ES2551097T3 - Vacuna contra Streptococcus pneumoniae - Google Patents
Vacuna contra Streptococcus pneumoniae Download PDFInfo
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- ES2551097T3 ES2551097T3 ES09173889.8T ES09173889T ES2551097T3 ES 2551097 T3 ES2551097 T3 ES 2551097T3 ES 09173889 T ES09173889 T ES 09173889T ES 2551097 T3 ES2551097 T3 ES 2551097T3
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- streptococcus pneumoniae
- vaccine against
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- against streptococcus
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Classifications
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- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/02—Bacterial antigens
- A61K39/09—Lactobacillales, e.g. aerococcus, enterococcus, lactobacillus, lactococcus, streptococcus
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- A61K39/02—Bacterial antigens
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/02—Bacterial antigens
- A61K39/09—Lactobacillales, e.g. aerococcus, enterococcus, lactobacillus, lactococcus, streptococcus
- A61K39/092—Streptococcus
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- A61K39/12—Viral antigens
- A61K39/125—Picornaviridae, e.g. calicivirus
- A61K39/13—Poliovirus
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- A61K39/00—Medicinal preparations containing antigens or antibodies
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- A61K39/29—Hepatitis virus
- A61K39/292—Serum hepatitis virus, hepatitis B virus, e.g. Australia antigen
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- A61K39/39—Medicinal preparations containing antigens or antibodies characterised by the immunostimulating additives, e.g. chemical adjuvants
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
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- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
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Abstract
Una composición inmunogénica que comprende al menos 2 proteínas de S. pneumoniae que son PhtD y neumolisina (Ply); y un adyuvante.
Description
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puede esperarse que alcance la piel yendo 1,5 mm por debajo de la superficie de la piel. La dermis se localiza entre el estrato córneo y la epidermis en la superficie y la capa subcutánea a continuación. Dependiendo del modo de transporte, la vacuna puede localizarse en último lugar exclusiva o principalmente dentro de la dermis, o puede en último lugar distribuirse dentro de la epidermis y de la dermis.
En otro aspecto de la invención, la presente invención puede contener ADN que codifique una o más proteínas de S. pneumoniae, de tal manera que la proteína se genere in situ. El ADN puede estar presente en cualquiera de una diversidad de sistemas de transporte conocidos por los expertos en la materia, incluyendo sistemas de expresión de ácidos nucleicos, sistemas de expresión de bacterias y de virus. Se conocen bien en la técnica numerosas técnicas de transporte génico, tales como las descritas por Rolland (Crit. Rev. Therap. Drug Carrier Systems 15:143-198, 1998) y las referencias citadas en el mismo. Los sistemas apropiados de expresión de ácidos nucleicos contienen las secuencias de ADN necesarias para la expresión en el paciente (tal como un promotor adecuado y una señal de terminación). Cuando el sistema de expresión es un microorganismo vivo recombinante, tal como un virus o una bacteria, el gen de interés puede insertarse en el genoma de un virus o una bacteria recombinantes vivos. La inoculación y la infección in vivo con este vector vivo darán lugar a la expresión in vivo del antígeno y la inducción de respuestas inmunes. Los virus y las bacterias usados para este fin son por ejemplo: poxvirus (por ejemplo, vacuna, viruela aviar, viruela del canario), alfavirus (virus de Sindvis, virus del bosque Semliki, virus de la encefalitis equina venezolana), adenovirus, virus adeno-asociados, picomavirus (poliovirus, rinovirus), herpesvirus (virus de la varicela zoster, etc.), Listeria, Salmonella, Shigella, Neisseria, BCG. Estos virus y bacterias pueden ser virulentos o atenuados en diversas formas para obtener vacunas vivas. Tales vacunas vivas también forman parte de la presente invención.
En un aspecto adicional de la presente invención se proporciona un procedimiento para fabricar una formulación de vacuna como se describe en el presente documento, en el que el procedimiento comprende mezclar una combinación de proteínas de acuerdo con la presente invención.
Preferentemente las composiciones antigénicas (y las vacunas) que contienen polisacáridos descritos anteriormente en el presente documento se liofilizan hasta que pueden usarse, en el punto en el que se reconstituyen extemporáneamente con diluyente. Más preferentemente se liofilizan en presencia de 3D-MPL y se reconstituyen extemporáneamente con solución salina.
La liofilización de las vacunas se conoce bien en la técnica. Típicamente, la vacuna líquida se seca por congelación en presencia de un agente anti-aglutinamiento por ejemplo azúcares tales como sacarosa o lactosa (presentes a una concentración inicial de 10-200 mg/ml). La liofilización típicamente se da a lo largo de una serie de etapas, por ejemplo un ciclo que empieza a -69 ºC, ajustando gradualmente a -24 ºC durante 3 horas, después reteniendo esta temperatura durante 18 horas, después ajustando gradualmente a -16 ºC durante 1 hora, después reteniendo esta temperatura durante 6 horas, después ajustando gradualmente a +34 ºC durante 3 horas y finalmente reteniendo esta temperatura durante 9 horas.
Las composiciones inmunogénicas y las vacunas de la presente invención pueden evaluarse en diversos modelos animales o con suero humano. Como una ilustración, los siguientes modelos animales pueden usarse para evaluar la infección neumocócica. Los ratones C3H/HeJ (6 a 8 semanas de edad pueden inmunizarse subcutáneamente con 15 g de proteína con adyuvante con 50 l de CFA, seguido 3-4 semanas después de refuerzo con 15 g de proteína con IFA. Para demostrar la protección pasiva y activa de la infección sistémica, a los ratones puede suministrarse intraperitonealmente un suero inmune o proteínas antes de la estimulación por inyección intraperitoneal con 15 a 90 neumococos LD50 en la semana 8-10. Adicionalmente, las proteínas pueden ensayarse en un modelo de colonización nasofaríngea de ratón por (Wu y col Microbial Pathogenesis 1997; 23:127-137).
Además de los ratones, las ratas bebés son susceptibles de colonización e infección por S. pneumoniae. En estudios protectores pasivos, puede darse la administración de suero inmune de ratón (100 l intraperitoneales o 10 l intranasales) antes de la estimulación con la administración intranasal de S. pneumoniae (10 l) en cachorros de rata bebé de 2-5 días de edad. La colonización puede determinarse poniendo en placa lavados nasales (20-40 l instilados, 10 l retirados).
Las interacciones favorables entre los componentes proteicos de la vacuna de combinación pueden demostrarse administrando una dosis de cada proteína en la vacuna que sería sub-protectora en una vacuna monovalente. La eficiencia protectora aumentada de la vacuna de combinación en comparación con las vacunas monovalentes puede atribuirse a una interacción favorable entre los componentes.
La presente invención se ilustra en los ejemplos acompañantes. Los ejemplos se llevan a cabo usando técnicas convencionales, que se conocen bien y son rutinarias para los expertos en la materia, salvo donde de otra manera se describen con detalles. Los ejemplos se entiende que ilustran la presente invención.
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Ejemplos
Ejemplo 1. Construcción y expresión de antígenos
NR1xR2
CbpA es una proteína expuesta en la superficie de 75 kDa que consiste en varios dominios. El dominio N-terminal comprende 2 repeticiones (R1 y R2) altamente conservadas y el dominio C-terminal comprende 10 secuencias repetitivas en tándem de 20 aminoácidos. Se preparó un truncado de CbpA para producir NR1XNR2, es decir, sin el dominio de unión a colina.
El gen de NR1XNR2 se amplificó, a través de PCR, a partir de ADN obtenido de una cepa de S. pneumoniae de un serotipo 4 (véase, por ejemplo, el documento WO97/41157 o el documento WO99/51266). La PCR se realizó con el Sistema de PCR de Alta fidelidad de expansión o Hi-Fi (Roche). Se compone de una mezcla que contiene polimerasa Taq y una polimerasa de corrección de pruebas. Debido a la actividad correctora de pruebas exonucleasa 3’-5’ inherente, el uso de Hi-Fi da como resultado una fidelidad aumentada 3 veces de la síntesis de ADN en comparación con la polimerasa Taq.
Los fragmentos de PCR se clonaron en un vector pGEM-T de pGEM-T Vector Systems (Promega). Esta etapa se necesita para facilitar la digestión de enzimas de restricción de fragmentos de PCR para la futura ligación. El vector pGEM-T se proporciona lineal y contiene protuberancias 3’-T. Estas protuberancias facilitan la inserción de los productos de PCR generados por polimerasas termoestables que añaden una única desoxiadenosina, en una forma independiente de la plantilla, en los extremos 3’ del fragmento amplificado.
Los fragmentos y los vectores se purificaron después de digestiones enzimáticas (digestiones con Ndel y Xbal) de acuerdo con el artículo de Benore-Parsons y col. (Nucleic Acids Research, 23, 4926-4927, 1995). Se liofilizó completamente una rebanada de agarosa durante 3-4 horas. Se añadió una solución de etanol-TE 1:1 al gel liofilizado. La muestra se mezcló suavemente durante 1 h, la agarosa se comprimió y se retiró completamente por centrifugación. Se recuperó el ADN del eluyente por precipitación de etanol.
El ADN que codifica NR1xR2 se clonó en un vector que contenía el promotor L largo del fago . La proteína de interés podría inducirse por calor cuando está presente en una cepa de E. coli AR 58 o por ácido nalidíxico en una cepa de E. coli AR 120.
Se fabricó durante toda la noche a 30 ºC un precultivo de bacterias. Este precultivo se diluyó aproximadamente 40 veces en un volumen total de 20 ml y se puso a 30 ºC hasta una D.O. de 0,4-0,6. Después, se hizo la inducción de calor a 42 ºC. Las muestras se tomaron a diferentes puntos de tiempo. Un ml de cultivo se centrifugó 5 minutos a 7000 rpm. El sobrenadante del cultivo se conservó a -20 ºC y los gránulos (el extracto total) se resuspendieron en 500 l de tampón de muestra (transferencia Western o análisis SDS-PAGE) o en 500 l de tampón de lisis y se incubaron 30 minutos a 37 ºC (ELISA). La composición del tampón de lisis es: SDS al 0,1 %, Desoxicolato al 0,1 %, citrato de Na: 0,015 M.
Las muestras se hicieron correr en un SDS-PAGE, se cargaron en un gel al 4-20 % (Novex, Invitrogen). La migración se dio a 200 V. Se realizó la tinción con azul Coomassie. Las muestras se cargaron en un gel al 4-20 % (Novex, Invitrogen) para una transferencia Western. La migración se dio a 200 V. El gel se transfirió a nitrocelulosa y las manchas se revelaron con anticuerpos policlonales -NR1XR2 de conejo (primer anticuerpo) y un anticuerpo conejo acoplado a fosfatasa alcalina (segundo anticuerpo).
Se observó una banda de aproximadamente 55 kDa por análisis de SDS-PAGE. Un clon, 28B2, se eligió a base del análisis de SDS-PAGE y se transfirió a fermentación. Este clon se secuenció y su secuencia se confirmó (aminoácidos 39 (es decir, después de la secuencia señal) a 446 = 406 aminoácidos).
La solubilidad de NR1XR2 también se estudió, después de la lisis de las bacterias inducida durante toda la noche seguido de centrifugación. Se realizaron un análisis de SDS-PAGE y un ensayo ELISA. NR1XR2 parecía recuperarse principalmente (> 95 %) en la fracción soluble.
R1xR2, PhtD, Sp91, (N)R1xR2-Sp91[dominio C-terminal] y Ply
Estos genes también se clonaron, se secuenciaron y se expresaron de forma similar a NR1xR2. R1xR2 contiene los aminoácidos 177 a 443 de CbpA (del serotipo 4N de S. pneumoniae), PhtD contiene los aminoácidos 21 (es decir, después de la secuencia señal) hasta el final (aminoácido 839 del serotipo 4N de S. pneumoniae), Sp91 empieza en el aminoácido 20 (VVA) hasta el final. Para las proteínas de fusión, R1xR2-Sp91Cterm contiene los aminoácidos 39446 de CbpA y los aminoácidos 271 hasta el fin de la traducción. Para ambas proteínas de fusión, se encuentran 2 aminoácidos adicionales (GS) entre las secuencias (N)R1xR2 y Sp91Cterm. Para todas las construcciones, se ha introducido un AGT 5’ del inicio del gen para permitir la transcripción y la traducción, lo que significa que hay una metionina N-terminal adicional en frente de cada secuencia mencionada anteriormente.
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2001
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