Virus World

A drug studied for cancer, COVID-19 and radiation injuries appears to be effective against Ebola in mice. | From cancer to COVID-19 to radiation injuries, and now Ebola: RedHill Bio reports that its drug opaganib appears to be effective against the virus in mice. RedHill Biopharma, in collaboration with the U.S. Army, announced Oct. 3 that twice-daily oral doses of the medication opaganib boosted survival from about six days in controls to 11 days in animals infected with the virus. In the group treated with the highest dose, 30% of the mice survived, compared to none of the controls. “Given the unmet medical need … these results with opaganib, an easy to distribute and administer oral small molecule drug, support its further investigation for use in treating Ebola,” study lead Rekha Panchal, Ph.D., principal investigator of therapeutics discovery at the U.S. Army Medical Research Institute of Infectious Diseases, said in a press release.

Opaganib is a host-directed antiviral, meaning it prevents a virus from hijacking a host’s cells for replication rather than destroying the pathogen directly. The drug mainly works by inhibiting the enzyme sphingosine kinase-2, or SPHK2, a key enzyme in a process called sphingolipid metabolism. Inhibiting sphingolipid metabolism with opaganib turns on processes that clear or repair infected cells, like autophagy and apoptosis. That mechanism has prompted studies on opaganib in a range of indications from cancer to COVID. Under the name Yeliva, the drug received orphan-drug designation from the FDA in 2017 for the treatment of bile duct cancer and has been tested for that indication through phase 2a. It’s also in a phase 2 study for prostate cancer. In 2021, the drug flopped in a phase 2/3 test on patients with severe COVID-19 pneumonia, though RedHill said at the time it would continue investigating the drug in patients who were earlier in the course of their disease.

In February 2023, opaganib was selected for investigation by the National Institutes of Health and the Radiation and Nuclear Countermeasures Program as a potential treatment for acute radiation syndrome. The move came on the back of preclinical studies in mice suggesting it could prevent damage from ionizing radiation. If the drug were to show efficacy against Ebola in humans, it would be only the third to do so. The two FDA-approved treatments for the virus both rely on antibodies that prevent it from entering the host’s cells and must be given by IV.

Red Hill Biopharma Press Release (Oct. 3, 2023):

https://www.redhillbio.com/news/news-details/2023/RedHill-and-U.S.-Army-Announce-Opaganibs-Ebola-Virus-Disease-Survival-Benefit-in-U.S.-Army-Funded-In-Vivo-Study/default.aspx 

It is now more than four decades since Professor Peter Piot sped from a clinical lab in the bustling Belgian city of Antwerp to a remote rainforest in the heart of Africa to investigate a mysterious epidemic. 

Three weeks earlier the microbiology lab where the then 27-year-old worked had received two vials of blood  transported halfway across the globe in a cheap blue thermos flask filled with ice. One of the test tubes had smashed, but at the time in 1976 Prof Piot and his colleagues were unaware of the danger lurking inside. The two vials contained a new but highly contagious virus which we now know as Ebola – a disease which has killed more than 2,000 people in a 13-month outbreak in the Democratic Republic of Congo (DRC). The blood samples were from Flemish nuns living in what was then known as Zaire, who had died of a mysterious haemorrhagic fever. Within three weeks the virus had killed 200 people in Yambuku, a small village in the Congolese forest home to a Belgian missionary outpost.  

“The discovery itself was an accident, or a coincidence,” Prof Piot says, sitting in his directors' office at the London School of Hygiene Tropical Medicine, which celebrated its 120th anniversary this autumn .  “We obviously did not know there was Ebola in the samples from Zaire. Looking back, probably the most dangerous moments were working in the lab in Antwerp.”

It wasn’t long before the team, examining the virus’ gigantic worm structure under a microscope, realised this was a new disease and sent the samples to the specialist Centre for Disease Control in the US for confirmation. Within weeks Prof Piot was on a flight – without so much as a valid passport. “I’m trying not to exaggerate, but in less than 48 hours I went from Antwerp to the tropical rainforest in northern Zaire,” he says. “It was extremely exciting, to be honest.”  

“I’d never been to Africa, I’d never investigated an epidemic, so I definitely did not qualify and in today’s world, I don’t think I would be allowed to do this.”

As Prof Piot recalls in his book, No Time to Lose, what followed were two adventure-filled but exhausting months, predominantly spent in the jungle some 600 miles from Zaire’s capital city, Kinshasa. An international team of scientists meticulously investigated the disease, which slowly petered out after killing 280 people......

Clinical trial data find an Ebola vaccine regimen safe, well tolerated, and produces a strong immune response in people over the age of one.  Welcome news for Ebola virus disease prevention was published yesterday in two papers presenting data showing that Johnson & Johnson’s (J&J) two-dose Ebola vaccine regimen is safe, well tolerated, and produces a strong immune response in people over the age of one. This news comes five years after the largest outbreak of Ebola since its discovery and just one month after an Ebola outbreak was declared in the Ivory Coast. The study aimed to assess the safety and long-term immunogenicity of a two-dose vaccine regimen. The first vaccine is the adenovirus type 26 vector-based vaccine encoding the Ebola virus glycoprotein (Ad26.ZEBOV). The second is the modified vaccinia Ankara vector-based vaccine, encoding glycoproteins from Ebola virus, Sudan virus, and Marburg virus, and the nucleoprotein from the Tai Forest virus (MVA-BN-Filo).  The authors found that the vaccine regimen was well tolerated and induced antibody responses to Zaire ebolavirus 21 days after the second dose in 98% of participants, with the immune responses persisting in adults for at least two years. Conducted in Sierra Leone, the EBOVAC-Salone  study is the first to assess the safety and tolerability of this vaccine regimen in a region affected by the 2014–2016 West African Ebola outbreak, which was the worst on record. It is also the first study reporting the evaluation of this vaccine regimen in children. The data were published in The Lancet Infectious Diseases in two separate papers: “Safety and immunogenicity of the two-dose heterologous Ad26.ZEBOV and MVA-BN-Filo Ebola vaccine regimen in children in Sierra Leone: a randomized, double-blind, controlled trial” and “Safety and long-term immunogenicity of the two-dose heterologous Ad26.ZEBOV and MVA-BN-Filo Ebola vaccine regimen in adults in Sierra Leone: a combined open-label, non-randomized stage 1, and a randomized, double-blind, controlled stage 2 trial.” 

During the 2014–16 outbreak of Ebola in West Africa, 28,652 cases and 11,325 deaths from Ebola were reported. Approximately 20% of cases were in children under 15 years, and children younger than five years are at a higher risk of death than adults. “This study represents important progress in the development of an Ebola virus disease vaccine regimen for children, and contributes to the public health preparedness and response for Ebola outbreaks,” said Muhammed Afolabi, MD, assistant professor at the London School of Hygiene and Tropical Medicine. The clinical trial recruited participants from September 2015 to July 2018. The study was divided into two stages. In stage one, 43 adults aged 18 years or older received the Ad26.ZEBOV vaccine followed by the MVA-BN-Filo vaccine after 56 days. In stage two, 400 adults and 576 children and adolescents (192 in each of the three age cohorts of 1–3, 4–11 and 12–17 years of age) were vaccinated with either the Ebola vaccine regimen (Ad26.ZEBOV followed by MVA-BN-Filo) or a single dose of a meningococcal quadrivalent conjugate vaccine followed by placebo on day 57. Adults participating in stage one of the study were offered a booster dose of A26.ZEBOV two years after the first dose which induced a strong immune response within seven days. “To protect people from Ebola, we will need a range of effective interventions,” said Daniela Manno, clinical assistant professor at the London School of Hygiene and Tropical Medicine. “These findings support the additional strategy of providing an Ad26.ZEBOV booster to previously immunized individuals at the start of an Ebola virus disease outbreak.” The study findings have already contributed to the approval and marketing authorization of the two-dose Ebola vaccine regimen in July 2020 by the European Medicines Agency, for use in both children and adults. It also contributed to the WHO Prequalification in April 2021, which will facilitate formal registrations of this vaccine regimen in countries at risk of Ebola virus disease outbreaks.

“The threat of future Ebola virus disease outbreaks is real and it’s important to remember that this disease has definitely not gone away,” noted Deborah Watson-Jones, PhD, clinical epidemiologist from the London School of Hygiene & Tropical Medicine. “Despite the additional global challenges around COVID-19, we must not slow down efforts to find effective ways of preventing Ebola virus epidemics and, should outbreaks occur, of containing them rapidly. Vaccines have a key role in meeting both of these objectives.” In May 2021, J&J said it would donate thousands of Ebola vaccine regimens in support of a WHO early access clinical program launched in response to an outbreak in Guinea and aimed at preventing Ebola in West Africa. The program began by vaccinating health workers, other frontline workers and others at increased risk of exposure to the Ebola virus in Sierra Leone. To date, more than 250,000 individuals participating in clinical trials and vaccination initiatives have received at least the first dose of the J&J Ebola vaccine regimen, including 200,000 who have been fully vaccinated. Further studies are being carried out in Sierra Leone to investigate whether the vaccines are safe and induce immune responses among infants aged under one year, and to follow up the adult and child participants over five years to assess the potential for long term protection. “This is an example of crucial research which brings together scientists from Africa with partners in the north and pharmaceutical companies to tackle a major public heath threat in Africa,” said Sir Brian Greenwood, MD, professor of clinical tropical medicine, London School of Hygiene and Tropical Medicine. The research in Kambia district was a collaboration between the London School of Hygiene & Tropical Medicine and Sierra Leone’s College of Medicine and Allied Health Sciences under the EBOVAC1 project.

See research published in The Lancet Infectious Diseases (Sept.13, 2021):

https://doi.org/10.1016/S1473-3099(21)00128-6  

https://doi.org/10.1016/S1473-3099(21)00125-0