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Vaccine Development Needs for Marburg Virus and Sudan Ebolavirus: Leveraging...
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Vaccine Development Needs for Marburg Virus and Sudan Ebolavirus: Leveraging Lessons Learned from the Zaire Ebolavirus

A special issue of Vaccines (ISSN 2076-393X). This special issue belongs to the section "Vaccines against Infectious Diseases".

Deadline for manuscript submissions: closed (30 June 2022) | Viewed by 35459

Special Issue Editors

Dr. Daniel Wolfe

E-Mail Website
Guest Editor
Biomedical Advanced Research and Development Authority, Department of Health and Human Services, Washington, DC 20201, USA
Interests: biodefense; vaccines; immunology; vaccine manufacturing; clinical trials
Dr. Kimberly L. Taylor

E-Mail Website
Guest Editor
National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services, Washington, DC 20201, USA
Interests: vaccine development; biodefense pathogens and emerging infectious diseases; preclinical testing
Dr. Lawrence A. Wolfraim

E-Mail Website
Guest Editor
National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services, Washington, DC 20201, USA
Interests: vaccine development; biodefense pathogens and emerging infectious diseases; preclinical testing; immunology; immune assays
Dr. Clint Florence

E-Mail Website
Guest Editor
National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services, Washington, DC 20201, USA
Interests: animal model; vaccine and advanced product development; biodefense; immunology; microbiology

Special Issue Information

Dear Colleagues,

Since 2014, we have seen dramatic progress in the field of Ebola vaccines, largely driven by the urgent need associated with the 2014–2016 epidemic in West Africa. The collective efforts from the filovirus community resulted in vaccines moving from preclinical development to a licensed vaccine by the end of 2019. However, the licensed vaccine protects only against Zaire ebolavirus and other related viruses (specifically Sudan ebolavirus and Marburg virus) still pose urgent threats.

The recent outbreak of Marburg virus highlights the urgent need for vaccines that could be used to help slow the spread of disease when these outbreaks inevitably occur. It also casts a light on our collective level of preparedness in terms of available medical countermeasures.

In this Special Issue, we aim to cover lessons learned from the Zaire ebolavirus vaccine development, and how this can/will be applied to vaccine development for Sudan ebolavirus and Marburg virus. Topics will include perspectives from the USG and product developers on the development of Zaire ebolavirus vaccines, challenges and lessons learned, regulatory strategies, and updates of licensed or lead candidates. Other topics will include the development of standardized tools, such as available immunological assays and animal models, and clinical trial network operations during outbreaks. The goal is to provide an overview of the current status of Marburg virus and Sudan ebolavirus vaccines and some of the key enabling technologies.

Dr. Daniel Wolfe
Dr. Kimberly L. Taylor
Dr. Lawrence A. Wolfraim
Dr. Clint Florence
Guest Editors

Manuscript Submission Information

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Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Vaccines is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Published Papers (15 papers)

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Research

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22 pages, 2167 KiB  
Article
Single-Shot ChAd3-MARV Vaccine in Modified Formulation Buffer Shows 100% Protection of NHPs
by Courtney L. Finch, Thomas H. King, Kendra J. Alfson, Katie A. Albanese, Julianne N. P. Smith, Paul Smock, Jocelyn Jakubik, Yenny Goez-Gazi, Michal Gazi, John W. Dutton III, Elizabeth A. Clemmons, Marc E. Mattix, Ricardo Carrion, Jr., Thomas Rudge, Jr., Alex Ridenour, Sovann F. Woodin, Ruth Hunegnaw, Nancy J. Sullivan and Rong Xu
Vaccines 2022, 10(11), 1935; https://doi.org/10.3390/vaccines10111935 - 15 Nov 2022
Cited by 2 | Viewed by 1734
Abstract
Marburg virus (MARV) is a virus of high human consequence with a case fatality rate of 24–88%. The global health and national security risks posed by Marburg virus disease (MVD) underscore the compelling need for a prophylactic vaccine, but no candidate has yet [...] Read more.
Marburg virus (MARV) is a virus of high human consequence with a case fatality rate of 24–88%. The global health and national security risks posed by Marburg virus disease (MVD) underscore the compelling need for a prophylactic vaccine, but no candidate has yet reached regulatory approval. Here, we evaluate a replication-defective chimpanzee adenovirus type 3 (ChAd3)-vectored MARV Angola glycoprotein (GP)-expressing vaccine against lethal MARV challenge in macaques. The ChAd3 platform has previously been reported to protect against the MARV-related viruses, Ebola virus (EBOV) and Sudan virus (SUDV), and MARV itself in macaques, with immunogenicity demonstrated in macaques and humans. In this study, we present data showing 100% protection against MARV Angola challenge (versus 0% control survival) and associated production of GP-specific IgGs generated by the ChAd3-MARV vaccine following a single dose of 1 × 1011 virus particles prepared in a new clinical formulation buffer designed to enhance product stability. These results are consistent with previously described data using the same vaccine in a different formulation and laboratory, demonstrating the reproducible and robust protective efficacy elicited by this promising vaccine for the prevention of MVD. Additionally, a qualified anti-GP MARV IgG ELISA was developed as a critical pre-requisite for clinical advancement and regulatory approval. Full article
(This article belongs to the Special Issue Vaccine Development Needs for Marburg Virus and Sudan Ebolavirus: Leveraging Lessons Learned from the Zaire Ebolavirus)
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33 pages, 10987 KiB  
Article
Development of a Well-Characterized Cynomolgus Macaque Model of Sudan Virus Disease for Support of Product Development
by Kendra J. Alfson, Yenny Goez-Gazi, Michal Gazi, Ying-Liang Chou, Nancy A. Niemuth, Marc E. Mattix, Hilary Staples, Benjamin Klaffke, Gloria F. Rodriguez, Priscilla Escareno, Carmen Bartley, Anysha Ticer, Elizabeth A. Clemmons, John W. Dutton III, Anthony Griffiths, Gabe T. Meister, Daniel C. Sanford, Chris M. Cirimotich and Ricardo Carrion, Jr.
Vaccines 2022, 10(10), 1723; https://doi.org/10.3390/vaccines10101723 - 15 Oct 2022
Viewed by 1814
Abstract
The primary objective of this study was to characterize the disease course in cynomolgus macaques exposed to Sudan virus (SUDV), to determine if infection in this species is an appropriate model for the evaluation of filovirus countermeasures under the FDA Animal Rule. Sudan [...] Read more.
The primary objective of this study was to characterize the disease course in cynomolgus macaques exposed to Sudan virus (SUDV), to determine if infection in this species is an appropriate model for the evaluation of filovirus countermeasures under the FDA Animal Rule. Sudan virus causes Sudan virus disease (SVD), with an average case fatality rate of approximately 50%, and while research is ongoing, presently there are no approved SUDV vaccines or therapies. Well characterized animal models are crucial for further developing and evaluating countermeasures for SUDV. Twenty (20) cynomolgus macaques were exposed intramuscularly to either SUDV or sterile phosphate-buffered saline; 10 SUDV-exposed animals were euthanized on schedule to characterize pathology at defined durations post-exposure and 8 SUDV-exposed animals were not part of the scheduled euthanasia cohort. Survival was assessed, along with clinical observations, body weights, body temperatures, hematology, clinical chemistry, coagulation, viral load (serum and tissues), macroscopic observations, and histopathology. There were statistically significant differences between SUDV-exposed animals and mock-exposed animals for 26 parameters, including telemetry body temperature, clinical chemistry parameters, hematology parameters, activated partial thromboplastin time, serum viremia, and biomarkers that characterize the disease course of SUDV in cynomolgus macaques. Full article
(This article belongs to the Special Issue Vaccine Development Needs for Marburg Virus and Sudan Ebolavirus: Leveraging Lessons Learned from the Zaire Ebolavirus)
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17 pages, 1126 KiB  
Article
Nonhuman Primates Are Protected against Marburg Virus Disease by Vaccination with a Vesicular Stomatitis Virus Vector-Based Vaccine Prepared under Conditions to Allow Advancement to Human Clinical Trials
by Christopher L. Cooper, Gavin Morrow, Maoli Yuan, John W. Coleman, Fuxiang Hou, Lucia Reiserova, Shui L. Li, Denise Wagner, Alexei Carpov, Olivia Wallace-Selman, Kristie Valentin, Yesle Choi, Aaron Wilson, Andrew Kilianski, Eddy Sayeed, Krystle N. Agans, Viktoriya Borisevich, Robert W. Cross, Thomas W. Geisbert, Mark B. Feinberg, Swati B. Gupta and Christopher L. Parksadd Show full author list remove Hide full author list
Vaccines 2022, 10(10), 1582; https://doi.org/10.3390/vaccines10101582 - 21 Sep 2022
Cited by 4 | Viewed by 5143
Abstract
Vaccines are needed to disrupt or prevent continued outbreaks of filoviruses in humans across Western and Central Africa, including outbreaks of Marburg virus (MARV). As part of a filovirus vaccine product development plan, it is important to investigate dose response early in preclinical [...] Read more.
Vaccines are needed to disrupt or prevent continued outbreaks of filoviruses in humans across Western and Central Africa, including outbreaks of Marburg virus (MARV). As part of a filovirus vaccine product development plan, it is important to investigate dose response early in preclinical development to identify the dose range that may be optimal for safety, immunogenicity, and efficacy, and perhaps demonstrate that using lower doses is feasible, which will improve product access. To determine the efficacious dose range for a manufacturing-ready live recombinant vesicular stomatitis virus vaccine vector (rVSV∆G-MARV-GP) encoding the MARV glycoprotein (GP), a dose-range study was conducted in cynomolgus macaques. Results showed that a single intramuscular injection with as little as 200 plaque-forming units (PFUs) was 100% efficacious against lethality and prevented development of viremia and clinical pathologies associated with MARV Angola infection. Across the vaccine doses tested, there was nearly a 2000-fold range of anti-MARV glycoprotein (GP) serum IgG titers with seroconversion detectable even at the lowest doses. Virus-neutralizing serum antibodies also were detected in animals vaccinated with the higher vaccine doses indicating that vaccination induced functional antibodies, but that the assay was a less sensitive indicator of seroconversion. Collectively, the data indicates that a relatively wide range of anti-GP serum IgG titers are observed in animals that are protected from disease implying that seroconversion is positively associated with efficacy, but that more extensive immunologic analyses on samples collected from our study as well as future preclinical studies will be valuable in identifying additional immune responses correlated with protection that can serve as markers to monitor in human trials needed to generate data that can support vaccine licensure in the future. Full article
(This article belongs to the Special Issue Vaccine Development Needs for Marburg Virus and Sudan Ebolavirus: Leveraging Lessons Learned from the Zaire Ebolavirus)
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10 pages, 854 KiB  
Article
Immune Correlates of Protection from Filovirus Efficacy Studies in Non-Human Primates
by Cheryl A. Triplett, Nancy A. Niemuth, Christopher Cirimotich, Gabriel Meister, Mimi Guebre-Xabier, Nita Patel, Mike Massare, Greg Glenn, Gale Smith, Kendra J. Alfson, Yenny Goez-Gazi and Ricardo Carrion, Jr.
Vaccines 2022, 10(8), 1338; https://doi.org/10.3390/vaccines10081338 - 18 Aug 2022
Cited by 6 | Viewed by 1607
Abstract
Non-human primate (NHP) efficacy data for several Ebola virus (EBOV) vaccine candidates exist, but definitive correlates of protection (CoP) have not been demonstrated, although antibodies to the filovirus glycoprotein (GP) antigen and other immunological endpoints have been proposed as potential CoPs. Accordingly, studies [...] Read more.
Non-human primate (NHP) efficacy data for several Ebola virus (EBOV) vaccine candidates exist, but definitive correlates of protection (CoP) have not been demonstrated, although antibodies to the filovirus glycoprotein (GP) antigen and other immunological endpoints have been proposed as potential CoPs. Accordingly, studies that could elucidate biomarker(s) that statistically correlate, whether mechanistically or not, with protection are warranted. The primary objective of this study was to evaluate potential CoP for Novavax EBOV GP vaccine candidate administered at different doses to cynomolgus macaques using the combined data from two separate, related studies containing a total of 44 cynomolgus macaques. Neutralizing antibodies measured by pseudovirion neutralization assay (PsVNA) and anti-GP IgG binding antibodies were evaluated as potential CoP using logistic regression models. The predictive ability of these models was assessed using the area under the receiver operating characteristic (ROC) curve (AUC). Fitted models indicated a statistically significant relationship between survival and log base 10 (log10) transformed anti-GP IgG antibodies, with good predictive ability of the model. Neither (log10 transformed) PsVNT50 nor PsVNT80 titers were statistically significant predictors of survival, though predictive ability of both models was good. Predictive ability was not statistically different between any pair of models. Models that included immunization dose in addition to anti-GP IgG antibodies failed to detect statistically significant effects of immunization dose. These results support anti-GP IgG antibodies as a correlate of protection. Total assay variabilities and geometric coefficients of variation (GCVs) based on the study data appeared to be greater for both PsVNA readouts, suggesting the increased assay variability may account for non-significant model results for PsVNA despite the good predictive ability of the models. The statistical approach to evaluating CoP for this EBOV vaccine may prove useful for advancing research for Sudan virus (SUDV) and Marburg virus (MARV) candidate vaccines. Full article
(This article belongs to the Special Issue Vaccine Development Needs for Marburg Virus and Sudan Ebolavirus: Leveraging Lessons Learned from the Zaire Ebolavirus)
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24 pages, 4005 KiB  
Article
Development of a Well-Characterized Cynomolgus Macaque Model of Marburg Virus Disease for Support of Vaccine and Therapy Development
by Kendra J. Alfson, Yenny Goez-Gazi, Michal Gazi, Ying-Liang Chou, Nancy A. Niemuth, Marc E. Mattix, Hilary M. Staples, Benjamin Klaffke, Gloria F. Rodriguez, Carmen Bartley, Anysha Ticer, Elizabeth A. Clemmons, John W. Dutton III, Anthony Griffiths, Gabe T. Meister, Daniel C. Sanford, Chris M. Cirimotich and Ricardo Carrion, Jr.
Vaccines 2022, 10(8), 1314; https://doi.org/10.3390/vaccines10081314 - 14 Aug 2022
Cited by 5 | Viewed by 1702
Abstract
Marburg virus (MARV) is a filovirus that can infect humans and nonhuman primates (NHPs), causing severe disease and death. Of the filoviruses, Ebola virus (EBOV) has been the primary target for vaccine and therapeutic development. However, MARV has an average case fatality rate [...] Read more.
Marburg virus (MARV) is a filovirus that can infect humans and nonhuman primates (NHPs), causing severe disease and death. Of the filoviruses, Ebola virus (EBOV) has been the primary target for vaccine and therapeutic development. However, MARV has an average case fatality rate of approximately 50%, the infectious dose is low, and there are currently no approved vaccines or therapies targeted at infection with MARV. The purpose of this study was to characterize disease course in cynomolgus macaques intramuscularly exposed to MARV Angola variant. There were several biomarkers that reliably correlated with MARV-induced disease, including: viral load; elevated total clinical scores; temperature changes; elevated ALT, ALP, BA, TBIL, CRP and decreased ALB values; decreased lymphocytes and platelets; and prolonged PTT. A scheduled euthanasia component also provided the opportunity to study the earliest stages of the disease. This study provides evidence for the application of this model to evaluate potential vaccines and therapies against MARV and will be valuable in improving existing models. Full article
(This article belongs to the Special Issue Vaccine Development Needs for Marburg Virus and Sudan Ebolavirus: Leveraging Lessons Learned from the Zaire Ebolavirus)
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18 pages, 5052 KiB  
Article
Protection against Marburg Virus and Sudan Virus in NHP by an Adenovector-Based Trivalent Vaccine Regimen Is Correlated to Humoral Immune Response Levels
by Machteld M. Tiemessen, Laura Solforosi, Liesbeth Dekking, Dominika Czapska-Casey, Jan Serroyen, Nancy J. Sullivan, Ariane Volkmann, Maria Grazia Pau, Benoit Callendret, Hanneke Schuitemaker, Kerstin Luhn, Roland Zahn and Ramon Roozendaal
Vaccines 2022, 10(8), 1263; https://doi.org/10.3390/vaccines10081263 - 5 Aug 2022
Cited by 9 | Viewed by 1990
Abstract
The Marburg virus (MARV) and Sudan virus (SUDV) belong to the filovirus family. The sporadic human outbreaks occur mostly in Africa and are characterized by an aggressive disease course with high mortality. The first case of Marburg virus disease in Guinea in 2021, [...] Read more.
The Marburg virus (MARV) and Sudan virus (SUDV) belong to the filovirus family. The sporadic human outbreaks occur mostly in Africa and are characterized by an aggressive disease course with high mortality. The first case of Marburg virus disease in Guinea in 2021, together with the increased frequency of outbreaks of Ebola virus (EBOV), which is also a filovirus, accelerated the interest in potential prophylactic vaccine solutions against multiple filoviruses. We previously tested a two-dose heterologous vaccine regimen (Ad26.Filo, MVA-BN-Filo) in non-human primates (NHP) and showed a fully protective immune response against both SUDV and MARV in addition to the already-reported protective effect against EBOV. The vaccine-induced glycoprotein (GP)-binding antibody levels appear to be good predictors of the NHP challenge outcome as indicated by the correlation between antibody levels and survival outcome as well as the high discriminatory capacity of the logistic model. Moreover, the elicited GP-specific binding antibody response against EBOV, SUDV, and MARV remains stable for more than 1 year. Overall, the NHP data indicate that the Ad26.Filo, MVA-BN-Filo regimen may be a good candidate for a prophylactic vaccination strategy in regions at high risk of filovirus outbreaks. Full article
(This article belongs to the Special Issue Vaccine Development Needs for Marburg Virus and Sudan Ebolavirus: Leveraging Lessons Learned from the Zaire Ebolavirus)
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10 pages, 593 KiB  
Article
Adapting Simon’s Two-Stage Design for Efficient Screening of Filovirus Vaccines in Non-Human Primates
by Nancy A. Niemuth, Carol L. Sabourin and Lucy A. Ward
Vaccines 2022, 10(8), 1216; https://doi.org/10.3390/vaccines10081216 - 29 Jul 2022
Viewed by 1482
Abstract
The cynomolgus monkey (Macaca fascicularis) non-human primate (NHP) is widely used for filovirus vaccine testing. To use limited BSL-4 resources efficiently and minimize NHP usage, Simon’s two-stage design was adapted to screen candidate Ebola virus (EBOV) vaccines in up to six [...] Read more.
The cynomolgus monkey (Macaca fascicularis) non-human primate (NHP) is widely used for filovirus vaccine testing. To use limited BSL-4 resources efficiently and minimize NHP usage, Simon’s two-stage design was adapted to screen candidate Ebola virus (EBOV) vaccines in up to six NHPs with two (optimal), three, or four NHPs in Stage 1. Using the optimal design, two NHPs were tested in Stage 1. If neither survived, the candidate was rejected. Otherwise, it was eligible for Stage 2 testing in four NHPs. Candidates advanced if four or more NHPs were protected over both stages. An 80% efficacious candidate vaccine had 88.5% probability of advancing, and a 40% efficacious candidate vaccine had 83% probability of rejection. Simon’s two-stage design was used to screen 27 EBOV vaccine candidates in 43 candidate regimens that varied in dose, adjuvant, formulation, or schedule. Of the 30 candidate regimens tested using two NHPs in Stage 1, 15 were rejected, nine were withdrawn, and six were tested in Stage 2. All six tested in Stage 2 qualified to advance in the product development pipeline. Multiple regimens for the EBOV vaccines approved by the European Medicines Agency (EMA) and the US Food and Drug Administration (FDA) in 2019 were tested in this program. This approach may also prove useful for screening Sudan virus (SUDV) and Marburg virus (MARV) vaccine candidates. Full article
(This article belongs to the Special Issue Vaccine Development Needs for Marburg Virus and Sudan Ebolavirus: Leveraging Lessons Learned from the Zaire Ebolavirus)
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27 pages, 5568 KiB  
Article
Assays for the Evaluation of the Immune Response to Marburg and Ebola Sudan Vaccination—Filovirus Animal Nonclinical Group Anti-Marburg Virus Glycoprotein Immunoglobulin G Enzyme-Linked Immunosorbent Assay and a Pseudovirion Neutralization Assay
by Thomas L. Rudge, Jr., Nicholas J. Machesky, Karen A. Sankovich, Erin E. Lemmon, Christopher S. Badorrek, Rachel Overman, Nancy A. Niemuth and Michael S. Anderson
Vaccines 2022, 10(8), 1211; https://doi.org/10.3390/vaccines10081211 - 29 Jul 2022
Cited by 6 | Viewed by 2175
Abstract
Since the discovery of the Marburg virus (MARV) in 1967 and Ebola virus (EBOV) in 1976, there have been over 40 reported outbreaks of filovirus disease with case fatality rates greater than 50%. This underscores the need for efficacious vaccines against these highly [...] Read more.
Since the discovery of the Marburg virus (MARV) in 1967 and Ebola virus (EBOV) in 1976, there have been over 40 reported outbreaks of filovirus disease with case fatality rates greater than 50%. This underscores the need for efficacious vaccines against these highly pathogenic filoviruses. Due to the sporadic and unpredictable nature of filovirus outbreaks, such a vaccine would likely need to be vetted through the U.S. Food and Drug Administration (FDA), following the Animal Rule or similar European Medicines Agency (EMA) regulatory pathway. Under the FDA Animal Rule, vaccine-induced immune responses correlating with survival of non-human primates (NHPs), or another well-characterized animal model, following lethal challenge, will need to be bridged for human immune response distributions in clinical trials. A correlate of protection has not yet been identified for the filovirus disease, but antibodies, specifically anti-glycoprotein (GP) antibodies, are believed to be critical in providing protection against the filovirus disease following vaccination and are thus a strong candidate for a correlate of protection. Thus, species-neutral methods capable of the detection and bridging of these antibody immune responses, such as methods to quantify anti-GP immunoglobulin G (IgG)-binding antibodies and neutralizing antibodies, are needed. Reported here is the development and qualification of two Filovirus Animal Nonclinical Group (FANG) anti-GP IgG Enzyme-Linked Immunosorbent Assays (ELISAs) to quantify anti-MARV and anti-Sudan virus (SUDV) IgG antibodies in human and NHP serum samples, as well as the development of pseudovirion neutralization assays (PsVNAs) to quantify MARV- and SUDV-neutralizing antibodies in human and NHP serum samples. Full article
(This article belongs to the Special Issue Vaccine Development Needs for Marburg Virus and Sudan Ebolavirus: Leveraging Lessons Learned from the Zaire Ebolavirus)
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15 pages, 2305 KiB  
Article
A Cloned Recombinant Vesicular Stomatitis Virus-Vectored Marburg Vaccine, PHV01, Protects Guinea Pigs from Lethal Marburg Virus Disease
by Wenjun Zhu, Guodong Liu, Wenguang Cao, Shihua He, Anders Leung, Ute Ströher, Michael J. Fairchild, Rick Nichols, Joseph Crowell, Joan Fusco and Logan Banadyga
Vaccines 2022, 10(7), 1004; https://doi.org/10.3390/vaccines10071004 - 23 Jun 2022
Cited by 6 | Viewed by 2307
Abstract
Marburg virus (MARV) is a negative-sense, single-stranded RNA virus that belongs to the Filoviridae family. Despite having caused numerous outbreaks of severe hemorrhagic fever with high case fatality rates, there are still no clinically approved therapeutics or vaccines to treat or prevent MARV [...] Read more.
Marburg virus (MARV) is a negative-sense, single-stranded RNA virus that belongs to the Filoviridae family. Despite having caused numerous outbreaks of severe hemorrhagic fever with high case fatality rates, there are still no clinically approved therapeutics or vaccines to treat or prevent MARV disease. Recombinant vesicular stomatitis viruses (rVSVs) expressing heterologous viral glycoproteins have shown remarkable promise as live-attenuated vaccine vectors, with an rVSV-based Ebola virus vaccine having received regulatory approval in the United States and numerous other countries. Analogous rVSV vaccine vectors have also been developed for MARV and have shown efficacy in several preclinical studies conducted in nonhuman primates. Here, we used a guinea pig model to confirm the protective efficacy of a cloned, rVSV-based candidate vaccine, termed PHV01, expressing the MARV variant Angola glycoprotein. Our results demonstrated that a single dose (2 × 106 PFU) of vaccine administered 28 days prior to challenge with a uniformly lethal dose of guinea-pig-adapted MARV variant Angola provided complete protection from death and disease. Moreover, protection was robust, with as little as 200 PFU of vaccine conferring significant protection. Not only does this study highlight the potential predictive value of the guinea pig model in the evaluation of MARV countermeasures, but it also demonstrates consistent and reproducible protection afforded by a clonal vaccine candidate. Indeed, this study identifies PHV01 as a suitable vaccine candidate for advanced development. Full article
(This article belongs to the Special Issue Vaccine Development Needs for Marburg Virus and Sudan Ebolavirus: Leveraging Lessons Learned from the Zaire Ebolavirus)
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32 pages, 5269 KiB  
Article
Natural History of Sudan ebolavirus to Support Medical Countermeasure Development
by Caroline Carbonnelle, Marie Moroso, Delphine Pannetier, Sabine Godard, Stéphane Mély, Damien Thomas, Aurélie Duthey, Ophélie Jourjon, Orianne Lacroix, Béatrice Labrosse, Hervé Raoul, Karen L. Osman, Francisco J. Salguero, Yper Hall, Carol L. Sabourin, Michael J. Merchlinsky, James P. Long, Lindsay A. Parish and Daniel N. Wolfe
Vaccines 2022, 10(6), 963; https://doi.org/10.3390/vaccines10060963 - 16 Jun 2022
Cited by 5 | Viewed by 2236
Abstract
Sudan ebolavirus (SUDV) is one of four members of the Ebolavirus genus known to cause Ebola Virus Disease (EVD) in humans, which is characterized by hemorrhagic fever and a high case fatality rate. While licensed therapeutics and vaccines are available in limited number [...] Read more.
Sudan ebolavirus (SUDV) is one of four members of the Ebolavirus genus known to cause Ebola Virus Disease (EVD) in humans, which is characterized by hemorrhagic fever and a high case fatality rate. While licensed therapeutics and vaccines are available in limited number to treat infections of Zaire ebolavirus, there are currently no effective licensed vaccines or therapeutics for SUDV. A well-characterized animal model of this disease is needed for the further development and testing of vaccines and therapeutics. In this study, twelve cynomolgus macaques (Macaca fascicularis) were challenged intramuscularly with 1000 PFUs of SUDV and were followed under continuous telemetric surveillance. Clinical observations, body weights, temperature, viremia, hematology, clinical chemistry, and coagulation were analyzed at timepoints throughout the study. Death from SUDV disease occurred between five and ten days after challenge at the point that each animal met the criteria for euthanasia. All animals were observed to exhibit clinical signs and lesions similar to those observed in human cases which included: viremia, fever, dehydration, reduced physical activity, macular skin rash, systemic inflammation, coagulopathy, lymphoid depletion, renal tubular necrosis, hepatocellular degeneration and necrosis. The results from this study will facilitate the future preclinical development and evaluation of vaccines and therapeutics for SUDV. Full article
(This article belongs to the Special Issue Vaccine Development Needs for Marburg Virus and Sudan Ebolavirus: Leveraging Lessons Learned from the Zaire Ebolavirus)
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Review

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17 pages, 1316 KiB  
Review
Lessons Learned from the Development and Roll-Out of the rVSVΔG-ZEBOV-GP Zaire ebolavirus Vaccine to Inform Marburg Virus and Sudan ebolavirus Vaccines
by Beth-Ann G. Coller, William Lapps, Jr., Mahum Yunus, Samantha Bruno, Michael J. Eichberg, Andrew Wen-Tseng Lee, Kenneth Liu, Rosybel Drury, Jules Millogo, Louis Robert Macareo, Thomas H. Armstrong, Jeffrey T. Blue, Lynne A. Isopi, Melissa Hughes, Susan M. VanRheenen, Jonathan Deutsch, Joan G. Tell and Sheri A. Dubey
Vaccines 2022, 10(9), 1446; https://doi.org/10.3390/vaccines10091446 - 1 Sep 2022
Cited by 3 | Viewed by 2240
Abstract
This review describes key aspects of the development of the rVSVΔG-ZEBOV-GP Ebola vaccine and key activities which are continuing to further expand our knowledge of the product. Extensive partnerships and innovative approaches were used to address the various challenges encountered during this process. [...] Read more.
This review describes key aspects of the development of the rVSVΔG-ZEBOV-GP Ebola vaccine and key activities which are continuing to further expand our knowledge of the product. Extensive partnerships and innovative approaches were used to address the various challenges encountered during this process. The rVSVΔG-ZEBOV-GP Ebola vaccine was initially approved by the European Medicines Agency and prequalified by the World Health Organization in November 2019. It was approved by the United States Food and Drug Administration in December 2019 and approved in five African countries within 90 days of prequalification. The development resulted in the first stockpile of a registered Ebola vaccine that is available to support outbreak response. This also provides insights into how the example of rVSVΔG-ZEBOV-GP can inform the development of vaccines for Sudan ebolavirus, Marburg virus, and other emerging epidemic diseases in terms of the types of approaches and data needed to support product registration, availability, and the use of a filovirus vaccine. Full article
(This article belongs to the Special Issue Vaccine Development Needs for Marburg Virus and Sudan Ebolavirus: Leveraging Lessons Learned from the Zaire Ebolavirus)
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14 pages, 479 KiB  
Review
Bridging Animal and Human Data in Pursuit of Vaccine Licensure
by Courtney L. Finch, William E. Dowling, Thomas H. King, Christian Martinez, Bai V. Nguyen, Ramon Roozendaal, Roxana Rustomjee, Mario H. Skiadopoulos, Ekaterina Vert-Wong, Ann Yellowlees and Nancy J. Sullivan
Vaccines 2022, 10(9), 1384; https://doi.org/10.3390/vaccines10091384 - 25 Aug 2022
Cited by 3 | Viewed by 1576
Abstract
The FDA Animal Rule was devised to facilitate approval of candidate vaccines and therapeutics using animal survival data when human efficacy studies are not practical or ethical. This regulatory pathway is critical for candidates against pathogens with high case fatality rates that prohibit [...] Read more.
The FDA Animal Rule was devised to facilitate approval of candidate vaccines and therapeutics using animal survival data when human efficacy studies are not practical or ethical. This regulatory pathway is critical for candidates against pathogens with high case fatality rates that prohibit human challenge trials, as well as candidates with low and sporadic incidences of outbreaks that make human field trials difficult. Important components of a vaccine development plan for Animal Rule licensure are the identification of an immune correlate of protection and immunobridging to humans. The relationship of vaccine-induced immune responses to survival after vaccination and challenge must be established in validated animal models and then used to infer predictive vaccine efficacy in humans via immunobridging. The Sabin Vaccine Institute is pursuing licensure for candidate filovirus vaccines via the Animal Rule and has convened meetings of key opinion leaders and subject matter experts to define fundamental components for vaccine licensure in the absence of human efficacy data. Here, filoviruses are used as examples to review immune correlates of protection and immunobridging. The points presented herein reflect the presentations and discussions during the second meeting held in October 2021 and are intended to address important considerations for developing immunobridging strategies. Full article
(This article belongs to the Special Issue Vaccine Development Needs for Marburg Virus and Sudan Ebolavirus: Leveraging Lessons Learned from the Zaire Ebolavirus)
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6 pages, 186 KiB  
Review
A U.S. Government-Coordinated Effort to Leverage Non-Human Primate Data to Facilitate Ebolavirus Vaccine Development
by Kimberly L. Taylor, Lynda Lanning, Lawrence Wolfraim, Sonia Shrivastava Gales, Colleen Sico, William E. Dowling, Lucy A. Ward, William C. Florence, Edwin Nuzum and Paula R. Bryant
Vaccines 2022, 10(8), 1201; https://doi.org/10.3390/vaccines10081201 - 28 Jul 2022
Cited by 1 | Viewed by 1441
Abstract
A United States Government (USG) interagency group, the Filovirus Animal Non-Clinical Group (FANG), has been established to support the development of biodefense medical countermeasures (MCMs). As both vaccines and therapeutics are licensed using “non-traditional pathways”, such as the U.S. Food and Drug Administration’s [...] Read more.
A United States Government (USG) interagency group, the Filovirus Animal Non-Clinical Group (FANG), has been established to support the development of biodefense medical countermeasures (MCMs). As both vaccines and therapeutics are licensed using “non-traditional pathways”, such as the U.S. Food and Drug Administration’s (FDA) Animal Rule (AR), non-human primate (NHP) models and associated assays have been developed and standardized across BSL4 testing sites to evaluate candidate products. Vaccine candidates are evaluated using these NHP models, and through this public–private partnership, a meta-analysis of NHP control data has been conducted and submitted to the FDA as a master file. This is an example of how existing NHP control data can be leveraged in lieu of conducting separate natural history studies at multiple testing facilities to demonstrate the consistency of a standardized animal model for vaccine development. As a result, animal use can be minimized and the duplication of effort avoided, thus reducing the amount of time needed to conduct additional studies, as well as the cost of vaccine candidate development. This successful strategy may be applied to other pathogens of high consequence for vaccine development, and shows how strategic preparedness for biodefense can be leveraged in response to outbreaks and public health emergencies. Full article
(This article belongs to the Special Issue Vaccine Development Needs for Marburg Virus and Sudan Ebolavirus: Leveraging Lessons Learned from the Zaire Ebolavirus)
12 pages, 280 KiB  
Review
Vaccine Licensure in the Absence of Human Efficacy Data
by Courtney L. Finch, Christian Martinez, Elizabeth Leffel, Mario H. Skiadopoulos, Adam Hacker, Betty Mwesigwa, Diadié Maïga, Ian Mugisa, Grant Munkwase and Roxana Rustomjee
Vaccines 2022, 10(3), 368; https://doi.org/10.3390/vaccines10030368 - 26 Feb 2022
Cited by 7 | Viewed by 2957
Abstract
Clinical vaccine development and regulatory approval generally occurs in a linear, sequential manner: Phase 1: safety, immunogenicity; Phase 2: immunogenicity, safety, dose ranging, and preliminary efficacy; Phase 3: definitive efficacy, safety, lot consistency; and following regulatory approval, Phase 4: post-marketing safety and effectiveness. [...] Read more.
Clinical vaccine development and regulatory approval generally occurs in a linear, sequential manner: Phase 1: safety, immunogenicity; Phase 2: immunogenicity, safety, dose ranging, and preliminary efficacy; Phase 3: definitive efficacy, safety, lot consistency; and following regulatory approval, Phase 4: post-marketing safety and effectiveness. For candidate filovirus vaccines, where correlates of protection have not been identified, and phase 2 and 3 efficacy of disease prevention trials untenable, large and/or protracted, each trial may span decades, with full licensure expected only after several decades of development. Given the urgent unmet need for new Marburg virus and Ebola Sudan virus vaccines, the Sabin Vaccine Institute hosted a key stakeholder virtual meeting in May 2021 to explore the possibility of licensure by use of an “animal rule-like” licensure process, based on a risk/benefit assessment specific to regional needs and informed by epidemiology. This may be appropriate for diseases where there are no or limited treatment options, and those prone to sporadic outbreaks with high rates of transmission, morbidity, and mortality. The discussion focused on two contexts: licensure within the Ugandan regulatory environment, a high burden country where Ebola vaccine trials are ongoing, and licensure by the United States FDA—a well-resourced regulatory agency. Full article
(This article belongs to the Special Issue Vaccine Development Needs for Marburg Virus and Sudan Ebolavirus: Leveraging Lessons Learned from the Zaire Ebolavirus)

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21 pages, 332 KiB  
Perspective
The Evolution of Medical Countermeasures for Ebola Virus Disease: Lessons Learned and Next Steps
by Ian Crozier, Kyla A. Britson, Daniel N. Wolfe, John D. Klena, Lisa E. Hensley, John S. Lee, Larry A. Wolfraim, Kimberly L. Taylor, Elizabeth S. Higgs, Joel M. Montgomery and Karen A. Martins
Vaccines 2022, 10(8), 1213; https://doi.org/10.3390/vaccines10081213 - 29 Jul 2022
Cited by 8 | Viewed by 2743
Abstract
The Ebola virus disease outbreak that occurred in Western Africa from 2013–2016, and subsequent smaller but increasingly frequent outbreaks of Ebola virus disease in recent years, spurred an unprecedented effort to develop and deploy effective vaccines, therapeutics, and diagnostics. This effort led to [...] Read more.
The Ebola virus disease outbreak that occurred in Western Africa from 2013–2016, and subsequent smaller but increasingly frequent outbreaks of Ebola virus disease in recent years, spurred an unprecedented effort to develop and deploy effective vaccines, therapeutics, and diagnostics. This effort led to the U.S. regulatory approval of a diagnostic test, two vaccines, and two therapeutics for Ebola virus disease indications. Moreover, the establishment of fieldable diagnostic tests improved the speed with which patients can be diagnosed and public health resources mobilized. The United States government has played and continues to play a key role in funding and coordinating these medical countermeasure efforts. Here, we describe the coordinated U.S. government response to develop medical countermeasures for Ebola virus disease and we identify lessons learned that may improve future efforts to develop and deploy effective countermeasures against other filoviruses, such as Sudan virus and Marburg virus. Full article
(This article belongs to the Special Issue Vaccine Development Needs for Marburg Virus and Sudan Ebolavirus: Leveraging Lessons Learned from the Zaire Ebolavirus)
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