Science in Society Archive

Virus Vaccine Made In Tobacco Plants to Control Ebola

Good idea but production must be strictly contained. Prof Joe Cummins

Ebola a deadly epidemic

A threadlike virus known as Ebola emerged in the 1970s, as one of the most lethal, naturally occurring pathogens on earth, killing up to 90 % of its victims, and producing a terrifying constellation of symptoms known as hemorrhagic fever [1]. An epidemic of Zaire Ebola virus in Western Africa continues. Some 1,427 people have died among 2,615 known cases since the outbreak was first identified in March, according to new figures released by the World Health Organization (WHO), with many more cases probably unreported, and there is no effective treatment or means of preventing infection [2].

In the past two decades there has been substantial research into developing and testing active and passive vaccines and antiviral drugs, although none have yet been licensed for use in humans. Active vaccines elicit immune memory and long term ability to produce antibodies to a pathogen while passive vaccines contain antibodies to a disease (rabies for example) but do not create the ability to produce antibodies. Heretofore,  active    vaccines or antiviral drugs have not been effective in treating Ebola infection in animals or people.

Vaccine of monoclonal antibodies

ZMapp, an experimental treatment rushed to two Americans infected with Ebola in Africa, is grown in specially modified leaves of tobacco. The vaccine, administered to Dr. Kent Brantly and Nancy Writebol, was only formulated in January, according to Larry Zeitlin, PhD, president of Mapp Biopharmaceuticals, the Californian company that co-developed the drug. It has been tested in monkeys, but had never been given to human patients before it was rushed to Brantly and Writebol who were exposed to the virus in Africa. Zeitlin says he hasn’t even had a chance to publish a scientific paper on the vaccine, which is a combination of three antibodies that are thought to help in two ways. One of the antibodies alerts the immune system to infected cells so they can be destroyed, says Erica Ollmann Saphire, a professor of immunology at the Scripps Research Institute in La Jolla, CA, who has been given a government grant to study the antibody cocktail. Saphire says the other two antibodies probably prevent the virus from multiplying [3].

Brantly got the first dose of ZMapp 9 days after falling ill, but had already received a blood transfusion from a 14-year old boy who survived an Ebola virus infection [4]. A Roman Catholic priest, 75-year old Miguel Pajares was also given ZMapp on being infected with Ebola, but died 2 days after receiving the drug. Libera, which has been affected by the outbreak, has secured enough ZMapp to treat 3 individuals.

ZMapp had previously been tested only on animals. A study published in 2012 found that Ebola-infected rhesus macaques survived when receiving the drug one hour after infection, and 4 out of 6 also survived when given the drug 24 or 48  hours after infection [5]. A second study published in November 2013 found that Ebola virus infected macaques survived after given ZMapp within 24 hours of infection, and 2 of 4 other monkeys treated within 48 hours after infection also survived. They also survived a second lethal exposure to the virus after 10 and 13 weeks, with a robust immune response [6].

On 6 August 2014, Peter Piot who co-discovered the Ebola virus and other scientists including the director of the Wellcome Trust, called for the release of ZMapp for affected African nations. An expert panel from the WHO announced on 12 August 2014 that [7] “In the particular circumstances of this outbreak, and provided certain conditions are met the panel reached consensus that  it is ethical to offer unproven interventions with as yet unknown efficacy and adverse effects as potential treatment or prevention.”

How ZMapp is produced

As ZMapp has not yet been published in detail in science journals, it is worth reviewing available publications on production of monoclonal antibodies in tobacco plants. The fundamental process for producing substantial quantities of pure clinical grade monoclonal antibodies in plants such as tobacco is called magnifection. The monoclonal antibodies recognizing a virus are isolated in mice then its genes ‘humanized’ by altering the genetic code words from mouse-specific to human-specific. The monoclonal antibody (Mab) genes are introduced into a plant virus replicon such as the tobacco mosaic virus replicon or a potato virus X replicon or frequently a binary mixture of the two replicons. The virus replicons are inserted into an Agrobacterium cell. The Agrobacterium vectors are introduced under mild vacuum into the leaves of the tobacco plant. The massive penetration of the tobacco leaf is followed by production of Mab making up as much as 10% of cytoplasmic protein of the tobacco leaf. The high level production of the Mab facilitates purification of the product [8] (Magnifection, Safe Pharming or Doomsday Device, SiS 42) [9], although it would be highly unsafe for this to be carried out on crops growing in the open field.

Mab have been developed as analytic reagents to detect the Ebola virus for at least a decade. Large quantities of Ebola virus humanized Mab could be produced within one week after delivery of the Mab genes to the plant [10].  

To conclude

Does the production of ZMapp in tobacco plants create a potential threat to the environment through release to the environment of transgenic material resulting from the production? Not if it produced within a strictly contained greenhouse facility isolated from the environment. There is a scheme to automate the production ZMapp production but the details of that proposal have not yet been divulged.

Is the treatment with ZMapp ethical prior to clinical approval of the vaccine?  As Ebola infection is lethal and debilitating, it seems morally imperative to employ the treatment.

Article first published 26/08/14



References

  1. Vincent Racaniello  Ebolavirus vaccines and antivirals. Virology Blog, 8 Aug. 2014 http://www.virology.ws/2014/08/08/ebolavirus-vaccines-and-antivirals/[8/12/2014
  2. “WHO warns of ‘shadow zones’ and unreported Ebola cases”, Stephanie nebehay ad Clair MacDougall, Reuters, 22 August 2014, http://www.reuters.com/article/2014/08/22/us-health-ebola-who-idUSKBN0GM0RW20140822
  3. Brenda Goodman. Experimental Ebola serum grown in tobacco leaves. WebMD http://www.webmd.com/news/20140804/ebola-virus-vaccine [8/12/2014 2:34:52 PM]
  4. ZMapp, Wikipedia, 22 August 2014, http://en.wikipedia.org/wiki/ZMapp
  5. Oliger Jr GG, Pettitt J, Kim D, et al. Delayed treatment of Ebola virus infection with plant-derived monoclonal antibodies provides protection in rhesus acaques. PNAS 2012, doi:10.1073/pnas.1213709109. (
  6. Qiu X, Audet J, Wong G, Fernando L, Bello A, Pillet S, Alimonti JB, Kobinger GP. Sustained protection against Ebola virus infection following treatment of infected nonhuman primates with Zmab. PMC 2013,  doi:10.1038/srep03365
  7.  “WHO experts give nod to using untested Ebola drugs”, Dennis Thompson, WebbMD, 12 August, http://www.webmd.com/news/20140812/who-experts-give-nod-to-using-untested-ebola-drugs
  8. Cummins J and Ho MW.  Magnifection, safe pharming or doomsday device? Science in Society 42 , 36, 2009.
  9. Castilho A, Bohorova N, Grass J, Bohorov O, Zeitlin L, Whaley K, Altmann F, Steinkellner H. Rapid high yield production of different glycoforms of Ebola virus monoclonal antibody. PLoS One 2011, 6(10), e26040. doi:10.1371/journal.pone.0026040.
  10. Lucht A1, Grunow R, Otterbein C, Möller P, Feldmann H, Becker S. Production of monoclonal antibodies and development of an antigen capture ELISA directed against the envelope glycoprotein GP of Ebola virus. Med Microbiol Immunol 2004, 193(4), 181-7.

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There are 2 comments on this article so far. Add your comment above.

Todd Millions Comment left 29th August 2014 07:07:34
Many other details on this are yet to be divulged.Why has the Centre for Disease Control obtained a patent on the new Ebola strain for instance?Why the sudden geographical dispersion of the new strain not conforming to previous outbreaks?Qui Bono?Any attempts to treat via vitiamin C drip,for comparison?Why so much coverage on this and no mention of the new flesh eating strain showing up from Florida to Texas?

Sarah Comment left 6th November 2014 17:05:37
To be clear, Zmapp is a treatment, not a vaccine. A vaccine stimulates the person's own immunity, but this treatment is just giving pre-made antibodies to the person while ill. There are a number of experimental vaccines that could be given to people prior to exposure to Ebola virus that have been developed and tested in non-human primates, and will probably be tested in humans soon.

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