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1.
Clin Vaccine Immunol ; 17(11): 1763-71, 2010 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-20861328

RESUMEN

Tuberculosis (TB) remains a major cause of illness and death worldwide, making a new TB vaccine an urgent public health priority. Purified protein derivative (PPD)-negative adults (n = 50) were equally randomized to receive 3 doses at 1-month intervals (at 0, 1, and 2 months) of one of the following vaccines: Mtb72F/AS02(A) (10 or 40 µg antigen), Mtb72F/saline (10 or 40 µg antigen), or AS02(A). Mtb72F/AS02(A) recipients received an additional dose 1 year after the first dose to evaluate if the elicited immune response could be boosted. Mtb72F/AS02(A) vaccines were locally reactogenic but clinically well tolerated, with transient adverse events (usually lasting between 1 and 4 days) that resolved without sequelae being observed. No vaccine-related serious adverse events were reported. Vaccination with Mtb72F/AS02(A) induced a strong Mtb72F-specific humoral response and a robust Mtb72F-specific CD4(+) T-cell response, both of which persisted at 9 months after primary immunization and for 1 year after the booster immunization. There was no significant difference between the magnitude of the CD4(+) T-cell response induced by the 10-µg and 40-µg Mtb72F/AS02(A) vaccines. The Mtb72F-specific CD4(+) T cells predominantly expressed CD40L; CD40L and interleukin-2 (IL-2); CD40L and tumor necrosis factor alpha (TNF-α); CD40L, IL-2, and TNF-α; and CD40L, IL-2, TNF-α, and gamma interferon (IFN-γ). Serum IFN-γ, but not TNF-α, was detected 1 day after doses 2 and 3 for the Mtb72F/AS02(A) vaccine but did not persist. Vaccine-induced CD8(+) T-cell responses were not detected, and no immune responses were elicited with AS02(A) alone. In conclusion, Mtb72F/AS02(A) is clinically well tolerated and is highly immunogenic in TB-naïve adults. The 10- and 40-µg Mtb72F/AS02(A) vaccines show comparable safety and immunogenicity profiles.


Asunto(s)
Inmunización Secundaria/métodos , Vacunas contra la Tuberculosis/efectos adversos , Vacunas contra la Tuberculosis/inmunología , Vacunación/métodos , Adolescente , Adulto , Anticuerpos Antibacterianos/sangre , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , Citocinas/metabolismo , Femenino , Experimentación Humana , Humanos , Masculino , Persona de Mediana Edad , Vacunas contra la Tuberculosis/administración & dosificación , Adulto Joven
2.
Hum Vaccin ; 5(7): 475-82, 2009 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-19587528

RESUMEN

Tuberculosis (TB) remains uncontrolled in many parts of the world and the development of an effective vaccine against TB represents a high priority unmet medical need. Healthy PPD (tuberculin purified protein derivative)-negative adult volunteers, aged 18-40 years received three doses of the candidate Mtb72F/AS02A vaccine according to a 0-1-2 months schedule in an open-label Phase I study (NCT00730795). Solicited, unsolicited and serious adverse events (AEs), hematological and biochemical laboratory parameters were assessed. Mtb72F-specific humoral responses were assessed by ELISA and cell-mediated immune (CMI) responses by intracellular cytokine staining (ICS) and short-term ELISPOT assays. CMI responses to the component peptides (Mtb39a and the Mtb32a C- and N-terminal antigen domains, Mtb32C and Mtb32N) were also assessed by ICS. The Mtb72F/AS02A vaccine appeared to be mainly locally reactogenic but this was considered acceptable, since these AEs were usually transient and resolved within 1-2 days. Most AEs reported were mild in intensity, no serious AEs occurred, no medically significant biochemical or hematological abnormalities related to vaccination were measured and all AEs resolved without sequelae. The vaccine induced statistically significant changes in humoral and CMI response measures. The Mtb72F antigen induced good production of IL-2 and IFNgamma in the ELISPOT assay and CD4(+) T cells expressing at least two activation markers (mainly CD40-L and IL-2) were observed with ICS. A similar CMI profile was observed with Mtb39a and Mtb32N. The induced CMI responses persisted for at least 6 months post-vaccination. All subjects were seropositive for anti-Mtb72F antibodies one month post-dose 2 and 6 months post-dose 3. This first trial in humans found Mtb72F/AS02A to have an acceptable tolerability, to be immunogenic in healthy adults and warrants further development of the vaccine.


Asunto(s)
Vacunas contra la Tuberculosis/efectos adversos , Vacunas contra la Tuberculosis/inmunología , Adulto , Anticuerpos Antibacterianos/sangre , Linfocitos T CD4-Positivos/química , Linfocitos T CD4-Positivos/inmunología , Antígenos CD40/análisis , Citocinas/biosíntesis , Citocinas/metabolismo , Ensayo de Inmunoadsorción Enzimática/métodos , Femenino , Experimentación Humana , Humanos , Inmunización Secundaria/métodos , Leucocitos Mononucleares/inmunología , Masculino , Persona de Mediana Edad , Enfermedades de la Piel/inducido químicamente , Vacunas contra la Tuberculosis/administración & dosificación , Adulto Joven
3.
Vaccine ; 25(21): 4203-12, 2007 May 22.
Artículo en Inglés | MEDLINE | ID: mdl-17442466

RESUMEN

We report the first safety and immunogenicity trial of the Plasmodium falciparum vaccine candidate FMP2.1/AS02A, a recombinant E. coli-expressed protein based upon the apical membrane antigen-1 (AMA-1) of the 3D7 clone formulated with the AS02A adjuvant. We conducted an open-label, staggered-start, dose-escalating Phase I trial in 23 malaria-naïve volunteers who received 8, 20 or 40microg of FMP2.1 in a fixed volume of 0.5mL of AS02A on a 0, 1, and 2 month schedule. Nineteen of 23 volunteers received all three scheduled immunizations. The most frequent solicited local and systemic adverse events associated with immunization were injection site pain (68%) and headache (29%). There were no significant laboratory abnormalities or vaccine-related serious adverse events. All volunteers seroconverted after second immunization as determined by ELISA. Immune sera recognized sporozoites and merozoites by immunofluorescence assay (IFA), and exhibited both growth inhibition and processing inhibition activity against homologous (3D7) asexual stage parasites. Post-immunization, peripheral blood mononuculear cells exhibited FMP2.1-specific lymphoproliferation and IFN-gamma and IL-5 ELISPOT assay responses. This is the first PfAMA-1-based vaccine shown to elicit both potent humoral and cellular immunity in humans. Encouraged by the potential of FMP1/AS02A to target host immunity against PfAMA-1 that is known to be expressed by sporozoite, hepatic and erythrocytic stages, we have initiated field trials of FMP2.1/AS02A in an endemic population in the Republic of Mali.


Asunto(s)
Antígenos de Protozoos/inmunología , Lípido A/análogos & derivados , Vacunas contra la Malaria/efectos adversos , Vacunas contra la Malaria/inmunología , Proteínas de la Membrana/inmunología , Plasmodium falciparum/inmunología , Proteínas Protozoarias/inmunología , Saponinas/inmunología , Adyuvantes Inmunológicos , Adolescente , Adulto , Animales , Anticuerpos Antiprotozoarios/sangre , Línea Celular , Proliferación Celular , Células Cultivadas , Cricetinae , Combinación de Medicamentos , Ensayo de Inmunoadsorción Enzimática , Escherichia coli/genética , Femenino , Técnica del Anticuerpo Fluorescente Indirecta , Cefalea , Humanos , Inmunización Secundaria , Interferón gamma/biosíntesis , Interleucina-5/biosíntesis , Leucocitos Mononucleares/inmunología , Lípido A/inmunología , Vacunas contra la Malaria/administración & dosificación , Masculino , Merozoítos/inmunología , Mesocricetus , Persona de Mediana Edad , Dolor , Plasmodium falciparum/crecimiento & desarrollo , Esporozoítos/inmunología , Vacunas Sintéticas/inmunología
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