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Africa

How does the Ebola serum work? An Ebola serum researcher explains

media A doctor uses a microscope to look at virus samples in a Biosafety Level III laboratory at the National Institute of Health in Lima, 12 August 2014. Reuters/Mariana Bazo

The World Health Organisation on Tuesday authorised the use of an experimental serum in the fight against the deadly Ebola virus. The ZMapp treatment is in the early stages of development and has only been tested on monkeys. However, it has been used to treat two US aid workers and a Spanish priest who were infected in Liberia. The serum is in short supply but the company has said it has sent all available doses to West Africa free of charge following an outcry over its use on foreign aid workers. RFI spoke to structural molecular biologist Erica Ollmann Saphire from the Scripps Research Institute, who worked on developing the Ebola serum.

Could you explain specifically how this ZMapp serum works?

A vaccine is something that would inspire your immune system to raise its own antibodies. In this antiserum we’re providing the antibodies immediately. So you’re conferring immediate immunity against the virus. In this serum there are three particular antibodies that work three different ways. Two of them actively neutralise or inactivate the virus. The other one flags the virus or infected cells for destruction by the immune system. So there are three parts that work in complementary ways to destroy the virus itself and alert the immune system to the presence of the attack.

It’s been used on the two US aid workers but failed in the case of the Spanish priest. Do we know whether it really made any difference in the case of the aid workers?

The doctors treating them seem to think that it did. We would not know for sure until we had done a clinical trial. For example, the aid workers had no identical twin that was infected with the same dose, on the same day, which was not treated. So you’re never sure until you’ve done that clinical trial that has a placebo as the alternative.

You wonder whether the age of the Spanish priest contributed to it not working in his case.

One does wonder. I mean clinical status differs. Another factor would be the time between infection and treatment. What we do know well from the laboratory animal studies is that the longer one waits for treatment, the more difficult it is to treat. If you offer the antibodies between 24 hours and three days after infection to the animals, they’ll all survive. But the longer one waits, the more difficult it is. Those animal studies, they’re given a very high dose. We don’t know what dose of virus the human receives because it’s always an accidental infection and for most of these medical infections, we don’t know the exact day of infection either.

What side effects could we possibly see from the use of this serum? Was there any indication of this through the testing on animals that you carried out?

There was no indication of side effects in the animals. I didn’t do those animal studies myself. Those were done by the Public Health Agency of Canada. So it’s not so much my expertise. None were noted worth reporting. Antibodies are generally safe and well-tolerated, especially if they are targeted against the virus. Possible side effects could be the person might be allergic to it in some way. Typically antibodies are quite safe and well-tolerated. There is a antiviral antibody therapy approved for RFV (Respiratory Syncytial Virus), the respiratory infection in babies.

How hard would it be to increase the manufacture of the ZMapp serum?

Not difficult. Right now it’s being manufactured in tobacco leaves because they can coax tobacco to make a lot of it for them. So they just need time to grow more tobacco leaves and have the vectors start expressing it in tobacco. So it could be made, maybe it would be two months.

Could you tell us more about where it comes from? You just mentioned tobacco leaves.

The original antibodies were identified by immunising mice. Then they swapped out the mouse sequences for human sequences in a process called humanisation. It’s quite straightforward to make a human drug. Then to express a lot of it, what they do is they have a viral vector called tobacco mosaic virus that only infects tobacco, that doesn’t infect humans. That tobacco mosaic virus has been engineered to encode the antibodies. So when the virus infects the tobacco leaf, the tobacco leaf becomes a small production factory for an antibody. This is done in a special greenhouse and then they harvest the leaves and they put them essentially in a giant juicer and purify the antibodies from the liquid.

The two main problems you seem to have mentioned so far are the immediate administration of this serum to people who’ve contracted Ebola and the fact that we don’t really know how much serum to give them.

Not quite. So on the first one, the key advantage of the antibody therapy is that it doesn’t have to be immediate. For every single animal to survive a very high dose of experimental virus, the antibody has to be given within three days. But even if they wait until Ebola hemorrhagic virus develops, they could save a great number. So the advantage of an antibody therapy over other therapies is it does give you a longer treatment window. But the treatment window is not infinite. The longer one waits, the more difficult it is to fight it. Because the longer one waits, the more virus there is in that patient, it will replicate and replicate. If you have a small amount of virus its easier for the antibody to clear it out, a very large amount of virus would be very difficult.

The issue of how much to give…

That was the subject of a clinical trial which was scheduled for 2015. That’s the normal process, it worked well in the test tubes, it worked well in the mice, worked well in the monkeys and then the human trial was scheduled for 2015. In that trial healthy volunteers would receive the antibody just to understand if there are any adverse affects. What dose of antibody should be given and how long does it last, the kinetics and those kinds of things. Because that trial hadn’t happened yet when the Ebola outbreak occurred, we don’t fully know the right dose to give a human and we don’t know the treatment window. We will never really know the human treatment window until we do a human trial during an outbreak. Because you would never intentionally any human Ebola virus, you can’t do human experiments. But if they were to do a randomised double-blind placebo controlled trial during this outbreak, we would have the answers to all those questions. We would know of the 100 people that received the drug, how many survive, and the 100 people that did not receive the drug how many survived. Within those ranges are those populations of people that did and did not receive the drug, we would probably have a range of ages and a range of clinical statuses, from people that were newly infected and otherwise still healthy, to people that were quite sick and people that were young and people that were old.

Do you anticipate an eventual vaccine for Ebola, with continued research in the future?

I do. There are candidate vaccines that also work well in animal models. That seems like a terrific idea for people that know that they are going into an outbreak situation or for scientists that work with Ebola virus in a lab every day.

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