An Update on Ebola

THE INTERNATIONAL community breathed a sigh of relief in the last quarter of 2019 when, more than 40 years since Ebola virus disease (EVD) was first identified, the World Health Organization (WHO) supported the use of and the European Commission and the U.S. Food and Drug Administration (FDA) approved the first vaccine for the prevention of EVD, which is caused by Zaire Ebola virus in humans. Called a “critical milestone in public preparedness and response,” approval of Merck & Co.’s Ervebo for individuals 18 years and older was no easy task, complete with fits, starts and near misses. However, with efficacy determined to be 100 percent, Ervebo is expected to offer untold benefits, particularly to those in Africa where outbreaks have caused the destruction of lives, families and communities. Yet, existing challenges remain, including the need for better EVD diagnostics and how to care for Ebola survivors.

Emergence of the VSV Vaccine

While EVD was originally documented in the 1970s, notoriety about the outbreak didn’t grow until 2014 with its spread in Guinea. Prior to that, scientists had been working on an EVD vaccine. But with only sporadic outbreaks, no testing beyond animal models and little opportunity to do so, there was little interest in the pharmaceutical community to develop such a costly endeavor.

In the 1990s, researchers in Marburg, Germany, began experimenting with a livestock virus called vesicular stomatitis virus, or VSV, for use as a vaccine delivery system. It was thought VSV could be an effective vehicle for a vaccine since it produces a rapid immune system response with high levels of antibodies. Already studied as a backbone to experimental vaccines for pathogens such as bird flu, measles, SARS and Zika, VSV was combined with Ebola genes, replacing the glycoprotein on the VSV with Ebola glycoprotein, allowing it to be studied at lower biocontainment levels.

The VSV construct was eventually brought to a Canadian national microbiology laboratory, a biosafety level four (BSL-4) facility, where work on a vaccine began. Mice were infected with the VSV virus containing the Ebola glycoprotein followed by the Ebola virus itself, and all survived. The method was then replicated in monkeys with good results. Therefore, the VSV vector loaded with the Ebola glycoprotein was determined safe and could be used to develop an EVD vaccine.

But vaccine development is expensive, estimated to cost around $1 billion, and although EVD outbreaks are deadly, they were sporadic. With little market incentive, it can be difficult for pharmaceutical companies to take on such a monumental task. So, the Canadian government granted $2 million for the creation of human-grade lots of the VSV vaccine for Ebola Zaire to be used in testing, which were then manufactured and tested by a German contract partner to ensure no inadvertent contamination.¹

In March 2014, WHO declared an EVD outbreak in Guinea. However, at that point, no testing on humans had been conducted. While EVD was originally documented in the 1970s, notoriety didn’t grow until 2014 with its spread in Guinea. However, at that point, no testing on humans had been conducted. Five months later, the outbreak became a global health emergency that would eventually infect 28,000, killing more than 11,000 across West Africa. According to WHO, 90 percent of those who become infected with EVD can die from it. It was then that Doctors Without Borders began urging the use of the VSV vaccine, and the Canadian government donated its version (other companies were also in vaccine development) to WHO. While NewLink Genetics held the license to develop the VSV vaccine, the company did not have the expertise to take on the clinical testing required, so Merck was identified as a new pharmaceutical partner for its capabilities, and it purchased NewLink’s license.²

However, since the VSV vaccine for EVD had never been tested in humans, the ethics of doing so in the midst of an outbreak were questioned. In response, an “ethical imperative” prevailed allowing Phase I trials, planned in part by the U.S. National Institutes of Health (NIH) and Walter Reed Army Institute for Research, to be conducted in 10 countries. Differing from traditional random study design with control and placebo groups, the EVD trials conducted during the outbreak included those with known exposure who were randomly assigned to an immediate or delayed vaccination. “Ebola virus disease is a rare but severe and often deadly disease that knows no borders. Vaccination is essential to help prevent outbreaks and to stop the Ebola virus from spreading when outbreaks do occur,” said Peter Marks, MD, PhD, director of the FDA’s Center for Biologics Evaluation and Research.³

By the time Phase III trials were ready in 2015 (with agreements in place in Liberia and Sierra Leone), WHO with the help of Doctors Without Borders initiated a cluster ring vaccination study of Ervebo in Guinea. In the study, people who had direct contact with anyone infected with EVD were vaccinated, as were their contacts, either immediately or with a 21-day delay. Results were promising, with the immediate cluster group showing no cases of EVD with symptom onset 10 days or more after receiving the vaccine, compared with 10 cases of EVD in the 21-day delayed cluster group. Similar antibody results were also seen in studies conducted in Sierra Leone, Liberia, Canada, Spain and the U.S. It was determined the vaccine had worked, so Merck moved forward in developing the rVSV-ZEBOV vaccine with the support of the Biomedical Advanced Research and Development Authority.¹

When a new outbreak of Ebola flared in August 2018 in Equateur, a province in the Democratic Republic of the Congo, compassionate use of Ervebo was approved, and vaccinations began eight days later. Since then, more than 3,300 in the Democratic Republic of the Congo have contracted EVD, making it the second worst outbreak on record. What makes the spread of EVD so challenging is the ability of the disease to relapse and subsequently spread in patients thought to be cured. This was the case in December 2019 when the outbreak in the Democratic Republic of the Congo, thought to be contained, resurfaced. Today, with thousands of EVD survivors, the risk of resurgence, though rare, is significant.⁴

In December 2019, FDA approved Ervebo supported by the Guinea study during the 2014-2016 outbreak, as well as additional studies mentioned above.³

The Need for EVD Diagnostics

Early symptoms of EVD can mirror diseases and infections from organisms to which it is closely related, which is why accurate and rapid diagnosis is key. But, until recently, clinical labs used specific tests to identify pathogens (e.g., PCR assays that identify certain genes such as those containing antimicrobial resistance markers), which often require specialized equipment and can take hours or days depending on the tests’ and the labs’ capabilities.5 In 2017, FDA cleared a diagnostic test for EVD, and in 2019 allowed marketing of a de novo test kit for rapid detection and presumptive diagnosis (that must be confirmed) of EVD antigens in human blood from both living and deceased persons who are suspected to have died from EVD. This rapid diagnostic test was previously authorized for emergency use under the FDA’s emergency use authorization (EUA). Additionally, there are 10 diagnostic tests available for emergency use also under EUA (one rapid antigen and nine molecular).⁶

Today, the development of new diagnostic techniques using nucleic acids from Ebola and Ebola-like computer-simulated organisms housed in FDA’s ARGOS database are filling gaps in a fundamental limitation of next-generation diagnostic testing by developing reference databases that analyze diagnostic test performance. Next-generation sequencing allows study of dangerous organisms without the high biosafety containment level requirements since they look at nucleic acids or organisms, which may be obtained from samples that have been rendered noninfectious.5 As part of this line of study, regulatory-grade reference sequence standards are urgently needed to help diagnose and rule out Ebola infection.

How to Care for Ebola Survivors

To date, there are no FDA-approved drugs to treat Ebola, although several experimental treatments are under development. EVD is not a high risk for the U.S. population because transmission is through direct contact with an infected animal (bat or primate) or person (live or dead), and this transmission has historically occurred primarily in Sub-Saharan Africa.

Current treatment recommended by the Centers for Disease Control and Prevention (CDC) is supportive therapy, balancing patients’ fluids and electrolytes, maintaining their oxygen status and blood pressure, and treating any complicating infections. Healthcare providers are trained to use standard precautions, and when they suspect a patient could meet the criteria for EVD exposure and symptoms, they immediately separate the patient from others, notify authorities and begin following CDC guidelines for protective personal equipment, testing and isolation. Numerous resources for handling a suspected EVD case can be found on the CDC website, the scope of which is well beyond this article.⁷

FDA and government partners are conducting studies in West Africa to better understand how EVD affects patients who have survived, as well as to learn how to more effectively treat survivors’ chronic health problems. Many survivors of EVD suffer headaches, joint pain and eye problems, although the causes of these aftereffects are not understood. These studies will explore human immunopathology for chronic post-EVD signs and symptoms and provide further understanding of the natural course of the disease and lasting health problems

Since 2016, Stanford University has been studying EVD in support of new treatment efforts. In 2019, FDA in collaboration with the National Institute of Allergy and Infectious Diseases (NIAID) and NIH began working with Stanford laboratories to apply new methods to the study of EVD and Zika tissue samples, which includes multiplexed ion beam imaging to identify viral cells or anatomical sites where viruses accumulate and persist. Stanford is also beginning to look at Quantum Barcoding (QBC), an experimental diagnostic single-cell technology that can rapidly measure multiple targets, including RNA, DNA and proteins, as a primary means to analyze single cells in a laboratory and field stations. At the conclusion of this collaboration in May 2021, Stanford will deploy QBC to a federal laboratory facility at NIH for onsite testing and use in high-containment laboratories, including BSL-4 labs.⁸

Back to the Future

As of this writing, the global COVID-19 pandemic has sickened more than three million worldwide and killed nearly 250,000. Science is again seeking answers. Phase III clinical trials of remdesivir, a drug developed by Gilead Sciences and unsuccessful against the 2014 Ebola outbreak, has shown promise in shortening recovery times in hospitalized patients with severe manifestations of this novel coronavirus. Double-blind clinical trials sponsored by the NIAID in the U.S. are still ongoing.⁹ Though not a cure, it may be a start, and as one door closes another opens as science continues to unravel the many questions surrounding what works and why. Discoveries found to be ineffective for one disease can become the lead candidate for another.