Dear Bill Gates - Don't Put All Your Eggs in One Basket for Ebola Research

              Dear Bill Gates, thank you for putting up 5.7 million dollars for research toward finding a treatment for Ebola. This disease potentially threatens the whole world. While everyone applauds your concern and financial contribution, a closer look suggests you might have leveraged your investment better. Potential Ebola treatments are like start-up companies. It would be better to spread your bets to see which potential therapeutic approaches have their science in order, have power against this disease, and are cost effective.  

First analyze your current bet on plasma antibody transfer, or “PAT”. Antibodies are produced by immune system B-cells to attack bacteria, virus or fungi that cause disease. Once the body has recovered from a disease, memory B-cells are primed to produce millions of antibodies specific for that particular disease in case that same germ ever attacks again. B-cells and the antibodies they produce are a key part of the immune system. They are what vaccines trigger and are the essence of what we call “immunity”. But antibodies do not work alone. They only tag the virus. They need phagocytic cells like macrophages to destroy viruses. Plus, antibodies and macrophages only attack the virus when it is outside a cell, not when it is inside a cell replicating. The idea of transferring only a person’s antibodies to another person has little scientific merit. Emil von Behring won the first Nobel Prize in Medicine in 1901 for the concept of blood serum transfer to treat a disease, before antibodies were ever discovered. He wrote his paper on the principles of serum therapy in 1892. However, he used whole blood including all the immune white blood cells, not just plasma with antibodies. Regardless, this idea is based on old medicine, well before the dawn of immunology and modern pharmacology offered alternatives. That was decades before we understood the intricacies of how the most complicated system in the body, the immune system, works. But to be successful against the diphtheria bacterium, the disease von Behring used it against, whole blood had to be administered early on in the disease. Many Ebola patients do not show up for treatment early in their disease. And von Behring used this against a bacterium, not a virus.

You would never use 1890s technology at Microsoft or any company you invested in. There must be a more modern approach utilizing what science has learned over the past century about virology and immunology. B-cells in an Ebola patient’s body furiously produce antibodies by the hundreds of millions. Transferring a pint or two of another Ebola survivor’s blood plasma antibodies may have some small effect. But given Ebola’s explosive replication rate the odds are probably not in favor of this approach. Some scientists argue that for a number of reasons, whole blood transfer would have a better chance than PAT. Whole blood would contain the critical CD4 and B-cells, as well as virus fighting interferons. In 1995 eight Ebola patients in the Congo received whole blood transfers from other survivors and seven lived. That is not conclusive proof whole blood transfusion from survivors works. That experiment needs to be repeated to confirm that effect. However regardless of PAT’s limited prospects for success, the process of plasma antibody or whole blood transfer therapy is hugely expensive, awkward, complicated and requires vast resources for coordination and new infrastructure. Surely this is the most inefficient approach ever devised to treating this disease. That is the opposite of leverage.  PAT is unusually expensive and complicated, for probably a very limited benefit. It would never pass cost/benefit analysis in a business setting.  

Examine the mechanics of survivor plasma antibody transfer more closely. PAT requires many survivor donors who can donate a limited amount of blood – about two pints each month. This approach must build and maintain multiple databases, set up additional organizational infrastructures, provide communication and transportation for all parties concerned, and pay for blood rendered to keep the plasma flowing. Second, PAT needs to test the blood for HIV, Lassa fever, hepatitis, syphilis plus other endemic equatorial pathogens. Technicians need to match blood types and have infrastructure in place – blood mobiles, blood banks, and cold chain logistical networks. That is not easy in countries with few paved roads, a plethora of potholes and no reliable energy supply. The cost of this therapy for one patient, delivering a few pints of blood to a particular person in a timely manner - exceeds the per capita gross national income in the three affected countries. That is a lot of work, a lot of complexity and a lot of expense for a marginal medical benefit – if it works at all. In the long run this is not sustainable in such an underdeveloped environment. It would be wiser to spread your research bets over several other approaches to treating Ebola virus disease (EVD) that are more medically and economically practical.  

The biggest problem with spending 5.7 million research dollars on plasma antibody transfer is that it creates a huge obstacle to conducting research on potentially more effective, more sustainable approaches to treating EVD. Other prospective therapies have a higher probability of being effective against Ebola. Plus they have less than one percent of the cost and complexity of acquiring, testing, refrigerating, matching and moving blood products around some of the poorest countries in the world. The millions of dollars spent on PAT research distracts attention from competing therapeutic approaches. It takes all the oxygen out of the air from discussing and testing more promising therapies. Such a massive investment – or gamble – on one questionable, antiquated experimental method of treatment monopolizes the available patient population that can be enrolled in clinical trials. PAT is so ill conceived that many thoughtful people would say it is not worth pursuing at all – maybe whole blood transfer, but not PAT. Some speculate the massive scale of this research project may even be a ruse to block competing modern, immunologically based research. The Economist magazine proposed a vastly superior approach to tackling Ebola when it editorialized ‘’different treatments need to be tested against each other in a systematic way to see which ones work and which ones will not.” Putting all your eggs in the PAT research basket blocks the way for the more rational approach to finding effective treatments for EVD that the Economist suggested. Competitive clinical trials of an array of currently approved antiviral drugs could be completed within two months at minimum cost – much less than a million dollars. All that is needed is the imagination and will to do it. This rational approach to research is being blocked on several fronts, including by PAT. 

So what should be tested?

Experimental drugs specifically designed for Ebola that have been in development in American, European and Japanese pharmaceutical laboratories for years certainly should all be tested. These include ZMapp, brincidofovir, favipiravir, TKM-Ebola and avigan. American and European governments and pharmaceutical companies have already spent over five hundred million dollars trying to develop anti-Ebola drugs, even before the current epidemic broke out. Now is the golden opportunity to test them against Ebola-Zaire. Some will not work. Others may be somewhat effective. Some of these experimental drugs may have serious negative side effects. But what side effect is worse than death in ten days from EVD?  A silver bullet drug may be in their pipeline, but do not count on it. After thirty years there is still no silver bullet drug - a ‘’cure’’ - for HIV. No matter what, any new drug will be terribly expensive. Who is going to pay? You? The American taxpayer? Someone else? Testing new experimental drugs and then producing the ones that work is a lengthy process. Meanwhile, doctors, nurses, teachers and ordinary people are dying by the score, even hundreds a week. Those people cannot wait for new, supposedly better drug development. They need something that works and is available NOW!

A rational scientific approach to research would test drugs that have been shown effective against other hemorrhagic fever epidemics in the past, as well as those that are effective against other viral diseases. In other words, currently available, antiviral drugs. Plasma antibody transfer and whole blood transfer both should be tested on a smaller scale despite their awkwardness, expense, complexity, and unsustainability, just to prove or disprove the concept. But that should be last, not first in line for research funds. A romantic concept that harks back to a past, more primitive age of medicine should not crowd out testing existing antiviral drugs that are already on the shelf. They are much more likely to stop the dying right now and be sustainable in the future. 

Existing candidate drugs that need to be tested and are known to be safe, effective, affordable, are the more than two dozen antiviral drugs that are already on the pharmacist’s shelf. Those include drugs to treat HIV, herpes, hepatitis and influenza. Broad spectrum antivirals are most likely to work, as well as medicines that demonstrate both antiviral and immune boosting properties. These include selenium and asacol – aspirin’s sister drug that does not prevent clotting. Among all medicines available, three potential candidates stand out; Truvada, selenium and aspirin/asacol/ibuprofen.

Truvada should be the prime candidate antiviral drug to test. Dr Gabriel Logan runs an Ebola treatment unit in Tubanville, Liberia. He treated fifteen confirmed Ebola patients with the HIV antiviral drug Lamivudine. That drug is also used to treat hepatitis. Thirteen of those fifteen patients survived, an 86.7% survival rate. Maybe this was just luck. However that initial success needs to be followed up with a well-organized clinical trial to confirm or deny this potentially significant therapeutic breakthrough. Amazingly no one has followed up on that flash of hope. Instead international medical forces have descended on Liberia to try to squelch research on both lamivudine and selenium. While Anthony Fauci of the US National Institutes of Health (NIH) gave Dr Logan thumbs-up publicly on television for his efforts, NIH representatives in Monrovia worked diligently to shut down the testing and use of lamivudine on Ebola patients. Why? Whose interests are they trying to protect?

Whether lamivudine works or not, Truvada is far more promising. Lamivudine is a first generation HIV drug, scarcely more potent than the first drug approved against HIV, AZT. Truvada combines not only lamivudine but two more powerful antiviral drugs into one combination tablet. Truvada is ten times as potent as lamivudine against HIV disease. It should be against Ebola too.

Selenium is not a drug – it is a nutritional supplement. But at doses higher than one milligram a day, it acts like a drug. Selenium works by multiple antiviral mechanisms. Because it is the keystone element of the immune system it is the strongest immune booster known to man. In an epidemic in China selenium supplements reduced death from Hantan hemorrhagic fever virus by 60%. In Angola it reduced death from Marburg virus – Ebola’s closest cousin – by 60% from what was anticipated. In August 2014 selenium supplement tablets were tested against Ebola at ELWA Hospital Ebola treatment unit (ETU) in Monrovia, Liberia. Even a dose of 1.2 mg of selenium, only 60% of what was recommended, increased survival rates by 54.5%. Patient survival increased from 44% to 68%. In Sierra Leone the few patients it was used on all quickly gained energy and strength within two days. Another benefit of selenium is that it helps prevent concurrent infections. It complements the antibiotic therapy Ebola patients are currently given to prevent co-infections.

 It should be considered an international medical scandal not to apply this proven effective treatment more broadly, as rapidly as possible. From both the immunological and virologic points of view, and in terms of cost and safety, the case for using selenium is strong. It is enough to say it works. Selenium supplementation has repeatedly been proven to be highly effective in reducing mortality in hemorrhagic fever epidemics. Compared to plasma antibody transfer, selenium therapy is superior from almost every point of view.

Plasma antibody transfer may really be a misnomer. Antibodies have a limited lifespan. When they are no longer needed they are gradually cleared from the blood since B-cells stop producing antibodies once the germ they have been primed to fight has been eliminated. What should really be transferred is memory B-cells primed to produce antibodies, or memory CD4 lymphocytes and macrophages. None of these would be transferred in PAT. The blood of Ebola survivors possess large amounts of antibodies to Ebola for a limited time once the virus has been cleared from the body and the person survives. Supplementing selenium tablets is probably a better way to increase antibody production naturally in an Ebola patient. Selenium helps protect, preserve and mobilize the patient’s immune system so their own B-cells produce more antibodies. Selenium tablets may not only be more effective in increasing antibodies and the overall immune response in patients, they also would be a hundred times cheaper and less complex than PAT.

Just as HIV causes the slow collapse of the immune system by depleting selenium, Ebola causes the rapid collapse of immune function, including B-cell function, by the same method. That means the Ebola patient’s B-cells won’t produce the number of antibodies needed to fight the disease. By helping maintain and restore immune competence, supplementation with selenium tablets may well lead to a bigger increase in Ebola antibodies than plasma antibody transfer.  

Aspirin/asacol, ibuprofen, and other non-steroidal anti-inflammatory drugs (NSAIDs) should also work against EVD.  How strongly, no one can say yet. Aspirin, asacol and ibuprofen all reduce fever, pain, and inflammation. They inhibit viral replication because they reduce the primary stimulant to the production of viral proteins in the nucleus, a human protein called NF-kappaB. In HIV disease asacol reduced viral replication approximately 80% as much as the first antiviral drug approved for HIV - AZT. Like selenium, NSAIDs are strong antioxidants. They help protect against the hyper-oxidative stress that blows holes in blood vessels that contributes to the only occasional hemorrhaging effect observed in Ebola virus disease. Since hemorrhaging is only observed in about 1% of Ebola patients and is a very late-stage symptom, even aspirin would be safe in 99% of patients. Aspirin may actually be extremely beneficial in EVD. For years the scientific literature has known that one of the main problems in EVD is disseminated intravascular coagulation, or DIC. Caused by the loss of selenium due to the virus, DIC causes massive blood clotting within blood vessels. Ibuprofen works the same way as aspirin only stronger. They both reduce the blood clotting and damage to blood vessels. Ibuprofen may be the best NSAID to use against EVD.  

Only a small percentage of patients ever suffer the hemorrhaging from which the disease gets its name. This rare symptom typically occurs very late in the disease when no therapy can possibly save lives. However all patients suffer the blood clotting blockages that occur from the outset of the illness due to the rapid loss of selenium. So “hemorrhagic” fever is really a misnomer. To be more scientifically accurate, EVD should be called Ebola “blood clotting” fever. The misunderstanding comes from the fact that whereas the rare instance of hemorrhaging is distinctive and visibly shocking, the systemic blood clotting is much less apparent to a doctor treating a patient in the forest village where Ebola typically has erupted in the past. Thus the “hemorrhagic” designation doctors have given this disease confounds their ability to understand its true nature. To this day it continues to confuse their efforts to treat it.   

So Bill Gates, if you really care about finding effective treatments for Ebola and helping save the world – spread your bets. Follow the sage advice of the Economist magazine. Plasma antibodies are a complex, expensive long shot. Better bet on the odds-on favorites; Truvada, selenium and NSAID drugs like aspirin and ibuprofen to quickly assemble a combination therapy that should be able to save 90% of those infected with this disease. With adequate funding and support, this strategy of conducting comparative clinical trials could be completed within two months. There would be no need to build tens of millions of dollars of blood banking infrastructure required for PAT – a losing medical technology is ever there was one. A highly effective combination of currently approved, safe antiviral drugs can be quickly developed if we intelligently apply the methodology of comparative clinical trials called for by the Economist. What is stopping us?

P.S. If anyone reading this letter knows Bill Gates, please pass this on to him.