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1.
Infect Immun ; 77(12): 5623-30, 2009 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-19786561

RESUMEN

Leprosy elimination has been a goal of the WHO for the past 15 years. Widespread BCG vaccination and multidrug therapy have dramatically reduced worldwide leprosy prevalence, but new case detection rates have remained relatively constant. These data suggest that additional control strategies, such as a subunit vaccine, are required to block transmission and to improve leprosy control. We recently identified several Mycobacterium leprae antigens that stimulate gamma interferon (IFN-gamma) secretion upon incubation with blood from paucibacillary leprosy patients, a group who limit M. leprae growth and dissemination. In this study, we demonstrate that M. leprae-specific mouse T-cell lines recognize several of these antigens, with the ML0276 protein stimulating the most IFN-gamma secretion. We then examined if the ML0276 protein could be used in a subunit vaccine to provide protection against experimental M. leprae infection. Our data demonstrate that combining ML0276 with either a Toll-like receptor 4 (TLR4) (EM005), TLR7 (imiquimod), or TLR9 (CpG DNA) agonist during immunization induces Th1 responses that limit local inflammation upon experimental M. leprae infection. Our data indicate that only the ML0276/EM005 regimen is able to elicit a response that is transferable to recipient mice. Despite the potent Th1 response induced by this regimen, it could not provide protection in terms of limiting bacterial growth. We conclude that EM005 is the most potent adjuvant for stimulating a Th1 response and indicate that while a subunit vaccine containing the ML0276 protein may be useful for the prevention of immune pathology during leprosy, it will not control bacterial burden and is therefore unlikely to interrupt disease transmission.


Asunto(s)
Antígenos Bacterianos/inmunología , Vacunas Bacterianas/inmunología , Inflamación/prevención & control , Lepra/inmunología , Lepra/prevención & control , Mycobacterium leprae/inmunología , Adyuvantes Inmunológicos/administración & dosificación , Animales , Recuento de Colonia Microbiana , Femenino , Inflamación/inmunología , Interferón gamma/metabolismo , Lepra/patología , Ratones , Ratones Endogámicos C57BL , Linfocitos T/inmunología , Receptores Toll-Like/agonistas , Vacunas de Subunidad/inmunología
2.
Hum Vaccin Immunother ; 15(5): 1139-1144, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-30724658

RESUMEN

Domestic measles, mumps, and rubella combined (MMR) vaccines were discontinued in 1993 in Japan because of the unexpected high incidence of aseptic meningitis. The introduction of an effective MMR vaccine with lower reactogenicity has been expected. A new MMR vaccine (JVC-001) was developed, using mumps RIT4385 strain in combination with Japanese measles AIK-C strain and rubella Takahashi strain (MR) vaccine. An open-label, randomized, phase I/II clinical study was conducted in 100 healthy Japanese children equally randomized to a JVC-001 group and an MR with monovalent mumps vaccine (Hoshino strain) group. Immunogenicity was assessed using a neutralization test (NT) for measles, hemagglutination inhibition (HI) test for rubella, and NT and enzyme-linked immune-sorbent assay (ELISA) for mumps strain with different genotypes (genotype A, B, D and G) on Day 0 and Day 42-56. Solicited and unsolicited adverse events (AEs) were recorded. Seroconversion rates of measles and rubella were both 100%. JVC-001 induced higher immunogenicity against mumps virus genotype G with seroconversion rate of 77.1% (95% confidence interval [CI]: 62.7-88.0%) compared to 65.3% (95% CI: 50.4-78.3%) in the control group. Geometric mean titer (GMT) was 12.5 (95% CI: 8.6-18.3) in the JVC-001 group and 7.1 (95% CI: 5.0-10.1) in the control group. JVC-001 also induced good immunogenicity against other genotypes (A, B and D). There was no apparent difference in the incidence of AEs between JVC-001 and the control groups. JVC-001 is safe and induces effective immunogenicity against measles, mumps, and rubella compared with the currently marketed vaccines in Japan.


Asunto(s)
Anticuerpos Antivirales/sangre , Inmunogenicidad Vacunal , Vacuna contra el Sarampión-Parotiditis-Rubéola/inmunología , Sarampión/prevención & control , Paperas/prevención & control , Rubéola (Sarampión Alemán)/prevención & control , Anticuerpos Neutralizantes/sangre , Femenino , Humanos , Lactante , Japón , Masculino , Vacuna contra el Sarampión-Parotiditis-Rubéola/administración & dosificación , Seroconversión , Vacunación
3.
Clin Vaccine Immunol ; 18(2): 254-9, 2011 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-21177914

RESUMEN

Leprosy is a debilitating chronic disease caused by infection with Mycobacterium leprae. A World Health Organization-directed control strategy based upon the identification and treatment of patients has resulted in a marked reduction in the number of registered worldwide leprosy cases over the last 20 years. Despite these efforts, the number of new leprosy cases detected each year now remains relatively stable, and M. leprae infection continues to pose a health problem. It is suggested that earlier diagnosis is required to strengthen control programs. In this study, we have examined the development of antigen-specific immunoglobulin responses within armadillos experimentally infected with M. leprae to identify those responses that develop most rapidly and robustly following infection. Antibody responses to the M. leprae-specific phenolic glycolipid I and several protein antigens previously demonstrated to have diagnostic potential were assessed. Our results identify several antigens that can provide early diagnosis of M. leprae infection but also indicate considerable variability in the development of antigen-specific antibodies. Our data suggest that a combination of antigens is likely required to provide accurate and early leprosy diagnosis.


Asunto(s)
Anticuerpos Antibacterianos/sangre , Técnicas Bacteriológicas/métodos , Lepra/diagnóstico , Mycobacterium leprae/inmunología , Animales , Antígenos Bacterianos , Armadillos , Modelos Animales de Enfermedad , Diagnóstico Precoz , Humanos , Inmunoensayo/métodos
4.
Clin Vaccine Immunol ; 15(11): 1659-65, 2008 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-18784342

RESUMEN

The identification of human T-cell antigens of Mycobacterium leprae could improve treatment and help to disrupt the transmission of leprosy by directing diagnosis and vaccine programs. This study screened a panel of M. leprae recombinant proteins for T-cell recall responses, measured by gamma interferon (IFN-gamma) production, among leprosy patients. After initial studies using peripheral blood mononuclear cells from leprosy patients, we transitioned our studies to simple whole-blood assays (WBA), which are more applicable in field or clinical settings. T-cell responses generated in WBA using blood from individuals in Goiânia, Brazil, demonstrated that several M. leprae antigens (ML0276, ML0840, ML1623, ML2044, and 46f) elicited >0.5 IU/ml IFN-gamma, and these proteins were classified as immunogenic and leprosy specific. Several of these individual antigens were recognized by cells from >60% of Brazilian paucibacillary (PB) leprosy patients, and ML0276, ML0840, ML1623, and 46f complemented each other such that 82% of PB patients had strong (>1.25 IU/ml IFN-gamma) responses to at least one of these proteins. These proteins were also recognized by cells from a significant proportion of the household contacts of multibacillary leprosy patients, but in contrast, few responses were observed in active tuberculosis patients or healthy control groups from areas of endemicity. Our results indicate several potential candidate antigens which may be useful for either leprosy diagnosis or vaccination and demonstrate the utility of leprosy WBA that can be applied broadly in clinical or field settings.


Asunto(s)
Antígenos Bacterianos/inmunología , Lepra/inmunología , Mycobacterium leprae/inmunología , Linfocitos T/inmunología , Adolescente , Adulto , Anciano , Proteínas Bacterianas/inmunología , Brasil , Células Cultivadas , Femenino , Humanos , Interferón gamma/biosíntesis , Masculino , Persona de Mediana Edad , Proteínas Recombinantes/inmunología
5.
Clin Vaccine Immunol ; 15(10): 1590-7, 2008 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-18716007

RESUMEN

Leprosy can be a devastating chronic infection that causes nerve function impairment and associated disfigurement. Despite the recent reduction in the number of registered worldwide leprosy cases as a result of the widespread use of multidrug therapy, the number of new cases detected each year remains relatively stable. The diagnosis of leprosy is currently based on the appearance of clinical signs and requires expert clinical, as well as labor-intensive and time-consuming laboratory or histological, evaluation. For the purpose of developing an effective, simple, rapid, and low-cost diagnostic alternative, we have analyzed the serologic antibody response to identify Mycobacterium leprae proteins that are recognized by leprosy patients. More than 100 recombinant antigens were analyzed in a protein array format to select those with discriminatory properties for leprosy diagnosis. As expected, multibacillary leprosy patients recognized more antigens with stronger antibody responses than paucibacillary leprosy patients. Our data indicate, however, that multibacillary patients can be distinguished from paucibacillary patients, and both of these groups can be segregated from endemic control groups. We went on to confirm the diagnostic properties of antigens ML0405 and ML2331 and the LID-1 fusion construct of these two proteins by enzyme-linked immunosorbent assay. We then demonstrated the performance of these antigens in rapid test formats with a goal of developing a point-of-care diagnostic test. A serological diagnostic test capable of identifying and allowing treatment of leprosy could reduce transmission, prevent functional disabilities and stigmatizing deformities, and facilitate leprosy eradication.


Asunto(s)
Antígenos Bacterianos , Lepra/diagnóstico , Mycobacterium leprae/aislamiento & purificación , Sistemas de Atención de Punto , Adolescente , Adulto , Anciano , Anticuerpos Antibacterianos/sangre , Femenino , Humanos , Masculino , Persona de Mediana Edad , Proteínas Recombinantes
6.
Infect Immun ; 75(11): 5290-7, 2007 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-17724073

RESUMEN

Leprosy is caused by infection with Mycobacterium leprae. The immune response of leprosy patients can be highly diverse, ranging from strong cellular responses accompanied by an apparent deficit of M. leprae-specific antibodies to strong humoral responses with a deficit of cell-mediated responses. Leprosy takes many years to manifest, and this has precluded analyses of disease and immune response development in infected humans. In an attempt to better define development of the immune response during leprosy we have developed an M. leprae ear infection model. Intradermal inoculation of M. leprae into the ear supported not only infection but also the development of a chronic inflammatory response. The inflammatory response was localized, comprising a T-cell infiltration into the ear and congestion of cells in the draining lymph nodes. The development of local chronic inflammation was prevented by rifampin treatment. Importantly, and in contrast to subcutaneous M. leprae footpad infection, systemic M. leprae-specific gamma interferon and antibody responses were detected following intradermal ear infection. These results indicate the utility of intradermal ear infection for both induction and understanding of the immune response during M. leprae infection and the identification or testing of new leprosy treatments.


Asunto(s)
Formación de Anticuerpos , Modelos Animales de Enfermedad , Oído/microbiología , Inmunidad Celular , Mycobacterium leprae/inmunología , Animales , Anticuerpos Antibacterianos/sangre , Femenino , Inflamación/inmunología , Inflamación/patología , Inyecciones Intradérmicas , Interferón gamma/biosíntesis , Ganglios Linfáticos/inmunología , Ganglios Linfáticos/patología , Ratones , Ratones Endogámicos C57BL , Bazo/inmunología , Linfocitos T/inmunología
7.
Clin Vaccine Immunol ; 14(11): 1400-8, 2007 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-17898185

RESUMEN

Leprosy is a chronic and debilitating human disease caused by infection with the Mycobacterium leprae bacillus. Despite the marked reduction in the number of registered worldwide leprosy cases as a result of the widespread use of multidrug therapy, the number of new cases detected each year remains relatively stable. This indicates that M. leprae is still being transmitted and that, without earlier diagnosis, M. leprae infection will continue to pose a health problem. Current diagnostic techniques, based on the appearance of clinical symptoms or of immunoglobulin M (IgM) antibodies that recognize the bacterial phenolic glycolipid I, are unable to reliably identify early-stage leprosy. In this study we examine the ability of IgG within leprosy patient sera to bind several M. leprae protein antigens. As expected, multibacillary leprosy patients provided stronger responses than paucibacillary leprosy patients. We demonstrate that the geographic locations of the patients can influence the antigens they recognize but that ML0405 and ML2331 are recognized by sera from diverse regions (the Philippines, coastal and central Brazil, and Japan). A fusion construct of these two proteins (designated leprosy IDRI diagnostic 1 [LID-1]) retained the diagnostic activity of the component antigens. Upon testing against a panel of prospective sera from individuals who developed leprosy, we determined that LID-1 was capable of diagnosing leprosy 6 to 8 months before the onset of clinical symptoms. A serological diagnostic test capable of identifying and allowing treatment of early-stage leprosy could reduce transmission, prevent functional disabilities and stigmatizing deformities, and facilitate leprosy eradication.


Asunto(s)
Anticuerpos Antibacterianos/sangre , Antígenos Bacterianos , Lepra/diagnóstico , Lepra/inmunología , Mycobacterium leprae/inmunología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Anticuerpos Antibacterianos/inmunología , Antígenos Bacterianos/inmunología , Niño , Diagnóstico Precoz , Femenino , Humanos , Inmunoglobulina G/sangre , Inmunoglobulina G/inmunología , Inmunoglobulina M/sangre , Inmunoglobulina M/inmunología , Lepra/microbiología , Masculino , Persona de Mediana Edad , Proteínas Recombinantes de Fusión/inmunología
8.
Clin Vaccine Immunol ; 13(3): 333-40, 2006 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-16522774

RESUMEN

Despite the success of multidrug therapy in reducing the number of registered leprosy cases worldwide, evidence suggests that Mycobacterium leprae continues to be transmitted. A serological diagnostic test capable of identifying and allowing treatment of early-stage disease could reduce transmission and prevent the onset of the disability, a common complication of the disease in later stages. Serological diagnosis based on antibody recognition of phenolic glycolipid I (PGL-I) cannot reliably identify individuals with lower bacterial indices (BI). One strategy that might improve this situation is the provision of highly specific serological antigens that may be combined with PGL-I to improve the sensitivity of diagnosis. Using serological expression cloning with a serum pool of untreated lepromatous leprosy (LL) patients, we identified 14 strongly reactive M. leprae proteins, 5 of which were previously unstudied. We present results suggesting that two of these proteins, ML0405 and ML2331, demonstrate the ability to specifically identify LL/borderline lepromatous (BL) patients on the basis of immunoglobulin G (IgG) reactivity. In a household contact study, LL index cases were identified on the basis of this reactivity, while household contacts of these patients demonstrated undetectable reactivity. At a serum dilution of 1:800, suitable to reduce background PGL-I IgM reactivity, two BL patients with a BI of <4 showed anti-human polyvalent immunoglobulin G, A, and M reactivity measured with a combination of ML0405, ML2331, and natural disaccharide O-linked human serum albumin (NDOHSA) (synthetic PGL-I) that was markedly higher than IgM reactivity to NDOHSA alone. We suggest that ML0405 and ML2331 may have utility in serological leprosy diagnosis.


Asunto(s)
Antígenos Bacterianos/sangre , Proteínas Bacterianas/sangre , Lepra/diagnóstico , Mycobacterium leprae/inmunología , Anticuerpos Antibacterianos/metabolismo , Reacciones Antígeno-Anticuerpo , Antígenos Bacterianos/inmunología , Proteínas Bacterianas/inmunología , Glucolípidos , Humanos , Lepra/inmunología , Lepra Lepromatosa/inmunología , Lepra Tuberculoide/inmunología , Análisis de Secuencia de Proteína
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