Date Published: October 17, 2012
Publisher: Hindawi Publishing Corporation
Author(s): Mary Kate Hart, George A. Saviolakis, Susan L. Welkos, Robert V. House.
The development of vaccines for microorganisms and bacterial toxins with the potential to be used as biowarfare and bioterrorism agents is an important component of the US biodefense program. DVC is developing two vaccines, one against inhalational exposure to botulinum neurotoxins A1 and B1 and a second for Yersinia pestis, with the ultimate goal of licensure by the FDA under the Animal Rule. Progress has been made in all technical areas, including manufacturing, nonclinical, and clinical development and testing of the vaccines, and in assay development. The current status of development of these vaccines, and remaining challenges are described in this chapter.
Certain highly pathogenic microorganisms and their products have the potential to be used as weapons against either military or civilian populations. The Centers for Disease Control and Prevention (CDC) classifies these agents into one of three categories (A, B, or C) according to seriousness of consequences following exposure (http://emergency.cdc.gov/agent/agentlist-category.asp; accessed April 7, 2011). The US Department of Defense (DoD) has a long history of developing therapeutics and prophylactics (vaccines) to protect the warfighter against offensive use of these agents. Until relatively recently, these countermeasures could be used under an investigational new drug application (IND) mechanism. Now, the DoD mandates that any such products administered to the US warfighters be licensed by the US Food and Drug Administration (FDA). Currently, DVC is developing two vaccines for DoD’s Joint Vaccine Acquisition Program (JVAP); these include a recombinant vaccine to protect against fatal botulism following inhalational exposure to the A1 and B1 serotypes of botulinum neurotoxin (rBV A/B), as well as a recombinant vaccine to protect against pneumonic plague following inhalational exposure to Yersinia pestis (Y. pestis) (rF1V). The specific performance and regulatory requirements, progress, challenges, and successes in each program are reviewed below.
There is a need for vaccines that can protect against respiratory exposure to botulinum neurotoxins and plague. Development of these vaccines by DVC is guided by the DoD performance requirements and demonstration of efficacy in accordance with the Animal Rule (21 CFR 601.91 Subpart H, “Approval of Biological Products When Human Efficacy Studies Are Not Ethical or Feasible”).
Licensure of the rBV A/B and rF1V vaccines will use the FDA Animal Rule. The Animal Rule was established by the FDA to allow development and licensure of products that could not otherwise be licensed using traditional efficacy testing. The Animal Rule may be used for licensure when efficacy studies are unethical due to high pathogenicity, and disease is rare enough in nature that field studies would be either impossible or at least impractical (http://www.fda.gov/OHRMS/DOCKETS/98fr/053102a.htm; accessed April 7, 2011).
The rBV A/B and rF1V vaccine candidates were initially developed at the US Army Medical Research Institute for Infectious Diseases (USAMRIID). They were transferred to JVAP (and subsequently to DVC) in an early stage of development. The target indication of these vaccines is protection of adults 18 to 55 years of age from disease caused by inhalational exposure to BoNT/A1, BoNT/B1, or Y. pestis.
One of the most difficult challenges of licensing vaccines under the FDA Animal Rule is to bridge the animal and human immune responses, demonstrating that the qualitative and/or quantitative immune responses generated in the animal studies are relevant to those observed in humans and can be used to predict clinical benefit and establish an effective dose. This requires a validated assay(s) that serves as a correlate of protection to bridge animal and clinical data. The challenges associated with this become significant if the mechanism(s) of immunity is not well understood, as is the case for plague.
Protection of the Nation’s warfighters and civilians is crucial to the defense of the United States. One of the threats faced by the warfighter and civilians is the offensive use of biological agents intended to either kill or incapacitate. Advanced development efforts for vaccines against botulinum neurotoxin and pneumonic plague are well on the way toward achieving the performance and efficacy objectives required to advance to pivotal testing prior to applying for FDA licensure.