What can we relearn from the Ebola epidemic?

On July 6, 1885, a mother and child appeared at Louis Pasteur’s laboratory. Everyone in France knew that he was working on a rabies vaccine, having previously been successful with anthrax and chicken cholera vaccines. Joseph Meister, then 11, had been badly bitten by a rabid dog. Two physicians, (Pasteur was not a medical doctor) agreed that death by rabies was almost inevitable. Their dilemma was that Pasteur’s treatment had protected rabbits and dogs from rabies, but had never been tried on a human being. Sound familiar? These are the same decisions that physicians and patients have had to take during the Ebola outbreak. The rabies vaccine and the ZMapp treatment available to the physicians in Africa and Atlanta were not thoroughly tested. Both were rushed into human experiments. Ebola and rabies are both terrifying infections, with near certain outcomes. Rabies virus is a distant relative of Ebola virus. Each virus causes havoc with fewer than 10 genes, some dedicated to making the virus and promoting its entry into human cells and others to silencing the host’s defenses — as all effective invaders do. Neither virus is passed as an aerosol. A commentator on the podcast “This Week in Virology” remarked that if Ebola virus was passed as an aerosol by coughing, like influenza, the death toll in Africa would be enormous. Some excited newscasters would have us believe that the ZMapp preparation used in Africa and then in Atlanta is a magic serum. It isn’t magic or a serum. Serum is the antibody-rich amber liquid left over after blood has clotted. Antibodies in serum harvested from horses were first used to treat diphtheria and tetanus in 1894. Nobody knew about antibodies then, but there was something in the serum of horses immunized with diphtheria or tetanus toxins that neutralized the toxins and gave victims a chance to survive. It was the first effective treatment of an infectious disease in progress, after rabies. More recently, sera collected from hundreds of people (gamma globulin) were used to treat people exposed to polio or hepatitis, but blood products can carry dangerous viruses like HIV and so this treatment has been supplanted. • • •The ZMapp antibodies that neutralize the Ebola virus come from a new technology. These so-called monoclonal antibodies, first produced in 1975, derive from a single immune system cell that produces only one type of antibody — in this case one that binds to Ebola virus. The cell divides exponentially, nourished in a flask, until vast numbers of cells are producing Ebola virus antibody. The technology has advanced dramatically since 1975 and monoclonal antibodies are now used for suppressing rheumatoid arthritis and other inflammatory conditions. One of the best known is Humira, which is an acronym for “human monoclonal antibody in rheumatoid arthritis.” It binds only a specific protein (tumor necrosis factor) that is involved in the inflammation that is the basis of the condition. Its technical name is “adalimumab,” the last three letters indicating that the drug is a monoclonal antibody. There are now FDA-approved monoclonal antibody treatments for many conditions. ZMapp is a combination of three monoclonal antibodies that stick to the outside of the Ebola virus and disable it. These antibodies do not harm healthy volunteers and they protect macaques infected with Ebola virus. Very similar antibodies have been used for years and there is little reason to think they are dangerous. Only a few patients have received ZMapp so far, but we all hope that more can be made and that these antibodies stop the disease. The problem is, they are expensive and difficult to administer in suboptimal medical facilities. They could be used to protect health care professionals working in West Africa, which has seen the deaths of many physicians and nurses, but they are not the full answer to the Ebola epidemic. What medicine needs for this and many other diseases is an effective vaccine and massive education and public health measures in Africa (and here in the United States!) so that the virus never has a chance. There are vaccines under development, which I will explain in a future column. For the information in this column, I am indebted to my colleague Prof. Vincent Racaniello, for his superb podcast on Ebola viruses; it is available at www.twiv.tv. But what of Joseph Meister? After Madame Meister’s pleading, Pasteur and the physicians agreed to go ahead, although Emile Roux, Pasteur’s closest medical colleague, refused to take part. Thirteen increasingly potent injections appeared to work. Joseph Meister lived a further 55 years and became the concierge at the Pasteur Institute.There is a world of difference between treating an evacuated Ebola-stricken patient in Atlanta and defeating a spreading epidemic in West Africa.The Ebola epidemic in Africa is abetted by poverty, a medical staff that has been cruelly affected by the disease and resistance to public health measures. At Emory University Hospital, a small tribe of infectious disease experts can be summoned when a patient arrives: dedicated physicians, nurses, and scientists will scour the scientific literature; the amount virus in the patient’s blood will be monitored; the patient will be hydrated and blood pressure maintained; experts in blood clotting will prevent hemorrhage and shock. Kidney function or liver damage will be assessed in labs that function around the clock. The now-famous ZMapp antibodies will be administered and, after a desperate play for time, the patient’s immune system will produce antibodies, the infection will be cleared and the patient who was evacuated from Liberia will leave the hospital to justified celebration. Yet, in a way, we have already lost the first engagement of this battle. Churchill said about Dunkirk that “wars are not won by evacuations,” and that is my sense here.• • •Ebola Zaire, the agent in the current epidemic, is a small virus with only seven proteins compared to the 20,000 or more in a human cell. Simple it may be, but the Ebola virus is deadly because some of its genes make proteins that guide the virus to the early warning radar stations of the human immune system. When these surveillance cells detect viruses, they secrete a protein called interferon, which activates other genes in many surrounding immune system cells; like a fire alarm, it orchestrates a response that would normally protect the victim. The Ebola virus short-circuits the protective response, giving itself an open field to infect and damage the endothelial cells that line blood vessels. That damage leads to the bleeding, dehydration and shock that kills patients.Supportive care shifts the odds in the patient’s favor and so do the antibodies in ZMapp, which soak up circulating virus and relieve the suppression of the immune system. The effectiveness of ZMapp in humans is only inferred because there are too few cases to be sure it works; but when macaque monkeys have been the subjects of ZMapp trials, which are often based in the USA and are international efforts with multiple authors, ZMapp saves the day. (Let’s be clear: There is always a control in these experiments — the infected but untreated macaques die.) Ebola Zaire is called a Category A Priority Pathogen, with bioterrorism potential. Live virus can only be studied in Biosafety Level 4 facilities, of which there are about 10 in the United States, although some BSL-3 labs were designed to surge to BSL-4 in an emergency. There is only one BSL-4 lab in West Africa — in Gabon, run as a French-Gabonese consortium.It would be more practical to give millions of people a vaccine, rather than the sophisticated antibodies in ZMapp, so that their immune systems would produce Ebola specific antibodies before Ebola virus infects them. Vaccines for polio, pneumonia, and other infections have already been successful in much of Africa. I have looked at ClinicalTrials.gov and the literature on PubMed.gov, both National Library of Medicine websites. Vaccines of various kinds have been tested for several years, but recently the technique has settled around an Ebola virus gene that produces the protein coating (a glycoprotein) that resides on the surface of the virus. To produce a vaccine, that gene is then transferred into another virus genome that has been disabled and is harmless. One such disabled adenovirus, called cAd3, has been used to infect macaques, whose immune systems then make antibody to the Ebola virus glycoprotein. When challenged with live Ebola virus, the vaccinated monkeys all survived. • • •Vaccine trials are about to begin on 20 volunteers at the NIH in Bethesda. In a month or two we will know if those volunteers produced antibodies against Ebola and whether there were any side effects. We will not know whether such antibodies will protect humans because no one is going to inject humans with live Ebola virus to find out. GlaxoSmithKline will produce thousands of doses during the trial, to be ready if the vaccine induces virus-neutralizing antibody. This must be produced in a shippable form and work with only one dose because boosters are not practical in Africa. After that, it will all come down to clinical trials in places where it is hard to do them for practical, ethical and other reasons, including the consent of the people to be vaccinated. There are other efforts underway — resources from WHO, CDC, Médecins Sans Frontières and other agencies are arriving in West Africa. Seven drugs that inhibit the virus are under development, according to This Week in Virology, a podcast hosted by Prof. Vincent Racaniello of Columbia University. In the meantime, for reasons we still don’t understand, the epidemic expands in a way that previous Ebola epidemics never did. Richard Kessin, Ph.D., is professor of pathology and cell biology at Columbia University and lives in Norfolk, Conn. His blog is at kessinscience.blogspot.com. Some scientific papers on Ebola are hard to find without access to a university library. Write to the author at rhk2@columbia.edu for assistance. The author’s recent novel, “The Famine of Men,” describes how a very different and, so far, hypothetical virus was discovered.