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You are here: Home / Publications / Bibliographies and Resource Guides / West Nile Virus Bibliography, 2004 -2007 / Vaccines/Immunology  Printer Friendly Page
West Nile Virus Bibliography, 2004-2007
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Brien, J.D. and J. Nikolich Zugich (2006). Immunological basis of age-related vulnerability to West Nile virus. Journal of Immunology 176(Suppl. S): S121. ISSN: 0022-1767.
Descriptors: immune system, West Nile fever, nervous system disease, viral disease, immune response, age related vulnerability.
Notes: Meeting Information: Annual Meeting of the American Association of Immunologists, Boston, Massachusettes, USA; May 12 -16, 2006.

Chiang, Y., C. Jensen, T. Holt, C. Waldbillig, D. Hathaway, N. Jennings, T. Ng, and H. Chu (2005). Demonstration of efficacy of a West Nile virus DNA vaccine in foals. Proceedings of the Annual Convention of the American Association of Equine Practioners 51(51): 183-190. ISSN: 0065-7182.
Descriptors: mosquito borne diseases, vaccine development, maternal immunity, antibody formation, plasmids, immunoglobulin G, viremia, foals, West Nile virus, DNA.
Notes: Meeting Information: December 3-7, 2005 in Seattle, Washington.

Davidson, A.H., J.L. Traub Dargatz, R.M. Rodeheaver, E.N. Ostlund, D.D. Pedersen, R.G. Moorhead, J.B. Stricklin, R.D. Dewell, S.D. Roach, R.E. Long, S.J. Albers, R.J. Callan, and M.D. Salman (2005). Immunologic responses to West Nile virus in vaccinated and clinically affected horses. Journal of the American Veterinary Medical Association 226(2): 240-245.
Abstract: OBJECTIVE: To compare neutralizing antibody response between horses vaccinated against West Nile virus (WNV) and horses that survived naturally occurring infection. DESIGN: Cross-sectional observational study. ANIMALS: 187 horses vaccinated with a killed WNV vaccine and 37 horses with confirmed clinical WNV infection. PROCEDURE: Serum was collected from vaccinated horses prior to and 4 to 6 weeks after completion of an initial vaccination series (2 doses) and 5 to 7 months later. Serum was collected from affected horses 4 to 6 weeks after laboratory diagnosis of infection and 5 to 7 months after the first sample was obtained. The IgM capture ELISA, plaque reduction neutralization test (PRNT), and microtiter virus neutralization test were used. RESULTS: All affected horses had PRNT titers > or = 1:100 at 4 to 6 weeks after onset of disease, and 90% (18/20) maintained this titer for 5 to 7 months. After the second vaccination, 67% of vaccinated horses had PRNT titers > or = 1:100 and 14% had titers < 1:10. Five to 7 months later, 33% (28/84) of vaccinated horses had PRNT titers > or = 1:100, whereas 29% (24/84) had titers < 1:10. Vaccinated and clinically affected horses' end point titers had decreased by 5 to 7 months after vaccination. CONCLUSIONS AND CLINICAL RELEVANCE: A portion of horses vaccinated against WNV may respond poorly. Vaccination every 6 months may be indicated in certain horses and in areas of high vector activity. Other preventative methods such as mosquito control are warranted to prevent WNV infection in horses.
Descriptors: horse diseases, viral vaccines, West Nile fever, West Nile virus, enzyme linked immunosorbent assay, mosquito control.

Despres, P., C. Combredet, M.P. Frenkiel, C. Lorin, M. Brahic, and F. Tangy (2005). Live measles vaccine expressing the secreted form of the West Nile virus envelope glycoprotein protects against West Nile virus encephalitis. Journal of Infectious Diseases 191(2): 207-214.
Abstract: The Schwarz strain of measles virus (MV), a live attenuated RNA virus, is one of the safest and most effective human vaccines available. Immunization with MV vaccine expressing heterologous antigen is an attractive strategy to prevent emerging viral diseases. West Nile virus (WNV), which recently emerged in North America, is an important mosquito-borne flavivirus that causes numerous cases of human encephalitis, thus urging the development of a vaccine. To evaluate the efficacy of recombinant MV for the prevention of WNV encephalitis, we constructed a live attenuated Schwarz MV (MVSchw-sE(WNV)) expressing the secreted form of the envelope glycoprotein from the virulent IS-98-ST1 strain of WNV. Inoculation of MV-susceptible mice with MVSchw-sE(WNV) induced both high levels of specific anti-WNV neutralizing antibodies and protection from a lethal challenge with WNV. Passive administration with antisera to MVSchw-sE(WNV) prevented WNV encephalitis in BALB/c mice challenged with a high dose of WNV. The present study is the first to report that a recombinant live attenuated vector based on an approved and widely used MV vaccine can protect against a heterologous, medically important pathogen.
Descriptors: encephalitis, measles vaccine, viral envelope proteins, West Nile virus, Cercopithecus aethiops, molecular cloning, inbred BalbC mice.

Eisenstein, M. (2005). Antibody neutralizes West Nile virus. Lab Animal 34(6): 10.
Descriptors: viral antibodies immunology, West Nile fever, West Nile virus cell line, mice, neutralization tests.

Epp, T., C. Waldner, K. West, F. Leighton, and H. Townsend (2005). Efficacy of vaccination for West Nile virus in Saskatchewan horses. Proceedings of the Annual Convention of the American Association of Equine Practioners 51(51): 180-182. ISSN: 0065-7182.
Descriptors: horses, mosquito borne diseases, inactivated vaccines, mosquito control, disease incidence, West Nile virus, Saskatchewan.
Notes: Meeting Information: December 3-7, 2005 in Seattle, Washington.

Gould, L.H., J. Sui, H. Foellmer, T. Oliphant, T. Wang, M. Ledizet, A. Murakami, K. Noonan, C. Lambeth, K. Kar, J.F. Anderson, A.M. de Silva, M.S. Diamond, R.A. Koski, W.A. Marasco, and E. Fikrig (2005). Protective and therapeutic capacity of human single-chain Fv-Fc fusion proteins against West Nile virus. Journal of Virology 79(23): 14606-14613. ISSN: 0022-538X.
Abstract: West Nile virus has spread rapidly across the United States, and there is currently no approved human vaccine or therapy to prevent or treat disease. Passive immunization with antibodies against the envelope protein represents a promising means to provide short-term prophylaxis and treatment for West Nile virus infection. In this study, we identified a panel of 11 unique human single-chain variable region antibody fragments (scFvs) that bind the envelope protein of West Nile virus. Selected scFvs were converted to Fc fusion proteins (scFv-Fcs) and were tested in mice for their ability to prevent lethal West Nile virus infection. Five of these scFv-Fcs, 11, 15, 71, 85, and 95, protected 100% of mice from death when given prior to infection with virus. Two of them, 11 and 15, protected 80% of mice when given at days 1 and 4 after infection. In addition, four of the scFv-Fcs cross-neutralized dengue virus, serotype 2. Binding assays using yeast surface display demonstrated that all of our scFvs bind to sites within domains I and II of West Nile virus envelope protein. These recombinant human scFvs are potential candidates for immunoprophylaxis and therapy of flavivirus infections.
Descriptors: viral antibodies, viral vaccines , West Nile fever prevention and control, West Nile virus, antibody specificity, immunoglobulin fragments, recombinant fusion proteins.

Iglesias, M.C., M.P. Frenkiel, K. Mollier, P. Souque, P. Despres, and P. Charneau (2006). A single immunization with a minute dose of a lentiviral vector-based vaccine is highly effective at eliciting protective humoral immunity against West Nile virus. Journal of Gene Medicine 8(3): 265-274.
Abstract: BACKGROUND: Lentiviral vectors, due to their capacity to transduce non-dividing cells, have become precious and worldwide used gene transfer systems. Their ability to efficiently and stably transduce dendritic cells (DCs) has led to their successful use as vaccination vectors for eliciting strong, specific and protective cellular immune responses mostly in anti-tumoral but also in anti-viral applications. However, the ability of lentiviral vectors to elicit an antibody-based protective immunity has, to date, not been evaluated. In the present study, we evaluated the potential of a lentiviral vector-based vaccine to elicit humoral immunity against West Nile virus (WNV). WNV is a mosquito-borne flavivirus that emerged in North America and causes encephalitis in humans, birds and horses. Neutralizing anti-WNV antibodies have been shown to be crucial for protection against WNV encephalitis. METHODS: The ability of lentiviral vector TRIP/sE(WNV), expressing the secreted soluble form of the envelope E-glycoprotein (sE(WNV)) from the highly virulent IS-98-ST1 strain of WNV, to induce a specific humoral response and protection against WNV infection was assessed in a mouse model of WNV encephalitis. RESULTS: Remarkably, a single immunization with a minute dose of TRIP/sE(WNV) was efficient at eliciting a long-lasting, protective and sterilizing humoral immunity, only 1 week after priming. CONCLUSIONS: This study broadens the applicability of lentiviral vectors as efficient non-replicating vaccines against pathogens for which a neutralizing humoral response is one active arm of the protective immunity. The TRIP/sE(WNV) lentiviral vector appears to be a promising tool for veterinary vaccination against zoonotic WNV.
Descriptors: antibody formation, lentivirus, viral vaccines, West Nile fever, West Nile virus, genetic vectors, immunization schedule, mice, transduction, viral envelope proteins.

Johnson, B.W., O. Kosoy, D.A. Martin, A.J. Noga, B.J. Russell, A.A. Johnson, and L.R. Petersen (2005). West Nile virus infection and serologic response among persons previously vaccinated against yellow fever and Japanese encephalitis viruses. Vector Borne and Zoonotic Diseases 5(2): 137-145. ISSN: 1530-3667.
Abstract: It is hypothesized that previous heterologous flaviviral exposure may modulate clinical illness among persons infected with West Nile virus (WNV). Little is known about the serological response in such persons. In summer 2003, a WNV outbreak occurred in Colorado, the location of the Centers for Disease Control and Prevention, Division of Vector-Borne Infectious Diseases (DVBID). DVBID employees, most previously vaccinated with yellow fever virus (YFV) or Japanese encephalitis virus (JEV) vaccines, were studied to determine whether previous vaccination affected symptom development among those subsequently infected with WNV during the outbreak, as well as their serological response. Serum samples collected in December 2003 and previously banked samples were tested using the plaque reduction neutralization test (PRNT) against WNV, Saint Louis encephalitis virus, dengue- 4 virus, JEV, and YFV. Specimens shown to have WNV antibody by PRNT were tested by IgM and IgG enzymelinked immunosorbent assays (ELISAs). Ten (9%) of 113 serosurvey participants had WNV neutralizing antibody titers in December 2003. PRNT titers from previous specimens showed that one of the ten had seroconverted to WNV before 2003. Of the remaining nine participants, seven reported illness in the summer of 2003, two of which were unvaccinated and five previously vaccinated. In the December 2003 specimens, five persons previously unvaccinated or vaccinated only against YFV had a fourfold or greater neutralizing titer with WNV than with other flaviviruses, whereas no persons previously vaccinated against JEV or JEV and YFV showed a similar difference in neutralizing titers. Eight of nine persons infected in 2003 had negative or indeterminate WNV MAC-ELISA results in the December 2003 sample; the ninth person was vaccinated against YFV one month previously, and was also YFV positive by MAC-ELISA. We conclude that previous flaviviral vaccination does not markedly affect the development of WNV fever and that the IgM antibody response in patients without neuroinvasive WNV disease is transient.
Descriptors: Japanese encephalitis vaccines, adverse effects, West Nile fever immunology, West Nile virus, yellow fever vaccine, viral biosynthesis, Colorado, enzyme linked immunosorbent assay.

Johnson, S. (2005). Avian titer development against West Nile virus after extralabel use of an equine vaccine. Journal of Zoo and Wildlife Medicine 36(2): 257-264. ISSN: 1042-7260.
Abstract: West Nile virus affects many animals, but the highest prevalence of morbidity and mortality is observed in birds, horses, and humans. The purpose of this study was to determine a protocol in birds of prey and corvids, using a vaccine developed for horses. The birds were assigned to five groups. Groups 1-4 received 0.25 ml, 0.5 ml, 0.75 ml, and 1.0 ml, respectively, and group 5 served as a control group. The greatest percentage of seroconversion (58.3%) was observed in the vaccine group that received a dose of 1.0 ml administered thrice, 3 wk apart. This report demonstrates that a vaccine developed for equines against West Nile virus can be administered to birds.
Descriptors: corvidae, falconiformes, strigiformes, treatment techniques, vaccination, protocol development for West Nile virus using equine vaccine, viral diseases, West Nile virus, immune response, antibodies.

Julander, J.G., Q.A. Winger, A.L. Olsen, C.W. Day, R.W. Sidwell, and J.D. Morrey (2005). Treatment of West Nile virus-infected mice with reactive immunoglobulin reduces fetal titers and increases dam survival. Antiviral Research 65(2): 79-85. ISSN: 0166-3542.
Abstract: The objectives of this study were to determine if injection of West Nile virus (WNV) into timed-pregnant mice would result in fetal infection and if administration of WNV-reactive immunoglobulin would increase dam survival and reduce fetal viral titers. Dams injected on 7.5 days post-coitus (dpc) had detectable viral titers in the placenta 10.5dpc with a mean titer of 10(4.9) 50% cell-culture infectious doses per gram of tissue (CCID(50)/g tissue). The mean placental titer increased to 10(8.6)CCID(50)/g tissue at 12.5dpc. Infectious virus was detectable 12.5dpc in 10 of 10 fetuses with a mean titer of 10(7.5)CCID(50)/g tissue. Treatment of dams (challenged with WNV on 7.5dpc) with WNV-reactive human immunoglobulin (Ig) on 8.5 and 9.5dpc resulted in a significant reduction of virus in fetuses as compared with non-reactive human Ig-treated females on 12.5dpc (P< or =0.001). Treatment also resulted in survival of dams to term. Treatment of dams with WNV-reactive human Ig on 12.5 and 13.5dpc also resulted in reduction of viral titer on 14.5dpc, indicating that later treatment may also be efficacious. This suggests that Ig treatment may be useful in treating fetal WNV infection in women.
Descriptors: viral antibodies, immunoglobulins, pregnancy complications, West Nile fever , West Nile virus, disease transmission, mice, infectious immunology.

Karaca, K., R. Bowen, L.E. Austgen, M. Teehee, L. Siger, D. Grosenbaugh, L. Loosemore, J.C. Audonnet, R. Nordgren, and J.M. Minke (2005). Recombinant canarypox vectored West Nile virus (WNV) vaccine protects dogs and cats against a mosquito WNV challenge. Vaccine 23(29): 3808-3813.
Abstract: The safety and efficacy of a canarypox vector expressing PrM and E genes of West Nile virus (WNV) (ALVAC-WNV) was evaluated in dogs and cats. One group of 17 dogs (vaccinated with 10(5.6) TCID(50)) and two groups of cats (groups 1 [n=14] vaccinated with 10(7.5) TCID(50) and 2 [n=8] 10(5.6) TCID(50)) were vaccinated twice at 28-day intervals. Fifteen dogs and eleven cats served as negative controls. The cats and dogs were challenged 120 and 135 days after the second immunization, respectively via the bites of Aedes albopictus mosquitoes infected with WNV. The first dose of vaccine induced a detectable antibody response in four dogs and five cats (one immunized with low and four with high doses). After the second dose, all the vaccinated dogs and all of the cats, immunized with high dose had detectable antibody titers, whereas only four of eight cats in the low dose group were seropositive. None of the vaccinated dogs and one vaccinated cat developed viremia following the WNV mosquito-challenge. In contrast, 14 of the 15 control dogs and 9 of the 11 control cats developed viremia. The experimental vaccine described in this study may be of value in the prevention of WNV infection in dogs and cats.
Descriptors: canarypox vector, cat diseases, dog diseases, viral vaccines, West Nile fever, West Nile virus, viral blood antibodies, synthetic genetics, viral envelope proteins, viral vaccines, West Nile fever prevention and control.

Ledizet, M., K. Kar, H.G. Foellmer, T. Wang, S.L. Bushmich, J.F. Anderson, E. Fikrig, and R.A. Koski (2005). A recombinant envelope protein vaccine against West Nile virus. Vaccine 23(30): 3915-3924.
Abstract: West Nile (WN) virus is a flavivirus that first appeared in North America in 1999. Since then, more than 600 human deaths and 22,000 equine infections have been attributed to the virus in the United States. We expressed a truncated form of WN virus envelope (E) protein in Drosophila S2 cells. This soluble recombinant E protein was recognized by antibodies from naturally infected horses, indicating that it contains native epitopes. Mice and horses produced high-titer antibodies when immunized with recombinant E protein combined with aluminum hydroxide. Immunized mice were resistant to challenge with a lethal viral dose. Sera from immunized horses, administered to naive mice, conferred resistance against a lethal WN viral challenge. In addition, sera of immunized horses neutralized West Nile virus in vitro, as demonstrated by plaque reduction assays. This recombinant form of E protein, combined with aluminum hydroxide, is a candidate vaccine that may protect humans and horses against WN virus infections.
Descriptors: viral envelope proteins, viral vaccines, West Nile fever, West Nile virus, immunologic adjuvants, aluminum hydroxide, cultured cells, drosophila, horses, passive immunization, immunoglobulin G biosynthesis, inbred C57BL mice, plaque assay, protein conformation, synthetic vaccines, viral envelope.

Long, M., E. Gibbs, K. Seino, M. Mellencamp, S. Zhang, S. Beachboard, and P. Humphrey (2005). Safety and efficacy of a live attenuated West Nile virus chimera vaccine in horses with experimentally induced West Nile virus clinical disease. Proceedings of the Annual Convention of the American Association of Equine Practioners 51(51): 177-179. ISSN: 0065-7182.
Descriptors: live vaccines, antibody formation, histopathology, immunity, West Nile virus, safety, efficacy, horses.
Notes: Meeting Information: December 3-7, 2005 in Seattle, Washington.

Mateo, R., S.Y. Xiao, H. Guzman, H. Lei, A.P. Da Rosa, and R.B. Tesh (2006). Effects of immunosuppression on West Nile virus infection in hamsters. American Journal of Tropical Medicine and Hygiene 75(2): 356-362. ISSN: 0002-9637.
Abstract: A research study, comparing the pathogenesis of experimental West Nile virus (WNV) infection in immunocompetent and immunosuppressed golden hamsters, is described. Cyclophosphamide was used to immunosuppress the animals. The immunosuppressed hamsters had a prolonged period of viremia, depressed humoral immune response, more extensive and severe pathology, and higher fatality rate than the untreated immunocompetent animals. Histopathological and immunohistochemical studies of tissues from the two groups showed that pathologic changes in the untreated infected animals were confined to the brain and spinal cord, whereas the histopathological changes and WNV antigen distribution in the immunosuppressed animals were much more extensive and diffuse, involving the adrenal, kidney, heart and lung, and brain and spinal cord. Results of this study in the hamster model provide insight into the increased severity of WNV infection observed in immunosuppressed people.
Descriptors: central nervous system, West Nile fever, West Nile virus, antibody formation, viral isolation and purification, Cercopithecus aethiops, cyclophosphamide, disease models, animal immunocompetence, immunocompromised host, immunosuppressive agents.

Mehlhop, E. and M.S. Diamond (2006). Protective immune responses against West Nile virus are primed by distinct complement activation pathways. Journal of Experimental Medicine 203(5): 1371-1381.
Abstract: West Nile virus (WNV) causes a severe infection of the central nervous system in several vertebrate animals including humans. Prior studies have shown that complement plays a critical role in controlling WNV infection in complement (C) 3(-/-) and complement receptor 1/2(-/-) mice. Here, we dissect the contributions of the individual complement activation pathways to the protection from WNV disease. Genetic deficiencies in C1q, C4, factor B, or factor D all resulted in increased mortality in mice, suggesting that all activation pathways function together to limit WNV spread. In the absence of alternative pathway complement activation, WNV disseminated into the central nervous system at earlier times and was associated with reduced CD8+ T cell responses yet near normal anti-WNV antibody profiles. Animals lacking the classical and lectin pathways had deficits in both B and T cell responses to WNV. Finally, and somewhat surprisingly, C1q was required for productive infection in the spleen but not for development of adaptive immune responses after WNV infection. Our results suggest that individual pathways of complement activation control WNV infection by priming adaptive immune responses through distinct mechanisms.
Descriptors: CD8 positive T lymphocytes, West Nile fever, West Nile virus antibodies, B lymphocytes immunology, central nervous system, knockout mice, spleen.

Mehlhop, E., K. Whitby, T. Oliphant, A. Marri, M. Engle, and M.S. Diamond (2005). Complement activation is required for induction of a protective antibody response against West Nile virus infection. Journal of Virology 79(12): 7466-7477. ISSN: 0022-538X.
Abstract: Infection with West Nile virus (WNV) causes a severe infection of the central nervous system (CNS) with higher levels of morbidity and mortality in the elderly and the immunocompromised. Experiments with mice have begun to define how the innate and adaptive immune responses function to limit infection. Here, we demonstrate that the complement system, a major component of innate immunity, controls WNV infection in vitro primarily in an antibody-dependent manner by neutralizing virus particles in solution and lysing WNV-infected cells. More decisively, mice that genetically lack the third component of complement or complement receptor 1 (CR1) and CR2 developed increased CNS virus burdens and were vulnerable to lethal infection at a low dose of WNV. Both C3-deficient and CR1- and CR2-deficient mice also had significant deficits in their humoral responses after infection with markedly reduced levels of specific anti-WNV immunoglobulin M (IgM) and IgG. Overall, these results suggest that complement controls WNV infection, in part through its ability to induce a protective antibody response.
Descriptors: viral blood antibodies, complement activation, West Nile fever, West Nile virus, complement c3 genetics, cricetinae, mice, neutralization tests, complement genetics, West Nile fever.

Monath, T.P., J. Liu, N. Kanesa Thasan, G.A. Myers, R. Nichols, A. Deary, K. McCarthy, C. Johnson, T. Ermak, S. Shin, J. Arroyo, F. Guirakhoo, J.S. Kennedy, F.A. Ennis, S. Green, and P. Bedford (2006). A live, attenuated recombinant West Nile virus vaccine. Proceedings of the National Academy of Sciences of the United States of America 103(17): 6694-6699.
Abstract: West Nile (WN) virus is an important cause of febrile exanthem and encephalitis. Since it invaded the U.S. in 1999, >19,000 human cases have been reported. The threat of continued epidemics has spurred efforts to develop vaccines. ChimeriVax-WN02 is a live, attenuated recombinant vaccine constructed from an infectious clone of yellow fever (YF) 17D virus in which the premembrane and envelope genes of 17D have been replaced by the corresponding genes of WN virus. Preclinical tests in monkeys defined sites of vaccine virus replication in vivo. ChimeriVax-WN02 and YF 17D had similar biodistribution but different multiplication kinetics. Prominent sites of replication were skin and lymphoid tissues, generally sparing vital organs. Viruses were cleared from blood by day 7 and from tissues around day 14. In a clinical study, healthy adults were inoculated with 5.0 log(10) plaque-forming units (PFU) (n = 30) or 3.0 log10 PFU (n = 15) of ChimeriVax-WN02, commercial YF vaccine (YF-VAX, n = 5), or placebo (n = 30). The incidence of adverse events in subjects receiving the vaccine was similar to that in the placebo group. Transient viremia was detected in 42 of 45 (93%) of ChimeriVax-WN02 subjects, and four of five (80%) of YF-VAX subjects. All subjects developed neutralizing antibodies to WN or YF, respectively, and the majority developed specific T cell responses. ChimeriVax-WN02 rapidly elicits strong immune responses after a single dose, and is a promising candidate warranting further evaluation for prevention of WN disease.
Descriptors: viral vaccines, West Nile virus, double blind method, Macaca fascicularis, molecular sequence data, neutralization tests, safety, T lymphocytes, attenuated recombinant vaccines, infectious clone of yellow fever, preclinical tests, ChimeriVax-WN02, prevention of WN fever.

Oliphant, T., M. Engle, G.E. Nybakken, C. Doane, S. Johnson, L. Huang, S. Gorlatov, E. Mehlhop, A. Marri, K.M. Chung, G.D. Ebel, L.D. Kramer, D.H. Fremont, and M.S. Diamond (2005). Development of a humanized monoclonal antibody with therapeutic potential against West Nile virus. Nature Medicine 11(5): 522-530.
Abstract: Neutralization of West Nile virus (WNV) in vivo correlates with the development of an antibody response against the viral envelope (E) protein. Using random mutagenesis and yeast surface display, we defined individual contact residues of 14 newly generated monoclonal antibodies against domain III of the WNV E protein. Monoclonal antibodies that strongly neutralized WNV localized to a surface patch on the lateral face of domain III. Convalescent antibodies from individuals who had recovered from WNV infection also detected this epitope. One monoclonal antibody, E16, neutralized 10 different strains in vitro, and showed therapeutic efficacy in mice, even when administered as a single dose 5 d after infection. A humanized version of E16 was generated that retained antigen specificity, avidity and neutralizing activity. In postexposure therapeutic trials in mice, a single dose of humanized E16 protected mice against WNV-induced mortality, and may therefore be a viable treatment option against WNV infection in humans.
Descriptors: monoclonal antibodies, viral envelope (E) protein, neutralization of West Nile virus in vivo, mice, treatment option.

Pletnev, A.G., D.E. Swayne, J. Speicher, A.A. Rumyantsev, and B.R. Murphy (2006). Chimeric West Nile/dengue virus vaccine candidate: Preclinical evaluation in mice, geese and monkeys for safety and immunogenicity. Vaccine 24(40-41): 6392-6404.
Abstract: A live attenuated virus vaccine is being developed to protect against West Nile virus (WN) disease in humans. Previously, it was found that chimeric West Nile/dengue viruses (WN/DEN4 and WN/DEN4Delta30) bearing the membrane precursor and envelope protein genes of WN on a backbone of dengue type 4 virus (DEN4) with or without a deletion of 30 nucleotides (Delta30) in the 3' noncoding region of the DEN4 part of the chimeric genome were attenuated and efficacious in mice and monkeys against WN challenge. Here, we report the generation of a clinical lot of WN/DEN4Delta30 virus and its further preclinical evaluation for safety and immunogenicity in mice, geese and monkeys. The vaccine candidate had lost neuroinvasiveness in highly sensitive immunodeficient mice inoculated intraperitoneally and had greatly reduced neurovirulence in suckling mice inoculated intracerebrally (IC). Compared to the wild-type WN parent, the chimeric virus was highly restricted in replication in both murine and human neuroblastoma cells as well as in brains of suckling mice. The WN/DEN4Delta30 virus failed to infect geese, indicating that chimerization of WN with DEN4 completely attenuated WN for this avian host. This observation suggests that the WN/DEN4 chimeric viruses would be restricted in their ability to be transmitted from vaccinees to domestic or wild birds. In monkeys, the WN/DEN4Delta30 vaccine candidate was highly immunogenic despite its low level of replication with undetectable viremia. Furthermore, the WN/DEN4Delta30 vaccine virus was safe and readily induced neutralizing antibodies against WN in monkeys immune to each of the four serotypes of dengue virus. These studies confirm the attenuation of WN/DEN4Delta30 for non-human primates, including dengue-immune monkeys, and demonstrate both a highly restricted replication (>10(8)-fold decrease) in the brain of mice inoculated IC and an absence of infectivity for birds, findings that indicate this vaccine should be safe for both the recipient and the environment.
Descriptors: West Nile virus, live attenuated vaccine, mice, monkeys, preclinical evaluation, geese, induced neutralizing antibodies.

Redig, P., M. Saggese, T. Tully, A. Roy, B. Ritchie, and A. Allison (2005). Update on West Nile virus disease and vaccine. In: Small animal and exotics: Proceedings of the North American Veterinary Conference, January 8, 2005-January 12, 2005, Orlando, Florida, USA, Eastern States Veterinary Association: Gainesville, USA, Vol. 19, p. 1197-1198.
Descriptors: West Nile virus, virus disease, vaccines, updates.

Samina, I., Y. Khinich, M. Simanov, and M. Malkinson (2005). An inactivated West Nile virus vaccine for domestic geese-efficacy study and a summary of 4 years of field application. Vaccine 23(41): 4955-4958.
Abstract: Following the isolation in 1997 of West Nile virus from the brains of geese with an acute neuroparalytic disease in Israel, which reappeared in the following years, an inactivated vaccine was prepared from suckling mouse brains. The brain homogenate was inactivated with formaldehyde and blended with mineral oil adjuvant. In 2000, the first flocks were vaccinated according to a schedule of two subcutaneous doses, commencing at the age of 2 weeks and given with a 2-weeks interval. In efficacy trials, the challenge virus was injected at 7 weeks by the intracranial route, and over 85% protection was recorded in vaccinated geese. In extensive field trials conducted in 2001--2003, the vaccine was demonstrated to be safe and efficacious, and over 3 million doses were manufactured in 2000--2003.
Descriptors: bird diseases, geese, Israel, inactivate vaccine for West Nile virus, vaccination of birds, challenge virus, 85% protection rate, field trials of vaccines.

Samuel, M.A. and M.S. Diamond (2006). Pathogenesis of West Nile Virus infection: a balance between virulence, innate and adaptive immunity, and viral evasion. Journal of Virology 80(19): 9349-9360. ISSN: 0022-538X.
Descriptors: immunity, natural immunology, West Nile fever, West Nile virus, central nervous system, disease susceptibility.

Samuel, M.A. and M.S. Diamond (2005). Alpha/beta interferon protects against lethal West Nile virus infection by restricting cellular tropism and enhancing neuronal survival. Journal of Virology 79(21): 13350-13361. ISSN: 0022-538X.
Abstract: West Nile virus (WNV) is a mosquito-borne flavivirus that is neurotropic in humans, birds, and other animals. While adaptive immunity plays an important role in preventing WNV spread to the central nervous system (CNS), little is known about how alpha/beta interferon (IFN-alpha/beta) protects against peripheral and CNS infection. In this study, we examine the virulence and tropism of WNV in IFN-alpha/beta receptor-deficient (IFN- alpha/betaR-/-) mice and primary neuronal cultures. IFN-alpha/betaR-/- mice were acutely susceptible to WNV infection through subcutaneous inoculation, with 100% mortality and a mean time to death (MTD) of 4.6 +/- 0.7 and 3.8+/- 0.5 days after infection with 10(0) and 10(2) PFU, respectively. In contrast, congenic wild-type 129Sv/Ev mice infected with 10(2) PFU showed 62% mortality and a MTD of 11.9 +/- 1.9 days. IFN-alpha/betaR-/- mice developed high viral loads by day 3 after infection in nearly all tissues assayed, including many that were not infected in wild-type mice. IFN-alpha/betaR-/- mice also demonstrated altered cellular tropism, with increased infection in macrophages, B cells, and T cells in the spleen. Additionally, treatment of primary wild-type neurons in vitro with IFN-beta either before or after infection increased neuronal survival independent of its effect on WNV replication. Collectively, our data suggest that IFN-alpha/beta controls WNV infection by restricting tropism and viral burden and by preventing death of infected neurons.
Descriptors: interferon alpha analysis, interferon beta analysis, West Nile fever , West Nile virus, antiviral agents, brain immunology, cultured cells, cultured, inbred mice, skeletal muscle, organ specificity, messenger RNA genetics, reverse transcriptase polymerase chain reaction, spinal cord , spleen, virus replication.

Samuel, M.A., K. Whitby, B.C. Keller, A. Marri, W. Barchet, B.R. Williams, R.H. Silverman, M.J. Gale, and M.S. Diamond (2006). PKR and RNase L contribute to protection against lethal West Nile Virus infection by controlling early viral spread in the periphery and replication in neurons. Journal of Virology 80(14): 7009-7019. ISSN: 0022-538X.
Abstract: West Nile virus (WNV) is a neurotropic, mosquito-borne flavivirus that can cause lethal meningoencephalitis. Type I interferon (IFN) plays a critical role in controlling WNV replication, spread, and tropism. In this study, we begin to examine the effector mechanisms by which type I IFN inhibits WNV infection. Mice lacking both the interferon-induced, double-stranded-RNA-activated protein kinase (PKR) and the endoribonuclease of the 2',5'-oligoadenylate synthetase-RNase L system (PKR(-/-) x RL(-/-)) were highly susceptible to subcutaneous WNV infection, with a 90% mortality rate compared to the 30% mortality rate observed in congenic wild-type mice. PKR(-/-) x RL(-/-) mice had increased viral loads in their draining lymph nodes, sera, and spleens, which led to early viral entry into the central nervous system (CNS) and higher viral burden in neuronal tissues. Although mice lacking RNase L showed a higher CNS viral burden and an increased mortality, they were less susceptible than the PKR(-/-) x RL(-/-) mice; thus, we also infer an antiviral role for PKR in the control of WNV infection. Notably, a deficiency in both PKR and RNase L resulted in a decreased ability of type I IFN to inhibit WNV in primary macrophages and cortical neurons. In contrast, the peripheral neurons of the superior cervical ganglia of PKR(-/-) x RL(-/-) mice showed no deficiency in the IFN-mediated inhibition of WNV. Our data suggest that PKR and RNase L contribute to IFN-mediated protection in a cell-restricted manner and control WNV infection in peripheral tissues and some neuronal subtypes.
Descriptors: endoribonucleases, meningoencephalitis, neurons, virus replication genetics, West Nile fever, West Nile virus metabolism, cerebellar cortex, endoribonucleases deficiency, type II interferon metabolism, macrophages, meningoencephalitis, knockout mice, organ specificity, superior cervical ganglion.

Sanchez, M.D., T.C. Pierson, D. McAllister, S.L. Hanna, B.A. Puffer, L.E. Valentine, M.M. Murtadha, J.A. Hoxie, and R.W. Doms (2005). Characterization of neutralizing antibodies to West Nile virus. Virology 336(1): 70-82. ISSN: 0042-6822.
Abstract: We produced nine monoclonal antibodies (MAbs) directed against the West Nile virus E glycoprotein using three different immunization strategies: inactivated virus, naked DNA, and recombinant protein. Most of the MAbs bound to conformation dependent epitopes in domain III of the E protein. Four of the MAbs neutralized WNV infection and bound to the same region of domain III with high affinity. The neutralizing MAbs were obtained from mice immunized with inactivated virus alone or in combination with a DNA plasmid. In contrast, MAbs obtained by immunization with a soluble version of the E glycoprotein did not exhibit neutralizing activity. These non-neutralizing antibodies were cross-reactive with several other flaviviruses, including Saint Louis encephalitis, Japanese encephalitis, Yellow Fever and Powassan viruses. Interestingly, some non-neutralizing MAbs bound with high affinity to domains I or III, indicating that both affinity and the precise epitope recognized by an antibody are important determinants of WNV neutralization.
Descriptors: monoclonal antibodies, viral immunology, West Nile virus, Japanese encephalitis virus, St. Louis encephalitis virus, tick borne diseases, enzyme linked immunosorbent assay, epitope mapping, glycoproteins, mice, tertiary protein structure, yellow fever virus.

Secko, D. (2005). Immunotherapy for West Nile virus infection. Canadian Medical Association Journal 173(6): 591.
Descriptors: monoclonal antibodies, immunotherapy trends, West Nile fever, West Nile virus, mice, survival analysis.

Seligman, S.J. (2006). Single nucleotide polymorphisms in human genes and increased susceptibility to West Nile Virus disease. Journal of Infectious Diseases 193(8): 1187-1188; Author Reply 1188.
Descriptors: single nucleotide polymorphism genetics, West Nile fever, genetic predisposition to disease, natural immunity genetics, mice, West Nile virus (WNV).
Notes: Comment On: J Infect Dis. 2005 Nov 15;192(10):1741-8.

Seregin, A., R. Nistler, V. Borisevich, G. Yamshchikov, E. Chaporgina, C.W. Kwok, and V. Yamshchikov (2006). Immunogenicity of West Nile virus infectious DNA and its noninfectious derivatives. Virology 356(1-2): 115-125. ISSN: 0042-6822.
Abstract: The exceptionally high virulence of the West Nile NY99 strain makes its suitability in the development of a live WN vaccine uncertain. The aim of this study is to investigate the immunogenicity of noninfectious virus derivatives carrying pseudolethal mutations, which preclude virion formation without affecting preceding steps of the viral infectious cycle. When administered using DNA immunization, such constructs initiate an infectious cycle but cannot lead to a viremia. While the magnitude of the immune response to a noninfectious replication-competent construct was lower than that of virus or infectious DNA, its overall quality and the protective effect were similar. In contrast, a nonreplicating construct of similar length induced only a marginally detectable immune response in the dose range used. Thus, replication-competent noninfectious constructs derived from infectious DNA may offer an advantageous combination of the safety of noninfectious formulations with the quality of the immune response characteristic of infectious vaccines.
Descriptors: West Nile virus, immunogenicity, DNA, infectious, non infectious, virulence, immune response, NY99 strain.

Sheets, R.L., J. Stein, T.S. Manetz, C. Andrews, R. Bailer, J. Rathmann, and P.L. Gomez (2006). Toxicological safety evaluation of DNA plasmid vaccines against HIV-1, Ebola, Severe Acute Respiratory Syndrome, or West Nile virus is similar despite differing plasmid backbones or gene-inserts. Toxicological Sciences 91(2): 620-630.
Abstract: The Vaccine Research Center has developed a number of vaccine candidates for different diseases/infectious agents (HIV-1, Severe Acute Respiratory Syndrome virus, West Nile virus, and Ebola virus, plus a plasmid cytokine adjuvant-IL-2/Ig) based on a DNA plasmid vaccine platform. To support the clinical development of each of these vaccine candidates, preclinical studies were performed to screen for potential toxicities (intrinsic and immunotoxicities). All treatment-related toxicities identified in these repeated-dose toxicology studies have been confined primarily to the sites of injection and seem to be the result of both the delivery method (as they are seen in both control and treated animals) and the intended immune response to the vaccine (as they occur with greater frequency and severity in treated animals). Reactogenicity at the site of injection is generally seen to be reversible as the frequency and severity diminished between doses and between the immediate and recovery termination time points. This observation also correlated with the biodistribution data reported in the companion article (Sheets et al., 2006), in which DNA plasmid vaccine was shown to remain at the site of injection, rather than biodistributing widely, and to clear over time. The results of these safety studies have been submitted to the Food and Drug Administration to support the safety of initiating clinical studies with these and related DNA plasmid vaccines. Thus far, standard repeated-dose toxicology studies have not identified any target organs for toxicity (other than the injection site) for our DNA plasmid vaccines at doses up to 8 mg per immunization, regardless of disease indication (i.e., expressed gene-insert) and despite differences (strengths) in the promoters used to drive this expression. As clinical data accumulate with these products, it will be possible to retrospectively compare the safety profiles of the products in the clinic to the results of the repeated-dose toxicology studies, in order to determine the utility of such toxicology studies for signaling potential immunotoxicities or intrinsic toxicities from DNA vaccines. These data build on the biodistribution studies performed (see companion article, Sheets et al., 2006) to demonstrate the safety and suitability for investigational human use of DNA plasmid vaccine candidates for a variety of infectious disease prevention indications.
Descriptors: DNA vaccines, viral vaccines, acquired immunodeficiency syndrome, ebola like viruses, HIV-1 genetics, hemorrhagic fever, rabbits, severe acute respiratory syndrome, tissue distribution, West Nile fever genetics, West Nile virus.

Sheets, R.L., J. Stein, T.S. Manetz, C. Duffy, M. Nason, C. Andrews, W.P. Kong, G.J. Nabel, and P.L. Gomez (2006). Biodistribution of DNA plasmid vaccines against HIV-1, Ebola, Severe Acute Respiratory Syndrome, or West Nile virus is similar, without integration, despite differing plasmid backbones or gene inserts. Toxicological Sciences 91(2): 610-619.
Abstract: The Vaccine Research Center has developed a number of vaccine candidates for different diseases/infectious agents (HIV-1, Severe Acute Respiratory Syndrome virus, West Nile virus, and Ebola virus, plus a plasmid cytokine adjuvant-IL-2/Ig) based on a DNA plasmid vaccine platform. To support the clinical development of each of these vaccine candidates, preclinical studies have been performed in mice or rabbits to determine where in the body these plasmid vaccines would biodistribute and how rapidly they would clear. In the course of these studies, it has been observed that regardless of the gene insert (expressing the vaccine immunogen or cytokine adjuvant) and regardless of the promoter used to drive expression of the gene insert in the plasmid backbone, the plasmid vaccines do not biodistribute widely and remain essentially in the site of injection, in the muscle and overlying subcutis. Even though approximately 10(14) molecules are inoculated in the studies in rabbits, by day 8 or 9 ( approximately 1 week postinoculation), already all but on the order of 10(4)-10(6) molecules per microgram of DNA extracted from tissue have been cleared at the injection site. Over the course of 2 months, the plasmid clears from the site of injection with only a small percentage of animals (generally 10-20%) retaining a small number of copies (generally around 100 copies) in the muscle at the injection site. This pattern of biodistribution (confined to the injection site) and clearance (within 2 months) is consistent regardless of differences in the promoter in the plasmid backbone or differences in the gene insert being expressed by the plasmid vaccine. In addition, integration has not been observed with plasmid vaccine candidates inoculated i.m. by Biojector 2000 or by needle and syringe. These data build on the repeated-dose toxicology studies performed (see companion article, Sheets et al., 2006) to demonstrate the safety and suitability for investigational human use of DNA plasmid vaccine candidates for a variety of infectious disease prevention indications.
Descriptors: vaccines, viral vaccines, acquired immunodeficiency syndrome, ebola-like viruses, HIV-1, hemorrhagic fever, inbred strains of mice, plasmids, promoter regions, severe acute respiratory syndrome, DNA administration, West Nile virus.

Shirato, K., H. Miyoshi, H. Kariwa, and I. Takashima (2006). The kinetics of proinflammatory cytokines in murine peritoneal macrophages infected with envelope protein-glycosylated or non-glycosylated West Nile virus. Virus Research 121(1): 11-16. ISSN: 0168-1702.
Abstract: The envelope (E) protein glycosylation status of the New York strain of West Nile (WN) virus is an important determinant of virus neuroinvasiveness. To elucidate the determinant of the difference between E protein-glycosylated and non-glycosylated WN virus infections, the cytokine expression of murine peritoneal macrophages infected with each virus was examined. Tumor necrosis factor (TNF) alpha and interleukin (IL)-1beta were up-regulated with replication of the E protein-glycosylated virus. Interferon (IFN) beta and IL-6 were up-regulated with the clearance of both viruses. These results suggest that TNFalpha and IL-1beta expression are related to the virulence of E protein-glycosylated WN virus.
Descriptors: interleukin 1 metabolism, peritoneal macrophages, tumor necrosis factor, alpha metabolism, viral envelope proteins, West Nile fever, cultured cells, glycosylation, inbred Balb C mice, up-regulation.

Shrestha, B., T. Wang, M.A. Samuel, K. Whitby, J. Craft, E. Fikrig, and M.S. Diamond (2006). Gamma interferon plays a crucial early antiviral role in protection against West Nile virus infection. Journal of Virology 80(11): 5338-5348. ISSN: 0022-538X.
Abstract: West Nile virus (WNV) causes a severe central nervous system (CNS) infection in humans, primarily in the elderly and immunocompromised. Prior studies have established an essential protective role of several innate immune response elements, including alpha/beta interferon (IFN-alpha/beta), immunoglobulin M, gammadelta T cells, and complement against WNV infection. In this study, we demonstrate that a lack of IFN-gamma production or signaling results in increased vulnerability to lethal WNV infection by a subcutaneous route in mice, with a rise in mortality from 30% (wild-type mice) to 90% (IFN-gamma(-/-) or IFN-gammaR(-/-) mice) and a decrease in the average survival time. This survival pattern in IFN-gamma(-/-) and IFN-gammaR(-/-) mice correlated with higher viremia and greater viral replication in lymphoid tissues. The increase in peripheral infection led to early CNS seeding since infectious WNV was detected several days earlier in the brains and spinal cords of IFN-gamma(-/-) or IFN-gammaR(-/-) mice. Bone marrow reconstitution experiments showed that gammadelta T cells require IFN-gamma to limit dissemination by WNV. Moreover, treatment of primary dendritic cells with IFN-gamma reduced WNV production by 130-fold. Collectively, our experiments suggest that the dominant protective role of IFN-gamma against WNV is antiviral in nature, occurs in peripheral lymphoid tissues, and prevents viral dissemination to the CNS.
Descriptors: West Nile virus, gamma interferon, infection, antiviral, CNS, mice, alpha-beta interferon, virus replication, dendritic cells.

Siger, L., R. Bowen, K. Karaca, M. Murray, S. Jagannatha, B. Echols, R. Nordgren, and J.M. Minke (2006). Evaluation of the efficacy provided by a Recombinant Canarypox-Vectored Equine West Nile Virus vaccine against an experimental West Nile Virus intrathecal challenge in horses. Veterinary Therapeutics Research in Applied Veterinary Medicine 7(3): 249-256.
Abstract: Efficacy of the Recombitek Equine West Nile Virus (WNV) vaccine was evaluated against a WNV intrathecal challenge model that results in WNV-induced clinical disease. Ten vaccinated (twice at days 0 and 35) and 10 control horses were challenged 2 weeks after administration of the second vaccine with a virulent WNV by intrathecal administration. After the challenge, eight of 10 controls developed clinical signs of encephalomyelitis whereas one vaccinate exhibited muscle fasciculation only once. Nine controls and one vaccinate developed a fever. Histopathology revealed mild to moderate nonsuppurative encephalitis in eight controls and one vaccinate. None of the vaccinates and all of the controls developed WNV viremia after challenge. All vaccinated horses developed antibodies to WNV after vaccination. These and results of previous studies demonstrate efficacy of the Recombitek WNV vaccine against WNV-induced clinical disease and natural challenge with WNV-infected mosquitoes.
Descriptors: Recombitek Equine West Nile Virus vaccine, WNV intrathecal challenge model, clinical studies, horses, development of encephalomyelitis, histopathology, antibodies to WNV, mosquito vectors.

Sitati, E.M. and M.S. Diamond (2006). CD4+ T-cell responses are required for clearance of West Nile virus from the central nervous system. Journal of Virology 80(24): 12060-12069. ISSN: 0022-538X.
Abstract: Although studies have established that innate and adaptive immune responses are important in controlling West Nile virus (WNV) infection, the function of CD4(+) T lymphocytes in modulating viral pathogenesis is less well characterized. Using a mouse model, we examined the role of CD4(+) T cells in coordinating protection against WNV infection. A genetic or acquired deficiency of CD4(+) T cells resulted in a protracted WNV infection in the central nervous system (CNS) that culminated in uniform lethality by 50 days after infection. Mice surviving past day 10 had high-level persistent WNV infection in the CNS compared to wild-type mice, even 45 days following infection. The absence of CD4(+) T-cell help did not affect the kinetics of WNV infection in the spleen and serum, suggesting a role for CD4-independent clearance mechanisms in peripheral tissues. WNV-specific immunoglobulin M (IgM) levels were similar to those of wild-type mice in CD4-deficient mice early during infection but dropped approximately 20-fold at day 15 postinfection, whereas IgG levels in CD4-deficient mice were approximately 100- to 1,000-fold lower than in wild-type mice throughout the course of infection. WNV-specific CD8(+) T-cell activation and trafficking to the CNS were unaffected by the absence of CD4(+) T cells at day 9 postinfection but were markedly compromised at day 15. Our experiments suggest that the dominant protective role of CD4(+) T cells during primary WNV infection is to provide help for antibody responses and sustain WNV-specific CD8(+) T-cell responses in the CNS that enable viral clearance.
Descriptors: West Nile virus, CNS, clearance, CD4+T cell responses, immune responses, spleen, serum, viral clearance.

Throsby, M., C. Geuijen, J. Goudsmit, A.Q. Bakker, J. Korimbocus, R.A. Kramer, M. Clijsters van der Horst, M. de Jong, M. Jongeneelen, S. Thijsse, R. Smit, T.J. Visser, N. Bijl, W.E. Marissen, M. Loeb, D.J. Kelvin, W. Preiser, J. ter Meulen, and J. de Kruif (2006). Isolation and characterization of human monoclonal antibodies from individuals infected with West Nile Virus. Journal of Virology 80(14): 6982-6992. ISSN: 0022-538X.
Abstract: Monoclonal antibodies (MAbs) neutralizing West Nile Virus (WNV) have been shown to protect against infection in animal models and have been identified as a correlate of protection in WNV vaccine studies. In the present study, antibody repertoires from three convalescent WNV-infected patients were cloned into an scFv phage library, and 138 human MAbs binding to WNV were identified. One hundred twenty-one MAbs specifically bound to the viral envelope (E) protein and four MAbs to the premembrane (prM) protein. Enzyme-linked immunosorbent assay-based competitive-binding assays with representative E protein-specific MAbs demonstrated that 24/51 (47%) bound to domain II while only 4/51 (8%) targeted domain III. In vitro neutralizing activity was demonstrated for 12 MAbs, and two of these, CR4374 and CR4353, protected mice from lethal WNV challenge at 50% protective doses of 12.9 and 357 mug/kg of body weight, respectively. Our data analyzing three infected individuals suggest that the human anti-WNV repertoire after natural infection is dominated by nonneutralizing or weakly neutralizing MAbs binding to domain II of the E protein, while domain III-binding MAbs able to potently neutralize WNV in vitro and in vivo are rare.
Descriptors: monoclonal antibodies immunology, viral immunology, viral envelope proteins, West Nile fever, West Nile virus, monoclonal genetics, viral genetics, antibody specificity, molecular cloning, mice, protein structure.

Wang, T., Y. Gao, E. Scully, C.T. Davis, J.F. Anderson, T. Welte, M. Ledizet, R. Koski, J.A. Madri, A. Barrett, Z. Yin, J. Craft, and E. Fikrig (2006). Gamma delta T cells facilitate adaptive immunity against West Nile virus infection in mice. Journal of Immunology 177(3): 1825-1832.
Abstract: West Nile (WN) virus causes fatal meningoencephalitis in laboratory mice, and gammadelta T cells are involved in the protective immune response against viral challenge. We have now examined whether gammadelta T cells contribute to the development of adaptive immune responses that help control WN virus infection. Approximately 15% of TCRdelta(-/-) mice survived primary infection with WN virus compared with 80-85% of the wild-type mice. These mice were more susceptible to secondary challenge with WN virus than the wild-type mice that survived primary challenge with the virus. Depletion of gammadelta T cells in wild-type mice that survived the primary infection, however, does not affect host susceptibility during secondary challenge with WN virus. Furthermore, gammadelta T cells do not influence the development of Ab responses during primary and at the early stages of secondary infection with WN virus. Adoptive transfer of CD8(+) T cells from wild-type mice that survived primary infection with WN virus to naive mice afforded partial protection from lethal infection. In contrast, transfer of CD8(+) T cells from TCRdelta(-/-) mice that survived primary challenge with WN virus failed to alter infection in naive mice. This difference in survival correlated with the numeric and functional reduction of CD8 memory T cells in these mice. These data demonstrate that gammadelta T cells directly link innate and adaptive immunity during WN virus infection.
Descriptors: gamma delta T cells, T lymphocyte subsets, West Nile fever, West Nile virus, adoptive transfer, CD8 positive T lymphocytes, genetic predisposition to disease genetics, cellular genetics, immunoglobulin G biosynthesis, immunoglobulin M biosynthesis, immunologic memory genetics, lymphocyte depletion, knockout inbred c57bl, mice, receptors.

Wilkins, P.A., A.L. Glaser, and S.M. McDonnell (2006). Passive transfer of naturally acquired specific immunity against West Nile Virus to foals in a semi-feral pony herd. Journal of Veterinary Internal Medicine 20(4): 1045-1047.
Abstract: Horses naturally exposed to West Nile Virus (WNV) or vaccinated against WNV develop humoral immunity thought to be protective against development of clinical disease in exposed or infected animals. No reports evaluate the efficacy of passive transfer of naturally acquired specific WNV humoral immunity from dam to foal. The purpose of this study was to investigate passive transfer of naturally acquired immunity to WNV to foals born in a herd of semi-feral ponies, not vaccinated against WNV, in an endemic area, with many dams having seroconverted because of natural exposure. Microwell serum neutralization titers against WNV were determined in all mares and foals. Serum IgG concentration was determined in foals by serial radial immunodiffusion. Differences in IgG concentration between seropositive and seronegative foals were examined by means of the Mann-Whitney U-test. Linear regression was used to evaluate the association between mare and foal titers. Seventeen mare-foal pairs were studied; 1 foal had inadequate IgG concentration. IgG concentration was not different between seronegative and seropositive foals (P = .24). Mare and foal titers were significantly correlated in foals with adequate passive transfer of immunity (Spearman's rho = .84; P < .001); >90% of the foal's titer was explained by the mare's titer (R2 = 0.91; P < .001). Passive transfer of specific immunity to WNV is present in pony foals with adequate passive transfer of immunity born to seroconverted mares.
Descriptors: horse diseases, maternally acquired immunology, West Nile fever, West Nile virus, horses.

Wolf, R.F., J.F. Papin, R. Hines Boykin, M. Chavez Suarez, G.L. White, M. Sakalian, and D.P. Dittmer (2006). Baboon model for West Nile virus infection and vaccine evaluation. Virology 355(1): 44-51. ISSN: 0042-6822.
Abstract: Animal models that closely mimic the human condition are of paramount significance to study pathogenic mechanisms, vaccine and therapy scenarios. This is particularly true for investigations that involve emerging infectious diseases. Nonhuman primate species represent an alternative to the more intensively investigated rodent animal models and in a number of instances have been shown to represent a more reliable predictor of the human response to infection. West Nile virus (WNV) has emerged as a new pathogen in the Americas. It has a 5% fatality rate, predominantly in the elderly and immune compromised. Typically, infections are cleared by neutralizing antibodies, which suggests that a vaccine would be efficacious. Previously, only macaques had been evaluated as a primate model for WNV vaccine design. The macaques did not develop WNV disease nor express the full complement of IgG subclasses that is found in humans. We therefore explored baboons, which exhibit the similar four IgG subclasses observed in humans as a new model for WNV infection and vaccine evaluation. In this present report, we describe the experimental infection of baboons with WNV and test the efficacy of an inactivated WNV vaccination strategy. All experimentally infected animals developed transient viremia and subsequent neutralizing antibodies. Anti-WNV IgM antibodies peaked at 20 days post-infection. Anti-WNV IgG antibodies appeared later and persisted past 60 days. Prior vaccination with chemically inactivated virus induced neutralizing titers and a fast, high titer IgG recall response, which resulted in lower viremia upon challenge. This report is the first to describe the development of the baboon model for WNV experimental infection and the utility of this model to characterize the immunologic response against WNV and a candidate WNV vaccine.
Descriptors: animal disease models, Papio, West Nile fever, West Nile virus vaccines, immunoglobulin G, immunoglobulin M, neutralization tests, viremia.

Yamshchikov, G., V. Borisevich, C.W. Kwok, R. Nistler, J. Kohlmeier, A. Seregin, E. Chaporgina, S. Benedict, and V. Yamshchikov (2005). The suitability of yellow fever and Japanese encephalitis vaccines for immunization against West Nile virus. Vaccine 23(39): 4785-4792. ISSN: 0264-410X.
Descriptors: West Nile virus, yellow fever, Japanese encephalitis, vaccine suitability, drug therapy.

Zohrabian, A., E.B. Hayes, and L.R. Petersen (2006). Cost-effectiveness of West Nile virus vaccination. Emerging Infectious Diseases 12(3): 375-380. ISSN: 1080-6040 .
Abstract: West Nile virus (WNV) was first detected in the Western Hemisphere in 1999 in New York City. From 1999 through 2004, >16,600 cases of WNV-related illnesses were reported in the United States, of which >7,000 were neuroinvasive disease and >600 were fatal. Several approaches are under way to develop a human vaccine. Through simulations and sensitivity analysis that incorporated uncertainties regarding future transmission patterns of WNV and costs of health outcomes, we estimated that the range of values for the cost per case of WNV illness prevented by vaccination was US 20,000 dollars-59,000 dollars(mean 36,000 dollars). Cost-effectiveness was most sensitive to changes in the risk for infection, probability of symptomatic illness, and vaccination cost. Analysis indicated that universal vaccination against WNV disease would be unlikely to result in societal monetary savings unless disease incidence increases substantially over what has been seen in the past 6 years.
Descriptors: vaccination economics, viral vaccines, West Nile fever prevention and control, cost benefit analysis, decision trees, health care costs, mortality.


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