Trapping The Ebola Virus

Though outbreaks of Ebola virus disease are not uncommon, the recent wave has indeed caused public health officials across the globe to press the panic button. As per World Health Organisation (WHO), as of September 3, more than 3,500 suspected cases have been reported from December from the four affected countries: Guinea, Liberia, Nigeria, Senegal, and Sierra Leone. Of these, recorded deaths cross 1,900.

Clearly, this zoonotic disease is very much on a killing spree. Recent news regarding mutations in the genetic material of the virus has only increased pressure on researchers. However, what has hit healthcare fraternities the most is the inability of the biotech industry to come up with remedies to keep Ebola under check.

Tough task

Over the last few years, sporadic incidences of Ebola outbreaks were reported in sub-Saharan-Africa. However, these pale in comparison to the current Ebola epidemic. Today, treatment available for Ebola is more of a supportive type. Though there are some molecules under trial none of them have got final approval from the US FDA.

“Ebola has a more severe disease pattern with high fatality. Biotech companies need to consider the disease epidemiology, disease burden and impact on human health.” Dr Babasaheb V Tandale Scientist D & Group Leader, Epidemiology Group, National Institute of Virology

“The current strain of Ebola is the most virulent that has been reported in early 2014,” points out Dr Babasaheb V Tandale, Scientist D & Group Leader, Epidemiology Group, National Institute of Virology (NIV). Designated to handle Ebola initiatives for the institute, he has been inundated with calls from across the country as NIV serves as the country’s foremost national laboratory in providing quick and accurate diagnostic services.

The NIV’s brief has been to research on emerging and re-emerging human viruses of public health concern and it has added Ebola to its already large list which includes HIV, KFD, hepatitis E, chikungunya, and H5N1/swine H1N1 among others. All these viruses cause considerable morbidity and mortality.

Speaking about Ebola, Tandale says, “Ebola has a more severe disease pattern with high fatality. Biotech companies need to consider the disease epidemiology, disease burden and impact on human health. It would also depend on risk assessments provided by the international health agencies. Market research and analysis is required prior to deciding priorities for investments. These factors may drive efforts for finding remedies for emerging infections. However, there may be additional challenges in science and technology tools for development of remedies by biotech/pharma companies.”

“Due to the highly virulent nature of the virus, the genetics of the negative single stranded RNA genome of the virus is also poorly understood, thus making it difficult to design target drugs.” Dr Manju Phadke, Asst. Professor, Dept. of Microbiology, SIES College of Arts, Science and Commerce, Mumbai

The task of finding a remedy is made extremely difficult because of the highly virulent nature of the virus. Dr Manju Phadke, Asst. Professor, Dept of Microbiology, SIES College of Arts, Science and Commerce, Mumbai, explains, “Due to the highly virulent nature of the virus, the genetics of the negative single stranded RNA genome of the virus is also poorly understood, thus making it difficult to design target drugs.” Phadke indicates that the mutations have made Ebola virus more transmissible and difficult to curb with targeted therapy.

“Epidemiology of any virus is very important from a drug discovery point of view. Epidemiology, many times, holds the answer for the cure of the disease.” Dr Amol Raut, Head, R&D, Chief Wellness Advisor, GeneSupport

Dr Amol Raut, Head, R&D, Chief Wellness Advisor, GeneSupport, talks about the importance of epidemiology in the process of drug development. He explains, “Epidemiology of any virus is very important from a drug discovery point of view. Epidemiology many times holds the answer for the cure of the disease. Other factors which are making the task difficult are the rate at which the infection spreads in the body. Ebola is a filovirus i.e. from the family Filoviridae. As compared to a retrovirus (like HIV which is the causative agent of AIDS) Ebola causes death in a much shorter time. This virus doesn’t wait for the immune system to get compromised. This deadly virus drives the protein synthesis in hosts which is essential for the haemorrhagic stages of the disease. There are shortcomings in terms of understanding the pathway and inoculation for Ebola, hence discovering a concrete cure is becoming a difficult task for scientists all over.”

Drugs available

As mentioned earlier, treatment for Ebola is mostly supportive in nature. It revolves around balancing fluid and electrolyte levels to prevent dehydration. With no specific drug or vaccine available to treat this disease, drugs are mostly administered to deal with the symptoms as they appear.

Phadke says, “Administration of anti-coagulants early in the infection to prevent or control intravascular coagulation in cases with confirmed diagnosis is critical. Administration of pro-coagulants later in the infection to control internal bleeding is the key factor in treating the disease. Besides this, maintaining the levels of blood gases, renal function and pain management is also important. Antibiotics can be administered to prevent secondary bacterial infections.” She adds, “The US FDA has allowed two drugs, produced by Mapp Biopharmaceuticals; ZMapp, a combination of three different monoclonal antibodies that bind to the surface protein of the Ebola virus and a  drug called TKM Ebola which targets the genetic single strand of negative sense RNA, which is the genome of the virus. The drug acts by interfering with the genetic code of the virus, thus preventing the synthesis of viral proteins which aid in the pathogenesis of the disease. However both these drugs are still in the experimental stages and it is too soon to understand their effectiveness.”

Echoing Phadke’s views, Tandale cautions that it is too early to gauge ZMapp’s effect. According to him, the best way is to conduct a randomised controlled clinical trial to compare outcomes of patients who receive the treatment to untreated patients. Tandale informs, “No such studies have been conducted. At this time, very few courses of this experimental treatment have been manufactured. The manufacturer has indicated that the available doses have been distributed. The efforts to undertake research on evaluation of the product safety and effectiveness are ongoing.”

Several experimental trials on animals are being conducted since early outbreaks to address the treatment issue and target the virus in the most effective way. The evolution of drugs is highly dependent on the responses shown by such drugs after through clinical trials.

Raut informs, “Apart from Zmapp, a drug named Favipiravir has been developed by a subsidiary of Fujifilm Holdings Japan. Although, there are different drugs in development there is no sign of getting a positive response from various people in the medical field.”

On the research front

As far as research is concerned, the most promising development till now remains the combination of antibodies that scientists are working upon.

“The outcome of this research is definitely going to be positive as the drug development process has speeded up to get the right cure to the infected population and save them,” says an optimistic Raut.

Current research is being conducted mainly at two levels: drug and vaccine development. However, at both the levels scientists have met with limited success. Immune sera is also one of the options that scientists are cautiously hopeful about.

While there is an ongoing effort to develop remedies like antiviral drugs, immune sera and vaccines against Ebola, Tandale also points out that it takes a lot of time to develop, test and get approval of regulatory authorities before a therapy can actually be put to use. To make matter worse, information about the remedies for Ebola is not available easily and there are lacunae in scientific data and evidence to evaluate them for Ebola, he avers.

Given the emergency, the WHO and other agencies have obviously decided to circumvent the usual procedures to ensure thatwork is carried out on a war footing.

Tandale informs that WHO had arranged a consultation of experts for experimental treatment and vaccines against Ebola on September 4-5. He adds, “Tekmira and Biocryst Pharmaceuticals have therapeutic candidates for Ebola in early development. A company called Newlink is developing an Ebola vaccine candidate. BioCryst is working to develop an antiviral drug to treat Ebola virus. Other candidate treatments for Ebola include AVI 7537, selective estrogen receptor modulators like clomiphene and toremifene, BCX-4430 and ST-383.” 

Despite a lot of hope pinned on vaccines to eradicate Ebola, not much tangible success has been seen. The US FDA has not yet approved any vaccine. Tandale says, “The US National Institute of Health (NIH’s) National Institute of Allergy and Infectious Diseases is working on developing an Ebola vaccine. Ebola vaccines were first tested in humans beginning in 2003. Human safety studies of an experimental Ebola vaccine developed by the NIH and GlaxoSmithKline are being planned. Another experimental Ebola vaccine, VSV-EBOV, has been developed by the Public Health Agency of Canada.”

Researchers are relying on Favipiravir because it inhibits RNA synthesis in influenza virus and strains of H5N1. This increases its chances of being a promising candidate as both Ebola virus and H5N1 virus have the same kind of negative strand RNA genome.

Future course for biotech companies

Like many other outbreaks, the Ebola wave may subside in future, but not before extracting a heavy toll in terms of lives lost. However, history shows that Ebola has the habit of striking back . The next Ebola outbreak could be even more severe, considering its mutating nature. Hence the biotech industry should continue efforts towards finding a preventive remedy for Ebola virus and remain alert.

“I think that the research and drug development on Ebola virus should be continued as we all know viruses tend to mutate. Hence, a mutated strain of the virus can be resistant to a drug which is under development right now. So, continuous observation and study of the virus should be done even after the outbreak subsides. History has proved that there have been sporadic out breaks of this virus and who knows, may be in future a mutated strain may cause a deadly outbreak, lethally damaging the human race. Moreover, the political scenario around the world is not so good; hence a continuous research on drug development front should be the aim as it can be used as a weapon for biological warfare. History has witnessed the use of anthrax (Bacillus anthracis) as a biological warfare weapon in world war and post-world war era. Hope for the best and prepare for the worst,” says Raut.

Though the Ebola outbreak has its origins in the African countries, its effects are evident across the globe. So being a worldwide concern, it is necessary for the world community/ governments to engage themselves in the efforts to control the virus. Especially, biotech experts need to come together to share their expertise.

“Biotech companies could identify the key emerging pathogens based on risk assessments. They could also consider development of partnerships with international health agencies. These would help create international platforms for sharing challenges and issues so that prioritisation could be possible. The initiatives that need to be considered include development of diagnostic capacities in terms of laboratory and epidemiological expertise including laboratory assays, antivirals, immune sera and vaccines against emerging viruses,” says Tandale.

Phadke opines, “Drugs like Favipir and SERMs are safe drugs as they are used in human beings for the treatment of H5N1 influenza and breast cancer respectively. These drugs should have been put on trials for the treatment of Ebola during the current outbreak. Research should be focused on the development of recombinant vaccines and immunovaccines. Work is already being carried out by companies in this direction. Cost cutting and budget cuts by government agencies as well as biotech and pharma companies should not be done. It is important to study new Ebola drugs and vaccines.”

Profit matters?

With a few exceptions, Ebola is predominantly confined to particular parts of the world and it goes into a lapse period after every outbreak. Is this the reason why pharma/biotech companies are reluctant to invest into its research, as it offers very limited profit margins? Experts feel so.

Raut says, “Yes, this can be one of the reasons for keeping pharma and biotech companies from investing in research (on Ebola). Ebola outbreaks are sporadic in nature, predominantly affecting low-income countries in the West African continent. Hence, pharma and biotech companies are likely to see very less pay off from these parts of the world and looking at the population it infects, the demand is very less. This makes the companies to invest less in such research and pharma companies have little incentive to pour their research and development money into curing a disease that surfaces in a sporadic manner. Hence it’s all dependent on the economics of drug development which is very commercial.”

“I agree partially with the limitations and hurdles for investing in development of remedies for emerging viruses by pharma/ biotech companies like difficulties in risk assessments, likelihood of emerging virus to have potential impact on human health locally and globally, and relative priorities of companies based on cost-benefit scales,” says Tandale.

He adds, “Diseases of the poor receive too little attention from medical researchers and pharma companies. We should be investing more to develop drugs and vaccines to combat diseases like Ebola. It would require a concerted effort with partnerships involving research networks, industry collaborations and initiatives of the international health agencies providing common platform to share difficulties and offer possible solutions so as to minimise the time required for development, testing, approvals and use remedies timely for decreasing impact of emerging infections on global human health.”

Since 1976, when the Ebola virus was first identified, the current Ebola epidemic is the largest and the most persistent. It has shown that an outbreak anywhere can escalate to be a risk everywhere, which wasn’t the case during previous outbreaks. Developing a stronger system to identify and stop future Ebola outbreaks is the moral imperative of governments and researchers across the globe. Hopefully, this Ebola outbreak has proved that the entire world is at the risk from such outbreaks, and with the increased focus of WHO and other agencies, we can expect more coordinated and collective efforts from different governments and health agencies. Global collaborations and funding will hopefully be incentive enough for biotech and pharma firms to continue their research and increase the chances of finding effective drugs and vaccines against Ebola and other such diseases soon.

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(The views/pinions provided by Dr Babasaheb Tandale are in his personal scientific capacity and do not represent NIV/ICMR or government departments as the official opinion and stand on any response/replies)