Recent Advances in Therapeutic Approaches Against Ebola Virus Infection.

BACKGROUND: Ebola virus (EBOV) is a genus of negative-strand RNA viruses belonging to the family Filoviradae that was first described in 1976 in the present-day Democratic Republic of the Congo. It has intermittently affected substantial human populations in West Africa and presents itself as a global health menace due to the high mortality rate of patients, high transmission rate, difficult patient management, and the emergence of complicated autoimmune disease-like conditions post-infection. OBJECTIVE: EBOV or other EBOV-like species as a biochemical weapon pose a significant risk; hence, the need to develop both prophylactic and therapeutic medications to combat the virus is unquestionable. METHODS: In this review work, we have compiled the literature pertaining to transmission, pathogenesis, immune response, and diagnosis of EBOV infection. We included detailed structural details of EBOV along with all the available therapeutics against EBOV disease. We have also highlighted current developments and recent advances in therapeutic approaches against Ebola virus disease (EVD). DISCUSSION: The development of preventive vaccines against the virus is proving to be a successful effort as of now; however, problems concerning logistics, product stability, multi- dosing, and patient tracking are prominent in West Africa. Monoclonal antibodies that target EBOV proteins have also been developed and approved in the clinic; however, no small drug molecules that target these viral proteins have cleared clinical trials. An understanding of clinically approved vaccines and their shortcomings also serves an important purpose for researchers in vaccine design in choosing the right vector, antigen, and particular physicochemical properties that are critical for the vaccine's success against the virus across the world. CONCLUSION: Our work brings together a comprehensive review of all available prophylactic and therapeutic medications developed and under development against the EBOV, which will serve as a guide for researchers in pursuing the most promising drug discovery strategies against the EBOV and also explore novel mechanisms of fighting against EBOV infection.

A review of broadly protective monoclonal antibodies to treat Ebola virus disease.

The filovirus vaccine and the therapeutic monoclonal antibody (mAb) research have made substantial progress. However, existing vaccines and mAbs approved for use in humans are specific to Zaire ebolavirus (EBOV). Since other Ebolavirus species are a continuing threat to public health, the search for broadly protective mAbs has drawn attention. Here, we review viral glycoprotein-targeting mAbs that have proved their broader protective efficacy in animal models. MBP134AF, the most advanced of these new-generation mAb therapies, has recently been deployed in Uganda during the Sudan ebolavirus outbreak. Furthermore, we discuss the measures associated with enhancing antibody therapies and the risks associated with them, including the rise of escape mutations following the mAb treatment and naturally occurring EBOV variants.

Randomized Trial of Vaccines for Zaire Ebola Virus Disease.

BACKGROUND: Questions remain concerning the rapidity of immune responses and the durability and safety of vaccines used to prevent Zaire Ebola virus disease. METHODS: We conducted two randomized, placebo-controlled trials - one involving adults and one involving children - to evaluate the safety and immune responses of three vaccine regimens against Zaire Ebola virus disease: Ad26.ZEBOV followed by MVA-BN-Filo 56 days later (the Ad26-MVA group), rVSVΔG-ZEBOV-GP followed by placebo 56 days later (the rVSV group), and rVSVΔG-ZEBOV-GP followed by rVSVΔG-ZEBOV-GP 56 days later (the rVSV-booster group). The primary end point was antibody response at 12 months, defined as having both a 12-month antibody concentration of at least 200 enzyme-linked immunosorbent assay units (EU) per milliliter and an increase from baseline in the antibody concentration by at least a factor of 4. RESULTS: A total of 1400 adults and 1401 children underwent randomization. Among both adults and children, the incidence of injection-site reactions and symptoms (e.g., feverishness and headache) was higher in the week after receipt of the primary and second or booster vaccinations than after receipt of placebo but not at later time points. These events were largely low-grade. At month 12, a total of 41% of adults (titer, 401 EU per milliliter) and 78% of children (titer, 828 EU per milliliter) had a response in the Ad26-MVA group; 76% (titer, 992 EU per milliliter) and 87% (titer, 1415 EU per milliliter), respectively, had a response in the rVSV group; 81% (titer, 1037 EU per milliliter) and 93% (titer, 1745 EU per milliliter), respectively, had a response in the rVSV-booster group; and 3% (titer, 93 EU per milliliter) and 4% (titer, 67 EU per milliliter), respectively, had a response in the placebo group (P<0.001 for all comparisons of vaccine with placebo). In both adults and children, antibody responses with vaccine differed from those with placebo beginning on day 14. CONCLUSIONS: No safety concerns were identified in this trial. With all three vaccine regimens, immune responses were seen from day 14 through month 12. (Funded by the National Institutes of Health and others; PREVAC ClinicalTrials.gov number, NCT02876328; EudraCT numbers, 2017-001798-18 and 2017-001798-18/3rd; and Pan African Clinical Trials Registry number, PACTR201712002760250.).

Forgotten Ebola vaccine could help in outbreak.

Merck unearths a frozen batch of an experimental vaccine it made years ago.

"Are You Sure It's Not the Corona Vaccine?" An Ebola Vaccine Trial During COVID-19 in DRC.

The COVID-19 pandemic began as an Ebola epidemic was unfolding in the Democratic Republic of the Congo. In this article, we examine how COVID-19 influenced experiences of an Ebola vaccine trial and attitudes towards medical research in Goma. First, critical debates about vaccine research became a forum in which to contest ineffective local governance and global inequality. Second, discussions about new COVID-19 therapeutics reignited critique of Western biomedical colonialism. Third, rumors were made powerful through everyday observations of the unexpected adaption of Ebola trial procedures in the pandemic. This illustrates the difficulties of maintaining participants' trust, when circumstances dictate protocol alterations mid-trial.

The ring vaccination trial design for the estimation of vaccine efficacy and effectiveness during infectious disease outbreaks.

The ring vaccination trial is a recently developed approach for evaluating the efficacy and effectiveness of vaccines, modeled after the surveillance and containment strategy of ring vaccination. Contacts and contacts of contacts of a newly identified disease case form a ring, and these rings are randomized as part of a cluster-randomized trial or with individual randomization within rings. Key advantages of the design include its flexibility to follow the epidemic as it progresses and the targeting of high-risk participants to increase power. We describe the application of the design to estimate the efficacy and effectiveness of an Ebola vaccine during the 2014-2016 West African Ebola epidemic. The design has several notable statistical features. Because vaccination occurs around the time of exposure, the design is particularly sensitive to the choice of per protocol analysis period. If incidence wanes before the per protocol analysis period begins (due to a slow-acting vaccine or a fast-moving pathogen), power can be substantially reduced. Mathematical modeling is valuable for exploring the suitability of the approach in different disease settings. Another statistical feature is zero inflation, which can occur if the chain of transmission does not take off within a ring. In the application to Ebola, the majority of rings had zero subsequent cases. The ring vaccination trial can be extended in several ways, including the definition of rings (e.g. contact-based, spatial, and occupational). The design will be valuable in settings where the spatio-temporal spread of the pathogen is highly focused and unpredictable.

Rapid Protection from COVID-19 in Nonhuman Primates Vaccinated Intramuscularly but Not Intranasally with a Single Dose of a Vesicular Stomatitis Virus-Based Vaccine.

The ongoing pandemic of coronavirus (CoV) disease 2019 (COVID-19) continues to exert a significant burden on health care systems worldwide. With limited treatments available, vaccination remains an effective strategy to counter transmission of severe acute respiratory syndrome CoV 2 (SARS-CoV-2). Recent discussions concerning vaccination strategies have focused on identifying vaccine platforms, number of doses, route of administration, and time to reach peak immunity against SARS-CoV-2. Here, we generated a single-dose, fast-acting vesicular stomatitis virus (VSV)-based vaccine derived from the licensed Ebola virus (EBOV) vaccine rVSV-ZEBOV, expressing the SARS-CoV-2 spike protein and the EBOV glycoprotein (VSV-SARS2-EBOV). Rhesus macaques vaccinated intramuscularly (i.m.) with a single dose of VSV-SARS2-EBOV were protected within 10 days and did not show signs of COVID-19 pneumonia. In contrast, intranasal (i.n.) vaccination resulted in limited immunogenicity and enhanced COVID-19 pneumonia compared to results for control animals. While both i.m. and i.n. vaccination induced neutralizing antibody titers, only i.m. vaccination resulted in a significant cellular immune response. RNA sequencing data bolstered these results by revealing robust activation of the innate and adaptive immune transcriptional signatures in the lungs of i.m. vaccinated animals only. Overall, the data demonstrate that VSV-SARS2-EBOV is a potent single-dose COVID-19 vaccine candidate that offers rapid protection based on the protective efficacy observed in our study. IMPORTANCE The vesicular stomatitis virus (VSV) vaccine platform rose to fame in 2019, when a VSV-based Ebola virus (EBOV) vaccine was approved by the European Medicines Agency and the U.S. Food and Drug Administration for human use against the deadly disease. Here, we demonstrate the protective efficacy of a VSV-EBOV-based COVID-19 vaccine against challenge in nonhuman primates (NHPs). When a single dose of the VSV-SARS2-EBOV vaccine was administered intramuscularly (i.m.), the NHPs were protected from COVID-19 within 10 days. In contrast, if the vaccine was administered intranasally, there was no benefit from the vaccine and the NHPs developed pneumonia. The i.m. vaccinated NHPs quickly developed antigen-specific IgG, including neutralizing antibodies. Transcriptional analysis highlighted the development of protective innate and adaptive immune responses in the i.m. vaccination group only.

Therapeutic vaccination strategies against EBOV by rVSV-EBOV-GP: the role of innate immunity.

Zaire Ebola virus (EBOV) is a member of the Filoviridae family. Infection with EBOV causes Ebola virus disease (EVD) characterized by excessive inflammation, lymphocyte death, coagulopathy, and multi-organ failure. In 2019, the FDA-approved the first anti-EBOV vaccine, rVSV-EBOV-GP (Ervebo® by Merck). This live-recombinant vaccine confers both prophylactic and therapeutic protection to nonhuman primates and humans. While mechanisms conferring prophylactic protection are well-investigated, those underlying protection conferred shortly before and after exposure to EBOV remain poorly understood. In this review, we review data from in vitro and in vivo studies analyzing early immune responses to rVSV-EBOV-GP and discuss the role of innate immune activation in therapeutic protection.

Ebola outbreaks: A stress test of the preparedness of medicines regulatory systems for public health crises.

In a globalized world, infectious diseases of international concern are inevitable. When they (re-)emerge, the regulatory system works towards mitigating their impact. Ebola outbreaks marked a turning point in regulatory preparedness and efforts led to the accelerated development of therapeutic agents, in a catastrophic environment. However, only one clinical trial determined a vaccine's efficacy. Key lessons were considered and applied thereafter. The collaborative work resulted in the approval of the first therapeutic options against Ebola, a milestone in public health preparedness. The response demonstrated the successful implementation of regulatory mechanisms fostering development, early access and assessment of therapeutic agents, and the flexibility to embrace innovative regulatory solutions. The current system is robust to address health crises and protect global health.

[Ebola, the first vaccines available]. / Ebola, des premiers vaccins disponibles.

In the recent years, Ebola virus has been responsible for several major epidemics. Research efforts have allowed the development and evaluation in the field of several vaccine candidates. At present, two of them are already approved and used in the fight against the virus in the Democratic Republic of Congo. This review aims to describe the different candidates, the clinical trials that have been conducted as well as the first results in the field.

TITLE: Ebola, des premiers vaccins disponibles. ABSTRACT: Ces dernières années, le virus Ebola a été responsable d'épidémies de grande ampleur. Les efforts de recherche ont permis la mise au point et l'évaluation sur le terrain de plusieurs candidats vaccins. À l'heure actuelle, deux sont déjà homologués et utilisés dans la lutte contre le virus en République démocratique du Congo. Cette revue se propose de faire le point sur les différents candidats vaccins, les essais cliniques qui ont été menés et les premiers résultats de terrain.

Estratégia usada em vacina contra o ebola pode ser aplicada para o coronavírus

Em entrevista à Agência FAPESP, Edécio Cunha Neto, professor do Instituto do Coração (Incor) da Faculdade de Medicina da Universidade de São Paulo (USP), explica como a estratégia usada para desenvolver uma candidata à vacina contra o ebola pode orientar na criação de um imunizante contra o novo coronavírus SARS-CoV-2, causador da COVID-19. O artigo An effective CTL peptide vaccine for ebola Zaire based on survivors’ CD8+ targeting of a particular nucleocapsid protein epitope with potential implications for Covid-19 vaccine design, (doi.org/10.1101/2020.02.25.963546), de CV Herst, S Burkholz, J Sidney, A Sette, PE Harris, S Massey, T Brasel, E Cunha Neto, DS Rosa, WCH Chao, R Carback, T Hodge, L Wang, S Ciotlos, P Lloyd e R Rubsamen, pode ser lido no bioRxiv em www.biorxiv.org/content/10.1101/2020.02.25.963546v2.abstract. E o artigo Coronavirus infections – more than just the common cold (10.1001/jama.2020.0757), de Catharine I. Paules, Hilary D. Marston e Anthony S. Fauci, pode ser lido no Journal of the American Medical Association (JAMA) em jamanetwork.com/journals/jama/fullarticle/2759815.

Safety, immunogenicity and risk-benefit analysis of rVSV-ΔG-ZEBOV-GP (V920) Ebola vaccine in Phase I-III clinical trials across regions.

To evaluate the risk-benefits balance of the rVSV-ΔG-ZEBOV-GP vaccine. We performed a systematic review to summarize data on safety, immunogenicity and efficacy. About 17,600 adults and 234 children received 11 different doses of the V920 vaccine ranging from 3000 to 100 million and 20 million plaque-forming units, respectively, during Phase I-III clinical trials. Cases of severe but transient arthritis were reported in about six and 0.08% of vaccinees in high-income countries (HICs) and low-middle-income countries (LMICs), respectively. The 20 million plaque-forming units dose yielded GP-specific antibody titres which peaked at day 28 with a pooled geometric mean titres of 2557.7 (95% CI: 1665.5-3934.2) versus 1156.9 (95% CI: 832.5-1649.2) but with similar seroconversion rates at 96% (95% CI: 87-100) versus 100% (95% CI: 90-100) for HICs and LMICs, respectively. Data from stringent Phase I-II clinical trials in LMICs and HICs and from the ring efficacy trials yielded a good risk-benefit balance of the V920 vaccine in adults, but also in children and pregnant and lactating women and HIV-infected people.

When money talks: Judging risk and coercion in high-paying clinical trials.

Millions of volunteers take part in clinical trials every year. This is unsurprising, given that clinical trials are often much more lucrative than other types of unskilled work. When clinical trials offer very high pay, however, some people consider them repugnant. To understand why, we asked 1,428 respondents to evaluate a hypothetical medical trial for a new Ebola vaccine offering three different payment amounts. Some respondents (27%) used very high pay (£10,000) as a cue to infer the potential risks the clinical trial posed. These respondents were also concerned that offering £10,000 was coercive- simply too profitable to pass up. Both perceived risk and coercion in high-paying clinical trials shape how people evaluate these trials. This result was robust within and between respondents. The link between risk and repugnance may generalize to other markets in which parties are partially remunerated for the risk they take and contributes to a more complete understanding of why some market transactions appear repugnant.

Guidelines for the management of pregnant and breastfeeding women in the context of Ebola virus disease

A paucity of scientific evidence exists on how to best treat pregnant or breastfeeding women with suspected or confirmed Ebola virus disease (EVD). Historical reports suggest that, among women who acquire EVD during pregnancy, there is increased mortality and morbidity, and a near 100% rate of adverse pregnancy outcomes. To save the lives of mothers and their babies, mitigate complications, and limit the spread of disease, it is critical that recommendations are made on the prevention, treatment, and surveillance of women who are exposed to EVD, acquire EVD during pregnancy or breastfeeding, or survive EVD with ongoing pregnancies. These guidelines are the first to provide such recommendations.

Guidelines for the management of pregnant and breastfeeding women in the context of Ebola virus disease

The Democratic Republic of Congo is currently experiencing the second largest Ebola outbreak in history, following a 2014-2016 outbreak in western Africa that had an estimated 28,000 cases. Investigational treatment and vaccination trials are ongoing, but data in the context of pregnancy and breastfeeding are limited. A paucity of scientific evidence exists on how to best treat pregnant or breastfeeding women with suspected or confirmed Ebola virus disease (EVD). Historical reports suggest that, among women who acquire EVD during pregnancy, there is increased mortality and morbidity, and a near 100% rate of adverse pregnancy outcomes. To save the lives of mothers and their babies, mitigate complications, and limit the spread of disease, it is critical that recommendations are made on the prevention, treatment, and surveillance of women who are exposed to EVD, acquire EVD during pregnancy or breastfeeding, or survive EVD with ongoing pregnancies. These guidelines are the first to provide such recommendations. They also cover the surveillance and management of ongoing pregnancies and adverse pregnancy-related events, the handling of bodily and pregnancy-related fluids during acute maternal infection and following recovery, and the management of subsequent pregnancies in Ebola survivors. These guidelines will be of interest to health policy-makers, emergency preparedness and response teams, and healthcare providers who work with pregnant or breastfeeding women in the context of Ebola. The guidelines are relevant to the WHO goal of ensuring one billion people are better protected from health emergencies by impacting maternal mortality, neonatal survival, and the transmission Ebola virus in the context of an Ebola epidemic. Specific recommendations cover 6 topics. These are: (i) the management of acute EVD in pregnant women, (ii) the management of pregnancies in women who develop EVD during pregnancy and those who survive EVD with an ongoing pregnancy, (iii) infection prevention and control (IPC) measures for pregnant women with acute EVD or who have recovered from EVD with ongoing pregnancies (with conception prior to EVD), (iv) IPC for women who become pregnant after recovering from EVD (with conception after EVD), (v) breastfeeding women with acute EVD or who have recovered from EVD, and (vi) vaccination recommendations for pregnant women who are at risk of acquiring EVD. Of note, some recommendations apply to both specific situations and in the context of rigorous research, such as the use of investigational therapeutics in pregnant women. Guidelines were developed in accordance with the WHO Handbook for Guideline Development, supported by a special WHO Guideline Steering Committee and a Guideline Development Group of international experts to formulate the recommendations. Scoping thematic discussions determined focus areas and key questions that were addressed in a systematic review. The quality of the evidence for key outcomes was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach, followed by the use of an evidence-to-decision framework to analyse the available evidence relating to specific questions. An expert technical consultation of the Guideline Development Group took place on 4­5 June 2019 in Geneva, Switzerland. Prior to the technical consultation, WHO Declaration of Interest forms were reviewed and approved. The Guideline Development Group evaluated the draft guidelines and external reviewers' reports prior to the WHO Guideline Review Committee approval of the final version.

Ebolavirus: Comparison of Survivor Immunology and Animal Models in the Search for a Correlate of Protection.

Ebola viruses are enveloped, single-stranded RNA viruses belonging to the Filoviridae family and can cause Ebola virus disease (EVD), a serious haemorrhagic illness with up to 90% mortality. The disease was first detected in Zaire (currently the Democratic Republic of Congo) in 1976. Since its discovery, Ebola virus has caused sporadic outbreaks in Africa and was responsible for the largest 2013-2016 EVD epidemic in West Africa, which resulted in more than 28,600 cases and over 11,300 deaths. This epidemic strengthened international scientific efforts to contain the virus and develop therapeutics and vaccines. Immunology studies in animal models and survivors, as well as clinical trials have been crucial to understand Ebola virus pathogenesis and host immune responses, which has supported vaccine development. This review discusses the major findings that have emerged from animal models, studies in survivors and vaccine clinical trials and explains how these investigations have helped in the search for a correlate of protection.