- Deadliest Outbreak Yet Shows no Sign of Abating
- Lack of Funds Hampered Clinical Development of Drugs and Vaccines
- Treatments Exist so Why are Doctors Left with no Cure to Offer the Infected?
You’ve undoubtedly seen or read ongoing—seemingly continuous—news stories about a serious outbreak of Ebola virus disease (EVD) in Africa, and the two infected American health workers who were brought back to the US for treatment. The title of this blog post is adapted from Sara Reardon’s article in venerable Nature magazine, which I draw from following a brief overview of EVD.
The current Ebola outbreak involving the most dangerous Zaire species has killed more than 1,000 and infected an estimated 1,975 people in West Africa. Sierra Leone, Guinea and Liberia have been hit the hardest, with Nigeria experiencing a handful of confirmed cases and 3 deaths. Tom Frieden, director of the U.S. Centers for Disease Control and Prevention, estimated the outbreak will take three to six months to contain under the best of circumstances. Although the outbreak is the deadliest to date, the chances of infection in the US is remote, albeit theoretically possible that one of the 10,000+ travelers to and from the region over the next three-months could carry the virus back to the US. “Ebola poses little risk to the U.S. general population,” Frieden is quoted as saying. Let’s all hope he’s right.
EVD – Key Facts
The following selected statements about EVD were taken from a World Health Organization (WHO) website that was updated on April 2014, and should be consulted for further details.
- EVD, formerly known as Ebola hemorrhagic fever, is a severe, often fatal illness in humans.
- EVD outbreaks have a case fatality rate of up to 90%.
- EVD outbreaks occur primarily in remote villages in Central and West Africa, near tropical rainforests.
- The virus is transmitted to people from wild animals and spreads in the human population through human-to-human transmission, with infection resulting from direct contact (through broken skin or mucous membranes) with the blood, secretions, organs or other bodily fluids of infected people, and indirect contact with environments contaminated with such fluids.
- EVD is a severe acute viral illness often characterized by the sudden onset of fever, intense weakness, muscle pain, headache and sore throat. This is followed by vomiting, diarrhea, rash, impaired kidney and liver function, and in some cases, both internal and external bleeding. Laboratory findings include low white blood cell and platelet counts and elevated liver enzymes.
- Severely ill patients require intensive supportive care. No licensed specific treatment or vaccine is available for use in people or animals.
Only 18,959 Nucleotides Encode Much Human Suffering
Like HIV and other RNA viruses, Ebola is encoded in a relatively tiny genome that nevertheless leads to huge problems for society through complex life cycle/human host molecular biology. As detailed elsewhere, the genome of the Zaire Africa Ebola virus—the most deadly species and the one involved in the current outbreak—is only 18,959 nucleotides in length and contains seven transcriptional units that direct synthesis of at least nine distinct primary translation products: the nucleoprotein (NP), virion protein (VP) 35, VP40, glycoprotein (GP), soluble glycoprotein (sGP), small soluble glycoprotein (ssGP), VP30, VP24 and the large (L) protein. L is the catalytic subunit of the polymerase complex. Ebola virus encodes a multi-protein complex to carry out replication and transcription. Ebola viral RNA synthesis requires the viral NP, VP35, VP30 and L proteins. Each Ebola virus mRNA is presumed to be efficiently modified with a 5′-7-methylguanosine (m7G) cap and a 3′ p(A) tail.
RT-PCR Enables Effective Diagnostics for Ebola Viral RNA
Ebola virus infections can be diagnosed definitively in a laboratory through several types of tests, such as antibody-capture enzyme-linked immunosorbent assay (ELISA), serum neutralization test, and virus isolation by cell culture. Not surprisingly, however, RT-PCR has been demonstrated to be highly specific and sensitive, as outlined in this abstract published by a collaborative team lead by the Diagnostic Systems and Virology Divisions at the United States Army Medical Research Institute of Infectious Diseases:
Viral hemorrhagic fever is caused by a diverse group of single-stranded, negative-sense or positive-sense RNA viruses belonging to the families Filoviridae (Ebola and Marburg), Arenaviridae (Lassa, Junin, Machupo, Sabia, and Guanarito), and Bunyaviridae (hantavirus). Disease characteristics in these families mark each with the potential to be used as a biological threat agent. Because other diseases have similar clinical symptoms, specific laboratory diagnostic tests are necessary to provide the differential diagnosis during outbreaks and for instituting acceptable quarantine procedures. We designed 48 TaqMan™-based polymerase chain reaction (PCR) assays for specific and absolute quantitative detection of multiple hemorrhagic fever viruses. Forty-six assays were determined to be virus-specific, and two were designated as pan assays for Marburg virus. The limit of detection for the assays ranged from 10 to 0.001 plaque-forming units (PFU)/PCR. Although these real-time hemorrhagic fever virus assays are qualitative (presence of target), they are also quantitative (measure a single DNA/RNA target sequence in an unknown sample and express the final results as an absolute value (e.g., viral load, PFUs, or copies/mL) on the basis of concentration of standard samples and can be used in viral load, vaccine, and antiviral drug studies.
According to WHO, Ebola was first detected in 1976 and strides have been made in developing sophisticated tests that can accurately diagnosis the virus, as demonstrated above. There is currently no FDA approved vaccine or treatment for Ebola, but that doesn’t mean one doesn’t exist.
Could Outbreak Have Been Avoided?
Although several vaccines and treatments for Ebola do exist, they are stalled in various stages of testing owing to a lack of funding and of international demand. So, for now, doctors have no cure to offer those with EVD and understaffed clinics must make do with isolating infected people, finding and quarantining their families, and educating the public on how to avoid spreading the disease.
The fact that the Ebola virus was identified almost 40 years ago and there’s been ongoing research ever since begs the question, “Was the current Ebola outbreak preventable?” According to Reardon, researchers such as Heinz Feldmann, a virologist at the US National Institute of Allergy and Infectious Disease (NIAID) in Hamilton, Montana, think that the situation could have been avoided. In 2005, Feldmann published a vaccine approach based on vesicular stomatitis virus (VSV) that has since yielded an Ebola vaccine that is effective in macaques. But money is not available to take the next step—testing the vaccine’s safety in healthy humans. Compared with malaria or HIV, “Ebola is just not that much of a public-health problem worldwide”, he told Reardon, and consequently draws little interest from public or private funders.
“What works for Ebola is good old-fashioned public health,” says Thomas Frieden, director of the US Centers for Disease Control and Prevention in Atlanta, Georgia, according to Reardon. “It would be great to have a vaccine, but it’s not easy to do and not clear who you’d test it on.”
There are other possible vaccines as well. The NIAID Vaccine Research Center in Bethesda, Maryland, has developed a vaccine that is carried by a chimpanzee adenovirus, similar to the virus that causes the common cold. The institute hopes to begin testing in healthy people as early as September. Barney Graham, deputy director of the research center, told Reardon that the institute is talking with the Food and Drug Administration (FDA) to speed up the approval process, a position that is strengthened by the outbreak in West Africa.
Biotechnology companies are also developing treatments at a pace that could now be accelerated, as we’ve seen with the ZMapp™ vaccine (discussed in detail below) that arrived in Liberia a few days ago. ZMapp™ was developed by Mapp Biopharmaceutical in San Diego, California. The potenital treament uses monoclonal antibodies (mAbs) that target the virus.
Another potential therapeutic backed by US$140 million from the US Department of Defense, is being tested by Tekmira in Burnaby, Canada. The treatment, called TKM-Ebola, uses chemically synthesized small RNA (siRNA) molecules to bind the virus and target it for destruction. The company began testing TKM-Ebola in humans in January, but in July of this year, the FDA put the study on hold until the company could provide more data on how the treatment works. According to an article in Streetsider.com, here’s what the CEO said in response to the FDA news:
“We have completed the single ascending dose portion of this study in healthy volunteers without the use of steroid pre-medication. The FDA has requested additional data related to the mechanism of cytokine release, observed at higher doses, which we believe is well understood, and a protocol modification designed to ensure the safety of healthy volunteer subjects, before we proceed with the multiple ascending dose portion of our TKM-Ebola Phase I trial,” said Dr. Mark Murray, President and CEO of Tekmira Pharmaceuticals. “We will continue our dialogue with the FDA, provided for under our Fast Track status, in order to advance the development of this important therapeutic agent.”
A treatment could be approved by the FDA on a ‘compassionate use’ basis, but that process would have to mesh with a host country’s rules. “A country has to request these things; it’s not something we can force on them,” says Gene Olinger, a virologist at the contract research organization MRIGlobal in Frederick, Maryland. “We have to follow their internal policies for drug development and for testing.” It appears that Liberia, at least, has made such a request and it has been honored.
Coincidentally (or maybe not so much), on August 7, the FDA reduced the full clinical hold on Tekmira’s TKM-Ebola drug to a partial hold, potentially enabling use of the compound in patients. It remains to be seen if the drug will be sent to West Africa to be administered, but such a move leaves some to wonder why the FDA can act so swiftly now but refused to do so back in July, prior to the outbreak.
Mapp’s ‘Mystery’ Ebola Virus Drug Said to be ‘Miraculous’
Major media outlets frequently employ attention-grabbing words—such as ‘mystery’ and ‘miraculous’—so it’s not surprising that these descriptors have been used in recent news reports about two American health workers in Liberia infected with Ebola virus. The Los Angeles Times reported that Mapp Biopharmaceutical’s experimental drug, ZMapp™, was given to Dr. Kent Brantly and Nancy Writebol under circumstances described by the LA Times as “a mysterious treatment.”
Intrigued by the ‘mystery,’ I did some quick research and found ZMapp™ had not been previously evaluated for safety in humans, and “very little of the drug is currently available,” according to LeafBio (San Diego, California), which is Mapp’s commercialization partner. In fact, the available supply of ZMapp™ is said to have been exhausted, according to a statement posted August 12, 2014 on Mapp’s website. The statement also notes that ZMapp™ is the result of a collaboration by Mapp, LeafBio, Defyrus Inc. (Toronto, Canada)—a biodefense company—and both the U.S. government and the Public Health Agency of Canada.
I went on to read that “ZMapp™ is composed of three ‘humanized’ mAbs manufactured in plants, specifically Nicotiana” (aka tobacco plant—and origin of the word nicotine). In other words, tobacco plants are cleverly repurposed by genetic engineering to produce mAbs suitable for use in humans, as detailed here in a review by Mapp that describes this approach as a “revolutionary advance” in antibody manufacturing.
The LA Times also said that CNN reported that the drug had prompted a ‘miraculous’ recovery and that Brantly’s condition improved within an hour after treatment, but that this was greeted with skepticism by longtime Ebola virus researchers.
This skepticism is based on the following series of quotes in the LA Times story:
‘I would be ecstatic if Larry’s product helped save these people, but I also need to be extremely cautious,’ said Thomas Geisbert, a professor of microbiology and immunology at the University of Texas Medical Branch at Galveston.
‘To say the whole thing cleared up in an hour, that doesn’t happen in reality,’ Geisbert said. ‘That’s like something that happens in a movie.’
Dr. Anthony Fauci, head of the National Institute of Allergy and Infectious Disease, said the company had manufactured only three ‘courses’ of the drug, and that two of them were provided to the American patients.
‘This was the first time it was put into humans, because all the previous work was done on animals and the results had been encouraging,’ Fauci said.
In closing, I’ll sadly add that it’s unfortunate—to say the least—that funding for timely development of an Ebola vaccine had not been forthcoming from some agencies that knew full well that it was only a matter of time for the next outbreak to occur in Africa. Corporations, however, seem to be stepping in where these agencies may have failed. On Monday, August 11, World Bank announced it will give $200M to help fund the fight against Ebola. Let’s all hope that the current crisis provides the necessary catalyst for that development so as to preclude yet another outbreak and more unnecessary deaths.
As always, your comments are welcomed.