Government-Owned Inventions; Availability for Licensing: Flavivirus Technologies, 4596-4598 [E8-1234]
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Federal Register / Vol. 73, No. 17 / Friday, January 25, 2008 / Notices
novel anti-HIV human monoclonal
antibody named X5. This antibody
demonstrates promise over conventional
anti-HIV antibodies because the X5
antibody exhibits a unique binding
activity compared to its counterparts. It
has been established that the initial
stage of HIV–1 entry into cells is
mediated by a complex between the
viral envelope glycoprotein (Env) such
as gp120-gp41, a receptor CD4 and a coreceptor CCR5. The X5 antibody binds
to an epitope on gp120 that is induced
by interaction between gp120 and the
receptor CD4 and enhanced by the coreceptor CCR5. The X5 antibody also
shows strong activity at very low levels
(in the range from 0.0001—0.1 Mg/ml
concentration based on the particular
isolate). Because it is a human antibody,
it can be administered directly into
patients so that it is an ideal candidate
for clinical trials. It also can be easily
produced because it was obtained by
screening of phage display libraries and
its sequence is known. Finally, since it
has neutralized all virus envelope
glycoproteins, including those from
primary isolates of different clades, the
epitope is highly conserved and
resistance is unlikely to develop.
Therefore, this antibody and/or its
derivatives including fusion proteins
with CD4 are good candidates for
clinical development.
The second invention (E–251–2004/0)
provides for pharmaceutical
compositions of, and methods of using
potent cross-reactive human
monoclonal antibodies to HIV.
Specifically, the invention describes a
competitive antigen panning (CAP)
method of isolating antibodies that bind
to the gp41 subunit of the HIV–1
envelope glycoprotein. Additionally, the
invention includes compositions of the
aforementioned antibodies and the
epitopes recognized by the antibodies.
Methods of using the invention in the
development of vaccine immunogens
for the treatment and prevention of HIV,
as well as the detection of HIV in a
mammal are also described. The
invention has significant implications in
the development of HIV inhibitors,
vaccines, and research tools for
understanding mechanisms of HIV
entry. Further development of the
disclosed invention may yield novel
therapies and methods in the prevention
of mother-to-child transmission of HIV,
treatment of accidental exposure to HIV,
and chronic infection in patients with
resistance to current therapies.
The prospective exclusive license will
be royalty bearing and will comply with
the terms and conditions of 35 U.S.C.
209 and 37 CFR 404.7. The prospective
exclusive license may be granted unless,
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within 60 days from the date of this
published Notice, NIH receives written
evidence and argument that establishes
that the grant of the license would not
be consistent with the requirements of
35 U.S.C. 209 and 37 CFR 404.7.
The field of use may be limited to the
development of human monoclonal
antibodies for use as a therapeutic or
preventative in HIV infection either
alone or in combination with other
compounds.
Properly filed competing applications
for a license filed in response to this
notice will be treated as objections to
the contemplated license. Comments
and objections submitted in response to
this notice will not be made available
for public inspection, and, to the extent
permitted by law, will not be released
under the Freedom of Information Act,
5 U.S.C. 552.
Dated: January 16, 2008.
Steven M. Ferguson,
Director, Division of Technology Development
and Transfer, Office of Technology Transfer,
National Institutes of Health.
[FR Doc. E8–1258 Filed 1–24–08; 8:45 am]
BILLING CODE 4140–01–P
DEPARTMENT OF HEALTH AND
HUMAN SERVICES
National Institutes of Health
Government-Owned Inventions;
Availability for Licensing: Flavivirus
Technologies
National Institutes of Health,
Public Health Service, HHS.
ACTION: Notice.
AGENCY:
SUMMARY: The inventions listed below
are owned by an agency of the U.S.
Government and are available for
licensing in the U.S. in accordance with
35 U.S.C. 207 to achieve expeditious
commercialization of results of
federally-funded research and
development. Foreign patent
applications are filed on selected
inventions to extend market coverage
for companies and may also be available
for licensing.
ADDRESSES: Licensing information and
copies of the U.S. patent applications
listed below may be obtained by writing
to the indicated licensing contact at the
Office of Technology Transfer, National
Institutes of Health, 6011 Executive
Boulevard, Suite 325, Rockville,
Maryland 20852–3804; telephone: 301/
496–7057; fax: 301/402–0220. A signed
Confidential Disclosure Agreement will
be required to receive copies of the
patent applications.
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Development of Antigenic Chimeric St.
Louis Encephalitis Virus/Dengue Virus
Type Four Recombinant Viruses (SLEV/
DEN4) as Vaccine Candidates for the
Prevention of Disease Caused by SLEV
Description of Invention: St. Louis
Encephalitis Virus (SLEV) is a
mosquito-borne flavivirus that is
endemic in the Americas and causes
sporadic outbreaks of disease in
humans. SLEV is a member of the
Japanese encephalitis virus serocomplex
and is closely related to West Nile Virus
(WNV). St. Louis encephalitis is found
throughout North, Central, and South
America, and the Caribbean, but is a
major public health problem mainly in
the United States. Prior to the outbreak
of West Nile virus in 1999, St. Louis
encephalitis was the most common
human disease caused by mosquitoes in
the United States. Since 1964, there
have been about 4,440 confirmed cases
of St. Louis encephalitis, with an
average of 130 cases per year. Up to
3,000 cases have been reported during
epidemics in some years. Many more
infections occur without symptoms and
go undiagnosed. At present, a vaccine or
FDA approved antiviral therapy is not
available.
The inventors have previously
developed a WNV/Dengue4Delta30
antigenic chimeric virus as a live
attenuated virus vaccine candidate that
contains the WNV premembrane and
envelope (prM and E) proteins on a
dengue virus type 4 (DEN4) genetic
background with a thirty nucleotide
deletion (Delta30) in the DEN4 3’-UTR.
Using a similar strategy, the inventors
have generated an antigenic chimeric
virus, SLE/DEN4Delta30. Preclinical
testing results indicate that
chimerization of SLE with DEN4Delta30
decreased neuroinvasiveness in mice,
did not affect neurovirulence in mice,
and appeared to overattenuate the virus
for non-human primates. Modifications
of the SLE/DEN4Delta30 vaccine
candidate are underway to improve its
immunogenicity.
This application claims live
attenuated chimeric SLE/DEN4Delta30
vaccine compositions and bivalent
WNV/SLE/DEN4Delta30 vaccine
compositions. Also claimed are methods
of treating or preventing SLEV infection
in a mammalian host, methods of
producing a subunit vaccine
composition, isolated polynucleotides
comprising a nucleotide sequence
encoding a SLEV immunogen, methods
for detecting SLEV infection in a
biological sample and infectious
chimeric SLEV.
Application: Immunization against
SLEV or SLEV and WNV.
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Development Status: Live attenuated
vaccine candidates are currently being
developed and preclinical studies in
mice and monkeys are in progress.
Suitable vaccine candidates will then be
evaluated in clinical studies.
Inventors: Stephen S. Whitehead,
Joseph Blaney, Alexander Pletnev, Brian
R. Murphy (NIAID).
Patent Status: U.S. Provisional
Application No. 60/934,730 filed 14 Jun
2007 (HHS Reference No. E–240–2007/
0–US–01).
Licensing Status: Available for
exclusive or non-exclusive licensing.
Collaborative Research Opportunity:
The NIAID Laboratory of Infectious
Diseases is seeking statements of
capability or interest from parties
interested in collaborative research to
further develop, evaluate, or
commercialize live attenuated virus
vaccine candidates for St. Louis
encephalitis virus. Please contact Dr.
Whitehead at 301–496–7692 for more
information.
Live Attenuated Virus Vaccines for La
Crosse Virus and Other Bunyaviridae
Description of Invention: La Crosse
virus (LACV), family Bunyaviridae, is a
mosquito-borne pathogen endemic in
the United States. LACV infection
results in 70–130 clinical cases a year
and is the major cause of pediatric
arboviral encephalitis in North America.
LACV was first identified as human
pathogen in 1960 after its isolation from
a 4 year-old girl from Minnesota who
suffered meningoencephalitis and later
died in La Crosse, Wisconsin. The
majority of LACV infections are mild
and never reported, however serologic
studies estimate annual infection rates
of 10–30/100,000 in endemic areas.
LACV is a member of the California
serogroup of viruses in the genus
Orthobunyavirus. The serogroup
contains members found on five
continents that include human
pathogens such as La Crosse, Snowshoe
hare, and Jamestown Canyon viruses in
North America; Guaroa virus in North
and South America; Inkoo and Tahyna
viruses in Europe; and Lumbo virus in
Africa. Children who recover from
severe La Crosse encephalitis may have
significantly lower IQ scores than
expected and a high prevalence (60% of
those tested) of attention-deficithyperactivity disorder. Seizure
disorders are also common in survivors.
LACV can also cause encephalitis in
immunosuppressed adults. Projected
lifelong economic costs associated with
neurologic sequelae range from
$48,775–3,090,398 per case. At present,
a vaccine or FDA approved antiviral
therapy is not available.
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This application principally claims
live attenuated LACV vaccine
compositions, but also includes subunit
vaccine compositions including
California encephalitis virus (CEV)
serogroup immunogens, attenuated and
inactivated CEV serogroup and chimeric
Bunyaviridae. Also claimed are methods
of treating or preventing CEV serogroup
infection in a mammalian host, methods
of producing a subunit vaccine
composition, isolated polynucleotides
comprising a nucleotide sequence
encoding a CEV serogroup immunogen,
methods for detecting LACV infection in
a biological sample and infectious
chimeric Bunyaviridae.
Application: Immunization against
Bunyaviridae.
Developmental Status: Live
attenuated vaccine candidates are
currently being developed and
preclinical studies in mice and monkeys
are in progress. Suitable vaccine
candidates will then be evaluated in
clinical studies.
Inventors: Stephen S. Whitehead,
Richard S. Bennett, Brian R. Murphy
(NIAID).
Publication: RS Bennett et al. Genome
sequence analysis of La Crosse virus and
in vitro and in vivo phenotypes. Virol
J. 2007 May 8;4:41.
Patent Status: U.S. Provisional
Application No. 60/920,691 filed 29 Mar
2007 (HHS Reference No. E–158–2007/
0–US–01); U.S. Provisional Application
No. 60/928,406 filed 08 May 2007 (HHS
Reference No. E–158–2007/1–US–01);
U.S. Provisional Application filed 29
Jun 2007 (HHS Reference No. E–158–
2007/2–US–01).
Licensing Status: Available for
exclusive or non-exclusive licensing.
Licensing Contact: Peter A. Soukas,
J.D.; 301/435–4646;
soukasp@mail.nih.gov.
Collaborative Research Opportunity:
The NIAID Laboratory of Infectious
Diseases is seeking statements of
capability or interest from parties
interested in collaborative research to
further develop, evaluate, or
commercialize live attenuated virus
vaccine candidates for La Crosse virus
and other Bunyaviridae. Please contact
Dr. Whitehead at 301–496–7692 for
more information.
Development of Dengue Virus Type 3
Vaccine Candidates Containing Either
(1) Nucleotide Deletions in the 3′-UTR
of the Genome Consisting of More Than
30 Contiguous Nucleotides in One or
Multiple Regions, or (2) a 3′-UTR
Derived From DEN4 and Containing the
A30 Nucleotide Deletion
Description of Technology: The
disease burden associated with dengue
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virus infection has increased over the
past several decades in the tropical and
semi-tropical regions of the world,
where over 2 billion people live at risk
of dengue infection. Annually, there are
an estimated fifty (50) to one hundred
(100) million cases of dengue fever,
making development of an effective
vaccine a priority. In addition, there is
a need for a ‘‘travelers vaccine’’ to
protect those visiting dengue virus
endemic areas, similar in scope to other
currently available ‘‘travelers vaccines’’,
such as hepatitis A vaccine.
The previously identified D30
attenuating mutation, created in each
dengue virus serotype by the removal of
30 homologous nucleotides from the 3′UTR, is capable of attenuating wild-type
strains of dengue virus type 1 (DEN1),
type 4 (DEN4) and to a limited extent
type 2 (DEN2). These DEN1D30 and
DEN4D30 viruses have been shown to be
both safe and immunogenic in humans.
However, the D30 mutation failed to
have an attenuating effect on dengue
virus type 3 (DEN3). To generate DEN3
vaccine candidates with a clearly
attenuated phenotype, viruses were
produced containing 3′-UTR deletions
consisting of extensions of the original
D30 mutation or additional mutations
which remove stem-loop structures
similar to those removed by D30. In
addition, the entire 3′-UTR of DEN3 was
replaced with the 3′-UTR derived from
DEN4 and containing the D30 mutation.
Studies in monkeys demonstrated that
these newly developed viruses are
highly attenuated, yet sufficiently
immunogenic to warrant their further
development for use as live attenuated
vaccine candidates. Such viruses are
anticipated to become the DEN3
component of a tetravalent vaccine
formulation designed to immunize
against all four dengue virus serotypes.
Application: Immunization against all
four serotypes of dengue virus.
Developmental Status: Vaccine
candidates have been synthesized and
preclinical studies have been
performed. The vaccine candidates of
this invention are slated to enter Phase
I clinical trials in the next year.
Inventors: Stephen S. Whitehead,
Joseph E. Blaney, Brian R. Murphy
(NIAID).
Patent Status: PCT Application No.
PCT/US2007/076004 filed 15 Aug 2007,
claiming priority to 15 Aug 2006 (HHS
Reference No. E–139–2006/0–PCT–02).
Licensing Status: Available for
exclusive or non-exclusive licensing.
Licensing Contact: Peter A. Soukas,
J.D.; 301/435–4646;
soukasp@mail.nih.gov.
Collaborative Research Opportunity:
The National Institute of Allergy and
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4598
Federal Register / Vol. 73, No. 17 / Friday, January 25, 2008 / Notices
Infectious Diseases, Laboratory of
Infectious Diseases, is seeking
statements of capability or interest from
parties interested in collaborative
research to further develop, evaluate, or
commercialize these vaccines. Please
contact Dr. Brian Murphy at 301–594–
1616 or bm25f@nih.gov for more
information.
jlentini on PROD1PC65 with NOTICES
Dengue Tetravalent Vaccine Containing
a Common 30-Nucleotide Deletion in
the 3′-UTR of Dengue Types 1, 2, 3, and
4
Description of Technology: The
invention relates to a dengue virus
tetravalent vaccine containing a
common 30-nucleotide deletion (D30) in
the 3′-untranslated region (UTR) of the
genome of dengue virus serotypes 1, 2,
3, and 4. The previously identified D30
attenuating mutation, created in dengue
virus type 4 (DEN4) by the removal of
30 nucleotides from the 3′-UTR, is also
capable of attenuating a wild-type strain
of dengue virus type 1 (DEN1). Removal
of 30 nucleotides from the DEN1 3′-UTR
in a highly conserved region
homologous to the DEN4 region
encompassing the D30 mutation yielded
a recombinant virus attenuated in
rhesus monkeys to a level similar to
recombinant virus DEN4D30. This
established the transportability of the
D30 mutation and its attenuation
phenotype to a dengue virus type other
than DEN4. The effective transferability
of the D30 mutation establishes the
usefulness of the D30 mutation to
attenuate and improve the safety of
commercializable dengue virus vaccines
of any serotype.
A tetravalent dengue virus vaccine
containing dengue virus types 1, 2, 3,
and 4 each attenuated by the D30
mutation is being developed. The
presence of the D30 attenuating
mutation in each virus component
precludes the reversion to a wild-type
virus by intertypic recombination. In
addition, because of the inherent genetic
stability of deletion mutations, the D30
mutation represents an excellent
alternative for use as a common
mutation shared among each component
of a tetravalent vaccine.
Inventors: Stephen S. Whitehead
(NIAID), Brian R. Murphy (NIAID),
Lewis Markoff (FDA), Barry Falgout
(FDA), Kathryn A. Hanley (NIAID),
Joseph E. Blaney (NIAID).
Patent Status: U.S. Patent Application
No. 10/970,640 filed 21 Oct 2004,
claiming priority to 03 May 2002 (HHS
Reference No. E–089–2002/1–US–02).
Licensing Contact: Peter A. Soukas,
J.D.; 301/435–4646;
soukasp@mail.nih.gov.
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Collaborative Research Opportunity:
The National Institute of Allergy and
Infectious Diseases, Laboratory of
Infectious Diseases, is seeking
statements of capability or interest from
parties interested in collaborative
research to further develop, evaluate, or
commercialize these vaccines. Please
contact Dr. Brian Murphy at 301–594–
1616 or bm25f@nih.gov for more
information.
Collaborative Research Opportunity:
The National Institute of Allergy and
Infectious Diseases, Laboratory of
Infectious Diseases, is seeking
statements of capability or interest from
parties interested in collaborative
research to further develop, evaluate, or
commercialize these vaccines. Please
contact Dr. Brian Murphy at 301–594–
1616 or bm25f@nih.gov for more
information.
Development of Mutations Useful for
Attenuating Dengue Viruses and
Chimeric Dengue Viruses
Description of Technology: Although
flaviviruses cause a great deal of human
suffering and economic loss, there is a
shortage of effective vaccines. This
invention relates to dengue virus
mutations that may contribute to the
development of improved dengue
vaccines. Site directed and random
mutagenesis techniques were used to
introduce mutations into the dengue
virus genome and to assemble a
collection of useful mutations for
incorporation in recombinant live
attenuated dengue virus vaccines. The
resulting mutant viruses were screened
for several valuable phenotypes,
including temperature sensitivity in
Vero cells or human liver cells, host cell
restriction in mosquito cells or human
liver cells, host cell adaptation for
improved replication in Vero cells, and
attenuation in mice or in mosquitoes.
The genetic basis for each observed
phenotype was determined by direct
sequence analysis of the genome of the
mutant virus. Mutations identified
through these sequencing efforts have
been further evaluated by reintroduction of the identified mutations,
singly, or in combination, into
recombinant dengue virus and
characterization of the resulting
recombinant virus for phenotypes. In
this manner, a menu of attenuating and
growth promoting mutations was
developed that is useful in fine-tuning
the attenuation and growth
characteristics of dengue virus vaccine
candidates. The mutations promoting
growth in Vero cells have usefulness for
the production of live or inactivated
dengue virus vaccines.
Inventors: Stephen S. Whitehead,
Brian R. Murphy, Kathryn A. Hanley,
Joseph E. Blaney (NIAID).
Patent Status: U.S. Patent No.
7,226,602 issued 05 Jun 2007 (HHS
Reference No. E–120–2001/0–US–04);
U.S. Patent Application No. 11/446,050
filed 02 Jun 2006 (HHS Reference No.
E–120–2001/0–US–10).
Licensing Contact: Peter A. Soukas,
J.D.; 301/435–4646;
soukasp@mail.nih.gov.
Date: January 10, 2008.
Steven M. Ferguson,
Director, Division of Technology Development
and Transfer, Office of Technology Transfer,
National Institutes of Health.
[FR Doc. E8–1234 Filed 1–24–08; 8:45 am]
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BILLING CODE 4140–01–P
DEPARTMENT OF HEALTH AND
HUMAN SERVICES
National Institutes of Health
Government-Owned Inventions;
Availability for Licensing
National Institutes of Health,
Public Health Service, HHS.
ACTION: Notice.
AGENCY:
SUMMARY: The inventions listed below
are owned by an agency of the U.S.
Government and are available for
licensing in the U.S. in accordance with
35 U.S.C. 207 to achieve expeditious
commercialization of results of
federally-funded research and
development. Foreign patent
applications are filed on selected
inventions to extend market coverage
for companies and may also be available
for licensing.
ADDRESSES: Licensing information and
copies of the U.S. patent applications
listed below may be obtained by writing
to the indicated licensing contact at the
Office of Technology Transfer, National
Institutes of Health, 6011 Executive
Boulevard, Suite 325, Rockville,
Maryland 20852–3804; telephone: 301/
496–7057; fax: 301/402–0220. A signed
Confidential Disclosure Agreement will
be required to receive copies of the
patent applications.
Monoclonal Antibodies Against Dengue
and Other Viruses With Deletion in Fc
Region
Description of Invention: The four
dengue virus (DENV) serotypes (DENV–
1 to DENV–4) are the most important
arthropod-borne flaviviruses in terms of
morbidity and geographic distribution.
Up to 100 million DENV infections
occur every year, mostly in tropical and
subtropical areas where vector
mosquitoes are abundant. Infection with
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]]>Agencies
[Federal Register Volume 73, Number 17 (Friday, January 25, 2008)]
[Notices]
[Pages 4596-4598]
From the Federal Register Online via the Government Printing Office [www.gpo.gov]
[FR Doc No: E8-1234]
-----------------------------------------------------------------------
DEPARTMENT OF HEALTH AND HUMAN SERVICES
National Institutes of Health
Government-Owned Inventions; Availability for Licensing:
Flavivirus Technologies
AGENCY: National Institutes of Health, Public Health Service, HHS.
ACTION: Notice.
-----------------------------------------------------------------------
SUMMARY: The inventions listed below are owned by an agency of the U.S.
Government and are available for licensing in the U.S. in accordance
with 35 U.S.C. 207 to achieve expeditious commercialization of results
of federally-funded research and development. Foreign patent
applications are filed on selected inventions to extend market coverage
for companies and may also be available for licensing.
ADDRESSES: Licensing information and copies of the U.S. patent
applications listed below may be obtained by writing to the indicated
licensing contact at the Office of Technology Transfer, National
Institutes of Health, 6011 Executive Boulevard, Suite 325, Rockville,
Maryland 20852-3804; telephone: 301/496-7057; fax: 301/402-0220. A
signed Confidential Disclosure Agreement will be required to receive
copies of the patent applications.
Development of Antigenic Chimeric St. Louis Encephalitis Virus/Dengue
Virus Type Four Recombinant Viruses (SLEV/DEN4) as Vaccine Candidates
for the Prevention of Disease Caused by SLEV
Description of Invention: St. Louis Encephalitis Virus (SLEV) is a
mosquito-borne flavivirus that is endemic in the Americas and causes
sporadic outbreaks of disease in humans. SLEV is a member of the
Japanese encephalitis virus serocomplex and is closely related to West
Nile Virus (WNV). St. Louis encephalitis is found throughout North,
Central, and South America, and the Caribbean, but is a major public
health problem mainly in the United States. Prior to the outbreak of
West Nile virus in 1999, St. Louis encephalitis was the most common
human disease caused by mosquitoes in the United States. Since 1964,
there have been about 4,440 confirmed cases of St. Louis encephalitis,
with an average of 130 cases per year. Up to 3,000 cases have been
reported during epidemics in some years. Many more infections occur
without symptoms and go undiagnosed. At present, a vaccine or FDA
approved antiviral therapy is not available.
The inventors have previously developed a WNV/Dengue4Delta30
antigenic chimeric virus as a live attenuated virus vaccine candidate
that contains the WNV premembrane and envelope (prM and E) proteins on
a dengue virus type 4 (DEN4) genetic background with a thirty
nucleotide deletion (Delta30) in the DEN4 3'-UTR. Using a similar
strategy, the inventors have generated an antigenic chimeric virus,
SLE/DEN4Delta30. Preclinical testing results indicate that
chimerization of SLE with DEN4Delta30 decreased neuroinvasiveness in
mice, did not affect neurovirulence in mice, and appeared to
overattenuate the virus for non-human primates. Modifications of the
SLE/DEN4Delta30 vaccine candidate are underway to improve its
immunogenicity.
This application claims live attenuated chimeric SLE/DEN4Delta30
vaccine compositions and bivalent WNV/SLE/DEN4Delta30 vaccine
compositions. Also claimed are methods of treating or preventing SLEV
infection in a mammalian host, methods of producing a subunit vaccine
composition, isolated polynucleotides comprising a nucleotide sequence
encoding a SLEV immunogen, methods for detecting SLEV infection in a
biological sample and infectious chimeric SLEV.
Application: Immunization against SLEV or SLEV and WNV.
[[Page 4597]]
Development Status: Live attenuated vaccine candidates are
currently being developed and preclinical studies in mice and monkeys
are in progress. Suitable vaccine candidates will then be evaluated in
clinical studies.
Inventors: Stephen S. Whitehead, Joseph Blaney, Alexander Pletnev,
Brian R. Murphy (NIAID).
Patent Status: U.S. Provisional Application No. 60/934,730 filed 14
Jun 2007 (HHS Reference No. E-240-2007/0-US-01).
Licensing Status: Available for exclusive or non-exclusive
licensing.
Collaborative Research Opportunity: The NIAID Laboratory of
Infectious Diseases is seeking statements of capability or interest
from parties interested in collaborative research to further develop,
evaluate, or commercialize live attenuated virus vaccine candidates for
St. Louis encephalitis virus. Please contact Dr. Whitehead at 301-496-
7692 for more information.
Live Attenuated Virus Vaccines for La Crosse Virus and Other
Bunyaviridae
Description of Invention: La Crosse virus (LACV), family
Bunyaviridae, is a mosquito-borne pathogen endemic in the United
States. LACV infection results in 70-130 clinical cases a year and is
the major cause of pediatric arboviral encephalitis in North America.
LACV was first identified as human pathogen in 1960 after its isolation
from a 4 year-old girl from Minnesota who suffered meningoencephalitis
and later died in La Crosse, Wisconsin. The majority of LACV infections
are mild and never reported, however serologic studies estimate annual
infection rates of 10-30/100,000 in endemic areas. LACV is a member of
the California serogroup of viruses in the genus Orthobunyavirus. The
serogroup contains members found on five continents that include human
pathogens such as La Crosse, Snowshoe hare, and Jamestown Canyon
viruses in North America; Guaroa virus in North and South America;
Inkoo and Tahyna viruses in Europe; and Lumbo virus in Africa. Children
who recover from severe La Crosse encephalitis may have significantly
lower IQ scores than expected and a high prevalence (60% of those
tested) of attention-deficit-hyperactivity disorder. Seizure disorders
are also common in survivors. LACV can also cause encephalitis in
immunosuppressed adults. Projected lifelong economic costs associated
with neurologic sequelae range from $48,775-3,090,398 per case. At
present, a vaccine or FDA approved antiviral therapy is not available.
This application principally claims live attenuated LACV vaccine
compositions, but also includes subunit vaccine compositions including
California encephalitis virus (CEV) serogroup immunogens, attenuated
and inactivated CEV serogroup and chimeric Bunyaviridae. Also claimed
are methods of treating or preventing CEV serogroup infection in a
mammalian host, methods of producing a subunit vaccine composition,
isolated polynucleotides comprising a nucleotide sequence encoding a
CEV serogroup immunogen, methods for detecting LACV infection in a
biological sample and infectious chimeric Bunyaviridae.
Application: Immunization against Bunyaviridae.
Developmental Status: Live attenuated vaccine candidates are
currently being developed and preclinical studies in mice and monkeys
are in progress. Suitable vaccine candidates will then be evaluated in
clinical studies.
Inventors: Stephen S. Whitehead, Richard S. Bennett, Brian R.
Murphy (NIAID).
Publication: RS Bennett et al. Genome sequence analysis of La
Crosse virus and in vitro and in vivo phenotypes. Virol J. 2007 May
8;4:41.
Patent Status: U.S. Provisional Application No. 60/920,691 filed 29
Mar 2007 (HHS Reference No. E-158-2007/0-US-01); U.S. Provisional
Application No. 60/928,406 filed 08 May 2007 (HHS Reference No. E-158-
2007/1-US-01); U.S. Provisional Application filed 29 Jun 2007 (HHS
Reference No. E-158-2007/2-US-01).
Licensing Status: Available for exclusive or non-exclusive
licensing.
Licensing Contact: Peter A. Soukas, J.D.; 301/435-4646;
soukasp@mail.nih.gov.
Collaborative Research Opportunity: The NIAID Laboratory of
Infectious Diseases is seeking statements of capability or interest
from parties interested in collaborative research to further develop,
evaluate, or commercialize live attenuated virus vaccine candidates for
La Crosse virus and other Bunyaviridae. Please contact Dr. Whitehead at
301-496-7692 for more information.
Development of Dengue Virus Type 3 Vaccine Candidates Containing Either
(1) Nucleotide Deletions in the 3'-UTR of the Genome Consisting of More
Than 30 Contiguous Nucleotides in One or Multiple Regions, or (2) a 3'-
UTR Derived From DEN4 and Containing the A30 Nucleotide Deletion
Description of Technology: The disease burden associated with
dengue virus infection has increased over the past several decades in
the tropical and semi-tropical regions of the world, where over 2
billion people live at risk of dengue infection. Annually, there are an
estimated fifty (50) to one hundred (100) million cases of dengue
fever, making development of an effective vaccine a priority. In
addition, there is a need for a ``travelers vaccine'' to protect those
visiting dengue virus endemic areas, similar in scope to other
currently available ``travelers vaccines'', such as hepatitis A
vaccine.
The previously identified [Delta]30 attenuating mutation, created
in each dengue virus serotype by the removal of 30 homologous
nucleotides from the 3'-UTR, is capable of attenuating wild-type
strains of dengue virus type 1 (DEN1), type 4 (DEN4) and to a limited
extent type 2 (DEN2). These DEN1[Delta]30 and DEN4[Delta]30 viruses
have been shown to be both safe and immunogenic in humans. However, the
[Delta]30 mutation failed to have an attenuating effect on dengue virus
type 3 (DEN3). To generate DEN3 vaccine candidates with a clearly
attenuated phenotype, viruses were produced containing 3'-UTR deletions
consisting of extensions of the original [Delta]30 mutation or
additional mutations which remove stem-loop structures similar to those
removed by [Delta]30. In addition, the entire 3'-UTR of DEN3 was
replaced with the 3'-UTR derived from DEN4 and containing the [Delta]30
mutation. Studies in monkeys demonstrated that these newly developed
viruses are highly attenuated, yet sufficiently immunogenic to warrant
their further development for use as live attenuated vaccine
candidates. Such viruses are anticipated to become the DEN3 component
of a tetravalent vaccine formulation designed to immunize against all
four dengue virus serotypes.
Application: Immunization against all four serotypes of dengue
virus.
Developmental Status: Vaccine candidates have been synthesized and
preclinical studies have been performed. The vaccine candidates of this
invention are slated to enter Phase I clinical trials in the next year.
Inventors: Stephen S. Whitehead, Joseph E. Blaney, Brian R. Murphy
(NIAID).
Patent Status: PCT Application No. PCT/US2007/076004 filed 15 Aug
2007, claiming priority to 15 Aug 2006 (HHS Reference No. E-139-2006/0-
PCT-02).
Licensing Status: Available for exclusive or non-exclusive
licensing.
Licensing Contact: Peter A. Soukas, J.D.; 301/435-4646;
soukasp@mail.nih.gov.
Collaborative Research Opportunity: The National Institute of
Allergy and
[[Page 4598]]
Infectious Diseases, Laboratory of Infectious Diseases, is seeking
statements of capability or interest from parties interested in
collaborative research to further develop, evaluate, or commercialize
these vaccines. Please contact Dr. Brian Murphy at 301-594-1616 or
bm25f@nih.gov for more information.
Dengue Tetravalent Vaccine Containing a Common 30-Nucleotide Deletion
in the 3'-UTR of Dengue Types 1, 2, 3, and 4
Description of Technology: The invention relates to a dengue virus
tetravalent vaccine containing a common 30-nucleotide deletion
([Delta]30) in the 3'-untranslated region (UTR) of the genome of dengue
virus serotypes 1, 2, 3, and 4. The previously identified [Delta]30
attenuating mutation, created in dengue virus type 4 (DEN4) by the
removal of 30 nucleotides from the 3'-UTR, is also capable of
attenuating a wild-type strain of dengue virus type 1 (DEN1). Removal
of 30 nucleotides from the DEN1 3'-UTR in a highly conserved region
homologous to the DEN4 region encompassing the [Delta]30 mutation
yielded a recombinant virus attenuated in rhesus monkeys to a level
similar to recombinant virus DEN4[Delta]30. This established the
transportability of the [Delta]30 mutation and its attenuation
phenotype to a dengue virus type other than DEN4. The effective
transferability of the [Delta]30 mutation establishes the usefulness of
the [Delta]30 mutation to attenuate and improve the safety of
commercializable dengue virus vaccines of any serotype.
A tetravalent dengue virus vaccine containing dengue virus types 1,
2, 3, and 4 each attenuated by the [Delta]30 mutation is being
developed. The presence of the [Delta]30 attenuating mutation in each
virus component precludes the reversion to a wild-type virus by
intertypic recombination. In addition, because of the inherent genetic
stability of deletion mutations, the [Delta]30 mutation represents an
excellent alternative for use as a common mutation shared among each
component of a tetravalent vaccine.
Inventors: Stephen S. Whitehead (NIAID), Brian R. Murphy (NIAID),
Lewis Markoff (FDA), Barry Falgout (FDA), Kathryn A. Hanley (NIAID),
Joseph E. Blaney (NIAID).
Patent Status: U.S. Patent Application No. 10/970,640 filed 21 Oct
2004, claiming priority to 03 May 2002 (HHS Reference No. E-089-2002/1-
US-02).
Licensing Contact: Peter A. Soukas, J.D.; 301/435-4646;
soukasp@mail.nih.gov.
Collaborative Research Opportunity: The National Institute of
Allergy and Infectious Diseases, Laboratory of Infectious Diseases, is
seeking statements of capability or interest from parties interested in
collaborative research to further develop, evaluate, or commercialize
these vaccines. Please contact Dr. Brian Murphy at 301-594-1616 or
bm25f@nih.gov for more information.
Development of Mutations Useful for Attenuating Dengue Viruses and
Chimeric Dengue Viruses
Description of Technology: Although flaviviruses cause a great deal
of human suffering and economic loss, there is a shortage of effective
vaccines. This invention relates to dengue virus mutations that may
contribute to the development of improved dengue vaccines. Site
directed and random mutagenesis techniques were used to introduce
mutations into the dengue virus genome and to assemble a collection of
useful mutations for incorporation in recombinant live attenuated
dengue virus vaccines. The resulting mutant viruses were screened for
several valuable phenotypes, including temperature sensitivity in Vero
cells or human liver cells, host cell restriction in mosquito cells or
human liver cells, host cell adaptation for improved replication in
Vero cells, and attenuation in mice or in mosquitoes. The genetic basis
for each observed phenotype was determined by direct sequence analysis
of the genome of the mutant virus. Mutations identified through these
sequencing efforts have been further evaluated by re-introduction of
the identified mutations, singly, or in combination, into recombinant
dengue virus and characterization of the resulting recombinant virus
for phenotypes. In this manner, a menu of attenuating and growth
promoting mutations was developed that is useful in fine-tuning the
attenuation and growth characteristics of dengue virus vaccine
candidates. The mutations promoting growth in Vero cells have
usefulness for the production of live or inactivated dengue virus
vaccines.
Inventors: Stephen S. Whitehead, Brian R. Murphy, Kathryn A.
Hanley, Joseph E. Blaney (NIAID).
Patent Status: U.S. Patent No. 7,226,602 issued 05 Jun 2007 (HHS
Reference No. E-120-2001/0-US-04); U.S. Patent Application No. 11/
446,050 filed 02 Jun 2006 (HHS Reference No. E-120-2001/0-US-10).
Licensing Contact: Peter A. Soukas, J.D.; 301/435-4646;
soukasp@mail.nih.gov.
Collaborative Research Opportunity: The National Institute of
Allergy and Infectious Diseases, Laboratory of Infectious Diseases, is
seeking statements of capability or interest from parties interested in
collaborative research to further develop, evaluate, or commercialize
these vaccines. Please contact Dr. Brian Murphy at 301-594-1616 or
bm25f@nih.gov for more information.
Date: January 10, 2008.
Steven M. Ferguson,
Director, Division of Technology Development and Transfer, Office of
Technology Transfer, National Institutes of Health.
[FR Doc. E8-1234 Filed 1-24-08; 8:45 am]
BILLING CODE 4140-01-P
