Plant‐made pharmaceuticals: from ‘Edible Vaccines’ to Ebola therapeutics

As I sat writing this ‘personal reflections’ manuscript in the spring of 2015, I was seeing press reports related to the use of tobacco to make an Ebola therapeutic called ZMapp. For several months newspaper articles, radio shows and hour-long TV documentaries have given the public unprecedented exposure to the fact that ‘plant-made pharmaceuticals’ (PMP) can be life-saving drugs. I have been asked by many nonspecialists – why tobacco? How can this work? After spending over twenty years doing research in this field and many, many hours in public policy meetings promoting PMPs as an important tool of public health, I do not tire of hearing the same questions. Although there is an increasing pipeline of new protein drugs that will come from plants for both human and animal health, the general public has little knowledge of these specialized tools and therefore limited support for the field. ZMapp has given us free advertising on an international scale that I could never have anticipated. On 4 August 2014, I opened an email from Larry Zeitlin – the President of Mapp Biopharmaceutical, Inc. in San Diego, California, USA. It was a short message that alerted me to the fact that ZMapp had been used to treat two missionaries in Liberia, and they were recovering from severe Ebola infection. By that afternoon, the newswires were alive with stories with titles such as ‘Secret serum likely saved Ebola patients’. It was hardly a secret to Larry and me, or our colleagues. Arizona State University (ASU) had received substantial grant funds in 2002, including a subcontract to our colleagues in San Diego. (Mapp Biopharmaceutical was incorporated the following year.) We had proposed to the U.S. Army that plants (specifically tobacco) could be used for rapid production of vaccines or monoclonal antibodies (mAbs) that might be necessary to protect us from bioterrorism. This was shortly after terrorist attacks on New York and the Pentagon in 2001, and the use of anthrax spores for a bioterror attack in the U.S. Senate building; funding for countermeasures was quickly becoming available. Our 2005 final report for the Army contract ended with the statement: ‘we have demonstrated that Ebola virus-specific “humanized” monoclonal antibodies can be produced using plant biotechnology’. Research on our plant-made vaccines and mAbs for biodefence has continued as collaborative programmes between Mapp and ASU, gradually involving a wider range of multidisciplinary participants. Chief among these were scientists at Kentucky Bioprocessing LLC, founded in 2006, Herta Steinkellner and her colleagues in Vienna who contributed host plant glycoengineering skills, Yuri Gleba and his colleagues at ICON Gentics and a skilled team at the Army Medical Research Institute for Infectious Diseases (USAMRIID) who conducted preclinical studies of our Ebola-related products. Back-to-back ASU/Mapp publications in 2011 described our success in protecting animal models from Ebola infection using plant-made vaccine or antibodies (Phoolcharoen et al., 2011; Zeitlin et al., 2011). Subsequent demonstration of protection of nonhuman primates using a cocktail of three tobacco-made anti-Ebola mAbs as a postexposure therapeutic paved the way for ZMapp’s use in human volunteers. I am sure all of us who participated even in some small part of ZMapp development remain amazed that in only 12 years this project could go from a hypothesis to a drug that is currently the leading Ebola therapeutic under evaluation. We are also amazed this happened with modest monetary support – only a fraction of what is normally spent on development of a new drug in the pharmaceutical industry. Early parts of my career had not seen such clearly defined outcomes.