Selection of Filovirus Isolates for Vaccine Development Programs

The continuing outbreaks of ebola virus disease highlight the ongoing threat posed by filoviruses. Fortunately, licensed vaccines and therapeutics are now available for Zaire ebolavirus. However, effective medical countermeasures, such as vaccines for other filoviruses such as Sudan ebolavirus and the Marburg virus, are presently in early stages of development and, in the absence of a large outbreak, would require regulatory approval via the U.S. Food and Drug Administration (FDA) Animal Rule. The selection of an appropriate animal model and virus challenge isolates for nonclinical studies are critical aspects of the development program. Here, we have focused on the recommendation of challenge isolates for Sudan ebolavirus and Marburg virus. Based on analyses led by the Filovirus Animal and Nonclinical Group (FANG) and considerations for strain selection under the FDA Guidance for the Animal Rule, we propose prototype virus isolates for use in nonclinical challenge studies.

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Accelerating Vaccine Development During the 2013–2016 West African Ebola Virus Disease Outbreak

Current Topics in Microbiology and Immunology - Marburg- and Ebolaviruses ◽

10.1007/82_2017_53 ◽

2017 ◽

pp. 229-261 ◽

Cited By ~ 1

Author(s):

Elizabeth S. Higgs ◽

Sheri A. Dubey ◽

Beth A. G. Coller ◽

Jakub K. Simon ◽

Laura Bollinger ◽

...

Keyword(s):

Ebola Virus ◽

Vaccine Development ◽

Virus Disease ◽

Disease Outbreak ◽

West African ◽

Ebola Virus Disease

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Macaque Monoclonal Antibodies Targeting Novel Conserved Epitopes within Filovirus Glycoprotein

Journal of Virology ◽

10.1128/jvi.02172-15 ◽

2015 ◽

Vol 90 (1) ◽

pp. 279-291 ◽

Cited By ~ 48

Author(s):

Zhen-Yong Keck ◽

Sven G. Enterlein ◽

Katie A. Howell ◽

Hong Vu ◽

Sergey Shulenin ◽

...

Keyword(s):

Monoclonal Antibodies ◽

Nonhuman Primates ◽

Ebola Virus ◽

Virus Disease ◽

Protective Efficacy ◽

Hemorrhagic Fever ◽

Marburg Virus ◽

Human Pathogens ◽

Content Type ◽

The Core

ABSTRACTFiloviruses cause highly lethal viral hemorrhagic fever in humans and nonhuman primates. Current immunotherapeutic options for filoviruses are mostly specific to Ebola virus (EBOV), although other members ofFiloviridaesuch as Sudan virus (SUDV), Bundibugyo virus (BDBV), and Marburg virus (MARV) have also caused sizeable human outbreaks. Here we report a set of pan-ebolavirus and pan-filovirus monoclonal antibodies (MAbs) derived from cynomolgus macaques immunized repeatedly with a mixture of engineered glycoproteins (GPs) and virus-like particles (VLPs) for three different filovirus species. The antibodies recognize novel neutralizing and nonneutralizing epitopes on the filovirus glycoprotein, including conserved conformational epitopes within the core regions of the GP1 subunit and a novel linear epitope within the glycan cap. We further report the first filovirus antibody binding to a highly conserved epitope within the fusion loop of ebolavirus and marburgvirus species. One of the antibodies binding to the core GP1 region of all ebolavirus species and with lower affinity to MARV GP cross neutralized both SUDV and EBOV, the most divergent ebolavirus species. In a mouse model of EBOV infection, this antibody provided 100% protection when administered in two doses and partial, but significant, protection when given once at the peak of viremia 3 days postinfection. Furthermore, we describe novel cocktails of antibodies with enhanced protective efficacy compared to individual MAbs. In summary, the present work describes multiple novel, cross-reactive filovirus epitopes and innovative combination concepts that challenge the current therapeutic models.IMPORTANCEFiloviruses are among the most deadly human pathogens. The 2014-2015 outbreak of Ebola virus disease (EVD) led to more than 27,000 cases and 11,000 fatalities. While there are five species ofEbolavirusand several strains of marburgvirus, the current immunotherapeutics primarily target Ebola virus. Since the nature of future outbreaks cannot be predicted, there is an urgent need for therapeutics with broad protective efficacy against multiple filoviruses. Here we describe a set of monoclonal antibodies cross-reactive with multiple filovirus species. These antibodies target novel conserved epitopes within the envelope glycoprotein and exhibit protective efficacy in mice. We further present novel concepts for combination of cross-reactive antibodies against multiple epitopes that show enhanced efficacy compared to monotherapy and provide complete protection in mice. These findings set the stage for further evaluation of these antibodies in nonhuman primates and development of effective pan-filovirus immunotherapeutics for use in future outbreaks.

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Early control of viral load by favipiravir promotes survival to Ebola virus challenge and prevents cytokine storm in non-human primates

PLoS Neglected Tropical Diseases ◽

10.1371/journal.pntd.0009300 ◽

2021 ◽

Vol 15 (3) ◽

pp. e0009300

Author(s):

Stéphanie Reynard ◽

Emilie Gloaguen ◽

Nicolas Baillet ◽

Vincent Madelain ◽

Jérémie Guedj ◽

...

Keyword(s):

Viral Load ◽

Ebola Virus ◽

Virus Disease ◽

Strongly Correlated ◽

Cytokine Storm ◽

Biological Functions ◽

Crucial Importance ◽

Immunological Parameters ◽

Virus Challenge ◽

Response To Stress

Ebola virus has been responsible for two major epidemics over the last several years and there has been a strong effort to find potential treatments that can improve the disease outcome. Antiviral favipiravir was thus tested on non-human primates infected with Ebola virus. Half of the treated animals survived the Ebola virus challenge, whereas the infection was fully lethal for the untreated ones. Moreover, the treated animals that did not survive died later than the controls. We evaluated the hematological, virological, biochemical, and immunological parameters of the animals and performed proteomic analysis at various timepoints of the disease. The viral load strongly correlated with dysregulation of the biological functions involved in pathogenesis, notably the inflammatory response, hemostatic functions, and response to stress. Thus, the management of viral replication in Ebola virus disease is of crucial importance in preventing the immunopathogenic disorders and septic-like shock syndrome generally observed in Ebola virus-infected patients.

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Offering patients more: how the West Africa Ebola outbreak can shape innovation in therapeutic research for emerging and epidemic infections

Philosophical Transactions of the Royal Society B Biological Sciences ◽

10.1098/rstb.2016.0294 ◽

2017 ◽

Vol 372 (1721) ◽

pp. 20160294 ◽

Cited By ~ 8

Author(s):

Amanda M. Rojek ◽

Peter W. Horby

Keyword(s):

West Africa ◽

Ebola Virus ◽

Virus Disease ◽

Nipah Virus ◽

Emerging Infectious Diseases ◽

Disease Outbreaks ◽

International Travel ◽

Marburg Virus ◽

World Health ◽

The West

Although, after an epidemic of over 28 000 cases, there are still no licensed treatments for Ebola virus disease (EVD), significant progress was made during the West Africa outbreak. The pace of pre-clinical development was exceptional and a number of therapeutic clinical trials were conducted in the face of considerable challenges. Given the on-going risk of emerging infectious disease outbreaks in an era of unprecedented population density, international travel and human impact on the environment it is pertinent to focus on improving the research and development landscape for treatments of emerging and epidemic-prone infections. This is especially the case since there are no licensed therapeutics for some of the diseases considered by the World Health Organization as most likely to cause severe outbreaks—including Middle East respiratory syndrome coronavirus, Marburg virus, Crimean Congo haemorrhagic fever and Nipah virus. EVD, therefore, provides a timely exemplar to discuss the barriers, enablers and incentives needed to find effective treatments in advance of health emergencies caused by emerging infectious diseases. This article is part of the themed issue ‘The 2013–2016 West African Ebola epidemic: data, decision-making and disease control’.

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Ebola and Other Filoviruses

10.1093/med/9780190604813.003.0002 ◽

2018 ◽

Author(s):

Lisa M. Bebell

Keyword(s):

Ebola Virus ◽

Inflammatory Responses ◽

Virus Disease ◽

Treatment Strategies ◽

Disease Outbreaks ◽

Marburg Virus ◽

Residual Effects ◽

Long Term Outcomes ◽

Pediatric Vaccination

Congenital and pediatric Ebola virus disease (EVD) and Marburg virus disease (MVD) are severe, even lethal infections. Historically, children have been underrepresented in filovirus disease outbreaks, and evidence-based treatment strategies are lacking. Existing data suggest that case fatalities are highest among children under four years of age, which is partially explained by higher virus concentrations in young children. Prevention and aggressive resuscitation, nutrition, and supportive care are the mainstays of management until filovirus-specific therapies can be developed. Differences in pediatric immune and inflammatory responses may necessitate unique approaches to pediatric vaccination and treatment. There are minimal safety or immunogenicity data in children, a crucial knowledge gap that must be addressed in future trials. Studying pediatric survivors of the 2014–2016 West Africa EVD outbreak will provide much-needed data on long-term outcomes and residual effects of filovirus disease while we await effective filovirus-specific vaccines and therapies.

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Viral Haemorrhagic Fevers and Malaria Co-Infections Among Febrile Patients Seeking Health Care in Tanzania

10.21203/rs.3.rs-1183528/v1 ◽

2021 ◽

Author(s):

Sima Rugarabamu ◽

Susan F. Rumisha ◽

Gaspary O. Mwanyika ◽

Calvin Sindato ◽

Hee-Young Lim ◽

...

Keyword(s):

Health Care ◽

Ebola Virus ◽

Virus Disease ◽

Marburg Virus ◽

Immunoglobulin M ◽

Sub Saharan Africa ◽

Infection Prevalence ◽

Haemorrhagic Fever ◽

Rapid Diagnostics ◽

Valley Fever

Abstract Background: In recent years there have been reports of viral haemorrhagic fever (VHF) epidemics in Sub-Saharan Africa where malaria is endemic. VHF and malaria have overlapping clinical presentations making differential diagnosis a challenge. The objective of this study was to determine the prevalence of selected zoonotic VHFs and malaria co-infections among febrile patients seeking health care in Tanzania. Methods: This facility-based cross-section study was carried out in Buhigwe, Kalambo, Kyela, Kilindi, Kinondoni, Kondoa, Mvomero, and Ukerewe districts in Tanzania. The study involved febrile patients seeking health care from primary healthcare facilities. Blood samples were collected and tested for infections due to malaria, Crimean-Congo haemorrhagic fever (CCHF), Ebola virus disease (EVD), Marburg virus disease (MVD), Rift Valley fever (RVF) and yellow fever (YF). Malaria infections were tested using rapid diagnostics tests while exposure to VHFs was determined by screening for immunoglobulin M antibodies using commercial enzyme-linked immunosorbent assays. Results: A total of 308 participants (mean age=35±18.9 years) were involved in the study. Of these, 54 (17.5%) had malaria infection and 15 (4.8%) were positive for IgM antibodies against VHFs (RVF=8; CCHF=2; EBV=3; MBV=1; YF=1). Six (1.9%) individuals had both VHF (RVF=2; CCHF=1; EVD=2; MVD=1) and malaria infections. The highest co-infection prevalence (0.6%), was observed among individuals aged 46-60 years (p<0.05). District was significantly associated with co-infection (p<0.05) with the highest prevalence recorded in Buhigwe (1.2%) followed by Kinondoni (0.9%) districts. Headache (100%) and muscle, bone, back and joint pains (83.3%) were the most significant complaints among those infected with both VHFs and malaria (p=0.001). Conclusions: Co-infections of VHF and malaria are prevalent in Tanzania and affect more the older than the younger population. Since the overlapping symptoms in co-infected individuals may challenge accurate diagnosis, adequate laboratory diagnosis should be emphasized in the management of febrile illnesses.

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Catching Chances: The Movement to Be on the Ground and Research Ready before an Outbreak

Viruses ◽

10.3390/v10080439 ◽

2018 ◽

Vol 10 (8) ◽

pp. 439 ◽

Cited By ~ 5

Author(s):

David Brett-Major ◽

James Lawler

Keyword(s):

West Africa ◽

Ebola Virus ◽

Democratic Republic ◽

Democratic Republic Of Congo ◽

Virus Disease ◽

Marburg Virus ◽

Just In Time ◽

The West ◽

The World ◽

Medical Countermeasures

After more than 28,000 Ebola virus disease cases and at least 11,000 deaths in West Africa during the 2014–2016 epidemic, the world remains without a licensed vaccine or therapeutic broadly available and demonstrated to alleviate suffering. This deficiency has been felt acutely in the two, short, following years with two Ebola virus outbreaks in the Democratic Republic of Congo (DRC), and a Marburg virus outbreak in Uganda. Despite billions of U.S. dollars invested in developing medical countermeasures for filoviruses in the antecedent decades, resulting in an array of preventative, diagnostic, and therapeutic products, none are available on commercial shelves. This paper explores why just-in-time research efforts in the field during the West Africa epidemic failed, as well as some recent initiatives to prevent similarly lost opportunities.

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Development of Pandemic Vaccines: ERVEBO Case Study

Vaccines ◽

10.3390/vaccines9030190 ◽

2021 ◽

Vol 9 (3) ◽

pp. 190

Author(s):

Jayanthi Wolf ◽

Risat Jannat ◽

Sheri Dubey ◽

Sean Troth ◽

Matthew T. Onorato ◽

...

Keyword(s):

Ebola Virus ◽

Virus Disease ◽

Development Program ◽

Cost Effective ◽

The United States ◽

Public And Private ◽

Ongoing Work ◽

United States Food ◽

Zaire Ebolavirus ◽

States Food

Preventative vaccines are considered one of the most cost-effective and efficient means to contain outbreaks and prevent pandemics. However, the requirements to gain licensure and manufacture a vaccine for human use are complex, costly, and time-consuming. The 2013–2016 Ebola virus disease (EVD) outbreak was the largest EVD outbreak to date and the third Public Health Emergency of International Concern in history, so to prevent a pandemic, numerous partners from the public and private sectors combined efforts and resources to develop an investigational Zaire ebolavirus (EBOV) vaccine candidate (rVSVΔG-ZEBOV-GP) as quickly as possible. The rVSVΔG-ZEBOV-GP vaccine was approved as ERVEBOTM by the European Medicines Authority (EMA) and the United States Food and Drug Administration (FDA) in December 2019 after five years of development. This review describes the development program of this EBOV vaccine, summarizes what is known about safety, immunogenicity, and efficacy, describes ongoing work in the program, and highlights learnings applicable to the development of pandemic vaccines.

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Protection from Ebola Virus Mediated by Cytotoxic T Lymphocytes Specific for the Viral Nucleoprotein

Journal of Virology ◽

10.1128/jvi.75.6.2660-2664.2001 ◽

2001 ◽

Vol 75 (6) ◽

pp. 2660-2664 ◽

Cited By ~ 114

Author(s):

Julie A. Wilson ◽

Mary Kate Hart

Keyword(s):

T Lymphocytes ◽

Cytotoxic T Lymphocytes ◽

Ebola Virus ◽

Vaccine Development ◽

Class I ◽

Lethal Challenge ◽

Virus Challenge ◽

Equine Encephalitis Virus ◽

Amino Terminal ◽

Cellular Immune

ABSTRACT Cytotoxic T lymphocytes (CTLs) are proposed to be critical for protection from intracellular pathogens such as Ebola virus. However, there have been no demonstrations that protection against Ebola virus is mediated by Ebola virus-specific CTLs. Here, we report that C57BL/6 mice vaccinated with Venezuelan equine encephalitis virus replicons encoding the Ebola virus nucleoprotein (NP) survived lethal challenge with Ebola virus. Vaccination induced both antibodies to the NP and a major histocompatibility complex class I-restricted CTL response to an 11-amino-acid sequence in the amino-terminal portion of the Ebola virus NP. Passive transfer of polyclonal NP-specific antiserum did not protect recipient mice. In contrast, adoptive transfer of CTLs specific for the Ebola virus NP protected unvaccinated mice from lethal Ebola virus challenge. The protective CTLs were CD8+, restricted to the Db class I molecule, and recognized an epitope within amino acids 43 to 53 (VYQVNNLEEIC) in the Ebola virus NP. The demonstration that CTLs can prevent lethal Ebola virus infection affects vaccine development in that protective cellular immune responses may be required for optimal protection from Ebola virus.

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Sex Differences in Immunity: Implications for the Development of Novel Vaccines Against Emerging Pathogens

Frontiers in Immunology ◽

10.3389/fimmu.2020.601170 ◽

2021 ◽

Vol 11 ◽

Author(s):

Anahita Fathi ◽

Marylyn M. Addo ◽

Christine Dahlke

Keyword(s):

Clinical Trials ◽

Sex Differences ◽

Ebola Virus ◽

Vaccine Development ◽

Virus Disease ◽

Emerging Infectious Diseases ◽

Vaccine Safety ◽

Emerging Infections ◽

Emerging Pathogens ◽

Vaccine Candidates

Vaccines are one of the greatest public health achievements and have saved millions of lives. They represent a key countermeasure to limit epidemics caused by emerging infectious diseases. The Ebola virus disease crisis in West Africa dramatically revealed the need for a rapid and strategic development of vaccines to effectively control outbreaks. Seven years later, in light of the SARS-CoV-2 pandemic, this need has never been as urgent as it is today. Vaccine development and implementation of clinical trials have been greatly accelerated, but still lack strategic design and evaluation. Responses to vaccination can vary widely across individuals based on factors like age, microbiome, co-morbidities and sex. The latter aspect has received more and more attention in recent years and a growing body of data provide evidence that sex-specific effects may lead to different outcomes of vaccine safety and efficacy. As these differences might have a significant impact on the resulting optimal vaccine regimen, sex-based differences should already be considered and investigated in pre-clinical and clinical trials. In this Review, we will highlight the clinical observations of sex-specific differences in response to vaccination, delineate sex differences in immune mechanisms, and will discuss the possible resulting implications for development of vaccine candidates against emerging infections. As multiple vaccine candidates against COVID-19 that target the same antigen are tested, vaccine development may undergo a decisive change, since we now have the opportunity to better understand mechanisms that influence vaccine-induced reactogenicity and effectiveness of different vaccines.

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