The USA Coronvirus Patent Story. Who Got there First? Work Leading to Patents Started Around 2003. 2022-04-26. Jorma Jyrkkanen.

https://pubchem.ncbi.nlm.nih.gov/patent/US-2006257852-A1 United States Patent Application 20060257852 Kind Code A1 Rappuoli; Rino ; et al. November 16, 2006 Severe acute respiratory syndrome coronavirus Abstract An outbreak of a virulent respiratory virus, now known as Severe Acute Respiratory Syndrome (SARS), was identified in Hong Kong, China and a growing number of countries around the world in 2003. The invention relates to nucleic acids and proteins from the SARS coronavirus. These nucleic acids and proteins can be used in the preparation and manufacture of vaccine formulations, diagnostic reagents, kits, etc. The invention also provides methods for treating SARS by administering small molecule antiviral compounds, as well as methods of identifying potent small molecules for the treatment of SARS. Inventors: Rappuoli; Rino; (Castelnuovo Berardenga, IT) ; Masignani; Vega; (Siena, IT) ; Stadler; Konrad; (Scharnstein, AU) ; Gregersen; Jens Peter; (Wetter, DE) ; Chien; David; (Alamo, CA) ; Han; Jang; (Lafayette, CA) ; Polo; John M.; (Danville, CA) ; Weiner; Amy; (Fairfield, CA) ; Houghton; Michael; (Danville, CA) ; Song; Hyun Chul; (Berkeley, CA) ; Seo; Mi-Young; (Yongin-si, KR) ; Donnelly; John; (Moraga, CA) ; Klenk; Hans Dieter; (Marburg, DE) ; Valiante; Nicholas; (Fremont, CA) Correspondence Address: Chiron Corporation;Intellectual Property - R440 P.O. Box 8097 Emeryville CA 94662-8097 US Assignee: Chiron Corporation Emeryville CA Family ID: 33304326 Appl. No.: 10/822303 Filed: April 9, 2004 Related U.S. Patent Documents Application Number Filing Date Patent Number 60462218 Apr 10, 2003 60462465 Apr 11, 2003 60462418 Apr 12, 2003 60462748 Apr 13, 2003 60463109 Apr 14, 2003 60463460 Apr 15, 2003 60463668 Apr 16, 2003 60463983 Apr 17, 2003 60463971 Apr 18, 2003 60464899 Apr 22, 2003 60464838 Apr 22, 2003 60465273 Apr 23, 2003 60465535 Apr 24, 2003 60468312 May 5, 2003 60473144 May 22, 2003 60495024 Aug 14, 2003 60505652 Sep 23, 2003 60510781 Oct 11, 2003 60529464 Dec 11, 2003 60536177 Jan 12, 2004 60560757 Apr 7, 2004 Current U.S. Class: 435/5 ; 435/325; 435/456; 435/69.3; 530/350; 536/23.72 Current CPC Class: A61K 2039/545 20130101; A61K 39/12 20130101; C12N 2770/20022 20130101; G01N 2333/165 20130101; G01N 2469/20 20130101; A61K 2039/55566 20130101; C12N 2770/20021 20130101; C12N 2770/20043 20130101; A61K 2039/5252 20130101; A61K 2039/55505 20130101; A61K 39/215 20130101; A61K 39/00 20130101; C12N 7/00 20130101; A61K 2039/55511 20130101; C12N 2770/20034 20130101; C12N 2770/20063 20130101; C12Q 1/701 20130101; C07K 2319/21 20130101; C07K 14/005 20130101; C12N 2770/20051 20130101; C07K 2317/76 20130101; C07K 2317/34 20130101; C07K 16/10 20130101 Class at Publication: 435/005 ; 435/069.3; 435/456; 435/325; 530/350; 536/023.72 International Class: C12Q 1/70 20060101 C12Q001/70; C07H 21/04 20060101 C07H021/04; C12N 15/86 20060101 C12N015/86; C07K 14/165 20060101 C07K014/165 Claims 1. An isolated polypeptide of the SARS virus. 2. The polypeptide of claim 1, wherein the polypeptide is a Spike (S) polypeptide, an Env (E) polypeptide, a Membrane (M) polypeptide, a hemagglutinin-esterase polypeptide (HE), a nucleocapsid (N) polypeptide, a ORF1a polypeptide, a ORF1ab polypeptide, a proteolytic fragment of a ORF1a polypeptide, or a proteolytic fragment of a ORF1ab polypeptide. 3. The polypeptide of claim 1, wherein the polypeptide comprises an amino acid sequence selected from the group consisting of SEQ ID NOS: 6039, 7232, 9766, 9767, 9768, 9769, 9770, 9771, 9772, 9773, 9774, 9775, 9776, 9777, 9778, 9779, 6042, 6043, 6044, 6045, 6046, 6047, 6048, 6049, 6050 or 6052. 4. The polypeptide of claim 1, wherein the polypeptide comprises an amino acid sequence having >75% sequence identity to an amino acid sequence selected from the group consisting of SEQ ID NOS: 6042, 6043, 6044, 6045, 6046, 6047, 6048, 6049, 6050, 6052, 9766, 9767, 9768, 9769, 9770, 9771, 9772, 9773, 9774, 9775, 9776, 9777, 9778, 9779, 9997, 9998, 10149, 10316, 10338, 10339, 10340, 10341, 10342, 10532, 10533, 10571, 10572, 10573, 10574, 10575, 10576, 10577, 10578, 10579, 11561, 11562, 11618, 11619, 11620, 11627, 11630, 11633 & 11636. 5. The polypeptide of claim 1, wherein the polypeptide comprises a fragment of at least 10 consecutive amino acids of an amino acid sequence selected from the group consisting of SEQ ID NOS: 6042, 6043, 6044, 6045, 6046, 6047, 6048, 6049, 6050, 6052, 9766, 9767, 9768, 9769, 9770, 9771, 9772, 9773, 9774, 9775, 9776, 9777, 9778, 9779, 9997, 9998, 10149, 10316, 10338, 10339, 10340, 10341, 10342, 10532, 10533, 10571, 10572, 10573, 10574, 10575, 10576, 10577, 10578, 10579, 11552, 11561, 11562, 11618, 11619, 11620, 11627, 11630, 11633 & 11636. 6. A polypeptide comprising an amino acid sequence having >80% sequence identity to an amino acid sequence selected from the group consisting of SEQ ID NOS: 6042, 6043, 6044, 6045, 6046, 6047, 6048, 6049, 6050, 6052, 9766, 9767, 9768, 9769, 9770, 9771, 9772, 9773, 9774, 9775, 9776, 9777, 9778, 9779, 9997, 9998, 10149, 10316, 10338, 10339, 10340, 10341, 10342, 10532, 10533, 10571, 10572, 10573, 10574, 10575, 10576, 10577, 10578, 10579, 11552, 11561, 11562, 11618, 11619, 11620, 11627, 11630, 11633 & 11636. 7. A polypeptide comprising an amino acid sequence that comprises a fragment of at least 10 consecutive amino acids of an amino acid sequence selected from the group consisting SEQ ID NOS: 6042, 6043, 6044, 6045, 6046, 6047, 6048, 6049, 6050, 6052, 9766, 9767, 9768, 9769, 9770, 9771, 9772, 9773, 9774, 9775, 9776, 9777, 9778, 9779, 9997, 9998, 10149, 10316, 10338, 10339, 10340, 10341, 10342, 10532, 10533, 10571, 10572, 10573, 10574, 10575, 10576, 10577, 10578, 10579, 11552, 11561, 11562, 11618, 11619, 11620, 11627, 11630, 11633 & 11636. 8. A polypeptide comprising an amino acid sequence having >80% sequence identity to SEQ ID NO: 6042, and/or comprising an amino acid sequence that comprises a fragment of at least 10 consecutive amino acids of SEQ ID NO: 6042, wherein the polypeptide is in the form of a trimer. 9. Nucleic acid encoding the polypeptide of any one of claims 1 to 8. 10. Nucleic acid according to claim 9, comprising a nucleotide sequence selected from the group consisting of SEQ ID NOS: 7191, 7273, 7275, 7277, 7279, 7281, 7283, 7285, 7287, 7289, 7291, 7292, 7293, 9968, 10066, 10084, 10299, 10505, 11323, 11563, 11639 & 11640. 11. A polynucleotide comprising a nucleotide sequence having >80% sequence identity to the nucleic acid of claim 9 or claim 10. 12. A polynucleotide comprising a fragment of at least 10 consecutive nucleotides of the nucleic acid of claim 9 or claim 10. 13. Antibody that recognizes the polypeptide of any one of claim 1 to 8. 14. The antibody of claim 13, wherein said antibody recognizes the polypeptide comprising the amino acid sequence of SEQ ID NO: 6042 or a fragment thereof. 15. The antibody of claim 14, wherein said antibody recognizes the polypeptide comprising the amino acid sequence of SEQ ID NO: 6042 or a fragment thereof in trimeric form. 16. The antibody of claim 13, wherein the antibody is a monoclonal antibody. 17. The antibody of claim 13, wherein the antibody is a human antibody. 18. An immunoassay for detecting a SARS virus antigen in a sample, comprising the step of contacting the sample with the antibody of any one of claims 13 to 17. 19. An immunoassay for detecting an antibody against a SARS virus antigen in a sample, comprising the step of contacting the sample with the polypeptide of any one of claims 1 to 8. 20. A method of detecting an antibody against a SARS virus antigen in a sample comprising contacting said sample with the polypeptide of any one of claims 1 to 8, under conditions suitable for binding said polypeptide to said antibody, if present, and detecting the binding of said polypeptide to said antibody. 21. A method for detecting a SARS virus antigen in a sample comprising contacting said sample with the antibody of any one of claims 13 to 17, under conditions suitable for binding said antibody to said antigen, if present, and detecting the binding of said antibody to said antigen. 22. A vaccine for the treatment or prevention of severe acute respiratory syndrome (SARS), comprising an inactivated SARS virus, a killed SARS virus, an attenuated SARS virus, a split SARS virus preparation, or at least one purified SARS virus antigens. 23. The vaccine of claim 22, comprising a purified polypeptide according to any one of claims 1 to 8. 24. The vaccine of claim 22 or claim 23, wherein the antigen is a purified SARS virus antigen in the form of a VLP. 25. The vaccine of any one of claims 22 to 24, further comprising an adjuvant. 26. The vaccine of claim 25, wherein the adjuvant is an aluminium salt or is MF59. 27. The vaccine of any one of claims 22 to 26, comprising more than one SARS virus antigen. 28. The vaccine of claim 27, wherein the antigens are selected from S, E, N and M. 29. The vaccine of claim 22, comprising an inactivated SARS virus. 30. The vaccine of claim 29, wherein said virus is inactivated by chemical or physical means. 31. The vaccine of claim 30, wherein said inactivation comprises treatment of the virus with an effective amount of one or more of the following agents selected from the group consisting of detergents, formaldehyde, formalin, .beta.-propriolactone, and UV light. 32. The vaccine of claim 30, wherein said inactivation comprises treatment of the virus with an effective amount of one or more of the following agents selected from the group consisting of methylene blue, psoralen and carboxyfullerene (C60). 33. The vaccine of claim 30, wherein said inactivation comprises treatment of the virus with an effective amount of one or more of the following agents selected from the group consisting of binary ethylamine, acetyl ethyleneimine and gamma irradiation. 34. The vaccine of claim 31, wherein said inactivation comprises treatment with .beta.-propriolactone. 35. The vaccine of claim 34, wherein said .beta.-propriolactone is used at a concentration of 0.01 to 0.5%. 36. The vaccine of claim 34, wherein said .beta.-propriolactone is used at a concentration of 0.5 to 0.2%. 37. The vaccine of claim 34, wherein said .beta.-propriolactone is used at a concentration of 0.025 to 0.1%. 38. A method of inactivating SARS virus comprising exposing the virus to an inactivation agent for 12 to 24 hours at refrigeration temperatures followed hydrolysis of any residual inactivating agent by elevating the temperature for three hours. 39. The method of claim 38, wherein the inactivation agent is .beta.-propriolactone. 40. The method of claim 38, wherein the refrigeration temperature is between 0.degree. C. and 8.degree. C. 41. The method of claim 38, wherein the elevated temperature is between 33.degree. C. and 41.degree. C. 42. A method for making an inactivated SARS vaccine comprising: a. innoculating a mammalian cell culture with SARS virus; b. cultivating the infected cells; c. harvesting SARS virus containing supernatant; d. inactivating the SARS virus; and e. purifying the inactivated SARS virus. 43. The method of claim 42, wherein said mammalian cell culture is derived from one or more of the cell types selected from the group consisting of fibroblast cells, endothelial cells, hepatocytes, keratinocytes, immune cells, mammary cells, smooth muscle cells, melanocyte cells, neural cells, prostate cells, renal cells, skeletal cells, liver cells, retinoblast cells and stromal cells. 44. The method of claim 42, wherein said mammalian cell culture is derived from a cell culture selected from the group consisting of human cells, non-human primate cells, HeLa cells, human diploid cells, fetal rhesus lung cells, human embryonic kidney cells, VERO cells, horse cells, cow cells, sheep cells, dog cells, cat cells or rodent cells. 45. The method of claim 42, wherein said mammalian cell culture is derived from VERO cells or fetal rhesus kidney cells. 46. The method of claim 42, wherein said mammalian cells are cultured in serum free media. 47. The method of claim 42, wherein said mammalian cells are cultured in protein free media. 48. The method of claim 42, wherein said inoculating step comprising absorbing the SARS virus onto the cell culture for 60 to 300 minutes. 49. The method of claim 42, wherein said inoculating step is conducted at 25.degree. C. to 40.degree. C. 50. The method of claim 42, wherein said purification step comprises one or more of the treatments selected from the group consisting of gradient centrifugation, ultracentrifugation, continuous-flow ultracentrifugation, chromatography, polyethylene glycol precipitation, and ammonium sulfate precipitation. 51. The method of claim 42, wherein said purification step comprises one or more of the treatments selected from the group consisting of ultrafiltration and dialfiltration. 52. The method of claim 50, wherein said chromatography treatment includes one or more of the chromatography treatments selected from the group consisting of ion exchange chromatography, size exclusion chromatography, and liquid affinity chromatography. 53. The method of claim 52, wherein said chromatography treatment includes use of one more chromatographic resins selected from the group consisting of an an anionic resin and a cationic resin. 54. The method of claim 52, wherein the ion exchange chromatography treatment includes a first step using a strong anion exchange resin and a second step using a strong cation exchange resin. 55. The method of claim 50, wherein said gradient centrifugation purification step comprises density gradient centrifugation. 56. The method of claim 42, wherein said purification step comprises a first step of chromatography purification and a second step of gradient centrifugation. 57. The method of claim 56, wherein said first chromatography purification step comprises liquid affinity chromatography. 58. The method of claim 56, wherein said second gradient centrifugation step comprises density gradient centrifugation. 59. A single-stranded oligonucleotide comprising a nucleotide sequence selected from the group consisting of SEQ ID NOS: 21-6020, 6076-6568, 6586-6587, 7292-7301, 7325-7328, 7332-7352, 7353-7385, 10235-10298, 10352-10504, 10580-11322 and 11325-11551. 60. A single-stranded oligonucleotide comprising the complement of the oligonucleotide of claim 59. 61. The oligonucleotide of claim 59 or claim 60, comprising 10-30 nucleotides. 62. The oligonucleotide of claim 61, comprising the nucleotide sequence of SEQ ID NO: 7292, SEQ ID NO: 7293, the complement of SEQ ID NO: 7292 or the complement of SEQ ID NO: 7293. 63. A kit comprising primers for amplifying a template sequence contained within a SARS virus nucleic acid target, the kit comprising a first primer and a second primer, wherein the first primer comprises a sequence substantially complementary to a portion of said template sequence and the second primer comprises a sequence substantially complementary to a portion of the complement of said template sequence, wherein the sequences within said primers which have substantial complementarity define the termini of the template sequence to be amplified. 64. The kit of claim 63, wherein the template sequence is contained within SEQ ID NO: 1 and/or SEQ ID NO: 2. 65. The kit of claim 63 or claim 64, wherein the first primer comprises a fragment of 8 or more nucleotides of SEQ ID NO: 1, and the second primer comprises a fragment of 8 or more nucleotides of the complement of SEQ ID NO: 1. 66. The kit of claim 63 or claim 64, wherein the first primer comprises a fragment of 8 or more nucleotides of SEQ ID NO: 2, and the second primer comprises a fragment of 8 or more nucleotides of the complement of SEQ ID NO: 2. 67. The kit of claim 63, wherein the first primer is an oligonucleotide according to any one of claims 59 to 62 and the second primer is an oligonucleotide according to any of claims 59 to 62. 68. The kit of any one of claims 63 to 67, further comprising a labeled probe that comprises either a fragment of 8 or more nucleotides of SEQ ID NO: 1 and/or SEQ ID NO: 2, or the complement of said fragment, which fragment is located within the template sequence. 69. The kit of any one of claims 63 to 68, wherein the first primer and/or the second primer comprises a nucleotide sequence selected from the group consisting of SEQ ID NOS: 21-6020, 6076-6568, 6586-6587, 7292-7301, 7325-7328, 7332-7352, 7353-7385, 10235-10298, 10352-10504, 10580-11322 and 11325-11551. 70. The kit of any one of claims 63 to 68, wherein the first primer and/or the second primer comprises the complement of a nucleotide sequence selected from the group consisting of SEQ ID NOS: 21-6020, 6076-6568, 6586-6587, 7292-7301, 7325-7328, 7332-7352, 7353-7385, 10235-10298, 10352-10504, 10580-11322 and 11325-11551. 71. A method of detecting the presence of SARS virus in a sample comprising providing a sample suspected of containing a SARS virus nucleic acid target, amplifying a template sequence contained within said SARS virus nucleic acid target with the kit of any one of claims 63 to 70, and detecting the amplified template sequence, wherein the presence of the amplified template sequence indicates the presence of SARS virus in said sample. 72. The method of claim 71, wherein said amplifying is accomplished using polymerase chain reaction, transcription mediated amplification, reverse transcription PCR, ligase chain reaction, strand displacement amplification or nucleic acid sequence-based amplification. 73. A double-stranded RNA molecule with a length from about 10 to about 30 nucleotides which is able to inactivate the SARS coronavirus in a mammalian cell. 74. The double-stranded RNA of claim 73, wherein the sequence of one of the strands is at least 90% identical to a target sequence, wherein the target sequence is a fragment of SEQ ID NO: 1 and/or SEQ ID NO: 2. 75. The double-stranded RNA of claim 73 or claim 74, wherein the target sequence comprising a nucleotide sequence selected from the group consisting of SEQ ID NOS: 7292, 7293, 7294, 7295, 7296, 7297, 7298, 7299, 7300 and 7301. 76. The double-stranded RNA of any one of claims 73 to 75, comprising at least one modified nucleotide. 77. A method for treating a patient suffering from SARS, comprising: administering to the patient a therapeutically effective dose of a molecule of less than 1000 g/mol. 78. The method of claim 77, wherein the molecule has an aromatic region and greater than one heteroatom selected from O, S, or N. 79. A method for treating a patient suffering from SARS, comprising: administering to the patient a therapeutically effective dose of a compound selected from: a nucleoside analog, a peptoid, an oligopeptide, a polypeptide a protease inhibitor, a 3C-like protease inhibitor, a papain-like protease inhibitor, or an inhibitor of an RNA dependent RNA polymerase. 80. A method for treating a patient suffering from SARS, comprising: administering to the patient a steroidal anti-inflammatory drug in combination with at least one antiviral compound. 81. A method for treating a patient suffering from SARS, comprising: administering to the patient a therapeutically effective dose of a compound selected from: acyclovir, gancyclovir, vidarabidine, foscamet, cidofovir, amantidine, ribavirin, trifluorothymidine, zidovudine, didanosine, zalcitabine, an antiviral compound listed in Table 1; an antiviral compound listed in Table 2; or an interferon. 82. The method of claim 81, wherein the interferon is an interferon-.alpha. or an interferon-.beta.. 83. The method of any one of claims 77 to 82, wherein the molecule or compound is delivered by inhalation. 84. A method of identifying a therapeutically active agent comprising the steps of: (a) contacting a therapeutically active agent with a cell infected with the SARS virus; (b) measuring attenuation of a SARS related enzyme. 85. A viral vector or particle for in vivo delivery of a nucleic acid of claim 9 or claim 10. 86. The viral vector of claim 85, wherein the vector is an adenovirus vector, a poxvirus vector or an alphavirus vector. 87. An alphavirus replicon particle comprising one or more SARS viral antigens. 88. The replicon particle of claim 87, wherein said SARS viral antigen is a spike protein. 89. The replicon particle of claim 87, wherein said particle comprises a replicon derived from Venezuelan Equine Encephalitis (VEE) and further comprises an envelope derived from Sindbus virus (SIN) or Semliki Forest Virus (SFV). 90. A vaccine comprising one or more SARS virus antigens and one or more respiratory virus antigens. 91. The vaccine of claim 90, wherein said respiratory virus antigens are selected from the group consisting of influenza virus, human rhinovirus (HRV), parainfluenza virus (PIV), respiratory syncytial virus (RSV), adenovirus, metapneumovirus, and rhinovirus. 92. The vaccine of claim 91, wherein said respiratory virus antigen is from influenza virus. 93. The vaccine of claim 90, wherein said respiratory virus antigen is from a coronavirus other than the SARS virus. 94. A polypeptide comprising an immunogenic, surface exposed fragment of the amino acid sequence SEQ ID NO: 6042. 95. The polypeptide of claim 94, wherein said fragment does not include the last 50 amino acids of the C-terminus of SEQ ID NO: 6042. 96. The polypeptide of claim 94, wherein said fragment does not include a transdomain region of SEQ ID NO: 6042. 97. The polypeptide of claim 94, wherein said fragment does not include a C-terminus cytoplasmic domain of SEQ ID NO: 6042. 98. The polypeptide of claim 94, wherein said fragment does not include a N-terminus signal sequence. 99. An isolated polynucleotide comprising a nucleic acid sequence selected from the group consisting of SEQ ID NOS: 9968 and 10066. 100. The polynucleotide of claim 99, wherein the polynucleotide comprising a nucleic acid sequence having >80% sequence identity to a polynucleotide sequence selected from the group consisting of SEQ ID NOS: 9968 and 10066. 101. An isolated polynucleotide comprising a fragment of at least 15 consecutive nucleic acids of a nucleic acid sequence selected from the group consisting of SEQ ID NOS: 9968 and 10066 and wherein said fragment does not consist entirely of SEQ ID NO: 10033. 102. An isolated polypeptide comprising an amino acid sequence encoded by any one of claims 99-101. 103. The polypeptide of claim 102, comprising an amino acid sequence selected from the group consisting of SEQ ID NOS: 9969-10032, 10067, and 10015. 104. The polypeptide of claim 103, wherein the amino acid sequence is selected from the group consisting of SEQ ID NOS: 9997, 9998 and 10015. 105. An expression construct for recombinant expression of a SARS virus spike protein wherein said construct comprises a nucleic acid sequence selected from the group consisting of SEQ ID NOS: 6578-6583. 106. A mammalian cell line stably expressing a SARS viral antigen. 107. The cell line of claim 106, wherein said cell line is a Chinese Hamster Ovary (CHO) cell. 108. The cell line of claim 106, wherein the SARS viral antigen is a spike protein or fragment thereof. 109. The cell line of claim 106, wherein the spike protein is truncated to remove the transmembrane sequence. 110. A method of identifying a therapeutically active agent comprising the steps of: (a) contacting a therapeutically active agent with a buffer comprising SARS enzyme; and (b) measuring attenuation of the SARS enzyme. 111. The method of claim 110 wherein the SARS enzyme is a SARS protease. 112. The method of claim 111 wherein the buffer further comprises a peptide with a SARS protease cleave site. 113. The method of claim 110 wherein the measurement is made by the measurement of fluorescence. 114. A vaccine of one of claims 22 to 37, and 90 to 93 further comprising an adjuvant. 115. The vaccine of claim 114 wherein the adjuvant is a SMIP. 116. The vaccine of claim 115 wherein the SMIP compound is selected from the group consisting of an acylpiperazine, a tryptanthrin, an indoledione, a tetrahydroisoquinoline, a benzocyclodione, an amino azavinyl compound, a thiosemicarbazone, a lactam, an aminobenzimidazole quinolinone, a hydropthalamide, a benzophenone, an isoxazole, a sterol, a quinazolinone, a pyrole, an anthraquinone, a quinoxaline, a triazine, an benzazole, and a pyrazolopyrimidine, or a pharmaceutically acceptable salt, ester, or prodrug thereof. 117. A method of vaccinating a subject comprising administering a vaccine of one of claims 22 to 37, and 90 to 93. 118. The method of claim 117 further comprising administering a SMIP. 119. A method for treating a patient of one of claims 77 to 82 further comprising administering at least one SMEP compound. 120. A method for treating a patient of one of claims 77 to 82 further comprising administering at least one SMIS compound. SUMMARY OF THE INVENTION [0008] The invention relates to nucleic acids and proteins from Severe Acute Respiratory Syndrome (SARS) virus. These nucleic acids and proteins can be used in the preparation and manufacture of vaccine formulations for the treatment or prevention of SARS. Such vaccine formulations may include an inactivated (or killed) SARS virus, an attenuated SARS virus, a split SARS virus preparation and a recombinant or purified subunit formulation of one or more SARS viral antigens. Expression and delivery of the polynucleotides of the invention may be facilitated via viral vectors and/or viral particles. [0009] The invention also relates to diagnostic reagents, kits (comprising such reagents) and methods which can be used to diagnose or identify the presence or absence of a SARS virus in a biological sample. The invention further includes non-coding SARS viral polynucleotide sequences, SARS viral sequences encoding for non-immunogenic proteins, conserved and variant SARS viral polynucleotide sequences for use in such diagnostic compositions and methods. [0010] The invention further relates to vaccine formulations comprising one or more SARS virus antigens and one or more other respiratory virus antigens. Additional respiratory virus antigens suitable for use in the invention include antigens from influenza virus, human rhinovirus (HRV), parainfluenza virus (PIV), respiratory syncytial virus (RSV), adenovirus, metapneumovirus, and rhinovirus. The additional respiratory virus antigen could also be from a coronavirus other than the SARS coronavirus. Preferably, the additional respiratory virus antigen is an influenza viral antigen. [0011] The compositions of the invention may further comprise one or more adjuvants. Adjuvants suitable for use in the invention include mucosal, transdermal or parenteral adjuvants. Mucosal adjuvants suitable for use in the invention include detoxified bacterial ADP-ribosylating toxins, such as E. coli heat labile toxoids (e.g., LTK63), chitosan and derivatives thereof, and non-toxic double mutant forms of Bordetella pertussis toxoids. Parenteral adjuvants suitable for use in the invention include MF59 and aluminum or aluminum salts. [0012] The invention also provides methods for treating SARS by administering small molecule compounds, as well as methods of identifying potent small molecules for the treatment of SARS. [0013] In one aspect of the invention a method of identifying a therapeutically active agent is provided comprising: (a) contacting the therapeutically active agent with a cell infected with the SARS virus; (b) measuring attenuation of a SARS related enzyme. [0014] In a more particular embodiment, the therapeutically active agent is a small molecule. In another more particular embodiment, the therapeutically active agent is a nucleoside analog. In another more particular embodiment the therapeutically active agent is a peptoid, oligopeptide, or polypeptide. In another embodiment the SARS related enzyme is SARS protease. In another embodiment the SARS related enzyme is SARS polymerase. In still another embodiment the SARS related enzyme is a kinase. Methods of identifying therapeutically active agents for treatment of SARS virus infection are further discussed in Section V below. [0015] In another aspect of the invention a method of treating a human infected with SARS is provided comprising administering a small molecule to a patient in need thereof. In one embodiment the small molecule is an inhibitor of SARS protease. In another embodiment the small molecule is an inhibitor of SARS polymerase. In another embodiment the SARS related enzyme is a kinase. In still another embodiment the small molecule is administered orally or parenterally. [0016] The invention also provides the use of such small molecules in the manufacture of a medicament for the treatment of severe acute respiratory syndrome. [0017] Small molecule compounds of the present invention include those of less than 1000 g/mol, preferably with an aromatic region and greater than one heteroatom selected from O, S, or N. Preferred small molecules include, but are not limited to acyclovir, gancyclovir, vidarabidine, foscamet, cidofovir, amantidine, ribavirin, trifluorothymidine, zidovudine, didanosine, zalcitabine, and combinations thereof. Interferons may also be used for treating patients, including interferon-.alpha. and interferon-.beta.. Interferon treatment has shown promise in treating SARS in monkeys (Enserink (2004) Science 303:1273-1275), particularly when pegylated (Haagmans et al. (2004) Nature Medicine 10:290-293). [0018] One aspect of the present invention relates to methods for identifying individuals exposed to, and biological samples containing SARS virus (SARSV), and to kits for carrying out the methods. Such methods can utilize nucleic acid detection techniques such as PCR, RT-PCR (the Coronaviridae are RNA viruses), transcription-mediated amplification (TMA), ligase chain reaction (LCR), branched DNA signal amplification assays, isothermal nucleic acid sequence based amplification (NASBA), other self-sustained sequence replication assays, boomerang DNA amplification, strand-displacement activation, cycling probe technology, or combinations of such amplification methods. Such nucleic acid detection techniques utilize oligonucleotides having nucleotide sequence similar to, or complementary to, the SARS viral genome, as primers (e.g., for amplification) and as probes (e.g., for capture or detection), as is well known in the art. [0019] Alternatively, or in addition to the nucleic acid detection methods described supra, the methods of the present invention can utilize various immunoassay techniques for detection of SARSV antigens and/or antibodies. [0020] Accordingly, the present invention relates to methods of identifying individuals exposed to SARSV, or biological samples containing SARSV, by detecting the presence of SARSV antigens using antibodies which specifically bind to the same. The antibodies are preferably monoclonal antibodies. Quantification of the amount of viral antigens present in a sample of an individual may be used in determining the prognosis of an infected individual. Preferably, the SARSV antigens to be detected are generally one of the structural proteins, particularly those present on the surface of the viral particles and include, for example, the spike glycoprotein (S), also called E2; the envelope (small membrane) protein (E), also called sM; the membrane glycoprotein (M), also called E1 ; the hemagglutinin-esterase glycoprotein (HE); also called E3; and the nucleocapsid phosphoprotein (N). In preferred embodiments, the antigens to be detected are the S, E and M proteins using antibodies to the same. [0021] The present invention relates to kits for identifying individual SARSV and reagents used in such kits. The kits comprise a first container which contains antibodies which specifically bind to a SARSV antigen and a second container which contains the SARSV antigen. The antibodies are preferably monoclonal antibodies. The kits may be adapted for quantifying the amount of antigen in a sample of an individual. Such information may be used in determining the prognosis of an infected individual. [0022] The present invention relates to methods of identifying individuals exposed to SARS virus, or biological samples containing SARSV, by detecting the presence of antibodies against SARS virus antigen in a sample using SARS antigen. Quantification of the amount of anti-SARS protein from SARS antibodies present in a sample of an individual may be used in determining the prognosis of an infected individual. Any one or more of the viral proteins (structural proteins or nonstructural proteins) may be used as antigen to detect the SARSV antibodies; preferably a SARSV antigen that is conserved amoung SARSV isolates is preferred. In this regard, nonstructural protein (e.g., Pol, Hel, 3CLp, MP, PLP1, PLP2) may be particularly useful. [0023] The present invention relates to kits for identifying individuals exposed to SARS and reagents used therein. The kits comprise a first container which contains antibodies which were produced in response to exposure to an antigen from SARS virus and a second container which contains the SARS antigen(s). The kits may be adapted for quantifying the amount of anti-SARS antibodies present in a sample of an individual. Such information may be used in determining the prognosis of an infected individual. [0024] The present invention relates to methods of identifying individuals exposed to SARS virus, or biological samples containing SARSV, by detecting the presence of nucleic acid from SARS virus. Quantification of the amount of SARS nucleic acid present in a sample of an individual may be used in determining the prognosis of an infected individual. The methods utilize oligonucleotide probes and/or primers that are similar or complementary in sequence to the SARSV genome or transcription or replication products. Preferred probes and primers are described herein. Also included in the present invention are kits for carrying out the methods of detecting the SARSV nucleic acid. [0025] The invention further includes a method for the treatment and/or prevention of SARS through the administration of a therapeutically effective amount of at least one antiviral compound from among those described in the US patents and published international patent applications listed in Table 1 and Table 2. In one embodiment of the method, the antiviral compound is a small molecule. In another embodiment, the antiviral compound is a protease inhibitor. In a further embodiment, the antiviral protease inhibitor is a 3C-like protease inhibitor and/or a papain-like protease inhibitor. In another embodiment, the antiviral compound is an inhibitor of an RNA-dependent RNA polymerase. In another embodiment, a first antiviral compound which is a protease inhibitor is administered with a second antiviral compound which is an RNA-dependent RNA polymerase inhibitor. The invention further provides for the administration of a steroidal anti-inflammatory drug in combination with at least one antiviral compound, for example, from the antiviral compounds described in the documents listed in Table 1 and Table 2. [0026] The invention further provides for a method for the treatment and/or prevention of SARS through the administration of a therapeutically effective amount of at least one antiviral compound from among those described in the US patents and published international patent applications listed in Table 1 and Table 2 by inhalation. In one embodiment of the method, the antiviral compound is a small molecule. In another embodiment, the antiviral compound is a protease inhibitor. In a further embodiment, the antiviral protease inhibitor is a 3C-like protease inhibitor and/or a papain-like protease inhibitor. In another embodiment, the antiviral compound is an inhibitor of an RNA dependent RNA polymerase. In another embodiment, a first antiviral compound which is a protease inhibitor is administered with a second antiviral compound which is an RNA-dependent RNA polymerase inhibitor. The invention further provides for the administration of a steroidal anti-inflammatory drug in combination with at least one antiviral compound, for example, from the antiviral compounds described in the documents listed in Table 1 and Table 2 by inhalation. The steroidal anti-inflammatory drug may be administered by inhalation for a local effect or administered for systemic absorption such as via an oral or intravenous route. [0027] The invention further provides the use of an antiviral compound, as defined above, in the manufacture of a medicament for the treatment of severe acute respiratory syndrome. [0028] The invention further provides for a kit for use by a consumer for the treatment and/or prevention of SARS. Such a kit comprises: (a) a pharmaceutical composition comprising a therapeutically effective amount of at least one antiviral compound from among those described in the US patents and published international patent applications listed in Table 1 and Table 2 and a pharmaceutically acceptable carrier, vehicle or diluent; (b) a container for holding the pharmaceutical composition; and, optionally; (c) instructions describing a method of using the pharmaceutical compositions for the treatment and or the prevention of SARS. The kit may optionally contain a plurality of antiviral compounds for the treatment of SARS wherein the anti viral compounds are selected from 3C-like protease inhibitors and papain-like protease inhibitors. In a further embodiment, the kit contains an antiviral compound which is an RNA-dependent RNA polymerase inhibitor. When the kit comprises more than one antiviral compound, the antiviral compounds contained in the kit may be optionally combined in the same pharmaceutical composition. [0029] An additional aspect of the invention provides for the use of at least one of the antiviral compounds described in the US patents and published international patent applications listed in Table 1 and Table 2 for the manufacture of a medicament for the treatment or prevention of SARS.