Ebola and ZMapp...A scientist explains

Aug 07 2014 Published by under Conduct of Science, Public Health

Erica Ollman Saphire (lab website, PubMed, RePORTER) was interviewed on KPBS in San Diego about the use of highly experimental antibody therapy for the US health workers infected with Ebola virus.

It's a pretty interesting viewpoint on basic science, translation to humans and what we do when an emergency situation like an infectious disease outbreak happens. I have been struck in past days about the huge international discussion this ZMapp treatment has been sparking. As you might expect, we have dark thoughts being expressed along the lines of "Why does this apparently miraculous treatment emerge all of a sudden when Americans are infected but it hasn't been given to suffering Africans, hmmmm?". There are all kinds of ethical issues to think about.

The television version linked below is 5 minutes but be sure to click on the link to the "midday edition" which is a longer voice interview. It gives a much fuller discussion.

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Additional Reading:

CDC: Questions and Answers on experimental treatments and vaccines for Ebola

Experimental Ebola drug based on research from Canada’s national lab

Ebola experimental drug, ZMapp sparks ethical controversy

UPDATE:
David Kroll on ZMapp

David Kroll on two other Ebola therapies

26 responses so far

  • becca says:

    How is this different (other than being much more biotech intense/expensive) from passive immunization? (which has also been used for Ebola http://en.wikipedia.org/wiki/Passive_immunity)

  • drugmonkey says:

    It IS passive immunization. The difference here is whether it is given as a prophylactic or therapeutically after infection. The CDC site says ZMapp "is being developed as a therapeutic but not to prevent infection".

    I would imagine that this has to do with the effective half-life of the antibodies? Or the expense?

    You'd probably know better than I whether there are antibody therapies that for [because science and medicine is weird, maaaang] reasons work better as therapy?

  • I did sort of feel the Yo, Is This Racist? response:

    "Yes, the ebola outbreak is very tragic and- What? White people are infected?! QUICK! Fly in the secret serum!!!"

  • drugmonkey says:

    yeah and what would happen if we DID rush in this "secret serum" (really journalism? really???) and then it turned out to have all kinds of bad effects in some of the African villagers that were treated prophylactically in the hot zone....

    OMMFG, TUSKEGEE! MENGELE! UNETHICAL TESTING ON POOR PEOPLE IN FAR OFF LANDS TO PROTECT THE WESTERNERS (EVENTUALLY)

    ....it's complicated.

  • Dr. Noncoding Arenay says:

    How about it being as simple as: being experimental, there isn't enough for hundreds of people in Africa. If they did decide to use it in Africa, then who gets it first? How do yo select the lucky recipients? What do you say to those who cannot get it?

  • drugmonkey says:

    Why isn't there enough? It's a conspiracy! Big Pharma something, something.

  • kevin. says:

    This is pretty much what they do with rabies now, but they've had a lot longer to work that out. It's still hells-expensive, and there just isn't enough material to be passively immunizing everyone. And there may well be reasons why it might work better/worse in certain ethnic groups.

  • gingerest says:

    It was crazy unethical to use it, it was done way outside the ordinary bounds of research and development even of drugs in life-threatening situations, and there is just no doubt at all that the fact these were privately-employed white American aid workers means that efforts went above and beyond, even though "above and beyond" meant a very poorly calculated evaluation of risk-benefit. UGH. Such a bad idea.

  • Dr. Noncoding Arenay says:

    @Gingerest Who is to take responsibility for two people dying while "risk-benefit evaluation" was being done? They got the treatment several days into their infection, which was pretty late as it is. Being very close to dying, I don't think the patients themselves gave a shit about risk-benefit evaluation. A last resort experimental therapy is better than certain death.

  • gingerest says:

    Not if it brings certain death faster!

  • DrugMonkey says:

    Pretty sure they had animal data to rely upon. It wasn't a total wild hair.

  • WH says:

    As the probability of death from a condition approaches 1, the "risk-benefit" ratio of an experimental treatment approaches zero. From what I've read, Brantly called his wife to say goodbye and told his doctors he thought he was dying- and he's a MD who had for months treated Ebola himself and watched people die of the disease. What's there to lose?

    If production of ZMapp is supported by US taxpayer dollars, I don't have a problem with it going to US citizens first. Clinical trials in Africa by Western pharma companies have a checkered past, and it wouldn't take much for the cry of racism to pop up.

  • bacillus says:

    @becca. A former colleague of mine contracted ebola during the first ever outbreak. It was a lab accident involving a hypodermic syringe and a struggling guinea pig. Long story short, he became very ill but survived , and thereafter regularly donated his blood to be used for passive immunization for the next poor unfortunate bastard. It is unimaginable that in the intervening thirty some years, Uncle Sam has not stockpiled similar antiserum from the many ebola survivors from subsequent outbreaks. If they have such material then they should be using it in Africa, since it was African blood that was used to make it.

  • Realistic Alias says:

    Arthur Caplan's take on this

    It is unimaginable that in the intervening thirty some years, Uncle Sam has not stockpiled similar antiserum from the many ebola survivors from subsequent outbreaks.

    Why Uncle Sam, why not the WHO?

    ....it's complicated.

    Yup.

  • bacillus says:

    @RA. Perhaps because the DoD would feel obligated to do so to protect their warfighters from a potential biological weapon, and their ebola scientists from a potential lab accident? WHO etc likely never forsaw a natural outbreak large enough to justify the expense, nor the skills or sense to pull it off. Neverthless, if any of the countries affected by the current outbreak has the ability to readily track down the survivors of previous outbreaks, they could do worse than use them as a source of protective antibodies.

  • As monoclonals, production of this drug can be readily scaled up in tissue culture bioreactors.

  • bacillus says:

    @CP. This is true. In fact the Public Health Agency of Canada has had a similar cocktail of anti-ebola antibodies produced in HEK cells using large-scale bioreactors at Canada's National Research Council. Unfortunately, HEK and other mammalian cell lines are a nightmare for regulatory approval versus antibodies raised in plant or insect cells. AFAIK, the US company is simply growing recombinant tobacco plants and extracting the antibodies from the leaves, rather than growing them in bioreactors, and the former takes much longer to scale up. This could explain why so little of it was available for use.

  • "Unfortunately, HEK and other mammalian cell lines are a nightmare for regulatory approval versus antibodies raised in plant or insect cells."

    For a disease as deadly as ebola, you'd think there'd be a regulatory sliding scale.

  • Oh, and I thought functional monoclonal antibodies could be produced in E. coli?

  • becca says:

    bacillus- good to know the passive immunization strategy is that well established. Of course, antibodies aren't the most stable things. I'm not sure about how long serum for passive immunization lasts... even if they've been stockpiling for 30 years, that doesn't mean they have 30 years worth of stocks.

    And yeah. Regulatory sliding scale would be sane here. I wouldn't worry much about eating HEK293 cells even if they weren't possibly saving me from Ebola.

  • Davis Sharp says:

    For a disease as deadly as ebola, you'd think there'd be a regulatory sliding scale.

    There is, that's why the patients at Emory are getting the ZMapp. And bacillus is right about companies going the route of plant production regulatory reasons. Besides, it's farming, you don't need to keep a sterile bioreactor to grow the plants.

    Perhaps because the DoD would feel obligated to do so to protect their warfighters from a potential biological weapon

    Well, we don't know that DoD is not doing that. But anyone using such a weapon would have to have a pretty advanced laboratory. Anyway, military personnel are exempt from the standard Human Subjects protections that we associate with research. So the Army may have already bought a bunch of ZMapp to use, when necessary, without informed consent (remember the anthrax vaccine?). But remember, even though there's no evidence that ZMapp can be used therapeutically in humans, there is even less less that it can be used prophylactically.

  • DrugMonkey says:

    RJ Reynolds, therapeutic pharmaceutical company. SMH.

  • Kevin. says:

    Antibodies have complex glycosylation patterns and disulfides making production in prokaryotes difficult/impossible. The antibodies themselves are quite stable, at high temperatures for too long could lies potency.

  • hidde ploegh says:

    and how about this?

    Protection against filovirus diseases by a novel broad-spectrum nucleoside analogue BCX4430.
    Warren TK, Wells J, Panchal RG, Stuthman KS, Garza NL, Van Tongeren SA, Dong L, Retterer CJ, Eaton BP, Pegoraro G, Honnold S, Bantia S, Kotian P, Chen X, Taubenheim BR, Welch LS, Minning DM, Babu YS, Sheridan WP, Bavari S.
    Nature. 2014 Apr 17;508(7496):402-5. doi: 10.1038/nature13027. Epub 2014 Mar 2.

  • "Antibodies have complex glycosylation patterns and disulfides making production in prokaryotes difficult/impossible."

    Oh, right. But monovalent functional FAb fragments and nanobodies can be made in prokaryotic cells.

  • chall says:

    CPP> It's not as easy producting functional MAb (or polyclonal antibodies) for use in humans. Not only eukaroyot cell tissue but a lot of cells are adherant rather than suspension so there goes the obvious biofermentor bulk yield.

    ALL> as for the regulatory sliding scale - it's pretty hard right now to get anything through even when you shift from "previously cleared antibody produced in cell line A[tm] to new cell line". Roughly $2mil to get cell line cleared and new batch oked when we checked last year in my job. I know it's for safety but a few of the tests should be possible to "collide from different labs/places" and not have to reinvent the wheel EVERY TIME.

    As for the growing of cells for antibodies, many cell lines (who makes great functional ab) are adherant and the yield from that will never compare to suspension cells (or eggs for that matter).

    And then there would be the discussion on "how efficatious" is the antibody treatment reall? Animal tests of the Zmapp and other ab here have focused on delivery of the drug within 6 hours of exposure to the virus. That's totally different than "being sick for 6 days". obvs.

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