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Ep 2023954 B1 (19) TZZ Z ¥_T (11) EP 2 023 954 B1 (12) EUROPEAN PATENT SPECIFICATION (45) Date of publication and mention (51) Int Cl.: (2006.01) of the grant of the patent: A61K 39/21 17.07.2013 Bulletin 2013/29 (86) International application number: PCT/US2007/011924 (21) Application number: 07809100.6 (87) International publication number: (22) Date of filing: 18.05.2007 WO 2007/136763 (29.11.2007 Gazette 2007/48) (54) IMMUNOLOGICAL COMPOSITION IMMUNOLOGISCHE ZUSAMMENSETZUNG COMPOSITION IMMUNOLOGIQUE (84) Designated Contracting States: (56) References cited: AT BE BG CH CY CZ DE DK EE ES FI FR GB GR • DATABASE BIOSIS [Online] BIOSCIENCES HU IE IS IT LI LT LU LV MC MT NL PL PT RO SE INFORMATION SERVICE, PHILADELPHIA, PA, SI SK TR US; 1 June 2004 (2004-06-01), CHIKHLIKAR PRIYA ET AL: "Inverted terminal repeat (30) Priority: 19.05.2006 US 801853 P sequences of adeno-associated virus enhance the antibody and CD8+ responses to a HIV-1 (43) Date of publication of application: p55Gag/LAMP DNA vaccine chimera" 18.02.2009 Bulletin 2009/08 XP002498298 Database accession no. PREV200400325965 & VIROLOGY, vol. 323, no. 2, (73) Proprietor: Sanofi Pasteur, Inc. 1 June 2004 (2004-06-01), pages 220-232, ISSN: Swiftwater, PA 18370 (US) 0042-6822 • KUMAR SANJEEV ET AL: "Development of a (72) Inventors: candidate DNA/MVA HIV-1 subtype C vaccine for • TARTAGLIA, James India" VACCINE, vol. 24, no. 14, March 2006 Aurora, ON (CA) (2006-03), pages 2585-2593, XP002498295 ISSN: • PANTALEO, Guiseppe 0264-410X 1011 Lausanne (CH) • DATABASE BIOSIS [Online] BIOSCIENCES • HARARI, Alexandri INFORMATION SERVICE, PHILADELPHIA, PA, 1011 Lausanne (CH) US;May 2006 (2006-05), GOONETILLEKE NILU ET AL: "Induction of multifunctional human (74) Representative: Cole, William Gwyn immunodeficiency virus type 1 (HIV- 1)-specific T avidity IP cells capable of proliferation in healthy subjects Kestrel House by using a prime-boost regimen of DNA- and Falconry Court modified vaccinia virus Ankara-vectored Baker’s Lane vaccines expressing HIV-1 gag coupled to CD8 Epping, Essex CM16 5DQ (GB) (+) T-cell epitopes" XP002498299 Database accession no. PREV200600433377 & JOURNAL OFVIROLOGY, vol. 80, no. 10, May 2006 (2006-05), pages 4717-4728, ISSN: 0022-538X Note: Within nine months of the publication of the mention of the grant of the European patent in the European Patent Bulletin, any person may give notice to the European Patent Office of opposition to that patent, in accordance with the Implementing Regulations. Notice of opposition shall not be deemed to have been filed until the opposition fee has been paid. (Art. 99(1) European Patent Convention). EP 2 023 954 B1 Printed by Jouve, 75001 PARIS (FR) (Cont. next page) EP 2 023 954 B1 • DATABASE BIOSIS [Online] BIOSCIENCES • DATABASE MEDLINE [Online] US NATIONAL INFORMATION SERVICE, PHILADELPHIA, PA, LIBRARY OF MEDICINE (NLM), BETHESDA, MD, US; January 2006 (2006-01), CEBERE INESE ET US; October 2004 (2004-10), CAPUTO AL: "Phase I clinical trial safety of DNA- and ANTONELLA ET AL: "Recent advances in the modified virus Ankara-vectored human development of HIV-1 Tat-based vaccines." immunodeficiency virus type 1 (HIV-1) vaccines XP002498303 Database accession no. administered alone and in a prime- boost regime NLM15544457 & CURRENT HIV RESEARCH OCT to healthy HIV-1-uninfected volunteers" 2004, vol. 2, no. 4, October 2004 (2004-10), pages XP002498300 Database accession no. 357-376, ISSN: 1570-162X PREV200600253680 & VACCINE, vol. 24, no. 4, • DATABASE MEDLINE [Online] US NATIONAL January 2006 (2006-01), pages 417-425, ISSN: LIBRARY OF MEDICINE (NLM), BETHESDA, MD, 0264-410X US; 15 December 2001 (2001-12-15), HEL Z ET AL: • MWAU MATILU ET AL: "A human "Potentiation of simian immunodeficiency virus immunodeficiency virus1 (HIV- 1)clade A vaccine (SIV)-specificCD4 (+)and CD8 (+) Tcell responses in clinical trials: stimulation of HIV- specific T- cell by a DNA-SIV and NYVAC-SIV prime/boost responses by DNA and recombinant modified regimen." XP002498304 Database accession no. vaccinia virus Ankara (MVA) vaccines in NLM11739541 & JOURNAL OF IMMUNOLOGY humans" JOURNAL OF GENERAL VIROLOGY, (BALTIMORE, MD. : 1950) 15 DEC 2001, vol. 167, vol. 85, no. Part 4, April 2004 (2004-04), pages no. 12, 15 December 2001 (2001-12-15), pages 911-919, XP002498296 ISSN: 0022-1317 7180-7191, ISSN: 0022-1767 • DATABASE MEDLINE [Online] US NATIONAL • DATABASE BIOSIS [Online] BIOSCIENCES LIBRARY OF MEDICINE (NLM), BETHESDA, MD, INFORMATION SERVICE, PHILADELPHIA, PA, US; 1991, NAYLOR P H ET AL: "Preclinical and US; January 2008 (2008-01), HARARI clinical studies on immunogenicity and safety of ALEXANDRE ET AL: "An HIV-1 clade C DNA the HIV-1 p17-based synthetic peptide AIDS prime, NYVAC boost vaccine regimen induces vaccine--HGP-30-KLH." XP002498301 Database reliable, polyfunctional, and long-lasting T cell accession no. NLM1823903 & INTERNATIONAL responses" XP002498305 Database accession JOURNAL OF IMMUNOPHARMACOLOGY 1991, no. PREV200800151089 & JOURNAL OF vol. 13 Suppl 1, 1991, pages 117-127, ISSN: EXPERIMENTAL MEDICINE, vol. 205, no. 1, 0192-0561 January 2008 (2008-01), pages 63-77, ISSN: • DATABASE BIOSIS [Online] BIOSCIENCES 0022-1007 INFORMATION SERVICE, PHILADELPHIA, PA, • MCCORMACK SHEENA ET AL: "EV02: a Phase I US;22 May 1999 (1999-05-22), SANDSTROMERIC trial to compare the safety and immunogenicity ET AL: "Therapeutic immunisation with of HIV DNA-C prime-NYVAC-C boost to NYVAC- recombinant gp160 in HIV-1 infection: A C alone." VACCINE 13 JUN 2008, vol. 26, no. 25, randomised double-blind placebo-controlled 13 June 2008 (2008-06-13), pages 3162-3174, trial" XP002498302 Database accession no. XP002498297 ISSN: 0264-410X PREV199900318851 & LANCET (NORTH AMERICAN EDITION), vol. 353, no. 9166, 22 May 1999 (1999-05-22), pages 1735-1742, ISSN: 0099-5355 2 EP 2 023 954 B1 Description Field of the Invention 5 [0001] The disclosure relates to immunological compositions for vaccinating human beings against infection by the Human Immunodeficiency Virus (HIV). Background of the Invention 10 [0002] Globally, by the end of 2001 40 million people were estimated to be infected with HIV (UNAIDS 2001). AIDS killed 2.3 million African people in 2001 and is now the fourth commonest cause of death worldwide. Over 90% of HIV infections occur in developing countries, with the majority of infections found in sub-Saharan Africa (28.1 million) and Asia and the Pacific (7.1 million). Because of the high cost of antiretroviral therapy, treatment of HIV infection is not a realistic approach in these countries nor is likely to be in the foreseeable future. There is an urgent need to explore other 15 approaches to control the epidemic, in particular preventative measures such as health education, treatment of sexually transmitted diseases, vaccines and topical microbicides. [0003] There is a broad scientific consensus that a successful vaccine to prevent HIV- 1 transmission must be able to elicit HIV-specific CD8+ cytotoxic T-lymphocytes (CTL) and also antibodies capable of neutralising primary HIV isolates (Nab). Major approaches toward this end include live, attenuated vaccines; inactivated viruses with adjuvants; subunit 20 vaccines with adjuvants; live-vector based vaccines; and DNA vaccines. Major concerns regarding safety issues have been raised for the use of live, attenuated vaccines in humans. The protective immunity generated in monkeys immunized with inactivated viruses with adjuvants is not virus- specific. Subunit vaccines, such as highly purified recombinant mon- omeric HIV-1 envelope proteins elicit neither virus-specific CTL nor antibody responses that can neutralize primary patients isolates of HIV-1, even when adjuvanted with potent immunostimulants. 25 [0004] At the present, combining DNA vaccines and live-vector based vaccines in prime-boost regimens appears to be the most promising vaccine strategies. For instance, in one study, macaques primed with NYVAC-HIV1 env or NYVAC-HIV env/gag-pol and boosted with HIV-1 gp120 or peptide were protected against HIV2 challenge. In another study, macaques primed with NYVAC-HIV-2 env/gag-pol or NYVAC-HIV-2env and boosted with HIV-2 envelope have been protected against i.v. HIV-2 challenge. Ongoing studies in humans include a Phase I trial using DNA- prime (1mg 30 or 2mg) and MVA-boost in 120 volunteers. There is a clear need in the art for effective immunological compositions for immunizing humans against HIV. Such compositions are provided by this disclosure. [0005] The prior art includes J. Gen Virol., 85, 2004, 911-9. This paper discloses a protocol involving DNA priming and MVA boashing, and wherein in each case the antigens are a gag p24/p17 fused to a string of CTL epitopes. 35 Brief Description of the Drawings [0006] Figure 1. Nucleotide sequence of NYVAC-HIV C plasmid 40 (pMA60gp120C/gagpolnef-C-14. Figure 2. Percentage of responders following administration of NYVAC alone or DNA following by NYVAC (prime- boost). Figure 3. Measurement of INF-γ-secreting T cells following administration of NYVAC alone or DNA following by NYVAC (prime-boost). 45 Figure 4. Difference in the magnitude of the immune following administration of NYVAC alone or DNA following by NYVAC (prime-boost). Figure 5. Representative flow cytometry profiles of env-specific INF-γ-secreting T cells following administration of NYVAC alone or DNA following by NYVAC (prime-boost). Figure 6. Correlation between the frequencies of INF- γ-secreting T cells measured by flow cytometry and ELISPOT. 50 Figure 7. Flow cytometry profiles of CD4 and CD8 T cells recognizing various peptides following administration of NYVAC alone or DNA following by NYVAC (prime-boost). Figure 8. IgG antibody levels at different time points following administration of NYVAC alone or DNA following by NYVAC (prime-boost). Figure 9. Analysis of the immune response 72 weeks following administration of NYVAC alone or DNA following 55 by NYVAC (prime-boost). 3 EP 2 023 954 B1 Summary of the Invention [0007] Disclosed herein are methods for immunizing human beings against HIV by inducing or enhancing a dominant CD4 T cell response against that agent.
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