WO2001002607A1 - Adenovirus carrying gag gene hiv vaccine - Google Patents
Adenovirus carrying gag gene hiv vaccine Download PDFInfo
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- WO2001002607A1 WO2001002607A1 PCT/US2000/018332 US0018332W WO0102607A1 WO 2001002607 A1 WO2001002607 A1 WO 2001002607A1 US 0018332 W US0018332 W US 0018332W WO 0102607 A1 WO0102607 A1 WO 0102607A1
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- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/51—Medicinal preparations containing antigens or antibodies comprising whole cells, viruses or DNA/RNA
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- C12N2710/10011—Adenoviridae
- C12N2710/10311—Mastadenovirus, e.g. human or simian adenoviruses
- C12N2710/10341—Use of virus, viral particle or viral elements as a vector
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- 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
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- 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
- C12N2740/16134—Use of virus or viral component as vaccine, e.g. live-attenuated or inactivated virus, VLP, viral protein
Definitions
- This invention relates to replication deficient adenovirus vectors comprising an optimized human immunodeficiency virus (HIV) gag gene under the control of a strong promoter, which are suitable for vaccines against HIV.
- HIV human immunodeficiency virus
- HTV-1 Human Immunodeficiency Virus- 1
- AIDS acquired human immune deficiency syndrome
- Vaccination is an effective form of disease prevention and has proven successful against several types of viral infection.
- determining ways to present HTV-1 antigens to the human immune system in order to evoke protective humoral and cellular immunity is a difficult task.
- free virus is present in low levels only. Transmission of HIV-1 is enhanced by cell-to-cell interaction via fusion and syncytia formation.
- antibodies generated against free virus or viral subunits are generally ineffective in eliminating virus-infected cells.
- European Patent Applications 0 638 316 (Published February 15, 1995) and 0 586 076 (Published March 9, 1994), (both assigned to American Home Products Corporation) describe replicating adenovirus vectors carrying an HIV gene, including env or gag.
- Various treatment regimens were used with chimpanzees and dogs, some of which included booster adenovirus or protein plus alum treatments.
- This invention relates to a vaccine composition
- a vaccine composition comprising a replication- defective adenoviral vector comprising at least one gene encoding an HIV gag protein, wherein the gene comprises codons optimized for expression in a human, and the gene is operably linked to a heterologous promoter.
- an adenoviral vaccine vector comprising: a replication defective adenoviral genome, wherein the adenoviral genome does not have a functional El gene, and the adenoviral genome further comprises a gene expression cassette comprising: i) a nucleic acid encoding a HIV gag protein, wherein the nucleic acid is codon optimized for expression in a human host; ii) a heterologous promoter is operatively linked to the nucleic acid encoding the gag protein; and iii) a transcription terminator .
- the El gene has been deleted from the adenoviral vector, and the HIV expression cassette has replaced the deleted El gene.
- the replication defective adenovirus genome does not have a functional E3 gene, and preferably the E3 gene has been deleted.
- This invention also relates to a shuttle plasmid vector comprising: an adenoviral portion and a plasmid portion, wherein said adenovirus portion comprises: a) a replication defective adenovirus genome which does not have a functional El gene; and b) a gene expression cassette comprising: a nucleic acid encoding an HTV gag protein, wherein the nucleic acid is codon optimized for expression in a human host; a heterologous promoter operably linked to the nucleic acid encoding the gag protein; and a transcription terminator.
- aspects of this invention include a host cell comprising the adenoviral vaccine vectors and/or the shuttle plasmid vectors, methods of producing the vectors comprising introducing the adenoviral vaccine vector into a host cell which expresses adenoviral El protein, and harvesting the resultant adenoviral vaccine vectors.
- Another aspect of this invention is a method of generating a cellular immune response against an HIV protein in an individual comprising administering to the individual an adenovirus vaccine vector comprising: a) a replication defective adenoviral vector, wherein the adenoviral vector does not have a functional El gene, and b) a gene expression cassette comprising: i) a nucleic acid encoding an HIV gag protein, wherein the nucleic acid is codon optimized for expression in a human host; ii) a heterologous promoter operatively linked to the nucleic acid encoding the gag protein; and iii) a transcription terminator.
- the individual is given more than one administration of adenovirus vaccine vector, and it may be given in a regiment accompanied by the administration of a plasmid vaccine.
- the plasmid vaccine comprises a plasmid encoding a codon-optimized gag protein, a heterologous promoter operably linked to the gag protein nucleic acids, and a transcription terminator. There may be a predetermined minimum amount of time separating the administrations.
- the individual can be given a first dose of plasmid vaccine, and then a second dose of plasmid vaccine.
- the individual may be given a first dose of adenovirus vaccine vector, and then a second dose of adenoviral vaccine vector.
- the plasmid vaccine is administered first, followed after a time by administration of the adenovirus vector vaccine.
- the adenovirus vaccine vector may be administered first, followed by administration of plasmid vaccine after a time.
- an individual may be given multiple doses of the same adenovirus serotype in either viral vector or plasmid form, or the virus may be of differing serotypes.
- FIGURE 1 is a graph showing the number of gag peptide-specific interferon-gamma secreting spjenocytes (x 106) from rats which were immunized with gag plasmid or Ad5FLgag.
- FIGURE 2 shows serum SEAP (secreted alkaline phosphatase) expression levels in rhesus monkeys following injection with FG Ad5-SEAP or SEAP DNA constructs.
- FIGURES 3A, 3B and 3C show anti-HTV gag cytotoxic T lymphocyte responses in three rhesus monkeys vaccinated with FG Ad5 tPAgag.
- Each panel represents the specific killing response of a particular monkeys (denoted as numbers 92x024 in FIGURE 3 A, 94x012 in FIGURE 3B, and 94x025 in FIGURE 3C) at various time points following immunization at 0, 8, and 24 weeks.
- the abscissa axis shows the effector/target (E/T) ratios of cultured T cells and B cells employed in this assay, while the ordinate axis shows specific lysis values obtained for each sample.
- FIGURES 4A-H show anti-HIV gag cytotoxic T lymphocyte responses in rhesus monkeys vaccinated with FG Ad5FLgag.
- Figures 4A, B, and C are the first group of monkeys, D,E,and F are the second, and G, H, and I are the third group. Each represents specific killing responses of each monkey receiving the indicated treatment.
- the abscissa axis shows the effector/target (E/T) ratios of cultured T cells and B cells employed in this assay, while the ordinate axis shows specific lysis values obtained for each sample. Specific lysis values of at least 10% difference between curves ⁇ gag peptide antigen are generally considered significant.
- the square symbols represent target cells treated with DMSO alone at the same concentration as samples containing peptides while the circles, triangles, and diamonds represent target cells treated with partial (F, G) or complete (H) gag peptide pools, respectively.
- FIGURES 5A-H show anti-HIV gag cytotoxic T lymphocyte responses in rhesus monkeys vaccinated with Ad2Flgag priming, followed by either Ad2Flgag or Ad5Flgag boosting.
- Each panel ( Figures 5A-G) represents specific killing responses of a group of three monkeys receiving the indicated treatment.
- the last panel ( Figure 5H) shows responses from two naive monkeys that were not vaccinated.
- the abscissa axis shows the effector/target (E/T) ratios of cultured T cells and B cells employed in this assay, while the ordinate axis shows specific lysis values obtained for each sample. Specific lysis values of at least 10% difference between curves ⁇ gag peptide antigen are generally considered significant..
- FIGURE 6 is the nucleic acid sequence (SEQ.ID.NO.l) of the optimized human HIV-1 gag open reading frame.
- FIGURE 7A shows construction of the adenovirus carrying codon- optimized gag.
- FIGURE 7B shows construction of the adenovirus carrying codon- optimized tPA-gag.
- FIGURE 8 is the nucleic acid sequence of the optimized tPA-gag open reading frame.
- adenoviral constructs gene constructs are named by reference to the genes contained therein, such as below:
- tPAgag refers to a fusion between the leader sequence of the tissue plasminogen activator leader sequence and an optimized HIV gag gene. .
- Ad5-tPAgag refers to an adenovirus serotype 5 replication deficient virus which carries an expression cassette which comprises a tissue plasminogen activator leader sequence fused to a codon-optimized gag gene which is under the control of the CMV promoter and contains Intron A.
- FI refers to a full length gene.
- Flgag refers to the full-length optimized gag gene.
- Ad5-Flgag refers to an adenovirus serotype 5 replication deficient virus which carries an expression cassette which comprises a full length optimized gag gene under the control of the CMV promoter and contains Intron A.
- FG Adenovirus means a First Generation adenovirus, i.e. a replication deficient adenovirus which has either a non-functional or deleted El region, and optionally a non-functional or deleted E3 region.
- Promoter means a recognition site on a DNA strand to which an RNA polymerase binds.
- the promoter forms an initiation complex with RNA polymerase to initiate and drive transcriptional activity.
- the complex can be modified by activating sequences such as enhancers or inhibiting sequences such as silencers.
- Leader means a DNA sequence at the 5' end of a structural gene which is transcribed along with the gene. This usually results a protein having an N- terminal peptide extension, often referred to as a pro-sequences.
- Intron refers to a section of DNA occurring in the middle of a gene which does not code for an amino acid in the gene product.
- the precursor RNA of the intron is excised and is therefore not transcribed into mRNA not translated into protein.
- “Cassette” refers to the a nucleic acid sequence which is to be expressed, along with its transcription and translational control sequences. By changing the cassette, a vector can express a different sequence. It has been found according to this invention that first generation adenoviral vectors carrying a codon-optimized HIV gag gene regulated with a strong heterologous promoter can be used as human anti-HIV vaccines, and are capable of inducing immune responses.
- the adenoviral vector which makes up the backbone of the vaccine construct of this invention is preferably a "first generation" adenoviral vector.
- This group of adenoviral vectors is known in the art, and these viruses are characterized by being replication-defective. They typically have a deleted or inactivated El gene region, and preferably additionally have a deleted or inactivated E3 gene region.
- the first generation replication incompetent adenovirus vector used is a serotype 5 adenovirus containing deletions in El (Ad5 base pairs 342-3523) and E3 (Ad5 base pairs 28133 to 30818)..
- the El deletions are preferably bp 559-3503 and the E3 deletions are preferably 28,812-29,773. (Genbank gb:J01917). Those of skill in the art can easily determine the equivalent sequences for other serotypes, such as serotypes 4, 12, 6, 17, 24, 33, 42, 31, 16.
- Adenoviral serotypes 2 and 5, particularly 5 are preferred for use in this invention, since at this point in time, more is known about these serotypes generally than other serotypes, and their complete DNA sequences are known.
- the prototype serotype 5 adenovirus has been completely sequenced (Chroboczek et al, 1992 J. Virology 186:280, which is hereby incorporated by reference.) They also belong to the subgroup C adenoviruses, which are not associated with human or rodent malignancies.
- any adenovirus serotype can be used in this invention, including non-human ones, as deletion of El genes should render all adenoviruses non-tumorogenic.
- adenoviral vectors can be constructed using known techniques, such as those reviewed in Hitt et al, 1997 "Human Adenovirus Vectors for Gene Transfer into Mammalian Cells” Advances in Pharmacology 40:137-206, which is hereby incorporated by reference.
- adenoviral vectors of this invention it is often convenient to insert them in to a plasmid or shuttle vector. These techniques are known and described in Hitt et al supra.
- This invention specifically includes both the adenovirus and the adenovirus when inserted into a shuttle plasmid.
- Viral vectors can be propagated in various El complementing cell lines, including the known cell lines 293 and PER.C6. Both these cell lines express the adenoviral El gene product. PER.C6 is described in WO 97/00326, published January 3, 1997, which is hereby incorporated by reference.
- the HIV gag gene selected to be expressed is of importance to the invention. Sequences for many genes of many HIV strains are publicly available in GENBANK and primary, field isolates of HIV are available from the National Institute of Allergy and Infectious Diseases (NIAID) which has contracted with Quality Biological (Gaithersburg, MD) to make these strains available. Strains are also available from the World Health Organization (WHO), Geneva Switzerland.
- the gag gene is from an HIV-1 strain (CAM- 1; Myers et al, eds. "Human Retroviruses and AIDS: 1995, IIA3-IIA19, which is incorporated by reference). This gene closely resembles the consensus amino acid sequence for the clade B (North American/European) sequence.
- a “triplet” codon of four possible nucleotide bases can exist in 64 variant forms. That these forms provide the message for only 20 different amino acids (as well as transcription initiation and termination) means that some amino acids can be coded for by more than one codon. Indeed, some amino acids have as many as six “redundant”, alternative codons while some others have a single, required codon. For reasons not completely understood, alternative codons are not at all uniformly present in the endogenous DNA of differing types of cells and there appears to exist variable natural hierarchy or "preference" for certain codons in certain types of cells.
- the amino acid leucine is specified by any of six DNA codons including CTA, CTC, CTG, CTT, TTA, and TTG (which correspond, respectively, to the mRNA codons, CUA, CUC, CUG, CUU, UUA and UUG).
- CTA CTC
- CTG CTT
- TTA TTA
- TTG TTA
- Exhaustive analysis of genome codon frequencies for microorganisms has revealed endogenous DNA of E. coli most commonly contains the CTG leucine-specifying codon, while the DNA of yeasts and slime molds most commonly includes a TTA leucine-specifying codon. In view of this hierarchy, it is generally held that the likelihood of obtaining high levels of expression of a leucine- rich polypeptide by an E. coli host will depend to some extent on the frequency of codon use.
- a gene rich in TTA codons will in all probability be poorly expressed in E. coli, whereas a CTG rich gene will probably highly express the polypeptide.
- yeast cells are the projected transformation host cells for expression of a leucine-rich polypeptide, a preferred codon for use in an inserted DNA would be TTA.
- one aspect of this invention is an adenovirus vector which specifically includes a gag gene which is codon optimized for expression in a human cellular environment.
- the diversity of function that typifies eukaryotic cells depends upon the structural differentiation of their membrane boundaries. To generate and maintain these structures, proteins must be transported from their site of synthesis in the endoplasmic reticulum to predetermined destinations throughout the cell. This requires that the trafficking proteins display sorting signals that are recognized by the molecular machinery responsible for route selection located at the access points to the main trafficking pathways. Sorting decisions for most proteins need to be made only once as they traverse their biosynthetic pathways since their final destination, the cellular location at which they perform their function, becomes their permanent residence.
- tPA tissue-specific plasminogen activator protein
- a number of sorting signals have been found associated with the cytoplasmic domains of membrane proteins such as di-Leucine amino acid motifs or tyrosine-based sequences that can direct proteins to lysosomal compartments.
- transport and extrusion from the cell of viral particles depend upon myristoylation of glycine residue number two at the amino terminus of gag.
- the tPA leader sequence has been attached 5' to the structural gene sequence.
- the optimized gag gene is incorporated into an expression cassette.
- the cassette contains a transcriptional promoter recognized by an eukaryotic RNA polymerase, and a transcriptional terminator at the end of the gag gene coding sequence.
- the promoter is a "strong" or "efficient” promoter.
- An example of a strong promoter is the immediate early human cytomegalovirus promoter (Chapman et al, 1991 Nucl.
- CMV-intA intron A sequence
- promoters such as the strong immunoglobulin, or other eukaryotic gene promoters
- RSV Rous sarcoma virus
- SV40 early/late promoters SV40 early/late promoters
- beta-actin promoter a preferred transcriptional terminator is the bovine growth hormone terminator.
- the combination of CMVintA-BGH terminator is particularly preferred although other promoter/terminator combinations in the context of FG adenovirus may also be used.
- a shuttle vector version of the adenovirus vector is often prepared.
- the shuttle vector contains an adenoviral portion and a plasmid portion.
- the adenoviral portion is essentially the same as the adenovirus vector discussed supra.containing adenoviral sequences (with non-functional or deleted El and E3 regions) and the gag expression cassette, flanked by convenient restriction sites.
- the plasmid portion of the shuttle vector often contains an antibiotic resistance marker under transcriptional control of a prokaryotic promoter so that expression of the antibiotic does not occur in eukaryotic cells. Ampicillin resistance genes, neomycin resistance genes and other pharmaceutically acceptable antibiotic resistance markers may be used.
- the shuttle vector To aid in the high level production of the polynucleotide by fermentation in prokaryotic organisms, it is advantageous for the shuttle vector to contain a prokaryotic origin of replication and be of high copy number.
- a number of commercially available prokaryotic cloning vectors provide these benefits. It is desirable to remove non-essential DNA sequences. It is also desirable that the vectors not be able to replicate in eukaryotic cells. This minimizes the risk of integration of polynucleotide vaccine sequences into the recipients' genome. Tissue-specific promoters or enhancers may be used whenever it is desirable to limit expression of the polynucleotide to a particular tissue type.
- the shuttle plasmid used is pAD.CMVI-FLHIVgag, was made using homologous recombination techniques.
- the shuttle vector was rescued into virus in PER.C6 cells.
- the shuttle plasmid was linearized by Pad restriction enzyme digestion and transfected into the PER.C6 cells using the calcium phosphate coprecipitate method.
- the plasmid in linear form is capable of replication after entering the PER.C6 cells and virus is produced.
- the infected cells and media were harvested after viral replication was complete.
- Standard techniques of molecular biology for preparing and purifying DNA constructs enable the preparation of the DNA immunogens of this invention.
- a method of clonal purification was used for clinical material.
- the virus obtained from transfection of the PER.C6 cells was serially diluted to extinction using 2-fold dilutions.
- the dilutions were then used to infect PER.C6 cells in 96 well plates using 24 wells for each solution At the end of a 14-day incubation period the wells were scored positive or negative using adenovirus specific PCR and gag ELISA. Virus positive wells at the highest dilutions were selected for expansion.
- the selected well was the only positive well out of 24 wells plated at that dilution giving 98% assurance of clonality Verification of that endpoint had been reached in the dilution series, and that virus positive wells that had insufficient virus to be detected in the initial screening had not been missed, was obtained by subculturing the original 96 well plated two additional times and re- scoring them This confirmed the clonality of the selected well.
- the selected virus was designated AD5FLgag.
- the adenoviral vaccine composition may contain physiologically acceptable components, such as buffer, normal saline or phosphate buffered saline, sucrose, other salts and polysorbate.
- physiologically acceptable components such as buffer, normal saline or phosphate buffered saline, sucrose, other salts and polysorbate.
- One preferred formulation has: 2.5-10 mM TRIS buffer, preferably about 5 mM TRIS buffer; 25-100 mM NaCl, preferably about 75 mM NaCl; 2.5-10% sucrose, preferably about 5% sucrose; 0.01 -2 mM MgCl2; and
- the pH should range from about 7.0- 9.0, preferably about 8.0.
- the preferred formulation contains 5mM TRIS, 75 mM NaCl, 5% sucrose, ImM MgCl2, 0.005% polysorbate 80 at pH 8.0 This has a pH and divalent cation composition which is near the optimum for Ad5 stability and minimizes the potential for adsorption of virus to a glass surface. It does not cause tissue irritation upon intramuscular injection. It is preferably frozen until use.
- adenoviral particles in the vaccine composition to be introduced into a vaccine recipient will depend on the strength of the transcriptional and translational promoters used and on the immunogenicity of the expressed gene product.
- an immunologically or prophylactically effective dose of lxl ⁇ 7 to 1x1012 particles and preferably about 1x1010 to lxlOll particles is administered directly into muscle tissue.
- Subcutaneous injection, intradermal introduction, impression through the skin, and other modes of administration such as intraperitoneal, intravenous, or inhalation delivery are also contemplated.
- booster vaccinations are to be provided. Following vaccination with HIV adenoviral vector, boosting with a subsequent HIV adenoviral vector and/or plasmid may be desirable.
- Parenteral administration such as intravenous, intramuscular, subcutaneous or other means of administration of interleukin-12 protein, concurrently with or subsequent to parenteral introduction of the vaccine compositions of this invention is also advantageous.
- Another aspect of this invention is the administration of the adenoviral vector containing the optimized gag gene in a prime/boost regiment in conjunction with a plasmid DNA encoding gag.
- this plasmid will be referred to as a "vaccine plasmid”.
- the preferred vaccine plasmids to use in this administration protocol are disclosed in pending U.S.
- VlJns-FL-gag which expresses the same codon-optimized gag gene as the adenoviral vectors of this invention.
- the vaccine plasmid backbone, designated VlJns contains the CMV immediate -early (IE) promoter and intron A, a bovine growth hormone-derived polyadenylation and transcriptional termination sequence as the gene expression regulatory elements, and a minimal pUC backbone (Montgomery et al, 1993 DNA Cell Biol. 12:777-783.
- IE immediate -early
- the pUC sequence permits high levels of plasmid production in E. coli and has a neomycin resistance gene in place of an ampicillin resistance gene to provide selected growth in the presence of kanamycin.
- adenoviral vector and/or vaccine plasmids of this invention polynucleotide may be unassociated with any proteins, adjuvants or other agents which impact on the recipients' immune system.
- the vector it is desirable for the vector to be in a physiologically acceptable solution, such as, but not limited to, sterile saline or sterile buffered saline.
- the vector may be associated with an adjuvant known in the art to boost immune responses, such as a protein or other carrier.
- Agents which assist in the cellular uptake of DNA such as, but not limited to, calcium ions, may also be used to advantage. These agents are generally referred to herein as transfection facilitating reagents and pharmaceutically acceptable carriers.
- Techniques for coating microprojectiles coated with polynucleotide are known in the art and are also useful in connection with this invention.
- the adenoviral vaccines of this invention may be administered alone, or may be part of a prime and boost administration regimen.
- a mixed modality priming and booster inoculation scheme will result in an enhanced immune response, particularly is pre-existing anti-vector immune responses are present.
- This one aspect of this invention is a method of priming a subject with the plasmid vaccine by administering the plasmid vaccine at least one time, allowing a predetermined length of time to pass, and then boosting by administering the adenoviral vaccine.
- Multiple primings typically, 1-4, are usually employed, although more may be used.
- the length of time between priming and boost may typically vary from about four months to a year, but other time frames may be used.
- a priming regimen may be particularly preferred in situations where a person has a pre-existing anti-adenovirus immune response.
- This invention also includes a prime and boost regimen wherein a first adenoviral vector is administered, then a booster dose is given. The booster dose may be repeated at selected time intervals.
- Another aspect of this invention is an assay which measures the elicitation of HIV-1 protein, including gag-specific cellular immunity, particularly cytotoxic T-lymphocyte (CTL) responses .
- CTL cytotoxic T-lymphocyte
- ELIspot and cytotoxicity assays, discussed herein, measure HIV antigen-specific CD8+ and CD4+ T lymphocyte responses, and can be used for a variety of mammals, such as humans, rhesus monkeys, mice, and rats.
- the ELIspot assay provides a quantitative determination of HIV- specific T lymphocyte responses.
- PMBC cells are cultured in tissue culture microtiter plates.
- An HTV-1 gag peptide pool that encompasses the entire 500 amino acid open reading frame of gag (50 overlapping 20mer peptides) is added to the cells and one day later the number of cells producing gamma interferon (or another selected interferon) is measured.
- Gamma interferon was selected as the cytokine visualized in this assay (using species specific anti-gamma interferon monoclonal antibodies) because it is the most common, and one of the most abundant cytokines synthesized and secreted by activated T lymphocytes.
- the number of spot forming cells (SPC) per million PBMCs is determined for samples in the presence and absence (media control) of peptide antigens.
- This assay may be set up to determine overall T lymphocyte responses (both CD8+ and CD4+) or for specific cell populations by prior depletion of either CD8+ or CD4+ T cells.
- ELIspot assays or variations of it, can be used to determine which peptide epitopes are recognized by particular individuals.
- T lymphocytes A distinguishing effector function of T lymphocytes is the ability of subsets of this cell population to directly lyse cells exhibiting appropriate MHC- associated antigenic peptides. This cytotoxic activity is most often associated with CD8+ T lymphocytes but may also be exhibited by CD4+ T lymphocytes.
- PBMC samples are infected with recombinant vaccinia viruses expressing antigens (e.g., gag) in vitro for approximately 14 days to provide antigen restimulation and expansion of memory T cells that are then tested for cytoxicity against autologous B cell lines treated either with peptide antigen pools. Specific cytotoxicity is measured compared to irrelevant antigen or excipient-treated B cell lines.
- the phenotype of responding T lymphocytes is determined by appropriate depletion of either CD8+ or CD4+ populations prior to the cytotoxicity assay. This assay is semi-quantitative and is the preferred means for determining whether CTL responses were elicited by the vaccine.
- Shuttle vector pHCMVIBGHpA 1 contains Ad5 sequences from bpl to bp 341 and bp 3534 to bp 5798 with a expression cassette containing human cytomegalovirus (HCMV) promoter plus intron A and bovine growth hormone polyadenylation signal.
- HCMV human cytomegalovirus
- the adenoviral backbone vector pAdEl-E3- (also named as pHVadl) contains all Ad5 sequences except those nucleotides encompassing the El and E3 region.
- Plasmid pVlJNStpaHTVgag contains tPA secretory signal sequence fused to the codon-optimized HIV gag nucleotides under the control of HCMV promoter plus intron A. It is described in pending U.S. patent application 09/017,981, filed February 3, 1998 and WO98/34640, published August 13, 1998, both of which are hereby incorporated by reference.
- Plasmid pVlR-FLHIV gag (also named as pVlR-HTVgag-opt) contains codon-optimized full-length HTV gag under the control of the HCMV promoter plus intron A.
- the tPAgag insert was excised from pVUNS-tPAgag by restriction enzymes Pstl and Xmal, blunt-ended, and then cloned into EcoRV digested shuttle vector pHCMVIBGHpAl .
- the orientation of the transgene and the construct were verified by PCR using the insert specific primers hCMV5'-4 (5' TAG CGG CGG AGC TTC TAC ATC 3' SEQ.ID.NO. _) and Gag3 -1 (5' ACT GGG AGG AGG GGT CGT TGC 3' SEQ.JD.NO._), restriction enzyme analysis (Real, SspBI), and DNA sequencing spanning from CMV promoter to the initiation of the gag.
- Shuttle plasmid pA 1 -CM VI- tpaHIVgag was digested with restriction enzymes BstZ17 and SgrAl and then co-transformed into E. coli strain BJ5183 with linearized (Clal digested) adenoviral backbone plasmid pAdEl-E3-. One colony was verified by PCR analysis. The vector was transformed to competent E. coli HBIOI for large quantity production of the plasmid.
- Clone No.9 was grown into large quantities through multiple rounds of amplification in 293 cells. One lot yielded of 1.7x1012 particles and a second lot yielded 6.7xl ⁇ l3 particles.
- the viral DNA was extracted by proteinase K digestion and confirmed by PCR and restriction enzyme (HindlTJ) analysis. The expression of tpaHIVgag was also verified by ELISA and Western blot analysis of the 293 or COS cells infected with the recombinant adenovirus. The recombinant adenovirus was used for evaluation in mice and rhesus monkeys.
- Ad5.FHIVgag Construction of Ad5.FHIVgag 1. Construction of adenoviral shuttle plasmid pA 1 -CMVI-FLHIVgag containing full length HIVgag under the control of human CMV promoter and intron A.
- the FLHIVgag insert was excised from pVlR-FLHTVgag by restriction enzyme Bglll and then cloned into BglTI digested shuttle vector pHCMVIBGHpAl. The orientation and the construct were verified by PCR using the insert specific primers (hCMV5'-4 and Gag3'-1), restriction enzyme analysis, and DNA sequencing.
- Shuttle plasmid pAl -CMVI-FLHIVgag was digested with restriction enzymes BstZ17 and SgrAl and then co-transformed into E. coli strain BJ5183 with linearized (Clal digested) adenoviral backbone plasmid pAdEl-E3-. Colonies #6 and #7 were verified by PCR analysis. The vectors were transformed to competent E. coli HB101 for large quantity production of the plasmid. The plasmids were verified by HindTH digestion.
- the pAd plasmids were linearized by restriction enzyme Pad and transfected to 293 cells using Lipofectamine (BRL). Two weeks later, 6 viruses (#6- 1.1, 6-1.2, 6-1.3, 7-1.1, 7-1.2, 7-1.3) were picked and grown in 293 cells in 35-mm plates. PCR analysis using the insert specific primers (hCMV5'-4 and Gag3'-1) of the adenoviral DNA verified the presence of HIV gag.
- Virus clone #6-1 was grown into large quantities through multiple rounds of amplification in 293 cells.
- the viral DNA was extracted by proteinase K digestion and confirmed by PCR, restriction enzyme (HindJ I, Bgl ⁇ , Bst E TJ, Xho I) analysis.
- HisndJ I, Bgl ⁇ , Bst E TJ, Xho I restriction enzyme
- a partial sequencing confirmed the junction between CMV promoter and the 5' end of HIV gag gene.
- the expression of FLHIVgag was also verified by ELISA and Western blot analysis of the 293 or COS cells infected with the recombinant adenovirus.
- the recombinant adenovirus was used for evaluation in mice and rhesus monkeys.
- FG adenovirus FL gag Construction of FG adenovirus FL gag.
- the full-length (FL) humanized gag gene was ligated into an adenovirus-5 shuttle vector, pHCMVIBGHpAl, containing Ad5 sequences from bp 1 to bp 341 and bp 3534 to bp 5798 with a expression cassette containing human CMV promoter plus intron A and bovine growth hormone polyadenylation signal.
- the orientation was confirmed by restriction enzyme digestion analysis and DNA sequencing. Homologous recombination in E.
- coli was employed using the shuttle plasmid, pAl-CMVI- FLHIVgag, and adenoviral backbone plasmid, pAdEl-E3-, to generate a plasmid form of the recombinant adenovirus containing the expression regulatory elements and FL gag gene, pAd.CMVI-FHIVgag.
- Appropriate plasmid recombinants were confirmed by restriction enzyme digestion.
- the pAd plasmid containing the gag expression cassette was linearized by restriction enzyme Pad and transfected to 293 cells (or PER.C6 cells for clinical development candidates) using Lipofectamine (BRL). Two weeks later, 6 viruses were picked and grown in 293 cells in 35-mm plates.
- PCR analysis using the insert specific primers (hCMV5'-4 and Gag3'-1) of the adenoviral DNA verified the presence of HIV gag.
- Virus clone #6-1 was grown into large quantities through multiple rounds of amplification in 293 cells.
- the viral DNA was extracted by proteinase K digestion and confirmed by PCR, restriction enzyme (HindUJ, BglJJ, BstEII, Xhol) analysis.
- a partial sequencing confirmed the junction between CMV promoter and the 5' end of HIV gag gene. Restriction enzyme analysis demonstrated that the viral genome was stable over the course of these passages.
- HIV gag was verified by ELISA and Western blot analysis of the 293 or COS cells infected with the recombinant adenovirus.
- the ELIspot assay is a quantitative determination of TV-specific T lymphocyte responses by visualization of gamma interferon secreting cells in tissue culture microtiter plates one day following addition of an HTV-1 gag peptide pool that encompasses the entire 500 amino acid open reading frame of gag (50 overlapping 20mer peptides) to PBMC samples.
- the number of spot forming cells (SPC) per million of PBMVs is determined for samples in the presence and absence (media control) of peptide antigens.
- the assay may be set up to determine overall T lymphocyte responses (both CD8+ and CD4+) or for specific cell populations by prior depletion of either CD8+ or CD4+ cells.
- the assay can be varied so as to determine which peptide epitopes are recognized by particular individuals.
- Cytotoxic T Lymphocyte Assays In this assay, PBMC samples are infected with recombinant vaccinia viruses expressing gag antigen in vitro for approximately 14 days to provide antigen restimulation and expansion of memory T cells. The cells are then tested for cytotoxicity against autologous B cell lines treated with peptide antigen pools. The phenotype of responding T lymphocytes is determined by appropriate depletion of either CD8+ or CD4+ cells.
- Adenovirus vectors coding for the gag antigen have consistently produced significantly stronger cellular immune responses than plasmid vectors in rodent species.
- Table 1 shows ELIspot data from mice vaccinated with Ad5FLgag in comparison with plasmid DNA. Spleens from five mice were pooled and the number of gag peptide-specific interferon-gamma secreting cells was determined.
- FIGURE 1 shows the ELIspot data from individual rats vaccinated with lOlO particles of adenovirus Ad5FLgag or with 0.4 mg FL gag plasmid. The mean response after one vaccination was 10-fold higher with adenovirus compared to plasmid. Both vaccines gave a boosted signal after a second vaccination, with the adenovirus vaccine signal 5-fold higher than the plasmid signal.
- FIGURE 2 shows that at the highest possible plasmid dose (5 mg), the antigen levels are 1,000-fold lower than the levels achieved using 10l0 particles of adenovirus, a dose which is ten fold lower than the maximum proposed clinical dose.
- FIGURE 3 shows that all three monkeys had developed strong bulk culture cytotoxicity responses against gag peptide sensitized autologous B cell lines following in vitro restimulation using vaccinia-gag for two weeks.
- Rhesus are a poor host for this viral strain, while about 40-60% of humans have significant neutralizing antibody responses (titers from 10-500).
- two groups of monkeys (6 and 7) were pre-exposed to FG adenovirus-SEAP vectors thrice and once, respectively, generating a range of neutralizing antibody responses in these monkeys that encompass the range observed in humans.
- FIGURES 4A-I show bulk culture cytotoxicity responses of these vaccines at 8 weeks post a single immunization. All monkeys (groups 1-5, Figures 4A-E) that had not been previously exposed to adenovirus-5 showed significant gag- specific cytotoxic responses at all doses using either biojector or needle while 5/6 vaccines that had been preexposed to adenovirus showed cytotoxic responses (groups 6-7, Figure 4F-G). Control animals have remained consistently negative in these assays (e.g., group 8, Figure 4H).
- Anti-gag ELIspot responses were also measured in all monkeys at eight weeks. Table 2, below is a summary of these responses that show that nearly all vaccines developed significant gamma-interferon responses to this vaccine, although prior exposure to adenovirus reduced response levels, and a dose response appears to have been obtained with the highest doses giving the best responses. In addition, in this experiment (as well as an independent experiment) no difference was observed for needle vs. biojector delivery of vaccine. CD4 T cell depletion of these samples showed that the ELIspot responses are largely due to CD8 T cells.
- DNA priming may enhance the cellular immune response to gag induced by adenovirus vaccination as shown below.
- Three rhesus monkeys which had been vaccinated four times with 1 mg of gag plasmid were boosted 4 months following the final DNA shot with 1011 particles of FG Ad FLgag.
- the cellular immune responses (measured by ELIspot and denoted as SFC/million PBMCs) to gag peptides in the monkeys primed with DNA and boosted with adenovirus appear significantly higher than adenovirus vaccination alone.
- the use of a DNA priming regimen may be particularly advantageous in humans who have preexisting anti- adenovirus immune responses.
- Boost were performed at week 0, 8, and 24.
- Boost were performed at week 0, 8, and 24.
- C. Determination of HIV-Specific T Lymphocyte Responses in HIV-t- Humans In order to qualify the CTL assays, PBMCs from HIV-1 -infected patients, classified as long-term nonprogessors (LTNPs) due to their ability to maintain low levels of systemic viremia and high CD4 + T cell counts over a period of years, were used to measure systemic specific CTL responses. As discussed above, several studies have reported that the presence of HIV-1 -specific CTL responses in infected individuals appears to correlate well with maintenance of disease-free infection.
- LTNPs long-term nonprogessors
- the ELIspot assay provides a quantitative determination of HTv * - specific T lymphocyte responses by visualization of gamma interferon-secreting cells in tissue culture microtiter plates one day following addition of an HIV-1 gag peptide pool that encompasses the entire 500 amino acid open reading frame of gag (50 overlapping 20mer peptides) to PBMC samples.
- Gamma interferon was selected as the cytokine visualized in this assay (using species specific anti-gamma interferon monoclonal antibodies) because it is the most common, and one of the most abundant cytokines synthesized and secreted by activated T lymphocytes.
- the number of spot forming cells (SPC) per million PBMCs is determined for samples in the presence and absence (media control) of peptide antigens.
- This assay may be set up to determine overall T lymphocyte responses (both CD8+ and CD4+) or for specific cell populations by prior depletion of either CD8+ or CD4+ T cells.
- ELIspot assays or variations of it, can be used to determine which peptide epitopes are recognized by particular individuals.
- a distinguishing effector function of T lymphocytes is the ability of subsets of this cell population to directly lyse cells exhibiting appropriate MHC- associated antigenic peptides. This cytotoxic activity is most often associated with CD8+ T lymphocytes but may also be exhibited by CD4+ T lymphocytes.
- PBMC samples are infected with recombinant vaccinia viruses expressing antigens (e.g., gag) in vitro for approximately 14 days to provide antigen restimulation and expansion of memory T cells that are then tested for cytoxicity against autologous B cell lines treated either with peptide antigen pools. Specific cytotoxicity is measured compared to irrelevant antigen or excipient-treated B cell lines.
- the phenotype of responding T lymphocytes is determined by appropriate depletion of either CD8+ or CD4+ populations prior to the cytotoxicity assay. This assay is the best means for determining whether CTL responses were elicited by the vaccine.
- Ad5 seropositive and seronegative individuals receive either 107 or 109 particles per dose on a 0, 6 month schedule. Some of the individuals who have received a single dose of 109 particled of Ad5gag will also receive three injections of HIV gag DNA with l ⁇ U particles of Ad5 gag. Also, individuals who are Ad5 seropositive and seronegative naive individuals will receive 10l 1 particles on a 0, 6 month schedule.
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CA002378539A CA2378539A1 (en) | 1999-07-06 | 2000-07-03 | Adenovirus carrying gag gene hiv vaccine |
US09/818,443 US6787351B2 (en) | 1999-07-06 | 2001-03-27 | Adenovirus carrying gag gene HIV vaccine |
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Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5672508A (en) * | 1996-01-23 | 1997-09-30 | Mitotix, Inc. | Inhibitors of cell-cycle progression, and uses related thereto |
US5859193A (en) * | 1988-11-23 | 1999-01-12 | Abbott Laboratories | Synthetic DNA derived recombinant HIV antigens |
Family Cites Families (19)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5643579A (en) | 1984-11-01 | 1997-07-01 | American Home Products Corporation | Oral vaccines |
US5716826A (en) * | 1988-03-21 | 1998-02-10 | Chiron Viagene, Inc. | Recombinant retroviruses |
EP0586076B1 (en) | 1992-08-07 | 2003-06-25 | Wyeth | Recombinant adenovirus vaccines |
FR2705686B1 (en) * | 1993-05-28 | 1995-08-18 | Transgene Sa | New defective adenoviruses and corresponding complementation lines. |
ES2196018T3 (en) | 1993-08-11 | 2003-12-16 | Wyeth Corp | RECOMBINANT ADENOVIRUS VACCINES. |
AU711269B2 (en) | 1994-08-16 | 1999-10-07 | Crucell Holland B.V. | Recombinant vectors derived from adenovirus for use in gene therapy |
ES2176360T3 (en) | 1994-12-30 | 2002-12-01 | Chiron Corp | COMBINATION OF GENES ADMINISTRATION VEHICLES. |
US6019978A (en) | 1995-06-05 | 2000-02-01 | The Wistar Institute Of Anatomy And Biology | Replication-defective adenovirus human type 5 recombinant as a vaccine carrier |
WO1996039178A1 (en) | 1995-06-05 | 1996-12-12 | The Wistar Institute Of Anatomy And Biology | A replication-defective adenovirus human type 5 recombinant as a vaccine carrier |
DK0833934T4 (en) | 1995-06-15 | 2012-11-19 | Crucell Holland Bv | Packaging systems for human recombinant adenovirus for use in gene therapy |
EE9800257A (en) | 1996-02-22 | 1999-02-15 | Merck & Co., Inc. | Synthetic HIV genes |
WO1997039771A1 (en) | 1996-04-22 | 1997-10-30 | The Government Of The United States Of America, Represented By The Secretary Of The Department Of Health And Human Services | Heterologous boosting immunizations |
CA2258568A1 (en) | 1996-06-21 | 1997-12-24 | Merck & Co., Inc. | Vaccines comprising synthetic genes |
IL131131A0 (en) | 1997-02-07 | 2001-01-28 | Merck & Co Inc | Synthetic hiv gag genes |
GB9711957D0 (en) | 1997-06-09 | 1997-08-06 | Isis Innovation | Methods and reagents for vaccination |
EP1199089A1 (en) | 1999-06-30 | 2002-04-24 | Javier Garrigues Mateo | Off side detection system |
GB9922361D0 (en) | 1999-09-21 | 1999-11-24 | Isis Innovation | Generating an immune response to an antigen |
JP2003516741A (en) | 1999-12-17 | 2003-05-20 | メルク エンド カムパニー インコーポレーテッド | Polynucleotide vaccines expressing codon-optimized HIV-1Nef and modified HIV-1Nef |
WO2001045748A1 (en) | 1999-12-22 | 2001-06-28 | Merck & Co., Inc. | Polynucleotide vaccines expressing codon optimized hiv-1 pol and modified hiv-1 pol |
-
2000
- 2000-07-03 EP EP00945133A patent/EP1200622A4/en not_active Withdrawn
- 2000-07-03 WO PCT/US2000/018332 patent/WO2001002607A1/en active Application Filing
- 2000-07-03 JP JP2001508378A patent/JP2003530307A/en not_active Withdrawn
- 2000-07-03 CA CA002378539A patent/CA2378539A1/en not_active Abandoned
-
2001
- 2001-03-27 US US09/818,443 patent/US6787351B2/en not_active Expired - Fee Related
-
2003
- 2003-06-13 US US10/461,030 patent/US20030228329A1/en not_active Abandoned
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5859193A (en) * | 1988-11-23 | 1999-01-12 | Abbott Laboratories | Synthetic DNA derived recombinant HIV antigens |
US5672508A (en) * | 1996-01-23 | 1997-09-30 | Mitotix, Inc. | Inhibitors of cell-cycle progression, and uses related thereto |
Non-Patent Citations (1)
Title |
---|
See also references of EP1200622A4 * |
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Also Published As
Publication number | Publication date |
---|---|
EP1200622A4 (en) | 2004-12-22 |
EP1200622A1 (en) | 2002-05-02 |
JP2003530307A (en) | 2003-10-14 |
US6787351B2 (en) | 2004-09-07 |
CA2378539A1 (en) | 2001-01-11 |
US20020061517A1 (en) | 2002-05-23 |
US20030228329A1 (en) | 2003-12-11 |
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