Virus World

Africa is grappling with not one, but two outbreaks of Marburg fever, a disease that causes symptoms and a death rate comparable to Ebola, its viral cousin.  Health officials in Tanzania announced Tuesday that they had confirmed the country’s first-ever Marburg outbreak, involving at least eight people so far, five of whom have died. One of the people who died is a health care worker. Across the continent, Equatorial Guinea has been combating its first-ever Marburg outbreak for several weeks now, though in an unusual turn of events for a viral hemorrhagic fever outbreak, scant information has been shared with the international community. The last update from the World Health Organization on that outbreak was issued nearly a month ago, on Feb. 25. Tanzanian Health Minister Ummy Mwalimu announced that the country’s national public health laboratory had confirmed that Marburg was the cause of an outbreak that was first reported last week. Five members of a single family are among the cases. At least 161 people who have been in contact with the cases have been identified and are being monitored. “We are working with the government to rapidly scale up control measures to halt the spread of the virus and end the outbreak as soon as possible,” Matshidiso Moeti, the WHO’s regional director for Africa, said in a statement.

Moeti noted that while Tanzania has not previously battled Marburg, it has coped with a number of health emergencies in recent years, including Covid-19, cholera, and dengue fever. “The lessons learnt, and progress made during other recent outbreaks should stand the country in good stead as it confronts this latest challenge,” she said.But Gary Kobinger, a veteran of numerous Ebola and Marburg responses, questioned that line of thinking, and urged the two countries to both be transparent and to accept outside help. “Managing a filovirus outbreak is completely different than a typical emergence of let’s say cholera or measles or even Rift Valley fever,” said Kobinger, who is director of the Galveston National Laboratory at the University of Texas Medical Branch. Marburg and Ebola viruses are both filoviruses. Kobinger said that even countries that have experience with these viruses struggle sometimes to contain outbreaks. “You need to act very fast. The first two weeks, three weeks are extremely important. And this is where you’re going to define the evolution of the outbreak,” he told STAT. “If you lose control of a SARS-CoV-2 outbreak, which happens, that’s one thing. If you lose control of an Ebola outbreak or a Marburg outbreak, you have a different problem on your hands.” Viral hemorrhagic fever outbreaks pose significant and unique challenges, because of their death rates, which are generally in the high double digits. These diseases spark panic in the communities in which they spread at the very time when community cooperation is essential to stop transmission.

“People are scared. One case in one village will shut down the place. And people will not want to go there and people that come out of there will be treated as if they are infected, potentially,” Kobinger said. “So it’s very difficult in terms of trade, in terms of social movement, in terms of social acceptance. It’s much more traumatic than Covid or something else.”bHistorically Marburg outbreaks have been smaller than Ebola outbreaks; there have been none that involved thousands of cases, like the Ebola outbreaks in West Africa (2014-2016) or in the Democratic Republic of the Congo (2018-2020). But in 2004-2005, 252 people were infected in an outbreak in Angola, with 227 or 90% of them dying. There are no licensed vaccines to protect against Marburg and no approved drugs. A WHO-led meeting in mid-February convened to explore whether there were supplies of experimental vaccines or drugs that could be tested in the Equatorial Guinea outbreak found there are few doses available to test. The outbreak in Equatorial Guinea dates back to at least early January; by late February, nine cases — one confirmed, four probable and four suspected — had been identified. It is not unusual to see probable and suspected cases in a viral hemorrhagic fever outbreak, especially in the early days. People die and are buried without a diagnosis. Even after authorities realize what they are dealing with and testing protocols are established, some families hide their dead so as to be able to perform burial rituals which, while important culturally, serve to spread the virus further. It is believed additional cases have been identified in Equatorial Guinea, but the country’s leadership has been unwilling to disclose the information.

An experimental vaccine against the Marburg virus (MARV) was shown to be safe and induced an immune response in a small, first-in-human clinical trial, according to a newly published paper in The Lancet. The vaccine, developed by researchers at the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health, could someday be an important tool to respond to Marburg virus outbreaks. This first-in-human, Phase 1 study tested an experimental MARV vaccine candidate, known as cAd3-Marburg, which was developed at NIAID’s Vaccine Research Center (VRC). This vaccine uses a modified chimpanzee adenovirus called cAd3, which can no longer replicate or infect cells, and displays a glycoprotein found on the surface of MARV to induce immune responses against the virus. The cAd3 vaccine platform demonstrated a good safety profile in prior clinical trials when used in investigational Ebola virus and Sudan virus vaccines developed by the VRC. MARV, a filovirus in the same family as Ebola virus, causes a rapidly progressive febrile illness that leads to shock and death in a large proportion of infected individuals. Many scientists think that MARV disease outbreaks in humans begin by when the virus makes the jump from its primary animal host, which is likely to be certain chronically infected bats in sub-Saharan Africa. The symptoms of MARV disease are akin to those seen with Ebola virus disease and can include fever, headache, chills, rash, abdominal pain, vomiting, and diarrhea. As the disease progresses, patients may suffer from multiple organ dysfunction, delirium, and significant bleeding from the gastrointestinal tract or other sites that may result in death. No approved vaccines or specific therapies are available for MARV disease, aside from supportive care. While some experimental vaccines have previously been tested, none have proven to be both highly effective and to provide durable protection. In areas of Africa where a vaccine for Marburg is most needed, a single-dose vaccine that could protect recipients over a long period of time would be a crucial part of quelling outbreaks.

In this study, 40 healthy adult volunteers were enrolled at the Walter Reed Army Institute of Research Clinical Trials Center in Silver Spring, Maryland. They received a single dose of either a low dose of the vaccine (1×1010 particle units) or a higher dose (1×1011 particle units). For safety, the volunteers were enrolled in a dose-escalation plan. Three participants received the lower dose. Then, when they did not exhibit severe adverse reactions after the first seven days, the trial proceeded to enroll the remaining 17 volunteers. The same procedure was also used for the higher-dose group. Volunteers were monitored for adverse reactions to the investigational vaccine and evaluated at regular intervals for 48 weeks to track their immune responses. The trial’s safety results were encouraging: There were no serious adverse events, and the experimental vaccine was well-tolerated. One participant in the higher dose group developed a fever following vaccination, but it resolved by the following day. In addition, the investigational vaccine appeared to induce strong, long-lasting immunity to the MARV glycoprotein: 95% of participants in the trial exhibited a robust antibody response after vaccination, and 70% maintained that response for more than 48 weeks. Plans are in place to conduct further trials of the cAd3-Marburg vaccine in Ghana, Kenya, Uganda, and the United States. If additional data supports the promising results seen in the Phase 1 trial, the cAd3-Marburg virus vaccine could someday be used in emergency responses to MARV outbreaks.

Research cited published in The Lancet (Jan. 28, 2023):

https://doi.org/10.1016/S0140-6736(22)02400-X 

A patient with the rare, but highly infectious Marburg virus disease has died in Guinea, according to a World Health Organization (WHO) statement on Monday. It's the first case of the Ebola-like virus in West Africa.  Samples of the virus, which causes hemorrhagic fever, were taken from the patient in Gueckedou. The statement added that the detection comes less than two months after Guinea declared an end to its most recent Ebola outbreak. "Gueckedou, where Marburg has been confirmed, is also the same region where cases of the 2021 Ebola outbreak in Guinea as well as the 2014--2016 West Africa outbreak were initially detected," according to the WHO statement. "Samples taken from a now-deceased patient and tested by a field laboratory in Gueckedou as well as Guinea's national haemorrhagic fever laboratory turned out positive for the Marburg virus. Further analysis by the Institut Pasteur in Senegal confirmed the result." Health authorities on Monday were attempting to find people who may have had contact with the patient as well as launching a public education campaign to help curb the spread of infection. An initial team of 10 WHO experts are on the ground to probe the case and support Guinea's emergency response. "We applaud the alertness and the quick investigative action by Guinea's health workers.

The potential for the Marburg virus to spread far and wide means we need to stop it in its tracks," Dr. Matshidiso Moeti, WHO regional director for Africa, said in the statement. According to WHO, the virus is transmitted to humans from fruit bats and can then be spread human-to-human through direct contact with the bodily fluids of infected people or surfaces and materials contaminated with these fluids. There are no vaccines or antiviral treatments to treat Marburg; however, there are treatments for specific symptoms that can improve patients' chances for survival. "Case fatality rates have varied from 24% to 88% in past outbreaks depending on virus strain and case management," the statement said. "In Africa, previous outbreaks and sporadic cases have been reported in Angola, the Democratic Republic of the Congo, Kenya, South Africa and Uganda." Marburg virus was first identified in 1967, when 31 people became sick in Germany and Yugoslavia in an outbreak that was eventually traced back to laboratory monkeys imported from Uganda. Since then the virus has appeared sporadically, with just a dozen outbreaks on record. Many of those involved only one diagnosed case. Marburg virus causes symptoms similar to Ebola, beginning with fever and weakness and often leading to internal or external bleeding, organ failure and death.

Equatorial Guinea has just confirmed its first outbreak of deadly Marburg virus, a hemorrhagic fever related to Ebola. Equatorial Guinea has just confirmed its first outbreak of Marburg virus, one of the families of hemorrhagic fevers related to Ebola. As with last year’s outbreak in Ghana, patient specimens had to be sent to the Institut Pasteur in Senegal for confirmation, as it requires specialized testing. One of eight samples has been confirmed thus far. There have been 16 suspected cases and 9 deaths so far. Symptoms of Marburg are nonspecific and include (the often abrupt onset of) fever, headache, nausea, vomiting and diarrhea, so it might be confused with many other infections. When there is blood in the emesis or stool, the diagnosis of a hemorrhagic fever becomes much clearer. The incubation period is from 2-21 days. Like Ebola, Marburg can be quite deadly, with an 88% fatality rate.

Unlike Ebola, we have no vaccines to protect people yet, or other specific treatments. Monoclonal antibodies have been used to successfully treat some people ill with Ebola, with a moderate reduction in death, from 49.4% to 35.1% for Ebanga (Ansuvimab-zykl) treatment. The vaccine for Ebola offered a 97.5% protection rate in the 2018-20 outbreak in the Democratic Republic of Congo, which was due to the Ebola Zaire strain. The most recent outbreak of Ebola in Africa occurred in Uganda in September 2022. It was due to a different strain, Ebola Sudan, for which we have no vaccines or specific treatment. For Marburg, Ebola Sudan, and other hemorrhagic fevers, treatment is supportive by providing fluids and electrolytes to avoid shock. The primary focus now will be controlling the spread of the infection, which occurs through these infected secretions or contaminated surfaces, and by quarantine. Patients who are symptomatic need to be carefully isolated. The WHO and local officials will provide education on infection control and supplies of gowns and gloves (PPE). Contact with bodies is common in many cultures and has previously been a source of transmission.

Marburg has now been seen in Ghana, Angola, Uganda, the Democratic Republic of the Congo, Kenya, and South Africa. The first outbreak was seen in 1967 in Germany and Serbia. It came from the importation of green monkeys from Angola. A quarter of the 31 people infected died. Subsequently, there were larger outbreaks in the DRC in 1998-2000, with 152 people and 83% mortality. The largest outbreak was in 2005 in Angola. There were 252 cases and a 90% death rate. This was thought to be caused by reusing contaminated transfusion equipment between patients. Egyptian Rousette bats, which live in caves and mines, are reservoirs for the Marburg virus. There have been infections among Uganda miners in 2007 from the Python Cave in Uganda. Subsequently, two tourists became infected from the same site, where they had gone caving. Bat guano or infected aerosols were the likely sources of transmission. One of the problems with Marburg, as with other animal-related infections (zoonosis), is that there is limited surveillance and diagnostic tests; until there is an outbreak, early cases are likely to be missed. Many of these events—called spillover events—occur because we encroach on wildlife. As we do this more—be it in mining, deforestation for cattle, or other disruptions of the environment, we can expect to see more such outbreaks.

Lloviu cuevavirus (LLOV) was the first identified member of Filoviridae family outside the Ebola and Marburgvirus genera. A massive die-off of Schreibers’ bent-winged bats (Miniopterus schreibersii) in the Iberian Peninsula in 2002 led to its discovery. Studies with recombinant and wild-type LLOV isolates confirmed the susceptibility of human-derived cell lines and primary human macrophages to LLOV infection in vitro. Based on these data, LLOV is now considered as a potential zoonotic virus with unknown pathogenicity to humans and bats. We examined bat samples from Italy for the presence of LLOV in an area outside of the currently known distribution range of the virus. We detected one positive sample from 2020, sequenced the complete coding sequence of the viral genome and established an infectious isolate of the virus. In addition, we performed the first comprehensive evolutionary analysis of the virus, using the Spanish, Hungarian and the Italian sequences. The most important achievement of this article is the establishment of an additional infectious LLOV isolate from a bat sample using the SuBK12-08 cells, demonstrating that this cell line is highly susceptible to LLOV infection. These results further confirms the role of these bats as the host of this virus, possibly throughout their entire geographic range. This is an important result to further understand the role of bats as the natural hosts for zoonotic filoviruses.

Preprint available at bioRxiv (Dec. 5, 2022):

https://doi.org/10.1101/2022.12.05.519067 

The vaccine provided protection from Ebola virus, Sudan virus, Marburg virus and Lassa virus. Scientists funded by the National Institutes of Health have developed an investigational vaccine that protected cynomolgus macaques against four types of hemorrhagic fever viruses endemic to overlapping regions in Africa. The University of Texas Medical Branch in Galveston and Profectus BioSciences of New York are developing and testing the candidate quadrivalent VesiculoVax vaccine, with support from NIH’s National Institute of Allergy and Infectious Diseases (NIAID) and Redeemer’s University in Nigeria.

The newly published study in the Journal of Clinical Investigation describes how the vaccine was created using a live-attenuated (weakened) vesicular stomatitis virus to deliver proteins that elicit protective immune responses. The proteins are from Ebola virus (Kikwit strain), Sudan virus (Boniface strain, which also causes Ebola virus disease), Marburg virus (Angola strain) and Lassa virus (Josiah strain). There are no licensed vaccines to provide protection from any of those viruses — all of which can cause severe disease and death — although the European Medicines Agency has recommended licensing a VSV-Ebola vaccine. Importantly, the monkeys infected in the study were exposed to different strains of Sudan virus (Gulu) and Lassa virus (0043/LV/14) than those in the candidate vaccine to help the researchers determine whether the vaccine would be cross-protective. Lassa 0043/LV/14 is circulating in an outbreak in Nigeria that began in 2018. Previous studies indicate that the investigational Ebola virus (Kikwit) vaccine will protect against other strains of Ebola virus.

The scientists inoculated 20 macaques with a primary and booster dose of quadrivalent VesiculoVax. The animals had five blood draws to check for an immune response, including on the day of initial vaccination and on days 10 and 28, then on day 56 when they received a booster inoculation, and again on day 66. On day 84 scientists infected the macaques with the four different hemorrhagic fever viruses and monitored them to day 112. Twelve additional macaques in the study who were infected with the four viruses but not vaccinated all became sick, but none of the vaccinated animals did. Only one of the 20 vaccinated animals had any of the four hemorrhagic fever viruses detectible (Lassa) following the study. The scientists state that the addition of the Lassa virus component to their multivalent vaccine is an exciting research advance as they already had developed an investigational trivalent vaccine that provided protection against Ebola, Sudan and Marburg viruses. The researchers now plan further vaccine tests against other strains of Lassa virus, and they want to further evaluate whether a single-dose quadrivalent vaccine appears safe and effective.

Published in the Journal of Clinical Investigation (October 22, 2019):

https://doi.org/10.1172/JCI131958