Learning from Ebola

Make no mistake: The Ebola crisis is not over.

The number of new cases continues to fall, but the disease that raged through three West African countries for the past year continues to smolder. So, too, does the burning need for health systems in these developing countries.

“Although the rate of progression of disease is thankfully reduced, it’s not over,” said HMS Dean Jeffrey S. Flier in his opening remarks.

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“When the last case comes, we don’t just forget about West Africa,” said Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases (NIAID). “We have a moral responsibility to do better.”

Fauci was speaking via video link to international experts in global health, virology, infectious disease, vaccines and therapeutics who were gathered at a Harvard Medical School symposium on March 5. They discussed the scientific questions that remain unanswered despite decades of research and considered ways around roadblocks to developing therapies to treat or prevent Ebola virus disease.

Caring for people who have Ebola today means providing supportive measures—offering intense rehydration to replace massive fluid loss, balancing electrolyte levels to prevent shock, avoiding organ failure and maintaining nutrition.

Implementing all four measures is arduous in the face of a virus that infects multiple cells in the body and rapidly depletes the body’s reserves. But it can be done, said Marshall Lyon, associate professor of medicine at Emory University School of Medicine, who led a team that cared for four patients airlifted to his hospital in Atlanta.

“There is nothing magic about taking care of them,” he said. “It doesn’t mean experimental therapies.”

It did mean preparation, training and teamwork, he said.

Paul Farmer, co-founder of Partners In Health, said he had never seen that sort of supportive care in Liberia, where the health system never recovered from a war 10 years ago. He is also the Kolokotrones University Professor of Global Health and Social Medicine and Head of the Department of Global Health and Social Medicine at HMS.

“The majority of people who die of Ebola don’t die of Ebola,” he said. “They die because they don’t have a health care system.”

Current public health efforts in West Africa are also hampered by incorrect information, said Jens Kuhn, lead virologist at NIAID. A campaign to discourage eating bush meat, for example, is misguided, but so is much of the published research on Ebola virus.

Because the number of researchers who study Ebola and other filoviruses is so small, he said, extrapolation and misinterpretation of single-center studies can lead to unwarranted conclusions.

“On pathogenesis, we actually have no clue,” he said. “I’m a molecular biologist and I would strongly encourage more basic science.”

John Mekalanos, an organizer of the forum and the Adele Lehman Professor of Microbiology and Molecular Genetics at HMS, said the issues are much broader than Ebola and extend to other emerging infections.

“We don’t know where the evolutionary race between microbes and our immune system will lead us,” he said.

Scientists have been trying to build a vaccine that would block the Ebola virus for many years, but they have been stymied by the complex pathway that the string-like virus uses to enter cells.

“There’s very little about the Ebola virus that is straightforward, starting with its morphology,” said Gary Nabel, chief scientific officer at Sanofi. That includes the path of getting vaccines out from labs to manufacturers and then to patients.

Erica Ollmann Saphire, professor of immunology and microbial science at the Scripps Research Institute, said a cocktail that combines three antibodies has shown promise, citing research that led to ZMapp, an experimental therapy that has been given to patients during the current outbreak. Two antibodies neutralize the virus and the third functions as an immune effector.

Nancy Sullivan, chief of the Biodefense Research Section in the Vaccine Research Center at NIAID, has been following the winding road of Ebola research for 10 years. She said that antibodies aren’t enough and that T cells in the immune system must be recruited to mount a response.

Decades of research have pushed some therapies into development and testing, but the current crisis has brought new urgency to accelerating the process.

Scientists in academia and in industry are screening existing drugs, such as an antiviral approved for flu treatment, to see if they might work against Ebola and be quickly deployed.

Testing vaccines in nonhuman primates has also been encouraging, shining a spotlight on a regulatory category called the “animal rule,” which, along with “accelerated approval,” is intended to balance safety with the need for an available treatment.

Vaccine trials in patients may be difficult in West Africa, and not only because cases are declining. Governments there have said they will not allow placebo-controlled trials that would give one group of people an inactive injection to compare their response to that of people who received the active vaccine.

The animal rule can be applied only when testing in humans is impossible. The accelerated approval rule allows regulators to make a decision based on a surrogate endpoint in people that indicates a reasonable likelihood of benefit and safety. Both approvals require follow-up studies after the treatment is administered.

Philip Krause, associate director for regulatory policy at the US Food and Drug Administration, said his agency recognizes its responsibility to move rapidly in an emergency, but he also underlined its commitment to safety.

“People see hurdles when the science is weak,” he said. “Hurdles rise when we want them to rise,” he said.

Richard Whitley, distinguished professor of pediatrics, professor of microbiology, medicine and neurosurgery at the University of Alabama, warned about emerging infections of the future while also noting progress in research seeking common compounds that would work against Ebola as well as MERS (Middle East respiratory syndrome), SARS (severe acute respiratory syndrome) and RSV (respiratory syncytial virus).

Barney Graham, deputy director of NIAID’s Vaccine Research Center, worries about chikungunya, a microbe that has been marching north from the Caribbean Basin. A change in one amino acid meant it could be spread by a different type of mosquito, thus allowing it to expand to new territories. While not as deadly as Ebola, it is still debilitating.

“As Ebola dies down, you’re going to hear more about it,” he said. “Will it take until it reaches Washington, D.C., to have a significant response?”

Farmer is wary of a shift in focus he called “Ebola triumphalism,” in which victory is declared before the job of improving health is done.

Dylan George, senior policy advisor, biological threat defense, in the White House Office of Science and Technology Policy, said the human tragedy will not be over when new cases disappear.

“Our objective is to get to zero and build capacity to avoid this going forward,” he said.

The event, held in the Joseph B. Martin Conference Center Amphitheater in the New Research Building at HMS, was made possible by grants from PhRMA (the Pharmaceutical Research and Manufacturers of America) and the HMS Max Finland Lecture Fund.