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WO2004110349A2 - Epitopes de lymphocytes t utiles en tant que vaccin contre le virus du syndrome respiratoire aigu severe (sras) et en tant qu'outils diagnostiques et procedes d'identification associes - Google Patents

Epitopes de lymphocytes t utiles en tant que vaccin contre le virus du syndrome respiratoire aigu severe (sras) et en tant qu'outils diagnostiques et procedes d'identification associes Download PDF

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Publication number
WO2004110349A2
WO2004110349A2 PCT/US2004/015026 US2004015026W WO2004110349A2 WO 2004110349 A2 WO2004110349 A2 WO 2004110349A2 US 2004015026 W US2004015026 W US 2004015026W WO 2004110349 A2 WO2004110349 A2 WO 2004110349A2
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seq
peptides
criimrcwl
epitopes
binding
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WO2004110349A3 (fr
Inventor
Morten Nielsen
Ole Lund
Claus Lundegaard
Peder Worning
Soren Buus
Soren Brunak
Sune Justesen
Christina Sylvester-Hvid
Gustav A. Roder
Kasper Lamberth
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Siga Technologies Inc
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Siga Technologies Inc
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Priority to IL171924A priority patent/IL171924A0/en
Anticipated expiration legal-status Critical
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    • 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
    • A61K39/215—Coronaviridae, e.g. avian infectious bronchitis 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
    • 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
    • A61K2039/53—DNA (RNA) vaccination
    • 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
    • C12N2770/00—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA ssRNA viruses positive-sense
    • C12N2770/00011—Details
    • C12N2770/20011—Coronaviridae
    • C12N2770/20022—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
    • C12N2770/00—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA ssRNA viruses positive-sense
    • C12N2770/00011—Details
    • C12N2770/20011—Coronaviridae
    • C12N2770/20034—Use of virus or viral component as vaccine, e.g. live-attenuated or inactivated virus, VLP, viral protein
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
    • G01N2333/005—Assays involving biological materials from specific organisms or of a specific nature from viruses
    • G01N2333/08—RNA viruses
    • G01N2333/165—Coronaviridae, e.g. avian infectious bronchitis virus

Definitions

  • the present invention relates to the identification of T-cell epitopes within Severe Acute Respiratory Syndrome (SARS) Virus, for use as diagnostic as well as prophylactic and therapeutic vaccine use.
  • SARS Severe Acute Respiratory Syndrome
  • the present invention also relates to subunit vaccines.
  • SARS Severe acute respiratory syndrome
  • SARS severe acute respiratory syndrome
  • the method derives weight-matrices describing the binding motif of a given MHC complex using a Monte Carlo Metropolis sampling of the sequence alignment space combined with the advanced techniques of sequence weighting and pseudo-count correction for low counts.
  • the input the method is amino acid peptide sequences knowing to bind to an MHC complex.
  • We measure the performance of the method by use of both the Pearson correlation coefficient and ROC curve plots.
  • the binding weight- matrices are calculated from peptides downloaded from the public databases of SYFPElTHI (Database for MHC ligands and peptide motifs, Immunogenics 50:213-219, 1999) and MHCPEP (V. Brusic, G. Rudy, A.P. Kyne and L-C. Harrison: MHCPEP, a database of MHC-binding peptides: update 1997 Nucleic Acids Research, (1998), Vol. 26, No. 1, pp. 368-371).
  • the hallmark of the immune system is its ability to recognise and distinguish between self (friend) and non-self (enemy).
  • the T cells do this by recognizing peptides that are bound to Major Histocompatibility Complex (MHC) complexes.
  • MHC Major Histocompatibility Complex
  • a number of methods for predicting the binding of peptides to MHC molecules have been developed (reviewed by Schirle M, Weinschenk T, Stevanovic S. Combining computer algorithms with experimental approaches permits the rapid and accurate identification of T cell epitopes from defined antigens. J. Immunol Methods. 2001 Nov 1; 257(1-2): 1-16) since the first motif methods was presented (Rothbard JB, Taylor WR. A sequence pattern common to T cell epitopes. EMBO J.
  • the present invention consists of T cell epitopes in Severe Acute Respiratory Syndrome Virus (SARS). More specifically there is provided 20 linear peptide epitopes for each of the HLA class I supertypes of A1 , A2, A3, A24, B7, B27, B44, B58 and B62, respectively, and 20 linear peptide epitopes for each of the HLA class Il alleles of DRB1 * 0401 , DRB1*1501, DRB1*0102, DRB1 * 0410, DRB1*0301, DRB1*1301, DRB1*0802, DRB1*1101 , DRB1*0701 and DRB5*0101 , respectively, from the SARS genome.
  • SARS Severe Acute Respiratory Syndrome Virus
  • the invention also consists of variants of these sequences.
  • this invention consists of a method to predict these sequences from genome data and to validate the predictions experimentally.
  • the present invention provides compositions including these epitopes for use in a vaccine and to induce a T cell response in a subject, or as a diagnostic tool.
  • Table 1 Data for the training and evaluation of the HLA class I binding prediction.
  • the first column gives the supertype names included in the calculation, the second column the number of unique 9mer peptides in the training set for corresponding supertype, the third column the HLA allele name for the evaluation set data, and the fourth and fifth columns the number of peptides and the number of binding peptides in the evaluation set, respectively.
  • Table 3 Prediction performance of the Gibbs sampler on the four evaluation datasets for different position specific weight values.
  • the first column gives the supertype name
  • the second column the motif positions with high importance for peptide binding
  • the fourth and fifth column the number of peptides in the training and test sets, respectively
  • the last five columns the predictive performance in terms of the Pearson correlation coefficient and Aroc for weight of 1, 2, 3, 5 and 9, respectively.
  • the last row gives the average performance over the 4 supertypes.
  • Table 4 Comparison of the prediction accuracy of the Gibbs sampler to that of TEPITOPE for the 10 datasets described in the text. The three columns gives name, the number of peptides and the number of peptides classified as binders for each of the datasets. The last two
  • the program samples possible alignments of the N sequences. For each alignment a log-odds score matrix is calculated as log(pi,j/qi), where pij is the frequency of amino acid i at position j in the alignment and qi the background frequency of that amino acid.
  • the values of pij are estimated using sequence weighting and pseudo-count correction for low counts. Sequence weighting is performed using either the method described by Henikoff and Henikoff (J. Mo/. Biol. 1994, 243574-578) or a clustering algorithm where sequences in a cluster are assigned a weight corresponding to 1/Nc, where Nc is the cluster size.
  • the weight of a sequence is then assigned as the sum of the amino acid weights.
  • the pseudo-count correction for low counts is performed using a Blosum weighting scheme (Altschul et al., Nucleic Acids Research, 1997, 25 173389- 3402).
  • the energy function guiding the Monte Carlo sampling is defined as
  • N(i j) is the concurrency number of amino acid i at position j in the alignment
  • p * (i j) is the pseudo-count and sequence weight corrected amino acid frequency of amino acid i and position j in the alignment
  • q(i) is the background frequency of amino acid j.
  • the probability of accepting a move in the Monte Carlo sampling is defined as
  • dE difference in energy between the end and start configurations and T a scale factor. Note that we seek to optimize the energy function, hence the positive sign for dE in the equation. T is a scale that is lowered during the calculation.
  • Prior knowledge of important positions in sequence motif can be included in the search by allowing for differential weighting of the positions in the motif.
  • position weights can provide an important guide for the Gibbs sampler when searching for a subtle sequence signal.
  • Weight-matrix calculation A simple use of the Gibbs sampler is the calculation of weight-matrices from preaiigned sequences. Here the matrix is calculated using the Gibbs sampler with zero Monte Carlo moves and zero T steps. The result is a weight-matrix calculated using the preaiigned sequences with inclusion of both pseudo- count correction and sequence weighting.
  • the Gibbs sampler has a series of free parameters defining the manner in which a weight-matrix is calculated from an alignment.
  • the important parameters are
  • the effective amino acid frequencies are estimated as described by Altschul et al. (Nucleic Acids Research, 1997, 25 173389-3402).
  • the effective sequence number is the number of clusters.
  • sequence weighting as described by Henikoff and Henikoff J. MoI. Biol. 1994, 243 574-578
  • the mean number of different amino acids in the alignment gives the effective sequence number. In both situations the effective amino acid frequency is calculated as
  • f is the observed frequency
  • g the pseudo-count frequency
  • a the effective sequence number
  • b the weight on the pseudo-count correction.
  • MHC class I binding We download peptides known to bind to MHC class I molecule from the databases of SYFPEITHI (Database for MHC ligands and peptide motifs, lmmunogenitics 50:213-219, 1999) and MHCPEP (V. Brusic, G. Rudy, A.P. Kyne and L.C. Harrison: MHCPEP, a database of MHC-binding peptides: update 1997 Nucleic Acids Research, (1998), Vol. 26, No. 1, pp. 368-371). Only peptides of length 9 were included.
  • the peptides were clustered into nine the supertypes (A1 , A2, A3, A24, B7, B27, B44, B58 and B62) described by Sette and Sydney (Immunogenetics 1999 Nov; 50 (3-4): 201-212).
  • Table 1 the number of unique peptides for each supertype is given.
  • These peptides constitute the training set for the estimation of MHC class I binding weight-matrices.
  • For 4 of the 9 supertypes (A1 , A2, A3 and B7) datasets of peptides for which the binding affinity to the MHC molecule has been measured by the method described by Sylvester-Hvid C. et al. (Tissue Antigens 2002 Apr;59 (4):251-258) and Buus S.
  • the set consists of 881 peptides extracted from the SYFPEITHI and MHCpep databases. The set is constructed so that no MHC molecule is represented with more than 5% of the peptides. The peptides are extracted in a window of 17, so that the C terminal of the epitope is at the central position 9.
  • the evaluation set is the HIV data set described by C. Kesmir et al. (C. Kesmir et al, Protein Eng 2002 Apr; 15 (4): 287-96).
  • the dataset consists of 509 unique peptides sequences.
  • We remove peptides that do not allow for a hydrophobic residue at the P1 position in the binding motif (Brusic V., et al. 1998, Bioinformatics 14 (2) 121-130). That is a peptide is removed if no hydrophobic residues are present at the first N-L+1 positions, where N is the peptide length and L is the motif length.
  • the hydrophobic filter leaves out 27 peptides.
  • the final training set has 482 unique peptides. The length distribution in the training set ranges from 9 to 30 residues.
  • the second column in the table states what motif positions have high importance for peptide binding for the specific supertype.
  • the residue set is determined as the set of anchor residue defined in the SYFPEITHI database, extended with auxiliary anchors if they occur at position 2 or 9.
  • position 3 and 9 are specified as anchor positions whereas position 2 and 7 are auxiliary anchor positions. This means that positions 2, 3 and 9 are included as positions with high weight in the motif search for this supertype. From the results stated in the table it is clear that a position specific weighting of 2-3 gives an improved predictive performance.
  • Equation 1 determines the acceptance of a move.
  • the alignment space of a set of sequences has a very large set of local minima position with close to identical energy. To get an - effective sampling of these local minima, we repeat 100 MC calculations with different start configurations and calculate the final weight-matrix as the average over the top 50 highest scoring weight-matrices.
  • anchor positions in the binding motif are located at position 1 , 4, 6 and 9, respectively, and we hence uses these positions with an increased weight to guide the Gibbs sampling.
  • Anchor positions estimated from a logo-plot of a weight-matrix calculated using the Gibbs sampler with equal weights on all positions gave similar results.
  • the 10 dataset are, 8 data sets described by Raghava G.P.S
  • variants of these peptides may be useful as for example a vaccine a diagnostic tool.
  • These variant peptides may differ in that the amino acid found in one or more positions of the original peptide are replaced by different amino acids.
  • These different amino acids may be selected in a number of ways.
  • a hydrophobic amino acid may for example be replaced by another hydrophobic amino acid.
  • Groups of interchangeable amino acids may for example be selected as polar (N and Q), charged (D, E, K, R and H), acidic (D, E), basic (K, R, H), ambivalent (P, T 1 S 1 C, A, G 1 Y and W) or hydrophobic (F 1 L 1 1, M and V).
  • Another way to construct groups of similar amino acid is to group those that have an substitution score above a given threshold such as 0 (zero) according to a amino acid substitution matrix such as Blosum 62 (Henikoff S, Henikoff JG. Amino acid substitution matrices from protein blocks. Proc Natl Acad Sci U S A. 1992 Nov 15; 89(22): 10915-9).
  • Yet another way to select variant peptides is to replace one or more amino aids with other amino acids with the aim of creating a variant peptide that is predicted to bind almost as good as or better than the original peptide.
  • the prediction may for example involve the use of a neural network method, a hidden Markov model or a matrix method.
  • Amino acids may also be replaced by other amino acids than the 20 amino acids normally found in proteins.
  • the variant peptides may also contain additional amino acids or fewer amino acids than the original peptide.
  • the variant peptides may for example be one amino acid longer or shorter in either the N or the C terminal end.
  • the binding of peptides to the HLA molecules can be verified experimentally for example by the method described by Sylvester-Hvid et al. (Sylvester-Hvid C, Kristensen N 1 Baji T, Ferre H, Lauemoller SL 1 WoIf XA, Lamberth K, Nissen MH, Pedersen LO 1 Buus S. Establishment of a quantitative ELISA capable of determining peptide - MHC class I interaction. Tissue Antigens. 2002 Apr;59(4):251-8). This can be used to verify that peptides that are predicted to bind a given HLA molecule, actually binds that molecule. The results from such experiments can be used to select a subset of peptides will undergo further testing to verify their utility in a vaccine.
  • normal human T cells can be measured by antigen stimulation using peptide-pulsed antigen presenting cells. Peptides purified following chemical synthesis will be added to cultures of human antigen-presenting cells (APC), in order to test stimulation of normal human T cells. This is a measurement of the abundance of epitope specific T cells in normal human blood products, and as well a determination that the binding affinity of the peptides for class I HLA is sufficient to trigger T cell activation.
  • APC human antigen-presenting cells
  • Human monocytes from peripheral blood of 3 HLA-A2 human donors, will be purified using adherence to glass wool and grown in culture for 2 days prior to peptide loading. Culture conditions will include commercially available lots of GM-CSF and IL-4 at reported concentrations. It has been demonstrated that exogenous peptides can be added in excess to such antigen presenting cells and displace peptides bound on cell surface class I HLA receptors.
  • T cell activation will be measured in two ways by the induction of T cell activation markers and by monitoring of IL-2 production.
  • CD69 is a proven T cell activation marker used in similar studies, and well be used in double-staining experiments with anti-CD3 antibody to determine T cell numbers.
  • Controls will consist of T cells incubated in identical conditions but lacking peptide-pulsed dendritic cells, and T cells exposed to a positive control peptide-APC population.
  • a positive control peptide from prior investigation of HIV T cell HLA-A2 peptides will be used. Results will be considered positive if parallel numbers of CD69+ T cells are generated in test peptide exposures compared to positive control, and if baseline numbers remain statistically reduced.
  • duplicate wells will be harvested and assayed by ELISA for the induction of IL-2, an interleukin expressed by activated T cells. Controls will be as described above, and individual peptides will be considered positive if parallel levels of IL-2 are generated in test peptide exposures compared to positive control, and if baseline numbers remain statistically reduced
  • Diagnostic kits are now available which allow flow cytometric detection of antigen specific T cells. These assays use the same principles employed in receptor binding assays described above - adding synthesized peptides to recombinant HLA molecules, but then extend this assay by measuring the ability of T cells to bind the HLA/peptide complex. This is accomplished by generating flourescently conjugated tetrameric complexes of peptide/HLA using avidin-biotin conjugation, and then measuring the number of fluorescently labeled T cells in a blood product.
  • Each peptide will be employed according to protocol, and HLA-A2 donor bloods (3/sample) will be tested for baseline levels of T cell recognition. It is expected that positive numbers in the range of 1:10 4 to 1:10 s be obtained from the na ⁇ ve T cell pool.
  • Baseline numbers will be generated using non-HLA-A2 donors as well as non- peptide loaded complexes. Again, HIV T cell epitopes will be tested as controls as well. Samples which have tested positive in the in vitro T cell stimulation assay will be chosen for testing by this method.
  • DNA vaccines can present multiple T cell epitopes in clustered and simple linear array on a vector, without excessive immunodominance of one or few epitopes.
  • Peptide epitopes will be chosen based on T cells stimulation indices, followed by generation of a short DNA vaccine construct to express these peptides intracellular ⁇ . Genetic constructs successful in this approach have previously been identified, and we will use this strategy in our experiments. A synthetic mini-gene will be constructed by overlapping oligonucleotides and confirmed by DNA sequence analysis. Known proteosome cleavage sites in will flank the peptide motifs mouse for enhanced processing. The expression cassette will be driven by a standard CMV promoter in a commercially available expression plasmid.
  • HLA-A2 Transgenic mice expressing HLA-A2 molecules in the complete absence of H- 2 class I molecules in an H-2Kb, H-2Db double KO context have been created, and used to determination the immunological response to viral T cell peptides known to be HLA-A2 specific.
  • Animals will be injected Lm. and boosted at 4 week intervals. Peripheral blood cells will be monitored for epitope specific T cells as described in Example 5, with pre-immunization blood cells measured for baseline levels.
  • Flow cytometric analysis of collected blood cell populations will be performed as described in Aim 3b, with the exception that secondary staining will be performed using anti-mouse CD3, anti-mouse CD4, and anti-mouse CD8 fluorescent antibodies to gain T cell number and subset information.

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Abstract

Selon un premier aspect, l'invention concerne des épitopes de lymphocytes T situés dans le génome du virus du syndrome respiratoire aigu sévère (SRAS). Plus particulièrement, il existe 180 épitopes de peptides linéaires de classe I et 200 épitopes linéaires de classe II provenant du génome du virus du SRAS. Selon un deuxième aspect, l'invention concerne des variants de ces séquences. Selon un troisième aspect, l'invention concerne un procédé de prédiction de ces séquences à partir de données du génome et de validation des prédictions de manière expérimentale. Selon un quatrième aspect, l'invention concerne des compositions comprenant ces épitopes, destinées à être utilisées dans un vaccin et à induire une réaction des lymphocytes T chez un sujet, ou en tant qu'outil diagnostique.
PCT/US2004/015026 2003-05-14 2004-05-14 Epitopes de lymphocytes t utiles en tant que vaccin contre le virus du syndrome respiratoire aigu severe (sras) et en tant qu'outils diagnostiques et procedes d'identification associes Ceased WO2004110349A2 (fr)

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IL171924A IL171924A0 (en) 2003-05-14 2005-11-13 T cell epitopes useful in a severe acute respiratory syndrome (sars) virus vaccine and as diagnostic tools and methods for identifying same

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