; Reproductive Tract Infections ; Disease Models, Animal
Language	English
Publishing date	2023-04-27
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Intramural
ZDB-ID	3019-3
ISSN	1537-6613 ; 0022-1899
ISSN (online)	1537-6613
ISSN	0022-1899
DOI	10.1093/infdis/jiad118
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Article ; Online: Protection from COVID-19 with a VSV-based vaccine expressing the spike and nucleocapsid proteins.

O'Donnell, Kyle L / Gourdine, Tylisha / Fletcher, Paige / Clancy, Chad S / Marzi, Andrea

Frontiers in immunology

2022 Volume 13, Page(s) 1025500

Abstract: Successful vaccine efforts countering the COVID-19 pandemic are centralized around the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike (S) protein as viral antigen and have greatly reduced the morbidity and mortality associated with ... ...

Abstract	Successful vaccine efforts countering the COVID-19 pandemic are centralized around the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike (S) protein as viral antigen and have greatly reduced the morbidity and mortality associated with COVID-19. Since the start of this pandemic, SARS-CoV-2 has evolved resulting in new variants of concern (VOC) challenging the vaccine-established immunologic memory. We show that vaccination with a vesicular stomatitis virus (VSV)-based vaccine expressing the SARS-CoV-2 S plus the conserved nucleocapsid (N) protein was protective in a hamster challenge model when a single dose was administered 28 or 10 days prior to challenge, respectively. In this study, only intranasal vaccination resulted in protection against challenge with multiple VOC highlighting that the addition of the N protein indeed improved protective efficacy. This data demonstrates the ability of a VSV-based dual-antigen vaccine to reduce viral shedding and protect from disease caused by SARS-CoV-2 VOC.
MeSH term(s)	Cricetinae ; Animals ; Humans ; COVID-19/prevention & control ; Nucleocapsid Proteins ; SARS-CoV-2 ; Pandemics ; Viral Vaccines
Chemical Substances	Nucleocapsid Proteins ; Viral Vaccines
Language	English
Publishing date	2022-10-24
Publishing country	Switzerland
Document type	Journal Article ; Research Support, N.I.H., Intramural
ZDB-ID	2606827-8
ISSN	1664-3224 ; 1664-3224
ISSN (online)	1664-3224
ISSN	1664-3224
DOI	10.3389/fimmu.2022.1025500
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Article ; Online: Rapid protection of nonhuman primates against Marburg virus disease using a single low-dose VSV-based vaccine.

O'Donnell, Kyle L / Feldmann, Friederike / Kaza, Benjamin / Clancy, Chad S / Hanley, Patrick W / Fletcher, Paige / Marzi, Andrea

EBioMedicine

2023 Volume 89, Page(s) 104463

Abstract: Background: Marburg virus (MARV) is the causative agent of Marburg virus disease (MVD) which has a case fatality rate up to ∼90% in humans. Recently, there were cases reported in Guinea and Ghana highlighting this virus as a high-consequence pathogen ... ...

Abstract	Background: Marburg virus (MARV) is the causative agent of Marburg virus disease (MVD) which has a case fatality rate up to ∼90% in humans. Recently, there were cases reported in Guinea and Ghana highlighting this virus as a high-consequence pathogen potentially threatening global public health. There are no licensed treatments or vaccines available today. We used a vesicular stomatitis virus (VSV)-based vaccine expressing the MARV-Angola glycoprotein (VSV-MARV) as the viral antigen. Previously, a single dose of 1 × 10 Methods: As we sought to lower the vaccination dose to achieve a higher number of vaccine doses per vial, we administered 1 × 10 Results: Vaccination resulted in uniform protection with no detectable viremia. Antigen-specific IgG responses were induced by both vaccine concentrations and were sustained until the study endpoint. Neutralizing antibody responses and antibody-dependent cellular phagocytosis were observed. The cellular response after vaccination was characterized by an early induction of NK cell activation. Additionally, antigen-specific memory T cell subsets were detected in all vaccination cohorts indicating that while the primary protective mechanism of VSV-MARV is the humoral response, a functional cellular response is also induced. Interpretation: Overall, this data highlights VSV-MARV as a viable and fast-acting MARV vaccine candidate suitable for deployment in emergency outbreak situations and supports its clinical development. Funding: This work was funded by the Intramural Research Program NIAID, NIH.
MeSH term(s)	Animals ; Humans ; Marburg Virus Disease/prevention & control ; Viral Vaccines ; Macaca fascicularis ; Vaccination ; Antibodies, Neutralizing
Chemical Substances	Viral Vaccines ; Antibodies, Neutralizing
Language	English
Publishing date	2023-02-10
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	2851331-9
ISSN	2352-3964
ISSN (online)	2352-3964
DOI	10.1016/j.ebiom.2023.104463
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Article ; Online: Serum from COVID-19 patients early in the pandemic shows limited evidence of cross-neutralization against variants of concern.

Griffin, Amanda J / O'Donnell, Kyle L / Shifflett, Kyle / Lavik, John-Paul / Russell, Patrick M / Zimmerman, Michelle K / Relich, Ryan F / Marzi, Andrea

Scientific reports

2022 Volume 12, Issue 1, Page(s) 3954

Abstract: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) results in a variety of clinical symptoms ranging from no or mild to severe disease. Currently, there are multiple postulated mechanisms that may push a moderate to severe disease into a ... ...

Abstract	Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) results in a variety of clinical symptoms ranging from no or mild to severe disease. Currently, there are multiple postulated mechanisms that may push a moderate to severe disease into a critical state. Human serum contains abundant evidence of the immune status following infection. Cytokines, chemokines, and antibodies can be assayed to determine the extent to which a patient responded to a pathogen. We examined serum and plasma from a cohort of patients infected with SARS-CoV-2 early in the pandemic and compared them to negative-control sera. Cytokine and chemokine concentrations varied depending on the severity of infection, and antibody responses were significantly increased in severe cases compared to mild to moderate infections. Neutralization data revealed that patients with high titers against an early 2020 SARS-CoV-2 isolate had detectable but limited neutralizing antibodies against the emerging SARS-CoV-2 Alpha, Beta and Delta variants. This study highlights the potential of re-infection for recovered COVID-19 patients.
MeSH term(s)	Adolescent ; Adult ; Aged ; Aged, 80 and over ; Broadly Neutralizing Antibodies/immunology ; COVID-19/immunology ; COVID-19/virology ; Chemokines/blood ; Cytokines/blood ; Female ; Humans ; Male ; Middle Aged ; Patient Acuity ; SARS-CoV-2/immunology ; Young Adult
Chemical Substances	Broadly Neutralizing Antibodies ; Chemokines ; Cytokines
Language	English
Publishing date	2022-03-10
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, N.I.H., Intramural
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-022-07960-4
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Article: VSV-Based Vaccines Reduce Virus Shedding and Viral Load in Hamsters Infected with SARS-CoV-2 Variants of Concern.

O'Donnell, Kyle L / Gourdine, Tylisha / Fletcher, Paige / Shifflett, Kyle / Furuyama, Wakako / Clancy, Chad S / Marzi, Andrea

Vaccines

2022 Volume 10, Issue 3

Abstract: The continued progression of the COVID-19 pandemic can partly be attributed to the ability of SARS-CoV-2 to mutate and introduce new viral variants. Some of these variants with the potential to spread quickly and conquer the globe are termed variants of ... ...

Abstract	The continued progression of the COVID-19 pandemic can partly be attributed to the ability of SARS-CoV-2 to mutate and introduce new viral variants. Some of these variants with the potential to spread quickly and conquer the globe are termed variants of concern (VOC). The existing vaccines implemented on a global scale are based on the ancestral strain, which has resulted in increased numbers of breakthrough infections as these VOC have emerged. It is imperative to show protection against VOC infection with newly developed vaccines. Previously, we evaluated two vesicular stomatitis virus (VSV)-based vaccines expressing the SARS-CoV-2 spike protein alone (VSV-SARS2) or in combination with the Ebola virus glycoprotein (VSV-SARS2-EBOV) and demonstrated their fast-acting potential. Here, we prolonged the time to challenge; we vaccinated hamsters intranasally (IN) or intramuscularly 28 days prior to infection with three SARS-CoV-2 VOC-the Alpha, Beta, and Delta variants. IN vaccination with either the VSV-SARS2 or VSV-SARS2-EBOV resulted in the highest protective efficacy as demonstrated by decreased virus shedding and lung viral load of vaccinated hamsters. Histopathologic analysis of the lungs revealed the least amount of lung damage in the IN-vaccinated animals regardless of the challenge virus. This data demonstrates the ability of a VSV-based vaccine to not only protect from disease caused by SARS-CoV-2 VOC but also reduce viral shedding.
Language	English
Publishing date	2022-03-12
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2703319-3
ISSN	2076-393X
ISSN	2076-393X
DOI	10.3390/vaccines10030435
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Article ; Online: Single-dose treatment with VSV-EBOV expressing Ebola virus-specific artificial miRNAs does not protect mice from lethal disease

O’Donnell, Kyle L / Callison, Julie / Feldmann, Heinz / Hoenen, Thomas / Marzi, Andrea

2023

Abstract: Although significant progress has been made in the development of therapeutics against Ebola virus (EBOV), we sought to expand upon existing strategies and combine an RNAi-based intervention with the approved VSV-EBOV vaccine to conjointly treat and ... ...

Abstract	Although significant progress has been made in the development of therapeutics against Ebola virus (EBOV), we sought to expand upon existing strategies and combine an RNAi-based intervention with the approved VSV-EBOV vaccine to conjointly treat and vaccinate patients during an outbreak. We constructed VSV-EBOV vectors expressing artificial miRNAs (amiRNAs) targeting sequences of EBOV proteins. In vitro experiments demonstrated a robust decrease in EBOV replication using a minigenome system and infectious virus. For in vivo evaluation, MA-EBOV-infected CD-1 mice were treated 24 hours after infection with a single dose of the VSV-EBOV-amiRNA constructs. We observed no difference in disease progression or survival compared to the control-treated mice. In summary, while amiRNAs decrease viral replication in vitro, the effect is not sufficient to protect mice from lethal disease, and this therapeutic approach requires further optimization.
Keywords	article ; Text ; ddc:570 ; Filovirus -- vesicular stomatitis virus -- post-exposure prophylaxis -- amiRNA -- RNAi -- Ebola virus disease -- animal model
Subject code	570
Language	English
Publishing date	2023-04-27
Publisher	Oxford University Press (OUP)
Publishing country	de
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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