Putting Ebola under the microscope

Whether in the field in Liberia during a raging Ebola outbreak or back in the lab in Montana, virologist Andrea Marzi thinks the reward is worth the risk when it comes to finding viable vaccines.

This article was originally published by Alexandra Hoegberg in Uppsala Reports #72.

Ebola-Makona Strain
An Ebola virus virion seen in a colorised transmission electron micrograph.

In fifth grade in elementary school, Dr Andrea Marzi got hooked on biology. In tenth grade, she learned about viruses. “I was always fascinated by that they’re not considered to live because they can’t replicate themselves – they always need a host – but they can kill you in a matter of days. So although they don’t live, they can kill you pretty efficiently,” she said.

That fascination would take her through a MSc degree in biology and a PhD in virology in her native Bavaria, southern Germany. When she encountered the opportunity to do a postdoc, she decided to pursue a fellowship abroad rather than staying within the realm of academic institutes, and ended up at the Public Health Agency of Canada (PHAC) in Winnipeg.

Dr Andrea Marzi, virologist at NIH/NIAID’s Rocky Mountain Laboratories. Photo: UMC

“For me, it became obvious that I wanted to work with the real virus, and not just with a part of it,” she explained. That was something she could do at the agency’s Special Pathogens Program in the National Microbiology Lab.

When her supervisor there – Dr Heinz Feldmann, MD, an expert on high containment viruses and a consultant for WHO – was offered a position as chief of the Laboratory of Virology at the National Institutes of Health’s (NIH) Rocky Mountain Laboratories in Montana, USA, Dr Marzi moved there too to finish her postdoc and later take a position as staff scientist.

With the move came also Dr Feldmann’s lab and some of his research projects – including the VSV-vaccine platform that had been developed at PHAC; a few years later it would turn out to be sorely needed in the battle against the most severe Ebola outbreak to ever hit the African continent.

A new strain of the Ebola virus was identified in March 2014 as the cause of a viral outbreak that had started in rural Guinea at the end of the previous year. The strain, known as EBOV-Makona, caused what WHO has called “the largest and most complex Ebola outbreak since the Ebola virus was first discovered in 1976”.

By early 2016, the outbreak was considered to be largely under control, and in March it was confirmed that the three worst-hit countries – Guinea, Liberia and Sierra Leone – had managed to interrupt their original chains of Ebola virus transmission. WHO declared that the disease was no longer considered a Public Health Emergency of International Concern on 29 March, even though new clusters of infection have flared up in the three countries during the first quarter of the year.

The fatality rate of EBOV-Makona is around 50% and lower than the approximately 90% rate of the 1976 outbreak, but the spread of the West African strain far exceeds previous occurrences of the virus. In the roughly two years since the disease broke out and up until 27 March 2016, WHO counted 28,646 confirmed, probable and suspected reported cases, and a death toll of 11,323. (All but 36 cases and 15 deaths occurred in Guinea, Sierra Leone or Liberia.)

By contrast, the death toll of all previous outbreaks combined – starting in 1976 and spanning 36 years – is estimated at about 1,590 people.

“In the beginning, people didn’t believe that it was actually Ebola virus, because it had never been found in West Africa; it was only known as a Central African disease,” Dr Marzi said when explaining how the lower fatality strain could have caused so much more damage than previous outbreaks.

Andrea Marzi analyzes PCR test results
Dr Marzi analyses Ebola test results from a hospital compound in Monrovia, Liberia. Photo: NIAID

“And West Africa is more densely populated than the areas where we generally see Ebola virus outbreaks in Central Africa. The people also trade a lot and travel a lot, so they cross the borders between Guinea, Liberia and Sierra Leone all the time… Plus the virus made its way into the capitals, and those are million-people strong cities.”

Battling the disease once it was spreading proved challenging. “WHO was so overwhelmed with everything, it was unbelievable,” Dr Marzi said, continuing: “All the hospitals, everything closed. The entire healthcare system shut down. There was nothing.” Subsequently, other ailments that could otherwise have been treated, such as malaria, also added to increasing death rates in the region.

Dr Marzi has first hand experience of the outbreak; she went to Liberia for a month at a time on two occasions in 2014, running Ebola diagnostics tests out of a field lab in the capital Monrovia in support of Doctors Without Borders and other organisations.

“Nobody over there had any diagnostics tests for Ebola… So when WHO really got short-handed, they reached out to us and we put together a team and went there,” she said. “It was really important to report back to the doctors quickly and tell them yes, this person has Ebola and this person doesn’t. When the patient comes in with clinical signs, everything presents pretty similarly – they’ll have a fever with Ebola, but also with malaria. You really want to minimise the time you keep those people together in the same tent of suspected Ebola cases.”

More impressive than her fieldwork, however, is the work Dr Marzi carried out back in the lab in Montana, where they researched the vesicular stomatitis virus-based vaccine known as VSV-EBOV. Dr Marzi – herself focused on analysing the mechanisms of how and why the vaccine works – and her colleagues at Rocky Mountain Laboratories were able to show that their vaccine was successful in macaque monkeys. It was purchased by the pharmaceutical company Merck, and clinical trials started in Guinea in spring 2015.

“I think [the vaccine] is very promising because it works quickly and it also works… against multiple different strains of Ebola virus, the old ones from 1976 and 1995, and the new one from the 2014-2015 outbreak,” Dr Marzi said. “Of course, we don’t know at this point how long the immunity will last. Do we need a booster vaccination and those kind of things?”

The success of phase 3 clinical trials with the VSV-EBOV vaccine in ring vaccinations in Guinea was shown in an interim analysis of the ongoing trial, published in The Lancet in July 2015. The trial included 90 clusters of people – totalling 7,651 individuals – participating between April 1-July 20 2015, where a cluster consisted of an infected patient, the people they had been in contact with, and contacts of contacts. 48 of the clusters were given the trial vaccine immediately, while the other 42 clusters received it after 21 days. In the group who were immediately vaccinated, no cases of Ebola symptom onset occurred, while among the 3,528 people who received the delayed vaccination, 16 persons contracted the virus.

43 serious adverse events were reported in the interim analysis, and out of them one adverse case of febrile fever was judged to be caused by the vaccine. Further assessment of adverse reactions was still ongoing at the time the paper was published.

On July 24 2015, four days after the trial ended, Guinea’s national regulatory authority and various ethics committees approved the continuation of the clinical trial, with immediate ring vaccinations for all individuals in newly detected clusters.

Ebola-A. Marzi RML training
Dr Marzi (foreground) in a biosafety level 4 research suite at Rocky Mountain Laboratories. Photo: NIAID

Whether we’ll see mass-vaccinations in at-risk communities in the future will be up to local authorities, Dr Marzi said. “Even if it’s not mass-vaccinations, at least vaccinate health care workers there, or military personnel – people who would get called to outbreaks quickly… Maybe people from WHO, Doctors Without Borders, all those people who are first responders for outbreak situations,” she opined. “I think for those kinds of groups, vaccination is definitely a viable option and I think it would be very beneficial.”

That the VSV-EBOV vaccine takes effect so quickly – the preliminary results from the Guinea trials suggest 100% efficacy after 10 days – is also an important aspect, not least in terms of deployment. A fast-acting vaccine allows for a shorter waiting-period before emergency responders can be safely sent out into the field.

“I just hope that we get an Ebola vaccine approved, because I don’t want an outbreak like this to happen again. It was bad enough,” Dr Marzi said.

“I also really, really hope that this entire scenario is setting a precedent.” She continued: “If an outbreak of this magnitude happens with something else, protocols could be in place and we can say: ok, it’s Lassa fever, it’s Marburg virus, it’s something like SARS – and we could move along quick and not have to wait for months or years in order to get those trials going.”

When asked if she’s ever concerned about the apparent safety risks that come with working daily with deadly viruses, both in the lab in Montana and in the field, Dr Marzi pragmatically replied: “In order to find vaccines and therapeutics against viruses, we need to understand how they work, how they cause disease, and in the end how people die of them.”

“Someone needs to do that work. It’s really rewarding when you get there, you identify a part of the virus that you can use as a vaccine or put into a vaccine platform, and then you do a few experiments and you see that it works,” she said, and concluded: “That’s really rewarding, and it’s worth the risk.”

This article was originally published by Alexandra Hoegberg in Uppsala Reports #72.


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