[Federal Register Volume 64, Number 217 (Wednesday, November 10, 1999)]
[Notices]
[Pages 61359-61361]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 99-29368]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

National Institutes of Health


Licensing Opportunity and/or Cooperative Research and Development 
Agreement (``CRADA'') Opportunity; Certain Live Attenuated Respiratory 
Syncytial Viruses (RSV) and Parainfluenza Viruses (PIV) for Use as 
Human Vaccines

AGENCY: National Institutes of Health, Public Health Service, DHHS.

ACTION: Notice.

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SUMMARY: The National Institutes of Health (NIH) is seeking Licensee(s) 
and/or a commercial collaborator(s) to further develop, test, and 
commercialize as live attenuated vaccines certain recombinant RSV and 
PIV strains and associated intellectual property developed in the 
Laboratory of Infectious Diseases (LID), Division of Intramural 
Research, National Institute of Allergy and Infectious Diseases 
(NIAID).

DATES: There is no date by which license applications must be received. 
Respondents who wish to be considered for the CRADA opportunity must 
submit a Capability Statement (described below in SUPPLEMENTARY 
INFORMATION) to the NIAID. Only written Capability Statements received 
by the NIAID on or before December 27, 1999 for consideration. 
Capability Statements should be forwarded to Michael R. Mowatt, Ph.D. 
at the address specified below.

FOR FURTHER INFORMATION CONTACT: Inquiries about these licensing 
opportunities should be addressed to Robert Benson, Ph.D., Patent 
Advisor, Office of Technology Transfer, National Institutes of Health, 
6011 Executive Boulevard, Suite 325, Rockville, Maryland 20852-3804, 
Telephone: (301) 496-7056 ext. 267; Facsimile: (301) 402-0220; Email: 
[email protected]. Information about Patent Applications and pertinent 
information not yet publicly described can be obtained under the terms 
of a Confidential Disclosure Agreement. Respondents interested in 
licensing the inventions will be required to submit an ``Application 
for License to Public Health Service Inventions''.
    Inquiries about the CRADA opportunity should be addressed to 
Michael R. Mowatt, Ph.D., Technology Development Manager, Office of 
Technology Development, NIAID, Building 31 Room 3B62, 31 Center Drive 
MSC 2137, Bethesda, MD 20892-2137, Telephone: (301) 435-8618, 
Facsimile: (301) 402-7123; Email: [email protected]. Respondents 
interested in the CRADA opportunity should be aware that it might be 
necessary to secure a license to the above-mentioned patent rights in 
order to commercialize products arising from a CRADA.

SUPPLEMENTARY INFORMATION: The inventions described below are owned by 
an agency of the U.S. Government and are available for licensing--in 
accordance with 35 U.S.C. 207 and 37 CFR part 404 to achieve 
expeditious commercialization of results of federally-funded research 
and development--and/or further development under one or more CRADAs in 
the clinically important applications described below.
    Human Respiratory Syncytial Viruses (HRSV), subgroups A and B 
(HRSV-A and HRSV-B, respectively), are the most common cause of serious 
respiratory tract infection in children and infants less than one year 
of age. RSV is responsible for more than 20% of all pediatric hospital 
admissions due to respiratory tract disease, and in the US is the cause 
of 91,000 hospitalizations and 4,500 deaths. No licensed vaccine is 
available to prevent disease by these viruses.
    Attenuated RSV strains for intranasal administration are the most 
promising candidate vaccines because they are efficacious even in the 
presence of passively transferred antibodies, the very situation found 
in the target population of infants with maternally derived anti-HRSV 
antibodies. Designed mutations can be introduced into the RSV genome or 
antigenome utilizing cDNA technology as a means of engineering suitably 
attenuated RSV strains. See Collins et al., Proc. Nat. Acad. Sci. USA 
92 11563-11567, 1995, and PCT/US96/15524, ``Production of Infectious 
Respiratory Syncytial Virus From Cloned Nucleotide Sequences'', which 
is available from NIH for licensing nonexclusively.
    Human Parainfluenza Viruses (HPIV), serotypes 1, 2, and 3 (HPIVs, 
HPIV2, and HPIV1, respectively), are in aggregate the second most 
common

[[Page 61360]]

cause of serious respiratory tract infection in children and infants 
less than one year of age. No licensed vaccine is available to prevent 
disease by any of these viruses. Attenuated HPIV strains are the most 
promising candidate vaccines for the same reasons noted above for 
attenuated RSV vaccines. The following seven recently filed patent 
applications are available for licensing for certain virus vaccine 
strains.

Production of Attenuated Chimeric Respiratory Syncytial Virus 
Vaccines From Cloned Nucleotide Sequences

    Inventors: Peter L. Collins, Stephen S. Whitehead and Brian R. 
Murphy.
    Serial Number: 09/291,894 (CIP of 08/892,403, PCT/US97/12269).
    Filing Date: April 13, 1999.
    This patent application broadly describes and claims RSV strains 
that are attenuated recombinant chimeras of two different RSV parental 
strains. The chimeras comprise a background genome or antigenome from 
one strain into which is isnerted or substituted genes or genomic 
segments from a heterologous RSV strain. Introduction of the 
heterologous gene can serve to (a) attenuate the background strain, 
and/or (b) change the immunogenicity of the background strain to the 
heterologous strain or (c) form a chimera with the immunogenicity of 
both the background and heterologous strains. A chimeric virus 
consisting of a RSV Group A background strain into which the F and G 
genes of the RSV Group B virus were substituted was shown to be 
infectious and to raise protective antibodies against RSV Group B in 
chimpanzees. Thus a candidate RSV vaccine strain of one Group with the 
proper balance of attenuation and immunogenicity can now be used to 
make a vaccine against the other Group just by switching the F and/or G 
genes. Certain candidate RSV vaccine strains are not available for 
licensing.

Production of Attenuated, Human-Bovine Chimeric Respiratory 
Syncytial Virus Vaccines

    Inventors: Ursula Buchholz, Peter L. Collins, Brian R. Murphy and 
Stephen S. Whitehead.
    Serial Number: 60/143,132.
    Filing Date: July 9, 1999.
    The inventors have shown that genes may be switched between human 
RSV (HRSV) and bovine RSV (BRSV) and a live, infectious and immunogenic 
chimeric virus can result. Based on this discovery, two approaches are 
contemplated to produce chimeric strains that are vaccine candidates, 
balanced in attenuation and immunogenicity. The first is to start with 
BRSV and substitute in the HRSV F and G genes; this has been done and 
the resulting chimeric strain shown to be highly attenuated in 
chimpanzees. Other HRSV genes or genome segments may be inserted to 
decrease attenuation. The other approach is to start with HRSV and 
introduce BRSV genes, other than the BRSV F and G genes. These host 
range mutants should be extremely stable because of the large number of 
nucleotide and amino acid sequence differences between bovine and human 
RSV genes.

Production of Recombinant Respiratory Syncytial Viruses Expressing 
Immune Modulatory Molecules

    Inventors: Peter L. Collins, Alexander R. Bukreyev, Brian R. Murphy 
and Stephen S. Whitehead.
    Serial Number: 60/143,425.
    Filing Date: July 13, 1999.
    With the goal of producing attenuated RSV vaccine strains with new 
and favorable properties, the cytokines, Interferon-gamma (IFN-
), Interleukin-2 (IL-2), Interleukin-4 (IL-4) and Granulocyte-
Macrophage Colony Stimulating Factor (GM-CSF) were inserted into the 
RSV genome. Utilizing murine versions of the cytokines and mice as 
animals models, all four recombinant RSVs were infectious, immunogenic, 
protective against RSV challenge, and produced substantial quantities 
of the given cytokine. RSV/IFN- and RSV/GM-CSF were 
particularly interesting because both were attenuated but with enhanced 
immunogenicity, a very desirable phenotype in attenuated virus vaccine 
strains. IL-2 insertion resulted in attenuation but no change in 
immunogenicity.

Production of Attenuated Respiratory Syncytial Viruses Vaccines 
Involving Modification of M2 Open Reading Frame (ORF) 2

    Inventors: Alison Bermingham, Peter L. Collins and Brian R. Murphy.
    Serial Number: 60/143,097.
    Filing Date: July 7, 1999.
    This application describes two inventions, both involving knocking 
out or ablating the expression of the second translational open reading 
frame encoded by the M2 gene (M2 ORF2) of RSV. The first invention is 
the finding that M2 ORF2 knockout viruses are infectious and 
immunogenic but are attenuated from 100-1000 fold in vitro. Thus, the 
M2 ORF2 knockout represents another attenuating mutation that can be 
mixed with other known mutations to produce RSV vaccine strains with 
the proper balance of attenuation and immunogenicity. The second 
invention involves the finding that while the implication of M2 ORF2 
knockouts is restricted compared to wildtype, the production of mRNA 
and viral proteins is increased 175-300%. Thus, even though the virus 
is attenuated, the expression of viral antigens is increased. As 
another application, these knockouts can be used to produce the 
immunogenic F and G proteins for use in subunit vaccines.

Recombinant PIV Vaccines Attenuated by Deletion or Ablation of a 
Non-Essential Gene

    Inventors: Anna P. Durbin, Peter L. Collins and Brian R. Murphy.
    Serial Number: 09/350,821.
    Filing Date: July 9, 1999, with priority to September 19, 1997.
    The present invention concerns the discovery that knocking out one 
or more of the non-essential C, D and/or V genes results in attenuated 
and immunogenic virus strains. A C knockout and DV double knockout of a 
human PIV3 (JS wildtype) strain were attenuated and protective in 
African Green Monkeys. Knockouts of the C, D and/or V genes represent 
another type of attenuation to be mixed with the other known mutations 
to generate PIV vaccine strains with the appropriate balance of 
attenuation and immunogenicity.

Attenuated, Human-Bovine Chimeric Parainfluenza Virus (PIV) 
Vaccines

    Inventors: Jane E. Bailly, Peter L. Collins, Brian R. Murphy and 
Anna P. Durbin.
    Serial Number: 60/143,134.
    Filed: July 9, 1999.
    The essence of the present invention is that bovine PIV (BPIV) 
gene(s) other than the hemagglutinin-neuraminidase (HN) and fusion (F) 
glycoprotein genes can be substituted for their counterparts in a NPIV 
genome or antigenome as a means of attenuation based on host range 
restrictions. Conversely, the genes that encode HPIV protective 
antigens, e.g., the HN and F genes, can be inserted into a BPIV genome 
or antigenome. Either approach can yield human/bovine PIV chimeras that 
are infectious and immunogenic but attenuated, due to host range 
effects, and thus are candidate vaccine strains. BPIV genes may serve 
as another means of modulating viral attenuation, e.g., in combination 
with other known attenuating mutations, as described above, in order to 
derive a suitably attenuated HPIV. Alternatively, starting from BPIV 
and inserting the antigenic HPIV F and/or NH genes, along with other 
HPIV genes or other attenuating mutations represents another path one

[[Page 61361]]

can take to an attenuated HPIV vaccine. Certain candidate human-bovine 
chimeric PIV vaccine strains are not available for licensing.

Production of Attenuated Negative Stranded RNA Virus Vaccines From 
Cloned Nucleotide Sequences

    Inventors: Brian R. Murphy, Peter L. Collins, Anna P. Durbin, and 
Mario H. Skiadopoulos.
    Serial Number: 60/129,006.
    Filling Date: April 13, 1999.
    Negative stranded RNA viruses (the Mononegavirales) include RSV, 
PIV, measles, mumps and rabies as human pathogens. Recombinant 
production of live attenuated virus strains as vaccine candidates has 
involved, for each virus, identifying attenuating mutations and 
producing recombinant virus strains with different combinations of 
mutations in a hunt for the right balance of attention and 
immunogenicity. This invention dramatically increases the number of 
mutations available. The inventors have shown that attenuating 
mutations in one negative stranded RNA virus can be ``transferred'' to 
homologous locations in other negative stranded RNA viruses, resulting 
in a transfer of the attenuation phenotype. Now, many of the 
attenuating mutations known for RSV or PIV can be transferred between 
each of these viruses, or into the other less studied members of this 
family. Also mutations identified in other paramyxoviruses, such as 
measles virus, can be transferred to RSV and PIV. Such transformations 
have been performed and show that this general approach works. Certain 
candidates RSV and PIV vaccine strains are not available for licensing.
    The CRADA will employ attenuated human-animal chimeric RSV and PIV 
strains developed in LID using recombinant DNA methodologies to (1) 
identify and characterize the mutations responsible for attenuation, 
(2) engineer viral strains suitably attenuated for use as human 
vaccines, and (3) evaluate the attenuated viruses as live vaccines in 
animals and humans.
    The LID has extensive experience in evaluating the safety, 
antigenicity, immunogenicity and efficacy of various human viral 
pathogens and vaccines thereof both in experimental animals and human 
volunteers. The Collaborator in this endeavor is expected to commit 
several scientists off-site to support the activities defined by the 
CRADA Research Plan.
    These scientists, in collaboration with investigators in the LID, 
would coordinate the production and release testing of the candidate 
vaccines, generate monoclonal antibodies needed for manufacture of 
clinical lots and for their clinical evaluation, and use molecular 
virologic techniques to generate attenuating mutations suitable for use 
in live vaccine candidates. In addition, it is expected that the 
Collaborator will provide funds to supplement LID's research budget for 
the project and would make a major funding commitment to support the 
safety, immunogenicity and efficacy studies for candidate vaccines 
developed under the CRADA.
    The capability statement must address, with specificity, each of 
the following selection criteria: (1) The technical expertise of the 
Collaborator's Principal Investigator and laboratory group in molecular 
virology, (2) Ability of Collaborator to manufacture experimental 
vaccine lots for parental administration under Good Manufacturing 
Practices (GMP) conditions, and (3) Ability to provide adequate and 
sustained funding to support the requisite vaccine safety and efficacy 
studies.

    Dated: October 26, 1999.
Mark Rohrbaugh,
Director, Office of Technology Development, NIAID.
    Dated: October 29, 1999.
Jack Spiegel,
Director, Division of Technology Development and Transfer, Office of 
Technology Transfer, NIH.
[FR Doc. 99-29368 Filed 11-9-99; 8:45 am]
BILLING CODE 4140-01-M