Sunday, February 23, 2014

Manufacturing of Recombinant Botulinum Neurotoxin Vaccine

PHOTO: http://iai.asm.org/

As the  Medical Countermeasure System Joint Vaccine Acquisition Program (MCS/JVAP), the advanced developer for the Department of Defence (DoD) responsible  for developing, producing and stockpiling FDA licensed vaccines to protect the Warfighter from biological agents puts out a Request for Information a requirement to develop and license a pre-exposure prophylaxis recombinant botulim neurotoxin serotype A and B vaccine, scientists, Jason Barash and Stephen Arnon at California Department of Public Health announced they had discovered the first new form of botulinum toxin in over forty years.  Moreover, the scientist published two reports describing their work online in the Journal of Infectious Diseases. As with previous study which could provide a recipe for would be bio-weaponeers, the genetic sequences were withheld.See: http://www.npr.org/blogs/health/2013/10/11/230957188/why-scientists-held-back-details-on-a-unique-botulinum-toxin

The recent discovery of Botulinum Type H, the most lethal of botulinum neurotoxins, with no known antidote is likely to concern bio-defence specialists. The previously known seven serotypes: A,B,C1,C2,D,E,F and G produced by the bacterium clostridium botilinum, block acetylcholine, a neurotransmitter which then leads to muscle paralysis. According to New Scientist, this is the first time a genetic sequence has been withheld from publication over security concerns. Patients are usually treated with monoclonal antibodies, immune proteins which react to the specific toxin type. In a March, 2013 report,  Medscape notes: 
In an abstract (Botulinum neurotoxin vaccines: past present, and future),  published by PubMed back in 2007, Smith, LA and Rusnak JM detail that 'In the early 1930's, a formalin-inactivated toxoid against botulium neurotoxin was first tested in humans. In 1965, a pentavalent botulinum toxiod (PBT) received Investigational New Drug (IND) status under the Centers for Disease Control's IND 161 (for at risk workers), and in 1991 under the United States Army's Office of the Surgeon General IND 3723 (for military deployment). This PBT vaccine has been shown to be safe with over 20,000 injections given to date, and continues to be used in at risk individuals. During the past decade, recombinant DNA technology has been employed to develop second generation vaccines to prevent botulism. Recombinant subunit vaccines utilizing the receptor-binding domains of botulinum neurtoxin (BoNT) have been shown to be safe and efficacious in protecting animal models against BoNT serotypes A, B, C1, D, E and F. In 2004, the first recombinant subunit vaccine [rBV A/B(Pichia pastoris) vaccine] was tested in humans during a phase 1 clinical trial. Results from that study demonstrated that the recombinant bivalent vaccine was safe and well tolerated at all dosage levels tested and stimulated serotype specific neutralizing antibodies among the majority of vaccine recipients. See: http://www.ncbi.nlm.nih.gov/pubmed/18197811

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Clostridium innocuum bacteria
"The US Food and Drug Administration (FDA) last Friday approved the first botulism antitoxin to neutralize all 7 known botulinum nerve serotypes valuable versatility for a drug in the nation's emergency medicine cabinet against a bioterrorist attack. The heptavalent botulism antitoxin (BAT,Cangene) had been available on an investigational basis from the Centers for Disease Control and Prevention (CDC). Cangene began supplying doses of BAT to the US Strategic National Stockpile in 2007 under a 427 million contract with the Department of Health and Human Services, according to a company press release. The CDC will distribute the stockpile antitoxin." See: http://www.medscape.com/viewarticle/781389

I would agree with Cangene's statement to the effect that "Currently, no specific, licensed therapies are available to treat all seven known serotypes" and "Given the inability to rapidly detect and identify botulinum neurotoxin (BoNT) serotypes in emergency situations, there is a critical need for a single effective treatment against all BoNT serotypes." See: http://www.raps.org/focus-online/news/news-article-view/article/2849/could-cangenes-botulism-antitoxin-become-the-seventh-product-approved-under-the.aspx

As a defence specialist, I would suggest that it is wise to recall in 1995, Iraq admitted it had produced 19,000 liters of botulinum toxin (See: http://www.fas.org/spp/starwars/crs/98042705_npo.html). Botulinum is listed by CDC and WHO as a Category A agent. It can and has been weaponized and poses a risk as bio-warfare agent.  In a 2005 Proceedings of the National Academy of Sciences (PNAS) announced it would publish a paper that presented a mathematical model of the possible consequences of deliberate botulinum toxin contamination of the US milk supply. The paper was authored by Dr. Lawrence Wein of Stanford University Graduate School of Business and Yifan Liu a graduate student. An overview is available here: http://www.nytimes.com/2005/05/30/opinion/30wein.html?pagewanted=all 
While I sat in on the ethics meetings to decide if Wein and Liu's study should be published in full, the first time such a meeting convened due to security concerns, botulinum and its potential use a weapon came to the foreground. Protection against such toxins is a vital aspect of national security. 
Dragon voice recognition





Jill Bellamy is an internationally recognized expert on biological warfare and defence. She has formerly advised NATO and for the past seventeen years has represented a number of bio-pharmaceutical and government clients working on procurement strategy between NATO MS and Washington DC. Her articles have appeared in the National Review, The Wall Street Journal, The Washington Post, The Sunday Times of London, Le Temps, Le Monde and the Jerusalem Post among other publications. She is a CBRN SME with the U.S. Department of Defence, Chemical, Biological, Radiological and Nuclear Defence Information Analysis Center and CEO of Warfare Technology Analytics, a private consultancy based in the Netherlands. She is an Associate Fellow with the Henry Jackson Society, UK.

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