WO2007004231A1 - Hiv-1 vaccinogens with immunomodulators - Google Patents

Hiv-1 vaccinogens with immunomodulators Download PDF

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Publication number
WO2007004231A1
WO2007004231A1 PCT/IN2005/000230 IN2005000230W WO2007004231A1 WO 2007004231 A1 WO2007004231 A1 WO 2007004231A1 IN 2005000230 W IN2005000230 W IN 2005000230W WO 2007004231 A1 WO2007004231 A1 WO 2007004231A1
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vaccinogens
gene
hiv
subtype
ind
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PCT/IN2005/000230
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French (fr)
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Pradeep Seth
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Pradeep Seth
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Priority to PCT/IN2005/000230 priority Critical patent/WO2007004231A1/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/005—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from viruses
    • 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
    • A61K2039/5256—Virus expressing foreign proteins
    • 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
    • C12N2710/00—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA dsDNA viruses
    • C12N2710/00011—Details
    • C12N2710/14011—Baculoviridae
    • C12N2710/14111—Nucleopolyhedrovirus, e.g. autographa californica nucleopolyhedrovirus
    • C12N2710/14141—Use of virus, viral particle or viral elements as a vector
    • C12N2710/14143—Use of virus, viral particle or viral elements as a vector viral genome or elements thereof as genetic vector
    • 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
    • C12N2740/00—Reverse transcribing RNA viruses
    • C12N2740/00011—Details
    • C12N2740/10011—Retroviridae
    • C12N2740/16011—Human Immunodeficiency Virus, HIV
    • C12N2740/16111—Human Immunodeficiency Virus, HIV concerning HIV env
    • C12N2740/16122—New viral proteins or individual genes, new structural or functional aspects of known viral proteins or genes
    • 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
    • C12N2740/00—Reverse transcribing RNA viruses
    • C12N2740/00011—Details
    • C12N2740/10011—Retroviridae
    • C12N2740/16011—Human Immunodeficiency Virus, HIV
    • C12N2740/16211—Human Immunodeficiency Virus, HIV concerning HIV gagpol
    • C12N2740/16222—New viral proteins or individual genes, new structural or functional aspects of known viral proteins or genes

Definitions

  • HIV-1 vaccinogens with immunomodulators HIV-1 vaccinogens with immunomodulators
  • This invention relates to the augmentation of HiV specific immune response in HIV infected individuals by co-immunization of the patients with HIV- 1 vaccinogens with immounomodulators like Immunostimulatory sequences (ISS)/ CpG motifs/ Oligodeoxynucleotides (ODNs), human interleukin-2 (protein or DNA), etc.
  • immounomodulators like Immunostimulatory sequences (ISS)/ CpG motifs/ Oligodeoxynucleotides (ODNs), human interleukin-2 (protein or DNA), etc.
  • AiDS is one of the most dreaded infections afflicting the human race today.
  • Human Immunodeficiency virus HIV
  • HIV Human Immunodeficiency virus
  • AIDS Acquired Immunodeficiency Syndrome
  • HIV infection the scenario is different.
  • the virus infects the CD4+ T cells which are the key cells required in mounting HIV specific immune response.
  • the immune response in unable to clear the virus from the body in HIV infected individuals and the virus continues to grow in these patients.
  • an alternate approach is to augment the immune response of the infected individuals in such a way that the virus, which are not cleared from the body of infected individuals by the antiretroviral drugs are destroyed or cleared by the HIV- 1 specific immune response in the patient.
  • the preventive vaccines induce HIV specific immune response which peaks at 4 to 8 weeks after
  • a sustained and broad based immune response is necessary for clearing the established virus infection from the body. This immune response should be maintained at or near its peak for several weeks so that any persisting virus from the body may be cleared.
  • immuno modulators !SS/ CpG motif / ODNs, human int ⁇ rleukin-2 (I L- 2) etc.
  • Object of this invention is to propose co-immunization of HIV infected individuals with HIV vaccinogens together with immunomod ⁇ lators like ISS/CpG motif/0 DNs, human IL-2 etc.
  • Another object of this invention is to propose co- immunization of HIV infected individuals with HIV vaccinogens and immune-modulators to augment the immune response.
  • a method for augmenting the immune response in HIV infected individuals which may help the patient in combating and controlling the virus replication in them, in accordance with this invention.
  • the immune response in an HiV infected is highly compromised due to uninhibited virus replication in the immune cells particularly CD4+ T helper lymphocytes, which are the key cells in mounting protective immunity.
  • the virus infection results in continuous destruction of these cells.
  • Lack of immune surveillance results not only to unabated HIV replication but also to several life threatening infections and malignancies the infected individuals.
  • the immune response of HIV infected individuals can be augmented by coiimunizing the infected individuals with HIV vaccines and immunomoduiators.
  • mice induced production of IFNy from spleen cells which was maximum after 72
  • Murine fL-2/lg gene was released from pVRCmlL-2/fg construct by restriction digestion with Pst I and Xba I. The released insert was polished by Klenow fragment to create the biunt ends.
  • the expression vector pJW4304 was double digested with Hind III and MlU l restriction enzymes. The linearised vector was polished by Klenow fragment, followed by CIAP treatment. Blunt end ligation was carried out using T4 DNA ligase. E.coli DhSo. cells were then transformed
  • mice co-immunteci with CpG motif 1826 ODA? and/or pJWmlL2/lg with HIV-1 Indian subtype C vacct ⁇ es NK-29692CO, NK-49426CO, NK-49587CO, NK-IND-tat-CO and NK-IND-nef-CO and recombinant viral vector
  • W-WD-tatCO and W- ⁇ ND-nefCO with a combination of CpG motif 1826ODN and pMmlL-2f!g construct was studied. It was observed that the augmentation of both arms of immune response (cell mediated as well as humoral immune response) by CpG motif and pJWm(L2/fg together was at least twice as much as it was observed with either of the immunomoduiators injected with the vaccinogens and lasted even after 24 weeks

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Biochemistry (AREA)
  • Biophysics (AREA)
  • Virology (AREA)
  • Genetics & Genomics (AREA)
  • General Health & Medical Sciences (AREA)
  • Molecular Biology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Peptides Or Proteins (AREA)

Abstract

Vaccinagens comprise recombinant plasmid vaccine constructs NK-29692CO, NK-49426CO, NK-49587CO, NK-IND-tat-CO and NK-IND-nef-CO and recombinant viral vector vaccine constructs VV-29692CO, VV 49426CO, VV 49587CO, VV-IND-tatCO and VV-IND-nefCO.

Description

HIV-1 vaccinogens with immunomodulators
Augmentation of HIV-1 specific Immune response in Human Immunodeficiency Virus Infected individuals by co-immunization of the patients with HIV-1
vaccinogens with immunomodulators. Field of Invention:
5 This invention relates to the augmentation of HiV specific immune response in HIV infected individuals by co-immunization of the patients with HIV- 1 vaccinogens with immounomodulators like Immunostimulatory sequences (ISS)/ CpG motifs/ Oligodeoxynucleotides (ODNs), human interleukin-2 (protein or DNA), etc.
i o Background of Invention:
AiDS is one of the most dreaded infections afflicting the human race today. Human Immunodeficiency virus (HIV) is the causative agent of Acquired Immunodeficiency Syndrome (AIDS).
Several antiretroviral drugs have been introduced to combat this virus
15 infection since last decade. Current therapy of HIV infection requires use of multiple drug combinations which resulted in dramatic improvements in the mortality and morbidity of HIV-disease. Despite all the therapeutic advantages achieved, eradication of the virus still remains impossible. In addition, new problems relating to the occurrence of resistance mutation in both circulating and 0 transmitted viruses are emerging. Development of resistant HIV strains is one of the main reasons of failure of antiretroviral therapy. In most other viral infections, like measles, chicken pox, or rubella etc. the virus is cleared from the body by an efficient and robust immune response, which an infected patient develops early during the course of infection. This immune response is generally very broad based and is sustained for several weeks and
5 months even after clearing the virus from the body. However, in HIV infection the scenario is different. The virus infects the CD4+ T cells which are the key cells required in mounting HIV specific immune response. As a result the immune response in unable to clear the virus from the body in HIV infected individuals and the virus continues to grow in these patients. i o Therefore, an alternate approach is to augment the immune response of the infected individuals in such a way that the virus, which are not cleared from the body of infected individuals by the antiretroviral drugs are destroyed or cleared by the HIV- 1 specific immune response in the patient. The preventive vaccines induce HIV specific immune response which peaks at 4 to 8 weeks after
15 receiving the complete course of HIV immunization. Thereafter, the immune response declines and by 16 weeks post-immunization it is undetectable. However, when the vaccine is challenged with the vaccinogens or the virus, a secondary type of immune response develops suggesting that the individual vaccine has a memory to the vaccinogens. This aspect of the immune response
20 is useful for prevention of infection. For clearing the established virus infection from the body, a sustained and broad based immune response is necessary. This immune response should be maintained at or near its peak for several weeks so that any persisting virus from the body may be cleared. In an alternate approach in the present invention, co-immunization of HIV- 1 vaccinogens with immuno modulators (!SS/ CpG motif / ODNs, human intεrleukin-2 (I L- 2) etc.) in H)V infected individuals will augment the virus specific immune response to combat and clear the virus from the body.
Objects of invention
Object of this invention is to propose co-immunization of HIV infected individuals with HIV vaccinogens together with immunomodυlators like ISS/CpG motif/0 DNs, human IL-2 etc. Another object of this invention is to propose co- immunization of HIV infected individuals with HIV vaccinogens and immune-modulators to augment the immune response.
Brief Description of the Invention:
According to this invention there is provided a method for augmenting the immune response in HIV infected individuals, which may help the patient in combating and controlling the virus replication in them, in accordance with this invention, The immune response in an HiV infected is highly compromised due to uninhibited virus replication in the immune cells particularly CD4+ T helper lymphocytes, which are the key cells in mounting protective immunity. The virus infection results in continuous destruction of these cells. As a result there is no immune surveillance in infected individuals. Lack of immune surveillance results not only to unabated HIV replication but also to several life threatening infections and malignancies the infected individuals. Although development of antiretroviral drugs have succeeded in improving the quality of life of the infected patients, the outrageous prohibitive cost of treatment is beyond reach of the majority of patients in developing countries. Further, development of resistance to the antiretroviral treatment and also toxicity in patients on prolonged treatment with these drugs have prompted scientists to develop alternate approaches for controlling virus replication in the infected individuals. However, it has been observed that some HiV infected individuals are able to control the replication of virus through an efficient immune response for several years. These are called Long term non-progressors. In addition there are other individuals who have been able to eliminate HIV from there body due to efficient HIV specific ceil mediated immune response but are HIV antibody negative. These are called Highly exposed seronegative individuals. Indicating thereby that if the immune response of HIV infected is modulated by immunomodulators in the presence of HiV vaccines, the infected individuals may be able to suppress and even eliminate HIV from their body.
According to this invention the immune response of HIV infected individuals can be augmented by coiimunizing the infected individuals with HIV vaccines and immunomoduiators. BKAMPLE:
Augmentation of immune response in Mice: a) CpG motif.
Unmet hylated and phosphothioated CpG motif sequence 5'- TCCATGA CβTTCCTG A CGTT-31 (1826-ODN) was synthesized. This unmethyiated ODN has 2 CpG motifs, separated by 7 bases in between them. Incubation of spleen ceiis from normal mice with of 2 μg of CpG motif alone in
mice induced production of IFNy from spleen cells which was maximum after 72
hours post-incubation b) Murine lnterleukin-2:
Murine fL-2/lg gene was released from pVRCmlL-2/fg construct by restriction digestion with Pst I and Xba I. The released insert was polished by Klenow fragment to create the biunt ends. The expression vector pJW4304 was double digested with Hind III and MlU l restriction enzymes. The linearised vector Was polished by Klenow fragment, followed by CIAP treatment. Blunt end ligation was carried out using T4 DNA ligase. E.coli DhSo. cells were then transformed
with recombinant plasmid pMlmfL-2/fg and screening was carried out for positive clones using double restriction digestions with Hind III and Sal !. in vitro expression was the murine IL-2 clone was tested in Cos-7 cells transfected with recombinant plasmid pJW mlL2/ig. Expression of pJWmlL2/lg in Cos -7 cells led to the secretion of 1L2 in the culture supernatants. The quantification of secreted IL-2 in the culture supernates was done by the murine IL-2 cytokine ELISA kit (R&D Systems), according to the manufacturer's instructions, thereby confirming the IL-2 protein expression. The amounts of murine IL-2 cytokine secreted in the medium increased reaching a maximum level at 72 hours post-transfection (2055 pg/ml). c) Immune response in mice co-immunteci with CpG motif 1826 ODA? and/or pJWmlL2/lg with HIV-1 Indian subtype C vacctøes NK-29692CO, NK-49426CO, NK-49587CO, NK-IND-tat-CO and NK-IND-nef-CO and recombinant viral vector
vaccine constructs W-29692CO, W 49426CO5 W-49S87CO, W-IND-tatCO and W-iND-nefCO } The immunization studies were performed in 4 phases. The immunized mice were euthanised at different time points following immunization and the spleen cells were assayed for CTL activity (cell mediated immune response) by IFNy-ELISpot assay and the serum samples were assayed for HIV- 1 specific
antibodies (humoral immune response) by ELISA. in the Phase-I study, dose response experiment was conducted for the HIV-1 Subtype C constructs NK- 29692CO, NK-49426CCX NK-49587CO, NK-IND-tat-CO and NK-IND-nef-CO to find out the optimum dose of these constructs required to induce optimum immune response in mice. The optimum dose each construct was 50μg. In
phase-!! studies optimum dose of CpQ motifs (1826-ODN) injected intradermal^ as immunomodulator along with HIV-1 subtype C DNA constructs (NK-29692CO, NK-49426CO, NK-49587CO, NK-IND-tat-CO and NK-IND-nef-CO) in mice was
tested and was found to be 2μg. It was also observed that the immune response augmented by this dose of CpG motif was very broad based at 8 weeks post immunization and was sustained at significantly high levels even at the end of 24 weeks. Whereas, without CpG motif the immune response induced by the same vaccinogens was narrow and declined to pre- immunization levels by 8 weeks after the immunization. In Phase-Ill study the optimum dose of pJWmlL-2/tg co- immunized intradermal^ as immunomodulatory agent along with the HIV- 1 subtype C recombinant DNA constructs and was found to be 25μg. Here also
augmentation of immune response was broad based at 6 weeks post- immunization but declined. However it was detectable albeit at low levels at 24 weeks post-immunization. In phase !V study immunomodulation of immune response induced by HiV vaccinogens injected as prime-boost strategy in mice (priming with NK-29692CO, NK-49426CO, NK-49587CO. liK-IND-iat-CQ and NK-IND-nef-CO and boosting two weeks later with recombinant viral vectors W- 29692CO, W 49426CO, W-495S7CO. W-WD-tatCO and W-ΪND-nefCO with a combination of CpG motif 1826ODN and pMmlL-2f!g construct was studied. It was observed that the augmentation of both arms of immune response (cell mediated as well as humoral immune response) by CpG motif and pJWm(L2/fg together was at least twice as much as it was observed with either of the immunomoduiators injected with the vaccinogens and lasted even after 24 weeks
post-immunization. These data clearly show that co-immunization mice with immunomodulators (CpG motif and/or murine lnterieukln-2 plasmid, pJWmlL2/lg) along with HIV-1 Indian subtype C vaccine constructs induces a robust and an extremely broad based CTL Immune response which
5 remains persistently at high levels even at 6 months post-immunization. Since broad based CTL activity is associated with controlling the replication of virus and also its clearance in those HiV infected individuals, who are long term non-progrεssors and highly exposed HIV seronegative individuals, I propose that this strategy of co-immunization of HiV infected i o individuals with immunomodulators like CpG motif (also called ODN or ISS), IL-2 etc. will be able to either control the virus replication to minimal levels or even clear the virus in HIV infected patients.

Claims

WE CLAIM:
1 , Vaccinogens comprise recombinant plasmid vaccine constructs NK- 29692CO, NK-4S426CO, NK-49S87CO, NK-ΪND-tat-CO and NK-IMD-nβf- CO and recombinant viral vector vaccine constructs W-29692CO, VV 49426CO. W-49S87CO, W-lND-tatC© and VV-IND ncfCO 2. Vaccinogens aβ ciaimed in claim 1 wherein the said recombinant plasmid NK-29692CO comprises HIV-I subtype C envelope gp120 gene mounted onto a plasmid vector.
3. Vaccinogens as ciaimed in claim 1 wherein the said recombinant viral vector W-29692CO comprises HlV-1 subtype C envelope gp120 gene inserted into the tk-gene locus of MVA.
4. Vaccinogens as claimed In claims 2 & 3 wherein the envelops gp120 gene was obtained from the Indian strain CHW-2%92.
5. Vaccinogens as claimed in claims 2 & & 3 wherein the envelope gp120 gene obtained from Indian strain CH18-296Θ2 was codon optimized for human codon frequency.
6. Vaccinogens as claimed in claim 1 wherein the said recombinant plasmid NK-49426CO comprises HIV-1 subtype C envelope gp120 gene mounted onto a plasmid vector.
7. Vaccinogens as claimed in claim 1 wherein the said recombinant viraJ vector W-48426CG comprises HlV- 1 subtype C envelope gp120 gene inserted into the tk-gene locus of MVA.
8. Vaceinogens as claimed in claims 6 & 7 wherein the envelope gp120 gene was obtained from the Indian strain SK3-49426.
9. Vaccinogens as claimed in claims 6 & & 7 wherein the envelope gp120 gene obtained from Indian strain SK3-49426 was codon optimized for human codon frequency.
10. Vaccinogens as claimed in claim 1 wherein the said recombinant plasm id NK-49587CO comprises HIV-1 subtype C gag-protease gene mounted onto a plasm id vector.
11. Vaccinogens as claimed in claim 1 wherein the said recombinant viral vector W-49S87CO comprises HIV-1 subtype C gag-protease gene inserted into the tk-gene locus of MVA. 12. Vaccinogens as claimed in claims 10 & 11 wherein the gag-protease gene was obtained from the Indian strain 49587.
13. Vaccinogens as claimed in claims 10 & & 11 wherein the gag-protease gene obtained from Indian strain 49587 was codon optimized for human codon frequency.
14. Vaccinogens as claimed in claim 1 wherein the said recombinant plasm id NK-IND-tatCO comprises HIV-1 subtype C tat gene mounted onto a plasm id vector. 15. Vaccinogens as claimed in claim 1 wherein the said recombinant viral vector W-IND-tatCO comprises HIV-1 subtype C tat gene inserted into the tk-gene locus of MVA. IΘ.Vaccinogens as claimed in claims 14 & 15 wherein the tat gen& was obtained from the consensus sequence of Indian HIV-1 subtype C strains. 1?.Vaccinogens as claimed in claims 14 & & 15 wherein the tat gene obtained from the consensus sequence of Indian HIV-1 subtype C strains was codon optimized for human codon frequency.
18.Vaccinogens as claimed in claim 1 wherein the said recombinant plasm id
NK-IND-nefCO comprises HIV-1 subtype C nef gene mounted onto a piasmid vector.
19.Vacciπogens as claimed in claim 1 wherein the said recombinant viraϊ vector W-iND-nefCO comprises HlV- 1 subtype C nef gene inserted into thB fk-gene locus of MVA. 20.Vaccinogens as claimed in claims 18 & 19 wherein the nef gene was obtained from the consensus sequence of Indian HIV-1 subtype C strains. 21.Vaccinogens as claimed in claims 18 & 19 wherein the nef gene obtained from consensus sequence of Indian HIV-1 subtype C strains was codon optimized for human codon frequency. 22.Vaccinogens as claimed in claim 1 were used for eliciting HiV- I subtype C specific immune response in mice and monkeys.
23. Immune response as claimed in claim 22 was further augmented by the immunomodulators
24-lmmunomodulators as claimed in claim 22 were CPG motifs and
Interleukϊn 2.
25.A method for augmenting the immune response comprising co-immunizing fhe host with a combination of vaccinogens and Immunomoduiafors. 26.A method as claimed in claim 25, wherein the said combinations are selected from (i) CPG motifs and recombinant plasm ids NK-29692CO, Nϋ4S42teθ, NK-49S87CO, NK-IND-tatCO, UK-iND-nefCO; (H) interieukin-2 and recombinant plasm ids NK-29692CO, NK-49426CO, NK- 49587CO, NK-lND-tatCO and NK-lND-nefCO; (lit) CPG motifs, interleukin -2 and recombinant piasmids NK-29692CO, NK<-4$42@€O, NK-49S87CO, N K-JN D-t at C O and NK-iND-nefCO; iv) CPG motifs and recombinant viral vector vaccine constructs W-29692CO, W 49426CCX
W-4SS87CO, W-IND-tatCO and W-IND-nefCO; v) lnterleukin-2 and recombinant viral vector vaccine constructs W-28692CO, W 4t42βCO, W-49S87CO, W-JND-tatCO and W-IND-nefCO and vi) CPG mtifs, interleukin-2 and recombinant viral vector vaccine constructs W- 29692CO5 W 49426CO, W-49S87CO, W-IND-tatCO and W-IND- nefCO.
27.A method as claimed in claim 22, wherein the immune response induced, was measured by ELlSA for H1V-1 specific antibodies and by IFNy- ELi Spot assay for anti HiV specific CTL activity in peripheral blood.
PCT/IN2005/000230 2005-07-04 2005-07-04 Hiv-1 vaccinogens with immunomodulators WO2007004231A1 (en)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2094296A2 (en) * 2006-11-17 2009-09-02 Duke University Multicomponent vaccine

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1335023A2 (en) * 1997-06-09 2003-08-13 Oxxon Pharmaccines Limited Methods and reagents for vaccination which generate a CD8 T cell immune response
WO2004052909A2 (en) * 2002-12-06 2004-06-24 Glaxo Group Limited Lna-cpg conjugates
WO2005016378A1 (en) * 2003-08-18 2005-02-24 All India Institute Of Medical Sciences An immunodeficiency virus (hiv) dna vaccine and to the process of preparation thereof

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1335023A2 (en) * 1997-06-09 2003-08-13 Oxxon Pharmaccines Limited Methods and reagents for vaccination which generate a CD8 T cell immune response
WO2004052909A2 (en) * 2002-12-06 2004-06-24 Glaxo Group Limited Lna-cpg conjugates
WO2005016378A1 (en) * 2003-08-18 2005-02-24 All India Institute Of Medical Sciences An immunodeficiency virus (hiv) dna vaccine and to the process of preparation thereof

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2094296A2 (en) * 2006-11-17 2009-09-02 Duke University Multicomponent vaccine
EP2094296A4 (en) * 2006-11-17 2011-09-14 Univ Duke Multicomponent vaccine

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