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1.
PLoS One ; 10(4): e0117820, 2015.
Artículo en Inglés | MEDLINE | ID: mdl-25927360

RESUMEN

BACKGROUND: A phase I randomised, controlled, single blind, dose escalation trial was conducted to evaluate safety and immunogenicity of JAIVAC-1, a recombinant blood stage vaccine candidate against Plasmodium falciparum malaria, composed of a physical mixture of two recombinant proteins, PfMSP-1(19), the 19 kD conserved, C-terminal region of PfMSP-1 and PfF2 the receptor-binding F2 domain of EBA175. METHOD: Healthy malaria naïve Indian male subjects aged 18-45 years were recruited from the volunteer database of study site. Fifteen subjects in each cohort, randomised in a ratio of 2:1 and meeting the protocol specific eligibility criteria, were vaccinated either with three doses (10 µg, 25 µg and 50 µg of each antigen) of JAIVAC-1 formulated with adjuvant Montanide ISA 720 or with standard dosage of Hepatitis B vaccine. Each subject received the assigned vaccine in the deltoid muscle of the upper arms on Day 0, Day 28 and Day 180. RESULTS: JAIVAC-1 was well tolerated and no serious adverse event was observed. All JAIVAC-1 subjects sero-converted for PfF2 but elicited poor immune response to PfMSP-1(19). Dose-response relationship was observed between vaccine dose of PfF2 and antibody response. The antibodies against PfF2 were predominantly of IgG1 and IgG3 isotype. Sera from JAIVAC-1 subjects reacted with late schizonts in a punctate pattern in immunofluorescence assays. Purified IgG from JAIVAC-1 sera displayed significant growth inhibitory activity against Plasmodium falciparum CAMP strain. CONCLUSION: Antigen PfF2 should be retained as a component of a recombinant malaria vaccine but PfMSP-1(19) construct needs to be optimised to improve its immunogenicity. TRIAL REGISTRATION: Clinical Trial Registry, India CTRI/2010/091/000301.


Asunto(s)
Antígenos de Protozoos/administración & dosificación , Vacunas contra la Malaria/administración & dosificación , Malaria Falciparum/prevención & control , Proteína 1 de Superficie de Merozoito/administración & dosificación , Plasmodium falciparum/inmunología , Proteínas Protozoarias/administración & dosificación , Adolescente , Adulto , Anticuerpos Antiprotozoarios/inmunología , Antígenos de Protozoos/efectos adversos , Antígenos de Protozoos/inmunología , Relación Dosis-Respuesta a Droga , Relación Dosis-Respuesta Inmunológica , Femenino , Vacunas contra Hepatitis B/administración & dosificación , Vacunas contra Hepatitis B/efectos adversos , Vacunas contra Hepatitis B/inmunología , Humanos , Inmunoglobulina G/inmunología , India , Vacunas contra la Malaria/efectos adversos , Vacunas contra la Malaria/inmunología , Malaria Falciparum/inmunología , Masculino , Manitol/administración & dosificación , Manitol/efectos adversos , Manitol/análogos & derivados , Proteína 1 de Superficie de Merozoito/efectos adversos , Proteína 1 de Superficie de Merozoito/inmunología , Persona de Mediana Edad , Ácidos Oléicos/administración & dosificación , Ácidos Oléicos/efectos adversos , Proteínas Protozoarias/efectos adversos , Proteínas Protozoarias/inmunología
2.
Vaccine ; 28(2): 452-62, 2009 Dec 11.
Artículo en Inglés | MEDLINE | ID: mdl-19857448

RESUMEN

In an effort to broaden the immune response induced by the RTS,S/AS02(A),vaccine, we have evaluated the immunogenicity of the RTS,S antigen when combined with MSP1(42) and with AMA1, antigens derived from the asexual blood stage. The objectives of this study were (i) to determine whether MSP1(42) and AMA1 vaccines formulated with the AS02(A) Adjuvant System were safe and immunogenic in the rhesus monkey model; (ii) to investigate whether MSP1(42) or AMA1 induced immune interference to each other, or to RTS,S, when added singly or in combinations at a single injection site; (iii) in the event of immune interference, to determine if this could be reduced when antigens were administered at separate sites. We found that MSP1(42) and AMA1 were safe and immunogenic, eliciting antibodies, and Th1 and Th2 responses using IFN-gamma and IL-5 as markers. When malaria antigens were delivered together in one formulation, MSP1(42) and RTS,S reduced AMA1-specific antibody responses as measured by ELISA however, only MSP1(42) lowered parasite growth inhibitory activity of anti-AMA1 antibodies as measured by in vitro growth inhibition assay. Unlike RTS,S, MSP1(42) significantly reduced AMA1 IFN-gamma and IL-5 responses. MSP1(42) suppression of AMA1 IFN-gamma responses was not seen in animals receiving RTS,S+AMA1+MSP1(42) suggesting that RTS,S restored IFN-gamma responses. Conversely, AMA1 had no effect on MSP1(42) antibody and IFN-gamma and IL-5 responses. Neither AMA1 alone or combined with MSP1(42) affected RTS,S antibody or IFN-gamma and IL-5 responses. Immune interference by MSP1(42) on AMA1 antibody responses was also evident when AMA1, MSP1(42) and RTS,S were administered concurrently at separate sites. These results suggest that immune interference may be complex and should be considered for the design of multi-antigen, multi-stage vaccines against malaria.


Asunto(s)
Antígenos de Protozoos/inmunología , Macaca mulatta/inmunología , Vacunas contra la Malaria/inmunología , Proteínas de la Membrana/inmunología , Proteína 1 de Superficie de Merozoito/inmunología , Plasmodium falciparum/inmunología , Proteínas Protozoarias/inmunología , Animales , Vacunas contra la Malaria/efectos adversos , Proteína 1 de Superficie de Merozoito/efectos adversos
3.
Vaccine ; 22(29-30): 3831-40, 2004 Sep 28.
Artículo en Inglés | MEDLINE | ID: mdl-15364429

RESUMEN

We compared the safety and immunogenicity of the recombinant Plasmodium falciparum MSP1(42) antigen formulated with four novel adjuvant systems (AS01B, AS02A, AS05 and AS08) to alum in rhesus monkeys. All five formulations of MSP1(42) were safe and immunogenic. Whereas, all MSP1(42) formulations tested generated high stimulation indices for lymphocyte proliferation (ranging from 27 to 50), the AS02A and AS01B formulations induced the highest levels of specific anti-MSP1(42) antibody. ELISPOT assays showed that the AS02A and AS01B vaccine formulations-induced different cytokine response profiles. Using the ratio of IFN-gamma/IL-5 secreting cells as the metric, the AS01B formulation induced a strong Th1 response, whereas the AS02A formulation induced a balanced Th1/Th2 response. The IFN-gamma response generated by AS02A and AS01B formulations persisted at least 24 weeks after final vaccination. The notable difference in Th1/Th2 polarization induced by the AS02A and AS01B formulations warrants comparative clinical testing.


Asunto(s)
Adyuvantes Inmunológicos , Vacunas contra la Malaria/inmunología , Proteína 1 de Superficie de Merozoito/inmunología , Plasmodium falciparum/inmunología , ADP-Ribosil Ciclasa/análisis , ADP-Ribosil Ciclasa 1 , Compuestos de Alumbre , Animales , Anticuerpos Antiprotozoarios/sangre , Antígenos CD/análisis , Antígenos CD40/análisis , Citocinas/análisis , Células Dendríticas/inmunología , Células Dendríticas/fisiología , Evaluación Preclínica de Medicamentos , Memoria Inmunológica , Interferón gamma/análisis , Interleucina-5/análisis , Activación de Linfocitos , Macaca mulatta , Vacunas contra la Malaria/toxicidad , Proteína 1 de Superficie de Merozoito/efectos adversos , Linfocitos T/inmunología , Factores de Tiempo , Vacunación , Vacunas Sintéticas/inmunología , Vacunas Sintéticas/toxicidad
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