RESUMO
BACKGROUND: West Nile virus (WNV) is the most common mosquito-borne infection in the United States. HydroVax-001 WNV is a hydrogen peroxide inactivated, whole virion (WNV-Kunjin strain) vaccine adjuvanted with aluminum hydroxide. METHODS: We performed a phase 1, randomized, placebo-controlled, double-blind (within dosing group), dose escalation clinical trial of the HydroVax-001 WNV vaccine administered via intramuscular injection. This trial evaluated 1 mcg and 4 mcg dosages of HydroVax-001 WNV vaccine given intramuscularly on day 1 and day 29 in healthy adults. The two dosing groups of HydroVax-001 were enrolled sequentially and each group consisted of 20 individuals who received HydroVax-001 and 5 who received placebo. Safety was assessed at all study days (days 1, 2, 4 and 15 post dose 1, and days 1, 2, 4, 15, 29, 57, 180 and 365 post dose 2), and reactogenicity was assessed for 14â¯days after administration of each dose. Immunogenicity was measured by WNV-specific plaque reduction neutralization tests (PRNT50) in the presence or absence of added complement or by WNV-specific enzyme-linked immunosorbent assays (ELISA). RESULTS: HydroVax-001 was safe and well-tolerated as there were no serious adverse events or concerning safety signals. At the 1 mcg dose, HydroVax-001 was not immunogenic by PRNT50 but elicited up to 41% seroconversion by WNV-specific ELISA in the per-protocol population (PP) after the second dose. At the 4 mcg dose, HydroVax-001 elicited neutralizing antibody responses in 31% of the PP following the second dose. In the presence of added complement, PRNT50 seroconversion rates increased to 50%, and 75% seroconversion was observed by WNV-specific ELISA. CONCLUSIONS: The HydroVax-001 WNV vaccine was found to be modestly immunogenic and well-tolerated at all dose levels.
Assuntos
Anticorpos Neutralizantes/imunologia , Vacinas contra o Vírus do Nilo Ocidental/uso terapêutico , Vírus do Nilo Ocidental/patogenicidade , Adolescente , Adulto , Anticorpos Antivirais/imunologia , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Testes de Neutralização , Vacinas de Produtos Inativados/uso terapêutico , Vírus do Nilo Ocidental/imunologia , Adulto JovemRESUMO
West Nile virus (WNV), a member of the Flavivirus genus, is a leading cause of viral encephalitis in the United States1. The development of neutralizing antibodies against the flavivirus envelope (E) protein is critical for immunity and vaccine protection2. Previously identified candidate therapeutic mouse and human neutralizing monoclonal antibodies (mAbs) target epitopes within the E domain III lateral ridge and the domain I-II hinge region, respectively3. To explore the neutralizing antibody repertoire elicited by WNV infection for potential therapeutic application, we isolated ten mAbs from WNV-infected individuals. mAb WNV-86 neutralized WNV with a 50% inhibitory concentration of 2 ng ml-1, one of the most potently neutralizing flavivirus-specific antibodies ever isolated. WNV-86 targets an epitope in E domain II, and preferentially recognizes mature virions lacking an uncleaved form of the chaperone protein prM, unlike most flavivirus-specific antibodies4. In vitro selection experiments revealed a neutralization escape mechanism involving a glycan addition to E domain II. Finally, a single dose of WNV-86 administered two days post-infection protected mice from lethal WNV challenge. This study identifies a highly potent human neutralizing mAb with therapeutic potential that targets an epitope preferentially displayed on mature virions.
Assuntos
Anticorpos Monoclonais/imunologia , Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/imunologia , Proteínas do Envelope Viral/imunologia , Febre do Nilo Ocidental/prevenção & controle , Vacinas contra o Vírus do Nilo Ocidental/uso terapêutico , Vírus do Nilo Ocidental/imunologia , Aedes , Animais , Anticorpos Monoclonais/uso terapêutico , Anticorpos Neutralizantes/uso terapêutico , Anticorpos Antivirais/uso terapêutico , Linhagem Celular , Chlorocebus aethiops , Células HEK293 , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Domínios Proteicos/imunologia , Células Vero , Febre do Nilo Ocidental/terapiaRESUMO
Mosquitos are responsible for a number of protozoal and viral diseases. Malaria, dengue, Japanese encephalitis (JE) and chikungunya epidemics occur commonly all over the world, leading to marked mortality and morbidity in children. Zika, Yellow fever and West Nile fever are others requiring prevention. Environmental control and mosquito bite prevention are useful in decreasing the burden of disease but vaccination has been found to be most cost-effective and is the need of the hour. RTS,S/AS01 vaccine is the first malaria vaccine being licensed for use against P. falciparum malaria. Dengvaxia (CYD-TDV) against dengue was licensed first in Mexico in 2015. A Vero-cell derived, inactivated and alum-adjuvanted JE vaccine based on the SA14-14-2 strain was approved in 2009 in North America, Australia and various European countries. It can be used from 2 mo of age. In India, immunization is carried out in endemic regions at 1 y of age. Another inactivated Vero-cell culture derived Kolar strain, 821564XY, JE vaccine is being used in India. Candidate vaccines against dengue, chikungunya and West Nile fever are been discussed. A continued research and development of new vaccines are required for controlling these mosquito-borne diseases.
Assuntos
Culicidae , Insetos Vetores , Vacinas/uso terapêutico , Animais , Culicidae/microbiologia , Culicidae/parasitologia , Culicidae/virologia , Vacinas contra Dengue/uso terapêutico , Humanos , Insetos Vetores/microbiologia , Insetos Vetores/parasitologia , Insetos Vetores/virologia , Vacinas contra Encefalite Japonesa/uso terapêutico , Vacinas Antimaláricas/uso terapêutico , Vacinas contra o Vírus do Nilo Ocidental/uso terapêutico , Vacina contra Febre Amarela/uso terapêutico , Infecção por Zika virus/prevenção & controleRESUMO
The persistence of West Nile virus (WNV) infections throughout the USA since its inception in 1999 and its continuous spread throughout the globe calls for an urgent need of effective treatments and prevention measures. Although the licensing of several WNV vaccines for veterinary use provides a proof of concept, similar efforts on the development of an effective vaccine for humans remain still unsuccessful. Increased understanding of biology and pathogenesis of WNV together with recent technological advancements have raised hope that an effective WNV vaccine may be available in the near future. In addition, rapid progress in the structural and functional characterization of WNV and other flaviviral proteins have provided a solid base for the design and development of several classes of inhibitors as potential WNV therapeutics. Moreover, the therapeutic monoclonal antibodies demonstrate an excellent efficacy against WNV in animal models and represent a promising class of WNV therapeutics. However, there are some challenges as to the design and development of a safe and efficient WNV vaccine or therapeutic. In this chapter, we discuss the current approaches, progress, and challenges toward the development of WNV vaccines, therapeutic antibodies, and antiviral drugs.
Assuntos
Antivirais/uso terapêutico , Febre do Nilo Ocidental/tratamento farmacológico , Febre do Nilo Ocidental/prevenção & controle , Animais , Anticorpos Monoclonais/farmacologia , Anticorpos Monoclonais/uso terapêutico , Anticorpos Antivirais/farmacologia , Anticorpos Antivirais/uso terapêutico , Antivirais/farmacologia , Ensaios Clínicos como Assunto , Descoberta de Drogas , Humanos , Proteínas do Envelope Viral/efeitos dos fármacos , Proteínas do Envelope Viral/imunologia , Febre do Nilo Ocidental/imunologia , Vacinas contra o Vírus do Nilo Ocidental/farmacologia , Vacinas contra o Vírus do Nilo Ocidental/uso terapêutico , Vírus do Nilo Ocidental/efeitos dos fármacos , Vírus do Nilo Ocidental/imunologiaRESUMO
UNLABELLED: Several ChimeriVax-Dengue (CYD)-based vaccination strategies were investigated as potential alternatives to vaccination with tetravalent CYD vaccine (CYD-TDV) in this phase IIa trial conducted in 2008-9 in 150 healthy adults. Participants were randomized and vaccinated on D0 and D105 (± 15 days). One group received bivalent CYD vaccine against serotypes 1 and 3 (CYD-1;3) on day 0 and CYD-2;4 on day 105 (± 15 days). Two groups received an injection at each timepoint of a tetravalent blend of CYD-1;3;4 and a VERO cell derived, live attenuated vaccine against serotype 2 (VDV-2), or the reference CYD-TDV. A fourth group received Japanese encephalitis (JE) vaccine on days -14, -7 and 0, followed by CYD-TDV on day 105. Viraemia was infrequent in all groups. CYD-4 viraemia was most frequent after tetravalent vaccination, while CYD-3 viraemia was most frequent after the first bivalent vaccination. Immunogenicity as assessed by 50% plaque reduction neutralisation test on D28 was comparable after the first injection of either tetravalent vaccine, and increased after the second injection, particularly with the blended CYD-1;3;4/ VDV-2 vaccine. In the bivalent vaccine group, immune response against serotype 3 was highest and the second injection elicited a low immune response against CYD 2 and 4. Immune responses after the first injection of CYD-TDV in the JE-primed group were in general higher than after the first injection in the other groups. All tested regimens were well tolerated without marked differences between groups. Bivalent vaccination showed no advantage in terms of immunogenicity. CLINICAL TRIAL REGISTRATION NUMBER: NCT00740155.
Assuntos
Anticorpos Antivirais/sangue , Vacinas contra Dengue/imunologia , Vírus da Dengue/imunologia , Dengue/imunologia , Viremia/sangue , Adolescente , Adulto , Anticorpos Neutralizantes/sangue , Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/imunologia , Dengue/prevenção & controle , Vacinas contra Dengue/efeitos adversos , Vacinas contra Dengue/uso terapêutico , Feminino , Humanos , Imunidade Celular/imunologia , Imunidade Humoral/imunologia , Vacinas contra Encefalite Japonesa/efeitos adversos , Vacinas contra Encefalite Japonesa/imunologia , Vacinas contra Encefalite Japonesa/uso terapêutico , Masculino , México , Testes de Neutralização , Vacinação , Vacinas Atenuadas/efeitos adversos , Vacinas Atenuadas/imunologia , Vacinas Atenuadas/uso terapêutico , Viremia/imunologia , Vacinas contra o Vírus do Nilo Ocidental/efeitos adversos , Vacinas contra o Vírus do Nilo Ocidental/imunologia , Vacinas contra o Vírus do Nilo Ocidental/uso terapêutico , Adulto JovemRESUMO
The mosquito-borne West Nile virus (WNV) causes human and animal disease with outbreaks in several parts of the world including North America, the Mediterranean countries, Central and East Europe, the Middle East, and Africa. Particularly in elderly people and individuals with an impaired immune system, infection with WNV can progress into a serious neuroinvasive disease. Currently, no treatment or vaccine is available to protect humans against infection or disease. The goal of this study was to develop a WNV-vaccine that is safe to use in these high-risk human target populations. We performed a vaccine efficacy study in non-human primates using the contemporary, pathogenic European WNV genotype 1a challenge strain, WNV-Ita09. Two vaccine strategies were evaluated in rhesus macaques (Macaca mulatta) using recombinant soluble WNV envelope (E) ectodomain adjuvanted with Matrix-M, either with or without DNA priming. The DNA priming immunization was performed with WNV-DermaVir nanoparticles. Both vaccination strategies successfully induced humoral and cellular immune responses that completely protected the macaques against the development of viremia. In addition, the vaccine was well tolerated by all animals. Overall, The WNV E protein adjuvanted with Matrix-M is a promising vaccine candidate for a non-infectious WNV vaccine for use in humans, including at-risk populations.
Assuntos
Febre do Nilo Ocidental/prevenção & controle , Vacinas contra o Vírus do Nilo Ocidental/uso terapêutico , Vírus do Nilo Ocidental/classificação , Animais , Anticorpos Antivirais/sangue , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Culicidae , Europa (Continente) , Imunidade Celular , Imunidade Humoral , Injeções Intradérmicas , Interferon gama/imunologia , Macaca mulatta , Estrutura Terciária de Proteína , Proteínas do Envelope Viral/imunologia , Carga Viral , Viremia/imunologiaRESUMO
Over the last years West Nile virus (WNV) lineage 2 has spread from the African to the European continent. This study was conducted to demonstrate efficacy of an inactivated, lineage 1-based, WNV vaccine (Equip WNV) against intrathecal challenge of horses with a recent isolate of lineage 2 WNV. Twenty horses, sero-negative for WNV, were enrolled and were randomly allocated to one of two treatment groups: an unvaccinated control group (T01, n=10) and a group administered with Equip WNV (T02, n=10). Horses were vaccinated at Day 0 and 21 and were challenged at day 42 with WNV lineage 2, Nea Santa/Greece/2010. Personnel performing clinical observations were blinded to treatment allocation. Sixty percent of the controls had to be euthanized after challenge compared to none of the vaccinates. A significantly lower percentage of the vaccinated animals showed clinical disease (two different clinical observations present on the same day) on six different days of study and the percentage of days with clinical disease was significantly lower in the vaccinated group. A total of 80% of the non-vaccinated horses showed viremia while only one vaccinated animal was positive by virus isolation on a single occasion. Vaccinated animals started to develop antibodies against WNV lineage 2 from day 14 (2 weeks after the first vaccination) and at day 42 (the time of onset of immunity) they had all developed a strong antibody response. Histopathology scores for all unvaccinated animals ranged from mild to very severe in each of the tissues examined (cervical spinal cord, medulla and pons), whereas in vaccinated horses 8 of 10 animals had no lesions and 2 had minimal lesions in one tissue. In conclusion, Equip WNV significantly reduced the number of viremic horses, the duration and severity of clinical signs of disease and mortality following challenge with lineage 2 WNV.
Assuntos
Doenças dos Cavalos/prevenção & controle , Cavalos/imunologia , Febre do Nilo Ocidental/veterinária , Vacinas contra o Vírus do Nilo Ocidental/uso terapêutico , Animais , Anticorpos Antivirais/sangue , Testes de Neutralização , Distribuição Aleatória , Viremia/veterinária , Febre do Nilo Ocidental/prevenção & controle , Vacinas contra o Vírus do Nilo Ocidental/imunologia , Vírus do Nilo OcidentalRESUMO
PURPOSE OF REVIEW: West Nile virus (WNV) is the most important cause of epidemic encephalitis in the United States. We review articles published in the last 18âmonths related to the epidemiology, immunology, clinical features, and treatment of this disease. RECENT FINDINGS: There was a resurgence in WNV disease in the United States in 2012. The WNV strain now predominant in the United States (NA/WN02) differs from the initial emergent isolate in 1999 (NY99). However, differences in the genetics of currently circulating United States WNV strains do not explain variations in epidemic magnitude or disease severity. Innate and acquired immunity are critical in control of WNV, and in some cases pathways are central nervous system specific. The clinical features of infection are now well understood, although nonconfirmed observations of chronic viral excretion in urine remain controversial. There is no specific antiviral therapy for WNV, but studies of antivirals specific for other flaviviruses may identify agents with promise against WNV. Phase I and II human WNV vaccine clinical trials have established that well tolerated and immunogenic WNV vaccines can be developed. SUMMARY: WNV remains an important public health problem. Although recent studies have significantly increased our understanding of host immune and genetic factors involved in control of WNV infection, no specific therapy is yet available. Development of a well tolerated, immunogenic, and effective vaccine against WNV is almost certainly feasible, but economic factors and the lack of predictability of the magnitude and location of outbreaks are problematic for designing phase III trials and ultimate licensure.
Assuntos
Epidemias , Febre do Nilo Ocidental/epidemiologia , Vírus do Nilo Ocidental/imunologia , Antivirais/uso terapêutico , Humanos , Estados Unidos/epidemiologia , Febre do Nilo Ocidental/imunologia , Febre do Nilo Ocidental/terapia , Vacinas contra o Vírus do Nilo Ocidental/uso terapêutico , Vírus do Nilo Ocidental/genéticaRESUMO
Recognition of conserved pathogen-associated molecular patterns (PAMPs) by host pattern recognition receptors (PRRs) results in the activation of innate signaling pathways that drive the innate immune response and ultimately shape the adaptive immune response. RepliVAX WN, a single-cycle flavivirus (SCFV) vaccine candidate derived from West Nile virus (WNV), is intrinsically adjuvanted with multiple PAMPs and induces a vigorous anti-WNV humoral response. However, the innate mechanisms that link pattern recognition and development of vigorous antigen-specific B cell responses are not completely understood. Moreover, the roles of individual PRR signaling pathways in shaping the B cell response to this live attenuated SCFV vaccine have not been established. We examined and compared the role of TLR3- and MyD88-dependent signaling in the development of anti-WNV-specific antibody-secreting cell responses and memory B cell responses induced by RepliVAX WN. We found that MyD88 deficiency significantly diminished B cell responses by impairing B cell activation, development of germinal centers (GC), and the generation of long-lived plasma cells (LLPCs) and memory B cells (MBCs). In contrast, TLR3 deficiency had more effect on maintenance of GCs and development of LLPCs, whereas differentiation of MBCs was unaffected. Our data suggest that both TLR3- and MyD88-dependent signaling are involved in the intrinsic adjuvanting of RepliVAX WN and differentially contribute to the development of vigorous WNV-specific antibody and B cell memory responses following immunization with this novel SCFV vaccine.
Assuntos
Imunidade Adaptativa/imunologia , Linfócitos B/imunologia , Fator 88 de Diferenciação Mieloide/fisiologia , Receptor 3 Toll-Like/fisiologia , Febre do Nilo Ocidental/imunologia , Vacinas contra o Vírus do Nilo Ocidental/imunologia , Vírus do Nilo Ocidental/imunologia , Animais , Anticorpos Antivirais/sangue , Células Produtoras de Anticorpos/imunologia , Linfócitos T CD8-Positivos/imunologia , Feminino , Citometria de Fluxo , Imunização , Ativação Linfocitária/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Transdução de Sinais , Febre do Nilo Ocidental/prevenção & controle , Vacinas contra o Vírus do Nilo Ocidental/uso terapêuticoRESUMO
West Nile virus (WNV) is now endemic in the USA. After the widespread surge of virus activity across the USA, research has flourished, and our knowledge base has significantly expanded over the past 10 years since WNV was first recognized in New York City. This article provides a review of the virology of WNV, history, epidemiology, clinical features, pathology of infection, the innate and adaptive immune response, host risk factors for developing severe disease, clinical sequelae following severe disease, chronic infection, and the future of prevention.
Assuntos
Febre do Nilo Ocidental/virologia , Vírus do Nilo Ocidental , Animais , Culicidae/virologia , Humanos , Imunidade Humoral/imunologia , Fatores de Risco , Estados Unidos/epidemiologia , Febre do Nilo Ocidental/diagnóstico , Febre do Nilo Ocidental/epidemiologia , Febre do Nilo Ocidental/imunologia , Febre do Nilo Ocidental/patologia , Febre do Nilo Ocidental/prevenção & controle , Vacinas contra o Vírus do Nilo Ocidental/uso terapêutico , Vírus do Nilo Ocidental/fisiologiaRESUMO
The emergence of West Nile virus (WNV) in North America in 1999 as a cause of severe neurological disease in humans, horses and birds stimulated development of vaccines for human and veterinary use, as well as polyclonal/monoclonal antibodies and other immunomodulating compounds for use as therapeutics. Although disease incidence in North America has declined since the peak epidemics in 2002-2003, the virus has continued to be annually transmitted in the Americas and to cause periodic epidemics in Europe and the Middle East. Continued transmission of the virus with human and animal disease suggests that vaccines and therapeutics for the prevention and treatment of WNV disease could be of great benefit. This article focuses on progress in development and evaluation of vaccines and immunotherapeutics for the prevention and treatment of WNV disease in humans and animals.
Assuntos
Epidemias/prevenção & controle , Imunoterapia/métodos , Febre do Nilo Ocidental/epidemiologia , Febre do Nilo Ocidental/prevenção & controle , Vacinas contra o Vírus do Nilo Ocidental/uso terapêutico , Doenças dos Animais/prevenção & controle , Animais , Humanos , Febre do Nilo Ocidental/veterinária , Vacinas contra o Vírus do Nilo Ocidental/imunologia , Vírus do Nilo Ocidental/imunologiaRESUMO
In this study, West Nile virus (WNV) envelope (rE) protein and its domain III (rDIII) were efficiently expressed in a cost-effective system based on insect larvae as non-fermentative living biofactories. Mice immunized with the partially purified rE or rDIII elicited high antibodies titers that neutralized viral infectivity in cell culture and in suckling mice. All vaccinated animals were fully protected when challenged with neurovirulent WNV NY99. Passive transfer of protective antibodies from immunized mothers to their offspring occurred both by transplacental and lactation routes. These results indicate that the insect-derived antigens tested may constitute potential vaccine candidates to be further evaluated.
Assuntos
Regulação Viral da Expressão Gênica , Proteínas do Envelope Viral/biossíntese , Proteínas do Envelope Viral/imunologia , Febre do Nilo Ocidental/prevenção & controle , Vacinas contra o Vírus do Nilo Ocidental/imunologia , Vírus do Nilo Ocidental/imunologia , Animais , Chlorocebus aethiops , Feminino , Insetos/genética , Insetos/imunologia , Larva/genética , Larva/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos DBA , Gravidez , Estrutura Terciária de Proteína/genética , Vacinas Sintéticas/administração & dosagem , Vacinas Sintéticas/biossíntese , Vacinas Sintéticas/imunologia , Células Vero , Proteínas do Envelope Viral/genética , Febre do Nilo Ocidental/imunologia , Vacinas contra o Vírus do Nilo Ocidental/uso terapêutico , Vírus do Nilo Ocidental/patogenicidadeRESUMO
Innate immune system activation is a critical step in the initiation of an effective adaptive immune response; therefore, activation of a class of innate pathogen receptors called pattern recognition receptors (PRR) is a central feature of many adjuvant systems. It has recently been shown that one member of an intracellular PRR, the NLRP3 inflammasome, is activated by a number of classical adjuvants including aluminum hydroxide and saponins [Eisenbarth SC, Colegio OR, O'Connor W, Sutterwala FS, Flavell RA. Crucial role for the Nalp3 inflammasome in the immunostimulatory properties of aluminium adjuvants. Nature 2008;453(June (7198)):1122-6; Li H, Willingham SB, Ting JP, Re F. Cutting edge: inflammasome activation by alum and alum's adjuvant effect are mediated by NLRP3. J Immunol 2008;181(July (1)):17-21]. Inflammasome activation in vitro requires signaling of both the Toll-like receptor (TLR) and NLRP3 in antigen-presenting cells. Here we present a class of nanomaterials endowed with these two signals for rapid optimization of vaccine design. We constructed this system using a simple approach that incorporates lipopolysaccharides (LPS) onto the surface of nanoparticles constructed from a biocompatible polyester, poly(lactic-co-glycolic acid) (PLGA), loaded with antigen. We demonstrate that LPS-modified particles are preferentially internalized by dendritic cells compared to uncoated nanoparticles and the system, when administered to mice, elicits potent humoral and cellular immunity against a model antigen, ovalbumin. Wild-type macrophages pulsed with LPS-modified nanoparticles resulted in production of the proinflammatory cytokine IL-1beta consistent with inflammasome activation. In comparison, NLRP3-deficient and caspase-1-deficient macrophages showed negligible production of IL-1beta. Furthermore, when endocytosis and lysosomal destabilization were inhibited, inflammasome activity was diminished, supporting the notion that nanoparticles rupture lysosomal compartments and behave as 'danger signals' [Hornung V, Bauernfeind F, Halle A, Samstad EO, Kono H, Rock KL, et al. Silica crystals and aluminum salts activate the NALP3 inflammasome through phagosomal destabilization. Nat Immunol 2008;9(August (8)):847-56]. The generality of this vaccination approach is tested by encapsulation of a recombinant West Nile envelope protein and demonstrated by protection against a murine model of West Nile encephalitis. The design of such an antigen delivery mechanism with the ability to stimulate two potent innate immune pathways represents a potent new approach to simultaneous antigen and adjuvant delivery.
Assuntos
Proteínas de Transporte/metabolismo , Nanopartículas/uso terapêutico , Vacinação/métodos , Febre do Nilo Ocidental/prevenção & controle , Adjuvantes Imunológicos/metabolismo , Adjuvantes Imunológicos/uso terapêutico , Animais , Formação de Anticorpos , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Proteínas de Transporte/imunologia , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Ácido Láctico/imunologia , Lipopolissacarídeos/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Proteína 3 que Contém Domínio de Pirina da Família NLR , Ácido Poliglicólico , Copolímero de Ácido Poliláctico e Ácido Poliglicólico , Proteínas do Envelope Viral/imunologia , Febre do Nilo Ocidental/imunologia , Febre do Nilo Ocidental/metabolismo , Vacinas contra o Vírus do Nilo Ocidental/imunologia , Vacinas contra o Vírus do Nilo Ocidental/uso terapêuticoRESUMO
Studies were performed with an inactivated vaccine against the mosquito-borne flavivirus, West Nile virus (WNV). The mammalian cell line, PER.C6, was selected as the platform for WNV growth since both the neurovirulent strains NY99 and ISR98 that cause epidemics in humans and high mortality in geese, respectively, could be propagated to high titers (10(9) to 10(10)TCID(50)/ml) on these cells. Based on the high DNA homology of the WNV envelope (E) protein and non-structural protein 5 (NS5), and identical neurovirulence in mice and geese, we concluded that NY99 and ISR98 viruses are closely related and therefore vaccine studies were performed with ISR98 as a model for NY99. A robust challenge model in domestic geese was set up resulting in 100% mortality within 7 days of intracranial challenge with 500 TCID(50) WNV. Geese were used to assess the efficacy and safety of an inactivated WNV vaccine produced on PER.C6 cells. Efficacy studies demonstrated 91.4% (53/58) protection of geese compared to no protection (0/13) in geese receiving a sham vaccine. A follow-up study in 1800 geese showed that the vaccine was safe with a survival rate of 96.6% (95% lower CL 95.7%). Initial studies on the correlates of protection induced by the vaccine indicate an important role for antibodies since geese were protected when injected intra-cranial with a mixture of serum from vaccinated, non-challenged geese and WNV. In all, these results provide a scientific basis for the development of an inactivated WNV vaccine based on NY99 produced on PER.C6 cells for human and equine use.
Assuntos
Gansos/virologia , Doenças das Aves Domésticas/prevenção & controle , Vacinas de Produtos Inativados/efeitos adversos , Vacinas de Produtos Inativados/uso terapêutico , Febre do Nilo Ocidental/veterinária , Vacinas contra o Vírus do Nilo Ocidental/efeitos adversos , Vacinas contra o Vírus do Nilo Ocidental/uso terapêutico , Animais , Animais Lactentes , Linhagem Celular , Humanos , Dose Letal Mediana , Camundongos , Doenças das Aves Domésticas/virologia , Retina/citologia , Resultado do Tratamento , Vacinas de Produtos Inativados/administração & dosagem , Vacinas de Produtos Inativados/imunologia , Replicação Viral , Febre do Nilo Ocidental/mortalidade , Febre do Nilo Ocidental/prevenção & controle , Febre do Nilo Ocidental/virologia , Vacinas contra o Vírus do Nilo Ocidental/administração & dosagem , Vacinas contra o Vírus do Nilo Ocidental/imunologia , Vírus do Nilo Ocidental/imunologia , Vírus do Nilo Ocidental/fisiologiaRESUMO
The spread of dengue virus (DV) via its Aedes mosquito vector throughout most of the tropics has led to a worldwide resurgence of epidemic dengue, including dengue hemorrhagic fever. For the first time in 60 years, the pipeline of dengue vaccines looks promising. Strains of each of the 4 DV serotypes, attenuated by passage in tissue culture or by recombinant DNA technology, have been formulated into tetravalent vaccines and have entered successful phase 1 and 2 clinical trials in the United States and Southeast Asia. Antibody-dependent enhancement of wild-type DV infections by the vaccine represents a unique safety issue, which is under investigation. The Pediatric Dengue Vaccine Initiative (funded by the Bill and Melinda Gates Foundation), the World Health Organization, industry, the US military, and governments of tropical countries are collaborating to accelerate dengue vaccine development and phase 3 vaccine efficacy trials in countries where dengue is endemic. A protective tetravalent vaccine must be licensed soon if dengue is to be brought under control.
Assuntos
Vacinas contra Dengue/uso terapêutico , Vírus da Dengue/imunologia , Dengue Grave/imunologia , Adolescente , Criança , Pré-Escolar , Ensaios Clínicos como Assunto , Vírus da Dengue/patogenicidade , Humanos , Lactente , Recém-Nascido , Dengue Grave/epidemiologia , Dengue Grave/prevenção & controle , Vacinas Atenuadas/uso terapêutico , Vacinas Sintéticas , Vacinas contra o Vírus do Nilo Ocidental/uso terapêuticoRESUMO
The study of the interaction between the West Nile virus envelope protein and monoclonal antibodies has provided insight into the molecular mechanisms of neutralization. Structural studies have identified an epitope on the lateral ridge of domain III of the West Nile virus E protein that is recognized by antibodies with the strongest neutralizing activity in vitro and in vivo. Antibodies that bind to this epitope are particularly inhibitory because they block infection at a post-attachment step and at concentrations that result in a low occupancy of the available sites on the virion.
Assuntos
Anticorpos Monoclonais/imunologia , Anticorpos Antivirais/imunologia , Antígenos Virais/imunologia , Proteínas do Envelope Viral/imunologia , Vacinas contra o Vírus do Nilo Ocidental/imunologia , Vírus do Nilo Ocidental/imunologia , Animais , Anticorpos Monoclonais/uso terapêutico , Afinidade de Anticorpos , Especificidade de Anticorpos , Reações Antígeno-Anticorpo , Antígenos Virais/química , Mapeamento de Epitopos , Humanos , Modelos Moleculares , Testes de Neutralização , Conformação Proteica , Proteínas do Envelope Viral/química , Febre do Nilo Ocidental/tratamento farmacológico , Febre do Nilo Ocidental/imunologia , Vacinas contra o Vírus do Nilo Ocidental/uso terapêuticoRESUMO
Seasonal epidemics of West Nile virus (WNV) infection now occur throughout North America, causing clinical symptoms ranging from fever to encephalitis. There are no specific treatment options or licensed vaccines. Several classically developed vaccine candidates are being evaluated in clinical trials. However, questions of safety and/or immunogenicity may limit their usefulness. Mapping of human and murine antibody repertoires against the WNV envelope protein after WNV infection have revealed important insights into the protective immune response against the virus. This review will give an overview of vaccines under development and summarize current data on E-protein antigenicity that could aid in the design of next generation WNV vaccines.
Assuntos
Anticorpos Monoclonais/uso terapêutico , Mapeamento de Epitopos , Proteínas do Envelope Viral/imunologia , Febre do Nilo Ocidental/prevenção & controle , Vacinas contra o Vírus do Nilo Ocidental/uso terapêutico , Vírus do Nilo Ocidental/imunologia , Animais , Desenho de Fármacos , Humanos , Epitopos Imunodominantes , Camundongos , Vacinação/tendências , Febre do Nilo Ocidental/imunologia , Febre do Nilo Ocidental/terapia , Vacinas contra o Vírus do Nilo Ocidental/imunologiaAssuntos
Infecções por Flavivirus/prevenção & controle , Flavivirus/imunologia , Medicina Tropical , Vacinas Virais/uso terapêutico , Animais , Vacinas contra Dengue/uso terapêutico , Infecções por Flavivirus/imunologia , Humanos , Vacinas contra Encefalite Japonesa/uso terapêutico , Vacinas contra o Vírus do Nilo Ocidental/uso terapêuticoAssuntos
Infecções por Flavivirus/prevenção & controle , Flavivirus/genética , Flavivirus/imunologia , Vacinas Virais/genética , Vacinas Virais/imunologia , Infecções por Flavivirus/imunologia , Infecções por Flavivirus/virologia , Humanos , Vacinas de DNA/genética , Vacinas de DNA/imunologia , Vacinas de DNA/uso terapêutico , Vacinas de DNA/virologia , Vacinas Virais/uso terapêutico , Vacinas contra o Vírus do Nilo Ocidental/genética , Vacinas contra o Vírus do Nilo Ocidental/imunologia , Vacinas contra o Vírus do Nilo Ocidental/uso terapêuticoRESUMO
BACKGROUND: West Nile virus (WNV) is a mosquito-borne flavivirus that can cause severe meningitis and encephalitis in infected individuals. We report the safety and immunogenicity of a WNV DNA vaccine in its first phase 1 human study. METHODS: A single-plasmid DNA vaccine encoding the premembrane and the envelope glycoproteins of the NY99 strain of WNV was evaluated in an open-label study in 15 healthy adults. Twelve subjects completed the 3-dose vaccination schedule, and all subjects completed 32 weeks of evaluation for safety and immunogenicity. The development of a vaccine-induced immune response was assessed by enzyme-linked immunosorbant assay, neutralization assays, intracelluar cytokine staining, and enzyme-linked immunospot assay. RESULTS: The vaccine was safe and well tolerated, with no significant adverse events. Vaccine-induced T cell and antibody responses were detected in the majority of subjects. Neutralizing antibody to WNV was detected in all subjects who completed the 3-dose vaccination schedule, at levels shown to be protective in studies of horses, an incidental natural host for WNV. CONCLUSIONS: Further assessment of this DNA platform for human immunization against WNV is warranted. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00106769 .