Government-Owned Inventions; Availability for Licensing, 63161-63165 [E8-25210]
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TABLE 2.—ESTIMATED ANNUAL RECORDKEEPING BURDEN1—Continued
No. of
Recordkeepers
Activity
Annual Frequency
per Recordkeeping
Total Annual
Records
Hours per
Record
Total
1 There
135,095
are no capital costs or operating and maintenance costs associated with this collection of information.
C. Costs Associated With Electronic
Submission
dwashington3 on PRODPC61 with NOTICES
Total Hours
There are no capital costs or operating
and maintenance costs associated with
the transition from paper to electronic
submissions. To create an SPL file and
submit it to FDA, a registrant would
need the following tools: A computer,
appropriate software, access to the
Internet, knowledge of terminology and
standards, and access to FDA’s ESG.
Registrants (and most individuals)
have computers and Internet access
available for their use. If a business does
not have an available computer or
access to the Internet, free use of
computers and Internet are usually
available at public facilities, e.g., a
community library; or they may request
a waiver from submitting the
information electronically.
Software is necessary to create a
‘‘document.’’ The SPL file or
‘‘document’’ may be created internally
by a business with experience with SPL
or a business may use a user-friendly
software (XForms)3 available at no cost
for industry use. In addition to the
software, FDA also provides technical
assistance, and other resources,
terminology, and data standards
regarding SPL files.4
Once the SPL file is created, the
registrant would upload the file through
the ESG. A digital certificate is needed
to use the ESG. The digital certificate
binds together the owner’s name and a
pair of electronic keys (a public key and
a private key) that can be used to
encrypt and sign documents. However,
a small fee of up to $20.00 is charged
for the digital certificate and the
registrant may need to renew the
certificate not less than annually. FDA
is not calculating this small fee as cost
of doing business because it is less than
or equal to the biannual courier costs
the registrant incurs for paper
submissions.
3 See https://www.fda.gov/oc/datacouncil/
xforms.html.
4 See https://www.fda.gov/oc/datacouncil/
spl.html.
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Dated: October 15, 2008.
Jeffrey Shuren,
Associate Commissioner for Policy and
Planning.
[FR Doc. E8–25338 Filed 10–22–08; 8:45 am]
BILLING CODE 4160–01–S
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.
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
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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.
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.
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
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Federal Register / Vol. 73, No. 206 / Thursday, October 23, 2008 / Notices
tetravalent vaccine containing a
common 30-nucleotide deletion
(Delta30) in the 3′-untranslated region
(UTR) of the genome of dengue virus
serotypes 1, 2, 3, and 4. The previously
identified Delta30 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
Delta30 mutation yielded a recombinant
virus attenuated in rhesus monkeys to a
level similar to recombinant virus
DEN4Delta30. This established the
transportability of the Delta30 mutation
and its attenuation phenotype to a
dengue virus type other than DEN4. The
effective transferability of the Delta30
mutation establishes the usefulness of
the Delta30 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 Delta30
mutation is being developed. The
presence of the Delta30 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
Delta30 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.
Live Attenuated Vaccine to Prevent
Disease Caused by West Nile Virus
Description of Technology: WNV has
recently emerged in the U.S. and is
considered a significant emerging
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disease that has embedded itself over a
considerable region of the U.S. WNV
infections have been recorded in
humans as well as in different animals.
To date, WNV has killed 294 people in
the U.S. and caused severe disease in
more than 4222 others. This project is
part of NIAID’s comprehensive
emerging infectious disease program,
which supports research on bacterial,
viral, and other types of disease-causing
microbes.
The methods and compositions of this
invention provide a means for
prevention of WNV infection by
immunization with attenuated,
immunogenic viral vaccines against
WNV. The invention involves a
chimeric virus form consisting of parts
of WNV and Dengue virus. Construction
of the hybrids and their properties are
described in detail in AG Pletnev et al.,
PNAS 2002; 99(5): 3036–3041.
The WNV chimeric vaccine does not
target the central nervous system, which
would be the case in an infection with
wild type WNV. The vaccine stimulates
strong anti-WNV immune responses,
even following a single dose of the
vaccine. When injected into mice, the
vaccine protected all of the immunized
animals from subsequent exposure to
the New York WNV strain. The vaccine
was also effective in primates.
The WNV vaccine may be used to
protect the human population,
particularly the elderly people, and
domestic animals from WNV infection
in the affected regions of the U.S. as
well as worldwide.
Inventors: Alexander G. Pletnev et al.
(NIAID).
Patent Status: U.S. Patent Application
No. 10/871,775 filed 18 Jun 2004 (HHS
Reference No. E–357–2001/1–US–02).
Licensing Status: Available for
exclusive or non-exclusive licensing for
developing a vaccine against WNV for
humans or veterinary use in accordance
with 35 U.S.C. 207 and 37 CFR Part 404.
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 is seeking statements
of capability or interest from parties
interested in collaborative research to
further develop, evaluate, and
commercialize this technology. Please
contact Percy Pan at 301–451–3523 or
panp@niaid.nih.gov for more
information.
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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 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 DEN1Delta30 and
DEN4Delta30 viruses have been shown
to be both safe and immunogenic in
humans. However, the Delta30 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
Delta30 mutation or additional
mutations which remove stem-loop
structures similar to those removed by
Delta30. In addition, the entire 3′-UTR
of DEN3 was replaced with the 3′-UTR
derived from DEN4 and containing the
Delta30 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.
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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
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.
Live Attenuated Virus Vaccines for La
Crosse Virus and Other Bunyaviridae
Description of Technology: 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.
This application principally claims
live attenuated LACV vaccine
compositions, but also includes subunit
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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: PCT Application No.
PCT/US2008/056099 filed 06 Mar 2008,
claiming priority to 29 Mar 2007 (HHS
Reference No. E–158–2007/3–PCT–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 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 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 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 Technology: 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
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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.
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: PCT Application No.
PCT/US2008/066445 filed 10 Jun 2008,
claiming priority to 14 Jun 2007 (HHS
Reference No. E–240–2007/0–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.
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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 live attenuated virus
vaccine candidates for St. Louis
encephalitis virus. Please contact Dr.
Whitehead at 301–496–7692 for more
information.
dwashington3 on PRODPC61 with NOTICES
Generation of Wild-Type Dengue
Viruses for Use in Rhesus Monkey
Infection Studies
Description of Technology: Dengue
virus is a positive-sense RNA virus
belonging to the Flavivirus genus of the
family Flaviviridae. Dengue virus is
widely distributed throughout the
tropical and semitropical regions of the
world and is transmitted to humans by
mosquito vectors. Dengue virus is a
leading cause of hospitalization and
death in children in at least eight
tropical Asian countries. There are four
serotypes of dengue virus (DEN–1,
DEN–2, DEN–3, and DEN–4) that
annually cause an estimated 50–100
million cases of dengue fever and
500,000 cases of the more severe form
of dengue virus infection known as
dengue hemorrhagic fever/dengue shock
syndrome (DHFIDSS). This latter
disease is seen predominately in
children and adults experiencing a
second dengue virus infection with a
serotype different than that of their first
dengue virus infection and in primary
infection of infants who still have
circulating dengue-specific maternal
antibody. A vaccine is needed to lessen
the disease burden caused by dengue
virus, but none is licensed.
Because of the association of more
severe disease with secondary dengue
virus infection, a successful vaccine
must induce immunity to all four
serotypes. Immunity is primarily
mediated by neutralizing antibody
directed against the envelope (E)
glycoprotein, a virion structural protein.
Infection with one serotype induces
long-lived homotypic immunity and a
short-lived heterotypic immunity.
Therefore, the goal of immunization is
to induce a long-lived neutralizing
antibody response against DEN–1, DEN–
2, DEN–3, and DEN–4, which can best
be achieved economically using live
attenuated virus vaccines. This is a
reasonable goal since a live attenuated
vaccine has already been developed for
the related yellow fever virus, another
mosquito-borne flavivirus present in
tropical and semitropical regions of the
world.
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The evaluation of live attenuated
dengue vaccine candidates in rhesus
monkeys requires wild type control
viruses for each of the four dengue
serotypes. These control viruses are
used for comparison to the attenuated
strains and post-vaccination challenge
to assess vaccine efficacy. As such,
these viruses need to be well
characterized and sufficiently pure to
ensure that they will replicate to
consistent levels in rhesus monkeys.
Characterization generally includes
sequence analysis, titration, and
evaluation in monkeys. The following
viruses have been characterized: (1)
DEN1 WP (2) DEN1 Puerto Rico/94 (3)
DEN2 NGC prototype (4) DEN2 Tonga/
74 (5) DEN3 Sleman/78 and (6) DEN4
Dominica/81.
Application: Dengue/flavivirus
vaccine studies, dengue/flavivirus
diagnostics, dengue/flavivirus research
tools.
Development Status: Materials are
available for transfer.
Inventors: Stephen S. Whitehead and
Joseph E. Blaney, Jr. (NIAID).
Publications:
1. AP Durbin, RA Karron, W Sun, DW
Vaughn, MJ Reynolds, JR Perreault, B
Thumar, R Men, C-J Lai, WR Elkins, RM
Chanock, BR Murphy, SS Whitehead. A
live attenuated dengue virus type 4
vaccine candidate with a 30 nucleotide
deletion in the 3′ untranslated region is
highly attenuated and immunogenic in
humans. Am J Trop Med Hyg. 2001 Nov;
65(5): 405–413.
2. SS Whitehead, B Falgout, KA
Hanley, JE Blaney Jr., L Markoff, BR
Murphy. A live, attenuated dengue virus
type 1 vaccine candidate with a 30nucleotide deletion in the 3′
untranslated region is highly attenuated
and immunogenic in monkeys. J Virol.
2003 Jan; 77(2): 1653–1657.
3. SS Whitehead, KA Hanley, JE
Blaney Jr., LE Gilmore, WR Elkins, BR
Murphy. Substitution of the structural
genes of dengue virus type 4 with those
of type 2 results in chimeric vaccine
candidates which are attenuated for
mosquitoes, mice, and rhesus monkeys.
Vaccine 2003 Oct 1; 21(27–30): 4307–
4316.
4. JE Blaney Jr., CT Hanson, KA
Hanley, BR Murphy, SS Whitehead.
Vaccine candidates derived from a
novel infectious cDNA clone of an
American genotype dengue virus type 2.
BMC Infect Dis. 2004 Oct 4;4:39.
5. JE Blaney Jr., CT Hanson, CY
Firestone, KA Hanley, BR Murphy, SS
Whitehead. Genetically modified, live
attenuated dengue virus type 3 vaccine
candidates. Am J Trop Med Hyg. 2004
Dec; 71(6): 811–821.
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6. JE Blaney Jr., JM Matro, BR
Murphy, SS Whitehead. Recombinant,
live-attenuated tetravalent dengue virus
vaccine formulations induce a balanced,
broad, and protective neutralizing
antibody response against each of the
four serotypes in rhesus monkeys. J
Virol. 2005 May; 79(9): 5516–5528.
7. JE Blaney Jr., NS Sathe, CT Hanson,
CY Firestone, BR Murphy, SS
Whitehead. Vaccine candidates for
dengue virus type 1 (DEN1) generated
by replacement of the structural genes of
rDEN4 and rDEN4Delta30 with those of
DEN1. Virol J. 2007 Feb 28; 4:23.
Patent Status: HHS Reference No. E–
042–2008/0—Research Tool. Patent
protection is not being pursued for this
technology.
Licensing Status: Available for
nonexclusive biological materials
licensing only.
Licensing Contact: Peter A. Soukas,
J.D.; 301–435–4646;
soukasp@mail.nih.gov.
Monoclonal Antibodies Against Dengue
and Other Viruses With Deletion in Fc
Region
Description of Technology: 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
any of the DENV serotypes may be
asymptomatic or may lead to classic
dengue fever or more severe dengue
hemorrhagic fever (DHF) and dengue
shock syndrome (DSS), which are
increasingly common in the dengue
endemic areas. Immunity to the same
virus serotype (homotypic immunity) is
life-long, whereas immunity to different
serotypes (heterotypic immunity) lasts
2–3 months so that infection with a
different serotype virus is possible.
DHF/DSS often occurs in patients with
second, heterotypic DENV infections or
in infants with maternally transferred
dengue immunity. Severe dengue is a
major cause of hospitalization, and
fatality rates vary from <1% to 5% in
children.
Antibody-dependent enhancement
(ADE) has been proposed as an
underlying pathogenic mechanism of
DHF/DSS. ADE occurs because
preexisting subneutralizing antibodies
and the infecting DENV form complexes
that bind to Fc receptor-bearing cells,
leading to increased virus uptake and
replication. ADE has been repeatedly
demonstrated in vitro using dengue
immune sera or monoclonal antibodies
and cells of monocytic and recently, B
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Federal Register / Vol. 73, No. 206 / Thursday, October 23, 2008 / Notices
and subtropical areas where Aedes
albopictus and Aedes aegypti
mosquitoes are abundant. Dengue
infection produces fever, rash, and joint
pain in humans. A more severe and lifethreatening form of dengue,
characterized by hemorrhagic fever and
hemorrhagic shock, has occurred with
increasing frequency in Southeast Asia
and Central and South America, where
all four dengue virus serotypes
circulate. A safe and effective vaccine
against dengue is currently not
available. Passive immunization with
monoclonal antibodies from non-human
primates or humans represents a
possible alternative to vaccines for
prevention of illness caused by dengue
virus.
The application claims monoclonal
antibodies that bind or neutralize
dengue type 1, 2, 3, and/or 4 viruses.
The application also claims fragments of
such antibodies retaining dengue virusbinding ability, fully human or
humanized antibodies retaining dengue
virus-binding ability, and
pharmaceutical compositions including
such antibodies. The application also
claims isolated nucleic acids encoding
the antibodies of the invention.
Additionally, application claims
prophylactic, therapeutic, and
diagnostic methods employing the
antibodies and nucleic acids of the
invention.
Application: Prophylaxis against
dengue serotypes 1, 2, 3 and 4.
Development Status: Antibodies have
been synthesized and preclinical studies
have been performed.
Inventors: Ching-Juh Lai and Robert
Purcell (NIAID).
Publications: The antibodies are
further described in:
1. R Men et al. Identification of
chimpanzee Fab fragments by repertoire
cloning and production of a full-length
humanized immunoglobulin G1
antibody that is highly efficient for
neutralization of dengue type 4 virus. J
Virol. 2004 May; 78(9): 4665–4674.
2. AP Goncalvez et al. Chimpanzee
Fab fragments and a derived humanized
immunoglobulin G1 antibody that
efficiently cross-neutralize dengue type
1 and type 2 viruses. J Virol. 2004 Dec;
Monoclonal Antibodies That Bind or
78(23): 12910–12918.
Neutralize Dengue Virus
3. AP Goncalvez et al. Epitope
Description of Technology: Among the determinants of a chimpanzee Fab
arthropod-borne flaviviruses, the four
antibody that efficiently crossdengue virus serotypes, dengue type 1
neutralizes dengue type 1 and type 2
virus (DENV–1), dengue type 2 virus
viruses map to inside and in close
(DENV–2), dengue type 3 virus (DENV– proximity to fusion loop of the dengue
3), and dengue type 4 virus (DENV–4
type 2 virus envelope glycoprotein. J
are most important in terms of human
Virol. 2004 Dec; 78(23): 12919–12928.
4. AP Goncalvez et al. Monoclonal
morbidity and geographic distribution.
antibody-mediated enhancement of
Dengue viruses cause dengue outbreaks
dengue virus infection in vitro and in
and major epidemics in most tropical
dwashington3 on PRODPC61 with NOTICES
lymphocytic lineages bearing Fc
receptors. ADE of DENV–2 infection has
also been demonstrated in monkeys
infused with a human dengue immune
serum.
We have identified chimpanzeehuman chimeric IgG1 mAbs capable of
neutralizing or binding to one or more
DENV serotypes. Cross-reactive IgG 1A5
neutralizes DENV–1 and DENV–2 more
efficiently than DENV–3 and DENV–4,
and type-specific IgG 5H2 neutralizes
DENV–4 at a high titer. Analysis of
antigenic variants has localized the IgG
1A5 binding site to the conserved fusion
peptide in E. Thus, IgG 1A5 shares
many characteristics with the crossreactive antibodies detected in
flavivirus infections.
This application claims a variant of an
antibody comprising a polypeptide in
the Fc region, which binds an Fc gamma
receptor (FcgammaR) with lower affinity
than the parent antibody. The variant
polypeptide comprises a deletion of
nine amino acids at the N-terminus of
the CH2 domain in the Fc region.
Introduction of the Fc variant abrogates
the antibody-mediated dengue virus
replication enhancing activity. This
invention has important implications
for the antibody-mediated prevention of
dengue virus infection.
Application: Immunization against
Dengue and/or flaviviruses.
Developmental Status: Antibody
candidates have been synthesized and
preclinical studies have been
performed.
Inventors: Ana Goncalvez, Robert
Purcell, C.J. Lai (NIAID).
Publication: AP Goncalvez et. al.
Monoclonal antibody-mediated
enhancement of dengue virus infection
in vitro and in vivo and strategies for
prevention. Proc Natl Acad Sci USA.
2007 May 29; 104(22): 9422–9427.
Patent Status: PCT Application No.
PCT/US2008/059313 filed 03 Apr 2008,
claiming priority to 04 Apr 2007 (HHS
Reference No. E–159–2007/3–PCT–01).
Licensing Status: Available for
exclusive or non-exclusive licensing.
Licensing Contact: Peter A. Soukas,
J.D.; 301–435–4646;
soukasp@mail.nih.gov.
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vivo and strategies for prevention. Proc
Natl Acad Sci U.S.A. 2007 May 29;
104(22): 9422–9427.
Patent Status: U.S. Patent Application
No. 10/582,006 filed 07 Jun 2006 (HHS
Reference No. E–066–2003/5–US–02);
Canadian Patent Application No.
2548808 filed 03 Dec 2004 (HHS
Reference No. E–066–2003/5–CA–03).
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
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 this technology. Please
contact Ching-Juh Lai at 301–594–2422
for more information.
Dated: October 14, 2008.
Richard U. Rodriguez,
Director, Division of Technology Development
and Transfer, Office of Technology Transfer,
National Institutes of Health.
[FR Doc. E8–25210 Filed 10–22–08; 8:45 am]
BILLING CODE 4140–01–P
DEPARTMENT OF HEALTH AND
HUMAN SERVICES
National Institutes of Health
Government-Owned Inventions;
Availability for Licensing
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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]]>Agencies
[Federal Register Volume 73, Number 206 (Thursday, October 23, 2008)]
[Notices]
[Pages 63161-63165]
From the Federal Register Online via the Government Printing Office [www.gpo.gov]
[FR Doc No: E8-25210]
-----------------------------------------------------------------------
DEPARTMENT OF HEALTH AND HUMAN SERVICES
National Institutes of Health
Government-Owned Inventions; Availability for Licensing
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 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.
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
[[Page 63162]]
tetravalent vaccine containing a common 30-nucleotide deletion
(Delta30) in the 3'-untranslated region (UTR) of the genome of dengue
virus serotypes 1, 2, 3, and 4. The previously identified Delta30
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 Delta30 mutation yielded
a recombinant virus attenuated in rhesus monkeys to a level similar to
recombinant virus DEN4Delta30. This established the transportability of
the Delta30 mutation and its attenuation phenotype to a dengue virus
type other than DEN4. The effective transferability of the Delta30
mutation establishes the usefulness of the Delta30 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 Delta30 mutation is being developed.
The presence of the Delta30 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 Delta30 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.
Live Attenuated Vaccine to Prevent Disease Caused by West Nile Virus
Description of Technology: WNV has recently emerged in the U.S. and
is considered a significant emerging disease that has embedded itself
over a considerable region of the U.S. WNV infections have been
recorded in humans as well as in different animals. To date, WNV has
killed 294 people in the U.S. and caused severe disease in more than
4222 others. This project is part of NIAID's comprehensive emerging
infectious disease program, which supports research on bacterial,
viral, and other types of disease-causing microbes.
The methods and compositions of this invention provide a means for
prevention of WNV infection by immunization with attenuated,
immunogenic viral vaccines against WNV. The invention involves a
chimeric virus form consisting of parts of WNV and Dengue virus.
Construction of the hybrids and their properties are described in
detail in AG Pletnev et al., PNAS 2002; 99(5): 3036-3041.
The WNV chimeric vaccine does not target the central nervous
system, which would be the case in an infection with wild type WNV. The
vaccine stimulates strong anti-WNV immune responses, even following a
single dose of the vaccine. When injected into mice, the vaccine
protected all of the immunized animals from subsequent exposure to the
New York WNV strain. The vaccine was also effective in primates.
The WNV vaccine may be used to protect the human population,
particularly the elderly people, and domestic animals from WNV
infection in the affected regions of the U.S. as well as worldwide.
Inventors: Alexander G. Pletnev et al. (NIAID).
Patent Status: U.S. Patent Application No. 10/871,775 filed 18 Jun
2004 (HHS Reference No. E-357-2001/1-US-02).
Licensing Status: Available for exclusive or non-exclusive
licensing for developing a vaccine against WNV for humans or veterinary
use in accordance with 35 U.S.C. 207 and 37 CFR Part 404.
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 is seeking statements of capability or
interest from parties interested in collaborative research to further
develop, evaluate, and commercialize this technology. Please contact
Percy Pan at 301-451-3523 or panp@niaid.nih.gov 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 DEN1Delta30 and DEN4Delta30 viruses have
been shown to be both safe and immunogenic in humans. However, the
Delta30 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 Delta30 mutation or additional
mutations which remove stem-loop structures similar to those removed by
Delta30. In addition, the entire 3'-UTR of DEN3 was replaced with the
3'-UTR derived from DEN4 and containing the Delta30 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.
[[Page 63163]]
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 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.
Live Attenuated Virus Vaccines for La Crosse Virus and Other
Bunyaviridae
Description of Technology: 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: PCT Application No. PCT/US2008/056099 filed 06 Mar
2008, claiming priority to 29 Mar 2007 (HHS Reference No. E-158-2007/3-
PCT-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 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
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 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 Technology: 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.
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: PCT Application No. PCT/US2008/066445 filed 10 Jun
2008, claiming priority to 14 Jun 2007 (HHS Reference No. E-240-2007/0-
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.
[[Page 63164]]
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
live attenuated virus vaccine candidates for St. Louis encephalitis
virus. Please contact Dr. Whitehead at 301-496-7692 for more
information.
Generation of Wild-Type Dengue Viruses for Use in Rhesus Monkey
Infection Studies
Description of Technology: Dengue virus is a positive-sense RNA
virus belonging to the Flavivirus genus of the family Flaviviridae.
Dengue virus is widely distributed throughout the tropical and
semitropical regions of the world and is transmitted to humans by
mosquito vectors. Dengue virus is a leading cause of hospitalization
and death in children in at least eight tropical Asian countries. There
are four serotypes of dengue virus (DEN-1, DEN-2, DEN-3, and DEN-4)
that annually cause an estimated 50-100 million cases of dengue fever
and 500,000 cases of the more severe form of dengue virus infection
known as dengue hemorrhagic fever/dengue shock syndrome (DHFIDSS). This
latter disease is seen predominately in children and adults
experiencing a second dengue virus infection with a serotype different
than that of their first dengue virus infection and in primary
infection of infants who still have circulating dengue-specific
maternal antibody. A vaccine is needed to lessen the disease burden
caused by dengue virus, but none is licensed.
Because of the association of more severe disease with secondary
dengue virus infection, a successful vaccine must induce immunity to
all four serotypes. Immunity is primarily mediated by neutralizing
antibody directed against the envelope (E) glycoprotein, a virion
structural protein. Infection with one serotype induces long-lived
homotypic immunity and a short-lived heterotypic immunity. Therefore,
the goal of immunization is to induce a long-lived neutralizing
antibody response against DEN-1, DEN-2, DEN-3, and DEN-4, which can
best be achieved economically using live attenuated virus vaccines.
This is a reasonable goal since a live attenuated vaccine has already
been developed for the related yellow fever virus, another mosquito-
borne flavivirus present in tropical and semitropical regions of the
world.
The evaluation of live attenuated dengue vaccine candidates in
rhesus monkeys requires wild type control viruses for each of the four
dengue serotypes. These control viruses are used for comparison to the
attenuated strains and post-vaccination challenge to assess vaccine
efficacy. As such, these viruses need to be well characterized and
sufficiently pure to ensure that they will replicate to consistent
levels in rhesus monkeys. Characterization generally includes sequence
analysis, titration, and evaluation in monkeys. The following viruses
have been characterized: (1) DEN1 WP (2) DEN1 Puerto Rico/94 (3) DEN2
NGC prototype (4) DEN2 Tonga/74 (5) DEN3 Sleman/78 and (6) DEN4
Dominica/81.
Application: Dengue/flavivirus vaccine studies, dengue/flavivirus
diagnostics, dengue/flavivirus research tools.
Development Status: Materials are available for transfer.
Inventors: Stephen S. Whitehead and Joseph E. Blaney, Jr. (NIAID).
Publications:
1. AP Durbin, RA Karron, W Sun, DW Vaughn, MJ Reynolds, JR
Perreault, B Thumar, R Men, C-J Lai, WR Elkins, RM Chanock, BR Murphy,
SS Whitehead. A live attenuated dengue virus type 4 vaccine candidate
with a 30 nucleotide deletion in the 3' untranslated region is highly
attenuated and immunogenic in humans. Am J Trop Med Hyg. 2001 Nov;
65(5): 405-413.
2. SS Whitehead, B Falgout, KA Hanley, JE Blaney Jr., L Markoff, BR
Murphy. A live, attenuated dengue virus type 1 vaccine candidate with a
30-nucleotide deletion in the 3' untranslated region is highly
attenuated and immunogenic in monkeys. J Virol. 2003 Jan; 77(2): 1653-
1657.
3. SS Whitehead, KA Hanley, JE Blaney Jr., LE Gilmore, WR Elkins,
BR Murphy. Substitution of the structural genes of dengue virus type 4
with those of type 2 results in chimeric vaccine candidates which are
attenuated for mosquitoes, mice, and rhesus monkeys. Vaccine 2003 Oct
1; 21(27-30): 4307-4316.
4. JE Blaney Jr., CT Hanson, KA Hanley, BR Murphy, SS Whitehead.
Vaccine candidates derived from a novel infectious cDNA clone of an
American genotype dengue virus type 2. BMC Infect Dis. 2004 Oct 4;4:39.
5. JE Blaney Jr., CT Hanson, CY Firestone, KA Hanley, BR Murphy, SS
Whitehead. Genetically modified, live attenuated dengue virus type 3
vaccine candidates. Am J Trop Med Hyg. 2004 Dec; 71(6): 811-821.
6. JE Blaney Jr., JM Matro, BR Murphy, SS Whitehead. Recombinant,
live-attenuated tetravalent dengue virus vaccine formulations induce a
balanced, broad, and protective neutralizing antibody response against
each of the four serotypes in rhesus monkeys. J Virol. 2005 May; 79(9):
5516-5528.
7. JE Blaney Jr., NS Sathe, CT Hanson, CY Firestone, BR Murphy, SS
Whitehead. Vaccine candidates for dengue virus type 1 (DEN1) generated
by replacement of the structural genes of rDEN4 and rDEN4Delta30 with
those of DEN1. Virol J. 2007 Feb 28; 4:23.
Patent Status: HHS Reference No. E-042-2008/0--Research Tool.
Patent protection is not being pursued for this technology.
Licensing Status: Available for nonexclusive biological materials
licensing only.
Licensing Contact: Peter A. Soukas, J.D.; 301-435-4646;
soukasp@mail.nih.gov.
Monoclonal Antibodies Against Dengue and Other Viruses With Deletion in
Fc Region
Description of Technology: 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 any of the
DENV serotypes may be asymptomatic or may lead to classic dengue fever
or more severe dengue hemorrhagic fever (DHF) and dengue shock syndrome
(DSS), which are increasingly common in the dengue endemic areas.
Immunity to the same virus serotype (homotypic immunity) is life-long,
whereas immunity to different serotypes (heterotypic immunity) lasts 2-
3 months so that infection with a different serotype virus is possible.
DHF/DSS often occurs in patients with second, heterotypic DENV
infections or in infants with maternally transferred dengue immunity.
Severe dengue is a major cause of hospitalization, and fatality rates
vary from <1% to 5% in children.
Antibody-dependent enhancement (ADE) has been proposed as an
underlying pathogenic mechanism of DHF/DSS. ADE occurs because
preexisting subneutralizing antibodies and the infecting DENV form
complexes that bind to Fc receptor-bearing cells, leading to increased
virus uptake and replication. ADE has been repeatedly demonstrated in
vitro using dengue immune sera or monoclonal antibodies and cells of
monocytic and recently, B
[[Page 63165]]
lymphocytic lineages bearing Fc receptors. ADE of DENV-2 infection has
also been demonstrated in monkeys infused with a human dengue immune
serum.
We have identified chimpanzee-human chimeric IgG1 mAbs capable of
neutralizing or binding to one or more DENV serotypes. Cross-reactive
IgG 1A5 neutralizes DENV-1 and DENV-2 more efficiently than DENV-3 and
DENV-4, and type-specific IgG 5H2 neutralizes DENV-4 at a high titer.
Analysis of antigenic variants has localized the IgG 1A5 binding site
to the conserved fusion peptide in E. Thus, IgG 1A5 shares many
characteristics with the cross-reactive antibodies detected in
flavivirus infections.
This application claims a variant of an antibody comprising a
polypeptide in the Fc region, which binds an Fc gamma receptor
(FcgammaR) with lower affinity than the parent antibody. The variant
polypeptide comprises a deletion of nine amino acids at the N-terminus
of the CH2 domain in the Fc region. Introduction of the Fc
variant abrogates the antibody-mediated dengue virus replication
enhancing activity. This invention has important implications for the
antibody-mediated prevention of dengue virus infection.
Application: Immunization against Dengue and/or flaviviruses.
Developmental Status: Antibody candidates have been synthesized and
preclinical studies have been performed.
Inventors: Ana Goncalvez, Robert Purcell, C.J. Lai (NIAID).
Publication: AP Goncalvez et. al. Monoclonal antibody-mediated
enhancement of dengue virus infection in vitro and in vivo and
strategies for prevention. Proc Natl Acad Sci USA. 2007 May 29;
104(22): 9422-9427.
Patent Status: PCT Application No. PCT/US2008/059313 filed 03 Apr
2008, claiming priority to 04 Apr 2007 (HHS Reference No. E-159-2007/3-
PCT-01).
Licensing Status: Available for exclusive or non-exclusive
licensing.
Licensing Contact: Peter A. Soukas, J.D.; 301-435-4646;
soukasp@mail.nih.gov.
Monoclonal Antibodies That Bind or Neutralize Dengue Virus
Description of Technology: Among the arthropod-borne flaviviruses,
the four dengue virus serotypes, dengue type 1 virus (DENV-1), dengue
type 2 virus (DENV-2), dengue type 3 virus (DENV-3), and dengue type 4
virus (DENV-4 are most important in terms of human morbidity and
geographic distribution. Dengue viruses cause dengue outbreaks and
major epidemics in most tropical and subtropical areas where Aedes
albopictus and Aedes aegypti mosquitoes are abundant. Dengue infection
produces fever, rash, and joint pain in humans. A more severe and life-
threatening form of dengue, characterized by hemorrhagic fever and
hemorrhagic shock, has occurred with increasing frequency in Southeast
Asia and Central and South America, where all four dengue virus
serotypes circulate. A safe and effective vaccine against dengue is
currently not available. Passive immunization with monoclonal
antibodies from non-human primates or humans represents a possible
alternative to vaccines for prevention of illness caused by dengue
virus.
The application claims monoclonal antibodies that bind or
neutralize dengue type 1, 2, 3, and/or 4 viruses. The application also
claims fragments of such antibodies retaining dengue virus-binding
ability, fully human or humanized antibodies retaining dengue virus-
binding ability, and pharmaceutical compositions including such
antibodies. The application also claims isolated nucleic acids encoding
the antibodies of the invention. Additionally, application claims
prophylactic, therapeutic, and diagnostic methods employing the
antibodies and nucleic acids of the invention.
Application: Prophylaxis against dengue serotypes 1, 2, 3 and 4.
Development Status: Antibodies have been synthesized and
preclinical studies have been performed.
Inventors: Ching-Juh Lai and Robert Purcell (NIAID).
Publications: The antibodies are further described in:
1. R Men et al. Identification of chimpanzee Fab fragments by
repertoire cloning and production of a full-length humanized
immunoglobulin G1 antibody that is highly efficient for neutralization
of dengue type 4 virus. J Virol. 2004 May; 78(9): 4665-4674.
2. AP Goncalvez et al. Chimpanzee Fab fragments and a derived
humanized immunoglobulin G1 antibody that efficiently cross-neutralize
dengue type 1 and type 2 viruses. J Virol. 2004 Dec; 78(23): 12910-
12918.
3. AP Goncalvez et al. Epitope determinants of a chimpanzee Fab
antibody that efficiently cross-neutralizes dengue type 1 and type 2
viruses map to inside and in close proximity to fusion loop of the
dengue type 2 virus envelope glycoprotein. J Virol. 2004 Dec; 78(23):
12919-12928.
4. AP Goncalvez et al. Monoclonal antibody-mediated enhancement of
dengue virus infection in vitro and in vivo and strategies for
prevention. Proc Natl Acad Sci U.S.A. 2007 May 29; 104(22): 9422-9427.
Patent Status: U.S. Patent Application No. 10/582,006 filed 07 Jun
2006 (HHS Reference No. E-066-2003/5-US-02); Canadian Patent
Application No. 2548808 filed 03 Dec 2004 (HHS Reference No. E-066-
2003/5-CA-03).
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 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
this technology. Please contact Ching-Juh Lai at 301-594-2422 for more
information.
Dated: October 14, 2008.
Richard U. Rodriguez,
Director, Division of Technology Development and Transfer, Office of
Technology Transfer, National Institutes of Health.
[FR Doc. E8-25210 Filed 10-22-08; 8:45 am]
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