Technology
Overview
Francisella
tularensis
is a Gram-negative, facultative intracellular pathogen that causes tularemia, a
debilitating and potentially fatal disease that affects humans and a wide range
of animals. Infections can be acquired through bites from an arthropod
vector, skin lesions, ingestion of contaminated food or water, and by inhalation
of a few as 10 bacteria. The low dose required to cause tularemia by
aerosol route resulted in the development of F. tularensis for use as a
biological weapon by several national weapons programs. The CDC has
classified F. tularensis as a Category A bioterrorism agent, members of
which are considered most serious in posing a risk to national security.
There is currently no approved vaccine available in the U.S. or Europe.
Thus, the development of a vaccine against F. tularensis is an
international priority.
Using
transposon mutagenesis process, mutant strains of F. novicida have been
generated. While F. novicida is not generally considered a human
pathogen, it displays a similar, if not greater, degree of virulence in mice as
other F. tularensis subspecies. In addition to their considerable
genomic similarity, the close relationship between F. novicida and F.
tularensis is further highlighted by their nearly identical 16S rDNA
sequences. The inventors performed a comprehensive screen to identify
essential Francisella virulence factors. The screen identified 13 genes
in which functional deletion conferred hypercytotoxicity in macrophages and
attenuation in mice. The results indicated that functionally deleting one or
more of these genes in other F. tularensis subspecies can be used to
generate immunogenic compositions for use against pathogenic subspecies.
Therefore, novel attenuated strains based on this approach can be utilized in
new vaccine candidates to prevent tularemia or for treating tularemia in
subjects previously infected with or exposed to
Francisella.
Market
Summary
According
to the Centers for Disease Control and Prevention, about 200 cases of tularemia
in humans are reported each year in the United States. However, as a
bioterrorism threat, the market for a vaccine is much greater. A World
Health Organization expert committee reported in 1970 that if 50 kg of virulent
F. tularensis was dispersed as an aerosol over a metropolitan area with a
population of 5 million there would an estimated 250,000 incapacitating
casualties, including 19,000 deaths. Aerosol dissemination of F.
tularensis in a populated area would be expected to result in the abrupt onset
of large numbers of cases of acute, non-specific febrile illness beginning 3 to
5 days later (incubation range, 1-14 days), with pleuropneumonitis developing in
a significant proportion of cases over the ensuing days and weeks. Without
antibiotic treatment, the clinical course could progress to respiratory failure,
shock and death. The overall mortality rate for severe Type A strains has
been 5-15%, but in pulmonic or septicemic cases of tularemia without antibiotics
treatment the mortality rate has been as high as 30-60%. With treatment, the
most recent mortality rates in the US have been 2%.
Competitive
Environment
The
development of a safe and effective tularemia vaccine has proven elusive. In the
United States, a live attenuated vaccine derived from avirulent F. tularensis
biovar palaearctica (type B) has been used to protect personnel routinely
working with F. tularensis and high-risk military personnel. This vaccine
is not available to the general public.
EpiVax,
Inc, a leader in genome-derived vaccines, has recently developed a tularemia
vaccine candidate (TuliVaxTM) that confers protective immunity.
Data on use of this vaccine candidate in mice is encouraging, but no human
trials have been conducted yet.
Inventor
Profile
Fred
Heffron, Ph.D.: Dr. Heffron received his B.A. in 1971 from the University
of Oregon. He completed his Ph.D. in Microbiology at the University of
Washington (1976). Dr. Heffron then conducted a postdoctoral fellowship at
the University of California, San Francisco from 1977-1979. He then held a
position as an Assistant Research Biochemist in the Department of Biochemistry
and Biophysics at UCSF. Dr. Heffron held a Senior Staff Investigator position at
the Cold Spring Harbor Laboratory followed by several years as an Associate
Member of the Department of Molecular Biology at the Scripps Clinic and Research
Foundation. He has been a member of Oregon Health and Science University
since 1988 and currently is a Professor in the Department of Molecular
Microbiology and Immunology.
Future
Research
The
inventors are continuing to test these novel vaccine candidates in mice.
Protective immunity will be analyzed using aerosol challenge in mice. The
candidates will then be tested in Rhesus macaques at the Oregon National Primate
Research Center.
Patent
Status
U.S.
provisional patent application filed.
Licensing
Opportunity
OHSU
1338 is available for collaborative research as well as exclusive
licensing.
