Biological Threats and Terrorism Assessing the Science and Response Capabilities: Workshop Summary (2002) / Chapter Skim
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4 The Research Agenda: Implications for Therapeutic Countermeasures to Biological Threats
4 The Research Agenda: Implications for Therapeutic Countermeasures to Biological Threats
Pages 113-147
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From page 113... ...
This is alarming given the increasing accessibility of the tools and knowledge needed to develop antibioticresistant strains of bioterrorist agents. There is concern that the situation will become ever worse with the recent FDA changes in clinical trial design requirements.
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From page 114... ...
The use of recombinant monoclonal antibodies is another option which has been implicated for use against several biothreat agents, including anthrax, smallpox, and botulinum neurotoxins. For example, recent research has shown that a small mixture of recombinant monoclonal antibodies provides complete protection in mice against botulinum neurotoxin type A
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From page 115... ...
Vice President, Infectious Diseases Drug Discovery Research and Clinical Investigation Eli Lilly and Company The Problem 115 The diversity of existing biological weapons and the ever increasing possibilities preclude simple therapeutic countermeasures to bioterrorism. Furthermore, response possibilities are rather limited even for known threats.
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From page 116... ...
Finally, the best deterrent against the use of a biological weapon of mass destruction may be a constant stream of new, innovative antibiotics and antivirals. Knowledge of such commitment and successful developments would surely dissuade the efforts of our enemies in such an arena.
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From page 117... ...
The European regulatory authorities and the FDA are now suggesting that a 10% delta be used routinely in drug development (FDA, 2001b) , and the FDA has now "disclaimed" the old step function on their web site (FDA, 2001a)
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From page 118... ...
TABLE 4-2 Number of patients for each indication with a one-sided 97.5% CI (assumes 75% evaluability) Indication Cure Rate 90% Power 90% Power 10% delta 15% delta A 85% Number of Studies: 2 1532 688 B 80% Number of Studies: 2 2248 1000 C 70% Number of Studies: 2 2948 1316 D 65% Number of Studies: 1 1598 710 Related to indication C TOTAL 8326 3714 80% Power 80% Power 10% delta 15% delta TOTAL 6226 2770
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From page 119... ...
PhRMA has suggested a number of alternate approaches to the FDA and the industry is more than willing to work with FDA, IDSA and other interested parties to address their concerns regarding clinical trial design in antibacterial development. However, the attempt by regulatory authorities to implement an across-the-board requirement for 10% delta trial designs has already wreaked irreparable damage to our ability to provide a reliable pipeline of new antibiotics for serious infections.
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From page 120... ...
At this time, technical difficulties may limit the prospects for weaponization of Crimean Congo HF and the hantaviruses, but like most problems, these are subject to solution. TABLE 4-3 Viral hemorrhagic fevers commonly mentioned in association with biological warfare or biological terrorism PRIMARY HEMORRHAGIC FEVERS (HF)
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From page 121... ...
The lack of a reservoir outside human-kind, the moderately higher transmissibility, and the existence of a highly effective vaccine that can be efficiently delivered combined to allow the eradication of the virus as a cause of natural disease. Monkeypox is another poxvirus which shares high aerosol stability and infectivity with smallpox but which has a much lower interhuman transmissibility and case fatality (Jezek and Penner, 1988~.
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From page 122... ...
Whether such viruses would be produced and could actually spread among human populations is another matter. The Solutions Biological warfare (BOO)
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From page 123... ...
Furthermore, availability of attenuated strains can be essential to expanding research activities, including antiviral drug development, to laboratories with lower levels of containment. Antiviral drugs could provide protection, subject to all the same problems of stockpiling and delivery as antibacterial agents now considered for use against such threats such as anthrax, plague, and tularemia.
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From page 124... ...
A Case Study A vaccine against Argentine hemorrhagic fever (Junin virus) provides insight into some of the obstacles.
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From page 125... ...
All the viruses in the arenavirus family are inhibited in cell culture by the antiviral drug ribavirin and there are substantial data to support the use of intravenous rite avirin in the treatment of Lassa fever (McCormick et al., 1986~. Preclinical and anecdotal human data for the use of the drug in other arenavirus infections strongly suggests it is efficacious (Peters, 2002~.
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From page 126... ...
The other human Rift Valley fever vaccine is a live-attenuated product that has been tested in 60 persons with a good safety profile and the elicitation of antibodies expected to be protective, based on preclinical studies and the experience with the inactivated vaccine in laboratory workers (Pittman PR, Morrill J Peters CJ, unpublished observations)
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From page 127... ...
First, we should understand how to make vaccine candidates that would be protective in realistic animal models against all the threat agents and that would utilize a technology feasible for human vaccine production. Second, we should have broadly reactive antiviral drugs or other therapeutic approaches that would be effective in families or at least genera of threat agents.
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From page 128... ...
One promising approach has been the design of inhibitors of NF kappa B intranuclear binding (Yang et al., 1999) to prevent the over exuberant inflammatory reaction thought to be a major pathogenetic mechanism of Lassa fever and other arenavirus diseases (Mahanty et al., 2001, Marta, et al., 1999~.
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From page 129... ...
Arenaviruses Junin vaccine, live -attenuated Ribavirin, intravenous Rift Valley Vaccine, inac fever tivated Not licensed in U.S. but preclinical studies met FDA requirements for IND.
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From page 130... ...
Will need decision as to whether to license based on preclinical data, human immune response (compared to experience with inactivated vaccine in lab workers) or field trial.
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From page 131... ...
, which are mutant forms of the protective antigen that block translocation, polyvalent inhibitors (PVI) , which are chemically synthesized inhibitors that block toxin assembly, and soluble forms of the toxin receptor, ATR, which block toxin attachment to cells.
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From page 132... ...
It is not completely understood how these mutated residues actually block translocation, but clearly they are potent inhibitors of toxin action. In cell culture, a one-to-one ratio of mutant to wild-type PA almost completely inhibits toxin action.
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From page 133... ...
PVIs block toxin action by prohibiting EF and LF from even binding to heptameric PA in the first place. PVIs are polyacrylamide polymers that act at multiple sites on the heptamer.
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From page 134... ...
Marks, M.D., Ph.D. Departments of Anesthesia and Pharmaceutical Chemistry University of California, San Francisco Botulinum Neurotoxins as Biothreat Agents The spore forming bacteria Clostridium botulinum secrete botulinum rotoxin (BoNT)
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From page 135... ...
Historically, such Ab has been made by hyperimmunzing either horses (equine antitoxin) or human volunteers (human botulinum immune globulin)
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From page 136... ...
With the advent of modern molecular biology techniques, however, it has become possible to make monoclonal antibodies that are far less immunogenic. Chimeric antibodies are made by grafting human antibody constant domains onto the murine variable domains, yielding antibodies which are approximately 75% human in sequence (Morrison et al., 1984~.
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From page 137... ...
To perform phage display, repertoires of antibody heavy and light chain variable domain genes are assembled and cloned into a phage vector to create libraries of scFv or Fabs displayed on the phage surface. The source of the variable region genes can be any species, including immunized humans.
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From page 138... ...
No single IgG significantly neutralized toxin in vivo, but combining mAb led to potent toxin neutralization. The most potent mAb pair protected mice challenged with 1500 LD50s of toxin, while combining all three mAb protected mice challenged with 20,000 LD50s of toxin (per 50,ug of antibody administered)
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From page 139... ...
Ab may also be useful for plague and the hemorrhagic fevers (Hill et al., 1997, Wilson et al., 2000~. Given the threats posed by these agents, rapid generation and evaluation of oligoclonal Ab for their neutralization is warranted.
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From page 140... ...
IND regulations may also be viewed as a mechanism for making an investigational product available. IND regulations have three basic components: an informed consent form, review of the protocols for planned use by an institutional review board, and a plan for the collection of safety and efficacy data from the human population in which the product is going to be used.
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From page 141... ...
The labeled regimen for post-exposure inhalational anthrax is a sixty-day dosing period. Safety databases of patients who received the drug for more than sixty days, patients who received the drug for sixty days, patients who received it for less fewer than sixty days, and patients who received other antibiotics all show similar adverse event rates.
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From page 142... ...
The Federal Register notice was published because product labels do not contain specific dosing information for post-exposure inhalational anthrax, even though scientific data support this labeling. The Federal Register notice states this, provides the dosing recommendations, and invites applications from manufacturers of these drugs to request labeling supplements.
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From page 143... ...
For example, because the murine Fc region is the most immunogenic part of a monoclonal, both chimeric and humanized antibodies, with human Fc regions, have been engineered and shown to exhibit much less immunogenicity in humans than whole murine antibodies. With regards to how antibodies are produced, there is some concern that phage display may create combinations of heavy and light chain genes that would raise unusual issues regarding immunogenicity.
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From page 144... ...
1986. Effect of ribavirin and tributylribavirin on Argentine hemorrhagic fever (Junin virus)
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From page 145... ...
1997. Molecular characterization of murine humoral immune response to botulinum neurotoxin type A binding domain as assessed using phage antibody libraries.
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From page 146... ...
1998. Crystal structure of botulinum neurotoxin type A and implications for toxicity.
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From page 147... ...
. Deconvoluting the immune response: Potent botulinum neurotoxin neutralization by oligoclonal antibody.
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