New Hope for Ebola?

Researchers often talk about a race between the Ebola virus and the people it infects. A patient wins the race only if the immune system manages to defeat the virus before it destroys most of his or her organs. A community wins the race if it can isolate the first few patients before the disease spreads. Humanity will win the race if it develops treatments and, ultimately, a vaccine before the virus gains a permanent toehold in the cities of the globe.

For years Ebola held a natural advantage. Outbreaks were too small (typically fewer than 100 people) and too short-lived (less than five months) to give researchers the chance to test potential therapies. By the time they could have put a clinical trial in place, the threat would have passed. Pharmaceutical companies and research groups found it difficult to justify spending money on a disease that, as horrible as it was, had taken 40 years to dispatch its first 1,600 victims. Other diseases seemed far more worrisome: malaria, tuberculosis and HIV killed more than three million people in 2013.

That steely calculus changed with the current, extraordinary Ebola outbreak in West Africa—the largest and longest on record. By mid-January at least 21,000 people had acquired Ebola in Sierra Leone, Liberia and Guinea, and more than 8,500 deaths could be attributed to the disease. International health leaders, realizing that further inaction might allow the virus to spread well beyond the outbreak zone, called for a massive international response to identify and isolate those who might be coming down with Ebola, build and staff dozens of emergency treatment centers to care for the sick, and recruit enough burial teams to safely dispose of the dead.

For the first time ever, scientists had an Ebola outbreak large enough and long enough to allow intensive clinical trials aimed at finding better treatments, one that might be impossible to stop without developing vaccines and new drugs. They also won, for the first time, widespread agreement to test some of these experimental therapies in the field. The unprecedented effort may prove more useful in tackling the next Ebola outbreak than in curtailing the ongoing epidemic. But if researchers are successful this time around, they may ensure that Ebola never has the upper hand for long when it attacks humans again (and it will).

Cunning killer

As startling as it might seem, given the tsunami of cases over the past 15 months, much remains unknown about the Ebola virus—where it lives, how it comes to occasionally attack humans and why more people do not become infected when it starts spreading. (On average, each individual in this outbreak has transmitted the virus to one or two others, unlike highly contagious illnesses such as measles, where each case typically infects 18 others.)

Although Ebola is not the most contagious of viruses, it is an exquisitely effective killer of humans and primates. As of the end of 2014, an estimated 70 percent of the people infected in West Africa had succumbed to the illness, usually within a matter of days—and often beyond the view of health authorities.

How quickly and completely Ebola overwhelms an individual depends on at least two factors: the amount of virus involved and how it first enters the body. After the first few viruses have jumped the species barrier—presumably from fruit bats—to people, it does not take much to keep the chain of transmission going. Many Ebola victims apparently become infected after preparing an infected relative's corpse for burial. Wiping the vomit from a patient's chin or cleaning up after an infected child's bout of diarrhea can also transmit the virus, which gains entry into people's bodies after caregivers touch their own eyes, lips, nose or mouth with their now contaminated hands. And if many viruses are injected directly into the bloodstream, as with an accidental needle stick injury, “I don't think anything's going to save you,” says Thomas Geisbert, a microbiologist at the University of Texas Medical Branch at Galveston. “You're just overwhelmed.”

Autopsies and pathology reports offer some of the best ways to learn about how viruses spread inside the body, but few have been conducted on Ebola victims because of the high risk of accidental infection to the people performing the necessarily invasive procedures. A recent scientific review identified only 29 human cases where an autopsy or postmortem biopsy had been performed in the disease's nearly 40-year history.

Nevertheless, animal and pathology studies conducted so far show that Ebola viruses make a devastating first strike on the immune system. Like other viruses, Ebola must harness the machinery of cells it infects to make more copies of itself. Among the initial targets are the so-called dendritic cells, which typically act as all-purpose sentries patrolling the tissues of the body, and macrophages, which consume damaged cells. Rather than trying to avoid these first responders, however, Ebola viruses actually seek them out and begin reproducing inside of them. This bold attack accomplishes two things: the viruses disrupt the cells' normal ability to jump-start the rest of the immune system, and they hitch a ride inside the cells, traveling unmolested to the lymph nodes, liver, spleen and other areas of the body.

As if such guerilla tactics were not enough, Ebola employs another trick to hide its presence: it puts up a decoy to distract the immune system. The virus forces the cells it infects to manufacture and release into the bloodstream large amounts of a substance called secreted glycoprotein, or sGP, which looks a lot like a crucial molecule (known as GP) that sticks out of the viruses' outer covering. Ordinarily the immune system would target the GP—and thereby kill the virus to which it is attached. By fooling the immune system into also attacking the sGP (which, of course, is not attached to the virus), Ebola further undermines the body's ability to mount an effective defense.

New treatments

The recent Ebola outbreak has taught doctors and health workers some practical ways of overcoming the virus. It has long been known that despite the early setbacks, the immune system can rally to defeat the virus if it is given enough time. Health care workers have confirmed in the current epidemic that they can buy their patients some of that time if they start giving them intravenous fluids soon after the first symptoms appear. The World Health Organization has okayed treating at least some patients with blood from survivors, which, by definition, must include plenty of antibodies, although no one knows whether the treatment works.

The risky decision to support an untested therapy showed how desperate the situation had grown in West Africa. The approach at least makes theoretical sense, however. Convalescent serum was successfully used in response to polio from the 1920s to the 1950s and to flu during the 1918 pandemic. The Bill & Melinda Gates Foundation has begun funding clinical trials of anti-Ebola serums in hard-hit Guinea.

Of course, thanks to the biotech revolution, scientists can now manufacture the necessary antibodies artificially and have done so in a preparation called ZMapp, which is made up of three so-called monoclonal antibodies that target the Ebola virus. ZMapp gained nearly mythical status last summer when Kent Brantly, an American missionary doctor who was infected with Ebola in Liberia, became the first person to receive the treatment. Media reports suggest that Brantly, gravely ill when his first transfusion started, improved rapidly, getting up to shower the next day. There were fewer than a dozen courses of treatment in existence when Brantly was treated (three transfusions equal one course); within a couple of weeks even this small supply was exhausted.

ZMapp was in the early stages of development—undergoing tests in animals—and commercial-scale production had not yet begun when the outbreak began. Manufacturing has since been geared up in the hopes that clinical trials in West Africa can start in the first quarter of 2015. But even if the drug proves to be effective, there is no hope that there will be enough ZMapp for all who might need it in the foreseeable future.

Physicians would not have had even this much material to work with had governments not started spending money trying to develop antidotes in case Ebola was ever turned into a bioweapon. Scientists at Canada's National Microbiology Laboratory and the U.S. National Institute of Allergy and Infectious Diseases (NIAID) researched and developed the antibodies in the cocktail and then licensed their production to Mapp Biopharmaceutical, which in turn depends on Kentucky BioProcessing to grow the antibodies in genetically modified tobacco plants. Kentucky BioProcessing can produce enough antibodies for between 17 and 25 treatment courses per batch; it takes 12 weeks to grow the plants and a couple more to process the material.

Efforts are afoot to try to substantially ramp up ZMapp output. The U.S. government—under its public health emergency authority—is considering bringing another producer onboard in a move that could potentially increase ZMapp output fourfold or fivefold. In addition, researchers are conducting studies in nonhuman primates to determine whether the number or volume of the infusions in a treatment course could be reduced, allowing supplies to be stretched.

Vaccine needed

So much time was lost early on in recognizing the true extent of Ebola's spread through West Africa that the epidemic has now fractured into dozens of different micro outbreaks, with varying epidemiological characteristics. Health care workers, military personnel and local communities are making heroic efforts to save lives and contain the disease. But experts worry that the longer the epidemic continues, the greater the risk that the world could face ongoing transmission of Ebola in pockets of West Africa. In addition, the paralyzing effect the virus has had on the health care systems of the affected countries could open the door to other public health crises, such as outbreaks of measles or even the resurgence of polio.

One of the best ways to forestall this grim future is to develop, test and distribute a successful vaccine—something that was impossible during previous smaller, shorter outbreaks. As case numbers in Guinea, Liberia and Sierra Leone exploded in late summer, the agencies guiding the international response determined that an effective vaccine might be the only way to halt the epidemic.

Safety studies of the two leading experimental vaccines—dubbed cAd3-EBO and rVSV-ZEBOV—were conducted on several hundred volunteers in the U.S., Canada, Europe and various unaffected African countries toward the end of 2014. Larger studies with thousands more people were to begin earlier this year in Liberia and Sierra Leone; trials in Guinea will follow.

The pace is unprecedented: a job that normally takes five to 10 years—the testing and scaled-up production of vaccine—is happening in less than a year. And yet, as the overall rate of new infections started to drop in Liberia toward the end of 2014, another wrinkle cropped up: Would there be enough sick people to determine if the vaccines were working?

No one involved in the Ebola response wants to see more cases. But the reality of vaccine research is that you can only find out if these experimental preparations work in settings where the targeted pathogen is spreading. If infection rates drop too low, the clinical study slated to enroll 27,000 people in Liberia will have to be expanded—adding to the cost, complexity and time it will take to get to the answers.

Organizers are still hoping to avoid that, says Charles Link, Jr., CEO of NewLink Genetics, an Iowa-based biotech company that is developing rVSV-ZEBOV in partnership with pharmaceutical giant Merck. The plan is to focus on the parts of Liberia where the infection rate is greater than average. Nothing is easy about the Ebola vaccines project, Link says: “The complexities are off the chart.”

The NewLink vaccine was designed by scientists at the Public Health Agency of Canada. It is composed of a modified live virus (vesicular stomatitis virus, or VSV) that is coupled with a portion of the primary protein found on the Ebola virus's surface. VSV sickens some livestock but is harmless to people; the virus generates a low-grade infection that provokes the immune system to pump out antibodies against the Ebola protein. But the vaccine cannot trigger the disease itself.

The other vaccine, cAd3-EBO, was originally developed by scientists at NIAID. GlaxoSmithKline acquired the rights to it when it bought Swiss vaccine developer Okairos in 2013. It is an inactivated (killed) vaccine that uses a genetically modified chimp adenovirus to present the key surface protein from the Ebola virus to the immune system.

Both experimental vaccines have pros and cons. The GlaxoSmithKline vaccine started off with more advanced testing than the NewLink vaccine. But the VSV vaccine is easier to make, and many more doses were available by late last December. Just how many depends on what preliminary studies show is needed to generate good levels of antibodies.

There are concerns that the GlaxoSmithKline vaccine might not be able to protect with a single dose. A two-dose delivery regimen—especially one that uses different vaccines for priming and boosting—would be phenomenally difficult, given the state of the health care infrastructure in the affected countries. It is expected that the NewLink vaccine will require only one shot, but it may induce mild (though nonetheless confusing) side effects such as low-grade fever, chills, muscle aches or headaches—in other words, precisely the same cluster of symptoms that foretell Ebola's arrival. In a world that uses those symptoms to detect Ebola infections, this will make sorting the sick from the well in the outbreak zone more challenging.

The Liberian trial is designed to contain three arms. Some recipients are receiving the GlaxoSmithKline vaccine, some are receiving the NewLink vaccine, and some are getting a placebo, perhaps a flu shot or a hepatitis B vaccine. A number of prominent scientists have argued in the pages of the Lancet and elsewhere that placebo-controlled trials in this situation are unethical. But the U.S. Food and Drug Administration, which would need to approve any preparation used by U.S. military or health organizations, has pushed for placebo-controlled trials. “We need to learn what helps and what hurts at the soonest possible time and in the most definitive way,” says Luciana Borio, who is leading the FDA'S Ebola response. “It's going to be important for generations to come, and we have to get this right.”

Jeremy Farrar, director of British charity foundation Wellcome Trust, which is funding a number of drug and vaccine trials, had been hoping for more innovative approaches—trials employing what is known as step-wedge and cluster-randomized designs—that allow everyone to get the active vaccine eventually. Still, he can live with a placebo-controlled trial. “I'm not absolutely comfortable with it,” he says. “But with a vaccine, which you are giving to healthy people when you don't know its safety profile and you don't know its efficacy, I actually can accept either a cluster-randomized or step-wedge design or a placebo-controlled design.”

Meanwhile a step-wedge trial will take place in Sierra Leone. That trial design uses the fact that it is impossible to vaccinate everyone at once to create a control group; you compare the rate of new infections in areas that have already received the vaccine with those in places where rollout has not yet taken place. The benefit: everyone gets vaccine; the disadvantage: it may take longer to determine if a vaccine works.

Guinea, too, will see some type of trial, although it is likely to be less ambitious. The infrastructure of the country is in worse shape than those of its neighbors, making operating clinical trials an even more difficult task. Marie-Paule Kieny, who is the WHO's point person in the international effort to develop Ebola vaccines and drugs, says the Guinean trial will vaccinate health care workers in an observational study that does not include a placebo arm. In addition, the Gates Foundation may fund a trial to see whether ring vaccination—vaccinating around a known case to try to prevent onward transmission—would be effective. (Ring vaccination is what finally vanquished smallpox in the 20th century.)

A series of other experimental vaccines are at different stages of development. Some of them are thought to be at least as promising as the GlaxoSmithKline and NewLink products. One made by Johnson & Johnson started safety trials in early January. But those that are trailing behind the GlaxoSmithKline and NewLink vaccines face a tough economic reality. In the race to defeat the deadly virus, fourth or fifth place is not likely to count. The future market for Ebola vaccines will be limited. Either the WHO or GAVI (the Vaccine Alliance) will most likely stockpile the product for use in future outbreaks. And some affluent countries will surely buy supplies as a shield against bioterrorism. But the market is unlikely to be much bigger. So unless one of the front-runners falters, those at the back of the pack may fall away. “The ones that come after the two first, they have a place only if the first two fail,” Kieny says.

Of course, the possibility that the entire vaccine effort might fail is never far from the minds of Ebola researchers and health care workers. Although the epidemic is no longer growing exponentially—as it was last September—the outbreak is still not under control. The number of new cases has fallen in large parts of Liberia, but disease transmission remains intense in the western and northern districts of Sierra Leone. Until the number of new cases drops to zero, however, the possibility of renewed resurgence and spread remains all too real.

Thousands of people died in 2014. Even with the continued efforts of many health care workers, burial teams and other volunteers, hundreds and possibly thousands more will, unfortunately, die in 2015. But the world will have a much better sense in the coming months of just how much farther and faster we need to run to finally outpace this dastardly virus.