Since 2013, medical experts in West Africa have been playing whack-a-mole with what looks like the same strain of Ebola virus, and we don't really know why it continues to pop back up.
Even though we keep hammering away at the virus with effective antibody treatments and vaccines, this incredibly fatal infection keeps re-emerging amongst a small subset of recovered patients, triggering new outbreaks wherever it does.
Several years after Guinea announced its first Ebola epidemic, for instance, a patient treated in the initial wave suddenly relapsed and began spreading the virus again.
Similarly, an Ebola patient in the Democratic Republic of Congo experienced a fatal relapse six months after they had already been treated with monoclonal antibodies. The patient was also vaccinated.
Even when our immune systems are on high alert, the virus seems to be getting away – but how?
Research on rhesus macaques has now found a potential hiding spot in the primate brain.
Past evidence suggests Ebola can avoid the human immune system in places like the testicles, the eye, the brain and the spinal cord, but this is the first study to show where the virus actually goes during antibody treatment and how it can re-emerge.
After analysing the brains of 36 macaques treated for Ebola who had survived for at least four weeks, scientists found a persistent viral reservoir in the fluid-filled cavities of the forebrain and brainstem in 7 of them.
"We found that about 20 percent of monkeys that survived lethal Ebola virus exposure after treatment with monoclonal antibody therapeutics still had persistent Ebola virus infection – specifically in the brain ventricular system, in which cerebrospinal fluid is produced, circulated, and contained – even when Ebola virus was cleared from all other organs," says Xiankun (Kevin) Zeng from the US Army Medical Research Institute of Infectious Diseases.
Two of the monkeys that had been successfully treated with monoclonal antibodies later died from a reinfection of the disease. Apart from their brains, no other part of their body showed signs of a reinfection.
The two fatal relapses were accompanied by a fever and severe inflammation in the brain's ventricles, as well as a medical condition resembling meningitis.
Macaques are obviously not humans, but their physiological response to Ebola is similar enough to our own that research can sometimes translate. Past studies have detected the Ebola virus in the cerebrospinal fluid of a few human survivors.
What's more, a British nurse who caught and recovered from Ebola while working in West Africa experienced a relapse in her brain in 2015, which caused meningitis-like symptoms similar to the two macaques detailed above. She has since made a full recovery.
The authors of the current study thus conclude that monoclonal antibody treatments may indeed not clear the entire brain of the Ebola virus. The ventricular system could be hiding a silent reservoir, which is harder for the immune system to reach.
Even though the authors found evidence of the Ebola virus in the primates' brain ventricles, they barely detected any signs of immunosuppressive cells. If given enough time, the immune system usually gets its fingers into the crevices of the brain as well, but this seems to be the last stage of the battle.
Among a dozen of the rhesus macaques that survived with antibody treatment, none showed evidence of the infection in their brains 120 days later. But for those immune systems that didn't quite get to the brain's ventricles, the chance of reinfection was much higher.
"Fortunately, with these approved vaccines and monoclonal antibody therapeutics, we are in a much better position to contain outbreaks," says Zeng.
"However, our study reinforces the need for long-term follow-up of Ebola virus disease survivors –even including survivors treated by therapeutic antibodies – in order to prevent [recurrence of the disease]. This will serve to reduce the risk of disease re-emergence, while also helping to prevent further stigmatization of patients."
The study was published in Science Translational Medicine.