Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K39/00—Medicinal preparations containing antigens or antibodies
  • A61K39/12—Viral antigens
  • A61K39/145—Orthomyxoviridae, e.g. influenza virus
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K39/00—Medicinal preparations containing antigens or antibodies
  • A61K39/12—Viral antigens
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K39/00—Medicinal preparations containing antigens or antibodies
  • A61K39/39—Medicinal preparations containing antigens or antibodies characterised by the immunostimulating additives, e.g. chemical adjuvants
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/12—Antivirals
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/12—Antivirals
  • A61P31/14—Antivirals for RNA viruses
  • A61P31/16—Antivirals for RNA viruses for influenza or rhinoviruses
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P37/00—Drugs for immunological or allergic disorders
  • A61P37/02—Immunomodulators
  • A61P37/04—Immunostimulants
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K39/00—Medicinal preparations containing antigens or antibodies
  • A61K2039/51—Medicinal preparations containing antigens or antibodies comprising whole cells, viruses or DNA/RNA
  • A61K2039/525—Virus
  • A61K2039/5252—Virus inactivated (killed)
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K39/00—Medicinal preparations containing antigens or antibodies
  • A61K2039/54—Medicinal preparations containing antigens or antibodies characterised by the route of administration
  • A61K2039/541—Mucosal route
  • A61K2039/543—Mucosal route intranasal
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K39/00—Medicinal preparations containing antigens or antibodies
  • A61K2039/545—Medicinal preparations containing antigens or antibodies characterised by the dose, timing or administration schedule
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K39/00—Medicinal preparations containing antigens or antibodies
  • A61K2039/555—Medicinal preparations containing antigens or antibodies characterised by a specific combination antigen/adjuvant
  • A61K2039/55511—Organic adjuvants
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K39/00—Medicinal preparations containing antigens or antibodies
  • A61K2039/555—Medicinal preparations containing antigens or antibodies characterised by a specific combination antigen/adjuvant
  • A61K2039/55511—Organic adjuvants
  • A61K2039/55561—CpG containing adjuvants; Oligonucleotide containing adjuvants
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K39/00—Medicinal preparations containing antigens or antibodies
  • A61K2039/58—Medicinal preparations containing antigens or antibodies raising an immune response against a target which is not the antigen used for immunisation
• • C—CHEMISTRY; METALLURGY
  • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
  • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
  • C12N2760/00—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA ssRNA viruses negative-sense
  • C12N2760/00011—Details
  • C12N2760/16011—Orthomyxoviridae
  • C12N2760/16111—Influenzavirus A, i.e. influenza A virus
  • C12N2760/16134—Use of virus or viral component as vaccine, e.g. live-attenuated or inactivated virus, VLP, viral protein

Definitions

• Vaccine protection against acute or chronic viral infection is facilitated by using, together with an anti-influenza vaccine, as an adjuvant or immuno-stimulant, a dsRNA.
• Adjuvants have been used to facilitate vaccines in affording immunization to protect animals including humans. Identifying an efficient and effective adjuvant is often a difficult task.
• Disclosed are methods of facilitating vaccine protection against an acute or chronic viral infection comprising the coordinated administration to a subject requiring protection an immunity-inducing amount of an anti-influenza vaccine together with, as an adjuvant, a dsRNA. Also disclosed are methods of facilitating vaccine protection against an acute or chronic viral infection
• dsRNA comprising administering to a subject requiring protection an immunity-inducing amount of an anti-influenza vaccine in combination with, as an adjuvant or immuno-stimulant, a dsRNA.
• the invention includes methods of facilitating vaccine protection against an acute or chronic viral infection comprising administering substantially simultaneously or sequentially to a subject requiring protection an immunity- inducing amount of an anti-influenza vaccine together in admixture with, as an adjuvant or immuno-stimulant, a dsRNA.
• This invention also includes methods of protecting animals, including humans, susceptible to avian influenza infections against viral-induced pathology secondary to both antigenic drift and shift (as evidenced by
• the invention further includes methods of enhancing immunization against influenza viruses by coordinated administration of a vaccine to patients together or conjointly a synthetic, specifically configured, double-stranded ribonucleic acid (dsRNA).
• dsRNA double-stranded ribonucleic acid
• the dsRNA of choice is Ampligen®, available from HEMISPHER x BIOPHARMA, 1617 JFK Boulevard, Philadelphia, PA USA., a synthetic, specifically configured, double-stranded ribonucleic acid (dsRNA) which retains the immunostimulatory and antiviral properties of other double-stranded RNA molecules (dsRNA) but exhibits greatly reduced toxicity.
• Ampligen® can stimulate host defense mechanisms including innate immunity.
• Ampligen® has the ability to stimulate a variety of dsRNA-dependent intracellular antiviral defense mechanisms including the 2', 5'-oligoadenylate synthetase/RNase L and protein kinase enzyme pathways. [0009] In the context of the present invention, what is meant by
• “coordinated” use is, independently, either (i) co-administration, i.e. substantially simultaneous or sequential administration of the vaccine and of the dsRNA, or (ii) the administration of a composition comprising the vaccine and the dsRNA in combination and in a mixture, in addition to optional pharmaceutically acceptable excipients and/or vehicles.
• the mismatched dsRNA may be of the general formula rl n •
• mismatched dsRNAs for use in the present invention are based on copolynucleotides selected from poly (C m ,U) and poly (C m G) in which m is an integer having a value of from 4 to 29 and are mismatched analogs of complexes of polyriboinosinic and polyribocytidilic acids, formed by modifying rl n • rC n to incorporate unpaired bases (uracil or guanine) along the polyribocytidylate (rC m ) strand.
• the dsRNA may be derived from r(I)• r(C) dsRNA by modifying the ribosyl backbone of polyriboinosinic acid (rl n ), e.g., by including 2'-O-methyl ribosyl residues.
• the mismatched may be complexed with an RNA-stabilizing polymer such as lysine cellulose.
• rl n • rC n the preferred ones are of the general formula rl n • T(C 11-I45 U) n . or rl n • r(C 29 ,G) n , and are described by Carter and Ts'o in U.S. Patent Nos. 4,130,641 and 4,024,222, the disclosures of which are hereby incorporated by reference.
• the dsRNA's described therein generally are suitable for use according to the present invention.
• the dsRNA may be the matched form, thus
• polyadenylic acid complexed with polyuridylic acid may also be used.
• Another aspect of the invention is the treatment of acute and chronic viral infections susceptible to vaccine prophylaxis therapy, available now or in the future including, for example, HIV, severe acute respiratory syndrome (SARS) and influenza including avian influenza employing a synergistic combination of an appropriate vaccine and a dsRNA.
• HIV severe acute respiratory syndrome
• influenza avian influenza employing a synergistic combination of an appropriate vaccine and a dsRNA.
• FIGURE 1 is a table showing the results of Example 1 ;
• FIGURE 2 is a table showing the results of Example 2;
• FIGURE 3 is a table showing the results of Example 3 using a trivalent influenza vaccine
• FIGURE 4 is a table showing the results of Example 3 using a trivalent vaccine plus Ampligen® intranasally;
• FIGURE 5 is a table showing a direct cross assessment according to
• FIGURE 6 is a table showing the results of Example 3.
• H5N1 avian influenza/Vietnam (H5N1) strain
• 05/06 Vaccine trivalent "seasonal" influenza vaccine for the
• influenza virus Vietnam strain i.e. as detected in nasal mucosal washings
• Example 1 Cross Protection Between Avian Influenza Strains
• IgA antibodies in- the nasal mucosa are IgA antibodies in- the nasal mucosa.
• the animals were then subjected to a challenge to avian influenza virus Vietnamese strain and, significantly, there was no virus detected in the nasal wash of the challenged animals receiving a combination of vaccine and Ampligen administered by the intranasal route while various amounts of virus were detected using the vaccine alone, Ampligen alone, intranasally, and a combination of vaccine and Ampligen administered subcutaneously.
• Example 2 Cross Protection Between Seasonal Influenza Vaccine and H5Nl
• A/VN IgG were prior to challenge and the third panel was subsequent to challenge with the Hong Kong strain.
• beneficial results were noted in the virus titer nasal wash subsequent to challenge with the best results achieved using the combination of Vietnam strain vaccine and Ampligen and subsequent challenge with the Hong Kong strain of the virus.
• A/VN virus titer in the nasal wash was rather insignificant for the combination of 0.1 ⁇ g AAHSf and 10 ⁇ g poly(I:C) as compared to a measurable value when the avian flu vaccine was used alone. From these data one may conclude the use of ⁇ oly(LC) as an adjuvant enables one to reduce by tenfold (in this example) the amount of avian influenza vaccine necessary to achieve significant rates of survival. [0044] Presence of the Ampligen appears to possess cross-protection ability against variant avian influenza viruses and thereby mitigate antigenic drift of the avian influenza virus. .
• Antigenic drift is a. change in structure of a virus, such as the internal and external proteins, glycoproteins, glycolipids, etc., due to fundamental change in the genomic content of the virus particle.
• dsRNAs reduce the phenomenon of viral escape and cellular damage attendant thereto.
• Viral escape is a process by which a virus or intracellular pathogen alters its host range or indirectly alters its susceptibility of antiviral or immunological therapies.
• This invention includes methods of cross-protecting animals, including humans, susceptible to avian influenza infections against viral-induced pathology secondary to both antigenic drift and shift (produced by mutations or rearrangement of the viral genetic material).
• FIG 3 seven groups of mice, five mice per group, were selected. Four of these groups were exposed to the 2005/2006 trivalent influenza vaccine either intranasally or subcutaneously. Within 21 days intranasal inoculation was repeated and within 14 days intranasal inoculation was completed again making a total of one initial inoculation and two boosters.
• mice Two weeks after the second booster the mice were then subjected to challenge with the avian influenza VNl 194 (H5N1) strain and assessed for the presence and amount of IgA anti-A/VN in a nasal wash and for IgG antibodies in serum. The results indicate that only with the presence Ampligen and
• Figure 4 shows that the only group of animals to survive the challenge with VN 1194 as assessed over a period of 18 days, was the group which received both the 05/06 trivalent vaccine plus the Ampligen intranasally . While antibodies were present in the blood serum they provided no effective protection against VNl 194 challenge but antibodies present in the nasal mucosa were effective to prevent infection and death over the period of time measured. These findings are significant as they demonstrate in this study protection against avian influenza H5N1 strains is conferred by the use of a trivalent seasonal vaccine administered intranasally with Ampligen as a vaccine adjuvant.
• Figure 5 shows the direct cross assessment, again indicating the quantities and amounts of 05/06 trivalent vaccine, Ampligen and route of administration but measuring for the antibodies to be elicited against the seasonal trivalent vaccine as measured either in the nasal mucosa or blood serum.
• the results show antibodies against the seasonal vaccine were present in the nasal mucosa of only those animals receiving both the trivalent 05/06 seasonal vaccine and Ampligen administered by the intranasal route.
• all of the groups had a certain elevated "baseline” level, but a significant increase was seen both times the vaccine was used with Ampligen.
• A/VN A/Vietnam (H5N1) 2.5 x 10 5 pfu / 2.5 ml (lung) and A/Vietnam (H5N1) 0.5 x 10 5 pfu / 0.5 ml (nasal)
• Infected control animals developed tachypnea, coughing, weight loss, and focal consolidating pneumonia.
• Vaccinated animals were symptom free, and protected from disease with normal appearing pulmonary tissue.

Landscapes

• Health & Medical Sciences (AREA)
• Life Sciences & Earth Sciences (AREA)
• Chemical & Material Sciences (AREA)
• Virology (AREA)
• Immunology (AREA)
• Public Health (AREA)
• Veterinary Medicine (AREA)
• General Health & Medical Sciences (AREA)
• Animal Behavior & Ethology (AREA)
• Pharmacology & Pharmacy (AREA)
• Medicinal Chemistry (AREA)
• Epidemiology (AREA)
• Microbiology (AREA)
• Mycology (AREA)
• General Chemical & Material Sciences (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Pulmonology (AREA)
• Organic Chemistry (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Oncology (AREA)
• Communicable Diseases (AREA)
• Engineering & Computer Science (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Molecular Biology (AREA)
• Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)

Priority Applications (5)

Applications Claiming Priority (6)

Publications (2)

Family

ID=38123418

Family Applications (1)

Country Status (6)

Cited By (4)

Families Citing this family (7)

Family Cites Families (11)

• 2006
  • 2006-12-06 JP JP2008544428A patent/JP2009518410A/ja active Pending
  • 2006-12-06 US US11/634,389 patent/US7943147B2/en active Active
  • 2006-12-06 CA CA2632516A patent/CA2632516C/en active Active
  • 2006-12-06 AU AU2006322073A patent/AU2006322073A1/en not_active Abandoned
  • 2006-12-06 WO PCT/US2006/046356 patent/WO2007067517A2/en not_active Ceased
  • 2006-12-06 EP EP06844824A patent/EP1957101A4/en not_active Withdrawn
• 2011
  • 2011-04-19 US US13/064,824 patent/US20110223198A1/en not_active Abandoned
• 2013
  • 2013-01-28 JP JP2013013055A patent/JP2013075920A/ja active Pending
• 2014
  • 2014-11-11 US US14/537,981 patent/US20150064216A1/en not_active Abandoned

Non-Patent Citations (1)

Also Published As

Similar Documents

Legal Events