WO2004045529A2 - West nile virus vaccine - Google Patents
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- WO2004045529A2 WO2004045529A2 PCT/US2003/036623 US0336623W WO2004045529A2 WO 2004045529 A2 WO2004045529 A2 WO 2004045529A2 US 0336623 W US0336623 W US 0336623W WO 2004045529 A2 WO2004045529 A2 WO 2004045529A2
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- C12N2770/24011—Flaviviridae
- C12N2770/24111—Flavivirus, e.g. yellow fever virus, dengue, JEV
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Definitions
- WEST NILE VIRUS VACCINE This invention relates to vaccines against West Nile virus.
- West Nile (WN) virus Since its earliest detection in the northern hemisphere, West Nile (WN) virus has continued to spread rapidly across North America. The first cases were diagnosed in the New York area in 1999, and by 2002 human mortality increased to over 150 cases and the virus spread has continued, reaching as far as California. The appearance of infected/dead birds indicates that there is a large pool of infected mosquitoes in the geographical areas of incidence. To date, there is no effective drug treatment against West Nile virus and methods of surveillance and prevention are not significantly impacting the number of cases of human infection. Thus, the risks of the virus migrating into the southern American continent, as well as an epidemic in underdeveloped countries, are extremely high.
- West Nile virus is a member of the flavivirus family. These viruses are small, enveloped, positive-strand RNA viruses that are of concern in many medical and veterinary settings throughout the world. Examples of flaviviruses in addition to West Nile virus include Yellow Fever virus, Japanese Encephalitis virus, and Dengue viruses.
- Flavivirus proteins are produced by translation of a single, long open reading frame to generate a polyprotein, which undergoes a complex series of post- translational proteolytic cleavages by a combination of host and viral proteases to generate mature viral proteins (Amberg et al., J. Virol. 73:8083-8094, 1999; Rice, "Flaviviridae,” In Virology, Fields (ed.), Raven-Lippincott, New York, 1995, Volume I, p. 937).
- the virus structural proteins are arranged in the polyprotein in the order C-prM-E, where "C” is capsid, "prM” (or “pre-membrane”) is a precursor of the viral envelope-bound M (membrane) protein, and “E” is the envelope protein. These proteins are present in the N-terminal region of the polyprotein, while the non-structural proteins (NS 1 , NS2A, NS2B, NS3, NS4A, NS4B, and NS5) are located in the C-terminal region of the polyprotein.
- the invention provides nucleic acid molecules that include sequences encoding the pre-membrane and envelope proteins of West Nile virus and the capsid and non-structural proteins of Yellow Fever virus.
- the West Nile virus pre- membrane or envelope proteins of these chimeras include one or more attenuating mutations, which can be, for example, an amino acid substitution at positions 107, 316, and/or 440 of the envelope protein.
- the amino acid substitution at position 107 can be leucine to phenylalanine (or a conservative amino acid thereof); the amino acid substitution at position 316 can be alanine to valine (or a conservative amino acid thereof); and the amino acid substitution at position 440 can be lysine to arginine (or a conservative amino acid thereof).
- the invention also includes chimeric flaviviruses encoded by the nucleic acid molecules described herein, as well as methods of inducing an immune response to West Nile virus in a subject by administration of such chimeric flaviviruses. Further, the invention includes the use of such chimeric flaviviruses in vaccination methods and their use in methods for preparing medicaments for use in such methods.
- the methods described herein can be carried out with subjects that are at risk of developing, but do not have, West Nile virus infection, as well as with subjects that are infected with West Nile virus.
- the invention also provides methods of making the chimeric flaviviruses described herein.
- the invention provides several advantages. For example, as is discussed in more detail below, the attenuating mutations of the viruses of the invention result in decreased neurovirulence, yet do not adversely impact the ability of the viruses to induce an effective immune response. Thus, the viruses of the invention provide an effective and safe approach to preventing and treating West Nile virus infection. Other features and advantages of the invention will be apparent from the following detailed description and the claims.
- FIG. 1 is a graph showing reciprocal neutralizing antibody titer (PRNT 50 ) results from ICR mice vaccinated with YF/WN wt or YF/WN FVR - Individual neutralizing antibody titers against YF/WN wt virus are shown.
- White symbols denote mice that did not survive IP challenge with WNV NY-99 strain. 100% survival was obtained in groups vaccinated with 10 3 pfu dose of YF/WN wt and with 10 5 pfu dose of YFAVN FVR - Only 40% mice survived challenge in the group vaccinated with 10 3 pfu of YF/WNFVR-
- the invention provides vaccines and methods for use in preventing and treating West Nile (WN) virus infection.
- the methods of the invention involve vaccination of subjects with a live, attenuated chimeric flavivirus that consists of a Yellow Fever virus in which the pre-membrane and envelope proteins have been' replaced with those of West Nile virus.
- the West Nile virus proteins of the chimeras of the invention include one or more attenuating mutations, as is described further below.
- the attenuating mutation is in the region of position 107, 316, or 440 (or a combination thereof) of the West Nile virus envelope protein.
- the mutations can thus be, for example, in one or more of amino acids 102-112, 311-321, and/or 435-445 of the West Nile envelope protein.
- lysine at position 107 can be replaced with phenylalanine
- alanine at position 316 can be replaced with valine
- lysine at position 440 can be replaced with arginine.
- substitutions can be made with other amino acids, such as amino acids that would result in a conservative change from those noted above.
- Conservative substitutions typically include substitutions within the following groups: glycine, alanine, valine, isoleucine, and leucine; aspartic acid, glutamic acid, asparagine, and glutamine; serine and threonine; lysine and arginine; and phenylalanine and tyrosine.
- a chimera of the invention includes each of the specific substitutions noted above.
- additional residues e.g., positions 138, 176, and/or 280
- the vaccines of the invention can be administered in amounts and by using methods that can readily be determined by persons of ordinary skill in this art.
- the vaccines can be administered and formulated, for example, as a fluid harvested from cell cultures infected with the chimeric virus.
- the live, attenuated chimeric virus can be formulated as a sterile aqueous solution containing between 10 and 10 , e.g., between 10 and 10 , infectious units (e.g., plaque-formmg units (pfu) or tissue culture infectious doses) in a dose volume of 0.1 to 1.0 ml, to be administered by, for example, subcutaneous, intramuscular, or intradermal routes.
- infectious units e.g., plaque-formmg units (pfu) or tissue culture infectious doses
- a mucosal route such as the oral route, can be selected.
- Selection of an appropriate amount of chimera to administer can be detennined by those of skill in this art, and this amount can vary due to numerous factors, e.g., the size and general health of the subject to whom the chimera is to be administered.
- the subject can be vaccinated a single time or, if necessary, follow-up immunization can take place.
- the vaccines can be administered as primary prophylactic agents to a subject that is at risk of West Nile virus infection.
- the vaccines can also be used as secondary agents for treating West Nile virus-infected subjects by stimulating an immune response against the infecting virus.
- adjuvants can be used to enhance the immunogenicity of the chimeric West Nile virus vaccines. Selection of appropriate adjuvants can readily be carried out by those of skill in this art.
- the invention is based, in part, on the following experimental results.
- Chimeric flaviviruses are constructed using the ChimeriVaxTM technology, which involves using a two-plasmid system that was previously described (see, e.g., U.S. Patent Application Serial Nos. 09/007,664, 09/121,587, and 09/452,638;
- the two- plasmid system provides plasmid stability in E. coli and a suitable method to manipulate the cloned yellow fever (YF) backbone, facilitating replacement of the YF prM and E genes with those of a flavivirus target.
- the West Nile (WN) virus prM and E genes used were cloned from WNV flamingo isolate 383-99, sequence GenBank accession number AF196835.
- Virus prME cDNA was obtained by RT-PCR (XL-PCR Kit, Perkin Elmer).
- the 5' end of WN prM gene was cloned precisely at the 3 'end of the YF 17D capsid gene by overlap-extension PCR using Pwo polymerase (Roche). This cloning step maintains the integrity of the cleavage/processing signal encoded at the 3' end of the YF capsid gene.
- the 3' end of the E gene was also cloned precisely at the 5 'end of the YF NS1 coding sequence by overlap-extension PCR.
- Point mutations were introduced at various E gene codons to produce variants of the original chimera coding for wild-type WN prME.
- Table 1 shows the mutation target sites and the oligonucleotide sequences used to create the YF/WN chimeras described below. Site mutations were confirmed by sequencing of the envelope proteins (prME region) of the resulting viruses.
- Virus cDNA templates for sequencing originated from RNA extracted from virus supernatants (Trizol LS, Invitrogen), followed by RT-PCR (XL-PCR Kit, Perkin Elmer) and sequencing with the use of synthetic primers (Invitrogen) and a CEQ 2000 sequencer (Beckman).
- Chimeric YF/WN i.e., ChimeriVaxTM-West Nile viruses were prepared by RNA transfection (passage 1 virus, PI) into a Vero E6 cell line (ATCC, CIDVR UMASS Medical Center Worcester, MA). Research master seeds (RMS) were prepared by additional amplifications (either passage 2 or 3 at a 0.001 MOI) in Vero E6 cells. Vero E6 cells were maintained in MEM (Invitrogen), 10% FBS (Hyclone).
- PMS preMaster Seeds
- SF-Vero serum free Vero cell line
- ATCC Baxter/Immuno Orth, Austria
- VT-Media a serum free, protein free media formulation
- the wild type WN virus used was a NY-99 strain (NY99- 35262-11 flamingo isolate) obtained from CDC, Fort Collins, CO (CDC stock designation B82332W) with two additional passages in Vero E6 cells to produce a Master Virus Bank.
- YF 17D is a commercial vaccine (YF-VAX®, Aventis Pasteur, Swiftwater, PA) used here after reconstitution of the lyophilized product or after one passage in Vero E6 cells (ATCC, Acambis Inc., Cambridge, MA).
- YF-VAX® Aventis Pasteur, Swiftwater, PA
- IP inoculation volumes were 100-200 ⁇ administered with a 25G syringe.
- IC intracerebrally
- Viruses were diluted in Ml 99 with HEPES buffer (Invitrogen) and 20% FBS (Hyclone) unless otherwise indicated. Plaque assays in Vero cells were carried out to verify the titer of virus inoculi (Monath et al., J. Virol. 74(4): 1742- 1751, 2000).
- mice were observed for a period of 21 days to determine neuroinvasion, neurovirulence, or survival after West Nile virus challenge. Morbidity and mortality were observed/scored and survivors were euthanized.
- mice were bled by the retroorbital route and serum was separated by centrifugation. Plaque reduction neutralization assays (PRNT) were used to measure titers of neutralizing antibody in serum.
- PRNT Plaque reduction neutralization assays
- Rhesus monkeys were vaccinated by subcutaneous administration of a single 0.5 ml dose of vaccine containing a nominal 4 loglO PFU.
- Viremia was measured by plaque assays of the diluted serum on Vero cells using serum samples collected daily between days 0 to 10 (Monath et al, J. Virol. 74(4): 1742- 1751, 2000).
- Neutralizing antibody levels were measured by plaque reduction neutralization titer assays (PRNT) (Monath et al., J. Virol. 74(4): 1742- 1751, 2000). Animals were challenged 64 days post vaccination with wild-type WN virus NY99.
- a YF/WN wt (i.e., ChimeriVaxTM-WN 01 ) construct without attenuating mutations in the E protein was passed six times in Vero E6 cells followed by six passages in suckling mice by the IC route.
- YF/WNF V R i-e., ChimeriVaxTM-WNo 2
- preMaster Seed and Research Master Seed constructs with 3 attenuating mutations introduced in the E protein were passed 12 and 10 times, respectively, in serum free, protein free SF-Vero cell substrate. All passages were performed with an initial 0.01 MOI followed by harvest on the third day and continuing without titration to determine virus potency.
- Virus titers used at each passage were later calculated by plaque assay. Neurovirulence of the passaged viruses was measured by adult or suckling mice inoculations IC. Viral RNA was then sequenced.
- the initial West Nile virus chimera encoded the envelope and premembrane protein genes of the WN NY99 wild type strain (i.e., YF/WN wt or ChimeriVaxTM- WN 01 ).
- This chimeric virus lacked the ability to cause encephalitis after IP inoculation at doses of 10 6 pfu in the ICR mouse (Table 2).
- Encephalitis was assessed by daily observation of changes in motor behavior, leading to paralysis and death.
- the YF/WN wt lack of neuroinvasion in the adult mouse was also observed in mice inoculated with the YF 17D vaccine by others (Ryman et al., Virology 230(2):376-
- the IC LD 50 of YF/WN wt was estimated here to be between 10 3 and 10 5 pfu.
- the neurovirulence phenotype of YF/WN wt is lower than that of YF 17D virus, where the ICR mice IC LD 50 is between 10 1 and 10 2 pfu.
- theYF/WN wt virus did not show a clear endpoint in the 21 day old mouse (Table 3).
- Amino acids in the envelope protein were changed to determine whether these changes would reduce the virulence of YF/WN chimeras. Changes in virulence were evaluated in the mouse model and compared to the neurovirulence of the original chimera YF/WN wt. Amino acid residues mapping to the YF/WN wt envelope (E) gene positions 107, 138, 176, and 280 were all mutated in a singular construct to encode amino acid residues F, K, V, and M, respectively. The new chimeric virus was identified as YF/WN FKVM - Chimeras were then constructed in which each amino acid residue in the FKVM group was singly mutated to assess its individual role in neurovirulence (Table 4).
- Mouse neurovirulence of viruses with single or multi-site mutations in the envelope protein gene of YF/WN wt was measured in 21 day old mice inoculated by the IC route with virus doses between 10 4 and 10 5 pfu. This assessment identified residues 107 and 280 (Table 4) and the combination of 316/440 (Table 5) as the more dominant attenuating mutations as measured by mouse mortality and relative average survival time (AST).
- the rhesus monkey neurovirulence phenotype of the West Nile chimeras was measured with the YF/WN wt construct and compared to that of the YF 17D vaccine.
- Rhesus monkeys were inoculated by the IC route with YF/WN wt and compared to YF 17D vaccine inoculates.
- the chimera induced viremia titers and duration similar to the YF 17D vaccine. This virus was not more neuro virulent than the YF vaccine, indicating that the YF/WN chimeras are as safe as the YF 17D vaccine.
- Post- vaccination viremia in rhesus macaques was of similar duration relative to that induced by the YF 17D vaccine, but lower in magnitude, with a linear correlation to the number of attenuating unique mutations in the chimeras (Table 8). Nevertheless, assessment of safety based on viscerotropism (or post vaccination viremia) shows that any one of the vaccine candidates tested in the macaque model is safer than YF 17D.
- Primers for site-directed mutagenesis to create mutant attenuated Yellow Fever/West Nile Virus Nucleotide changes that introduce a new amino acid are indicated in bold. Silent restriction sites introduced are underlined. Primers indicated with an * (asterisk) are cloning primers used to sub-clone the fragment. One incorporates a nucleotide change while the other does not.
- YF/WN wt P2 indicates a second-generation passage virus on Vero cells. West Nile virus strains are typically neuroinvasive after IP inoculation. Table 3
- mice inoculated IC were Taconic ICR 3-4 week old females. Results of three independent experiments are shown.
- mice inoculated IC were Taconic ICR strain 3-4 week old females.
- Viremia (log 10 pfu) post vaccination; rhesus monkeys were inoculated by the subcutaneous route with YF 17D or YF/WN vaccine candidates as specified.
- T081 YF 17D 4.49 1.3 1.0 1.5 2.0 0 0 0 0 0 0 0 0 0
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Abstract
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Priority Applications (14)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2004553787A JP4683926B2 (en) | 2002-11-15 | 2003-11-13 | West Nile virus vaccine |
CA2505942A CA2505942C (en) | 2002-11-15 | 2003-11-13 | West nile virus vaccine |
AT03783570T ATE452900T1 (en) | 2002-11-15 | 2003-11-13 | VACCINE AGAINST THE WEST NILE VIRUS |
KR1020057008744A KR101150584B1 (en) | 2002-11-15 | 2003-11-13 | West nile virus vaccine |
BRPI0316346A BRPI0316346B1 (en) | 2002-11-15 | 2003-11-13 | nucleic acid molecule, chimeric flavivirus, use of said flavivirus and method of manufacturing chimeric flavivirus vaccine against West Nile virus |
AU2003290985A AU2003290985B2 (en) | 2002-11-15 | 2003-11-13 | West nile virus vaccine |
EP03783570A EP1575979B1 (en) | 2002-11-15 | 2003-11-13 | West nile virus vaccine |
MXPA05005140A MXPA05005140A (en) | 2002-11-15 | 2003-11-13 | West nile virus vaccine. |
DE60330708T DE60330708D1 (en) | 2002-11-15 | 2003-11-13 | VACCINE AGAINST WEST NILE VIRUS |
US10/715,868 US7507415B2 (en) | 2002-11-15 | 2003-11-17 | West nile virus vaccine |
IL168584A IL168584A (en) | 2002-11-15 | 2005-05-15 | West nile virus vaccine |
HK06103120.1A HK1083192A1 (en) | 2002-11-15 | 2006-03-10 | West nile virus vaccine |
US12/409,120 US8088391B2 (en) | 2002-11-15 | 2009-03-23 | West nile virus vaccine |
IL202978A IL202978A (en) | 2002-11-15 | 2009-12-27 | West nile virus vaccine |
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Application Number | Priority Date | Filing Date | Title |
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US42659202P | 2002-11-15 | 2002-11-15 | |
US60/426,592 | 2002-11-15 |
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Application Number | Title | Priority Date | Filing Date |
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US10/715,868 Continuation-In-Part US7507415B2 (en) | 2002-11-15 | 2003-11-17 | West nile virus vaccine |
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WO2004045529A2 true WO2004045529A2 (en) | 2004-06-03 |
WO2004045529A3 WO2004045529A3 (en) | 2004-08-26 |
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PCT/US2003/036623 WO2004045529A2 (en) | 2002-11-15 | 2003-11-13 | West nile virus vaccine |
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US (2) | US7507415B2 (en) |
EP (1) | EP1575979B1 (en) |
JP (1) | JP4683926B2 (en) |
KR (1) | KR101150584B1 (en) |
AT (1) | ATE452900T1 (en) |
AU (1) | AU2003290985B2 (en) |
BR (1) | BRPI0316346B1 (en) |
CA (1) | CA2505942C (en) |
DE (1) | DE60330708D1 (en) |
ES (1) | ES2337893T3 (en) |
HK (1) | HK1083192A1 (en) |
IL (2) | IL168584A (en) |
MX (1) | MXPA05005140A (en) |
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Also Published As
Publication number | Publication date |
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HK1083192A1 (en) | 2006-06-30 |
AU2003290985A1 (en) | 2004-06-15 |
BRPI0316346B1 (en) | 2016-05-31 |
MXPA05005140A (en) | 2005-08-19 |
IL202978A (en) | 2013-11-28 |
ZA200503871B (en) | 2006-08-30 |
EP1575979B1 (en) | 2009-12-23 |
IL168584A (en) | 2010-12-30 |
AU2003290985B2 (en) | 2010-04-01 |
EP1575979A2 (en) | 2005-09-21 |
RU2376374C2 (en) | 2009-12-20 |
ES2337893T3 (en) | 2010-04-30 |
RU2005118419A (en) | 2006-01-20 |
US20050053624A1 (en) | 2005-03-10 |
WO2004045529A3 (en) | 2004-08-26 |
CA2505942C (en) | 2012-03-13 |
IL202978A0 (en) | 2011-08-01 |
CA2505942A1 (en) | 2004-06-03 |
EP1575979A4 (en) | 2006-06-21 |
KR101150584B1 (en) | 2012-06-27 |
JP4683926B2 (en) | 2011-05-18 |
US20070275015A9 (en) | 2007-11-29 |
BR0316346A (en) | 2005-09-27 |
US8088391B2 (en) | 2012-01-03 |
KR20050072143A (en) | 2005-07-08 |
ATE452900T1 (en) | 2010-01-15 |
JP2006506092A (en) | 2006-02-23 |
US20100086564A1 (en) | 2010-04-08 |
US7507415B2 (en) | 2009-03-24 |
DE60330708D1 (en) | 2010-02-04 |
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