En junio de 2006, la División de Servicios de Conservación del Departamento de Agricultura de Colorado publicó las Reglas actualizadas relativas a la administración y aplicación de la ley de malezas nocivas de Colorado (8 CCR 1206-2). El Colorado Noxious Weed Act está contenido en 35-5.5-101 a 119, C. R.S. (2003) y se aplica a todos en Colorado. En la ley se especifican tres listas de malezas nocivas y las reglas actualizadas especifican qué plantas están actualmente en cada una de estas listas. Los peores ofensores de malas hierbas nocivas están en la Lista A (categoría 1) y deben ser erradicados en todo el estado. Lista B (categoría 2) malas hierbas nocivas deben ser manejados. Los planes futuros que se están desarrollando relacionados con las malas hierbas nocivas en la Lista C (Categoría 3) son proporcionar recursos adicionales de educación, investigación y control biológico a las jurisdicciones que opten por requerir el manejo de estas especies. Ahora, simplemente haga clic en el nombre de cada lista para ver las fotografías de todas las plantas en ella. Estas páginas ayudarán a las personas afectadas por la Ley de malezas nocivas de Colorado a identificar visualmente las plantas que deben erradicar y / o administrar. Las plantas en cada una de las listas están en orden alfabético por su nombre común, con su nombre científico siempre entre paréntesis. Cuando esté disponible, haga clic en el nombre de la planta resaltada para ver las hojas de datos basadas en Estados Unidos para esa hierba. Al preparar esta guía se utilizaron como fuentes las mejores fotografías gratuitas de todo el mundo, disponibles en Internet. Las fotos fueron mejoradas, según sea necesario, para ayudar a los espectadores a identificar las malas hierbas nocivas de Colorado con un esfuerzo mínimo. Para visitar el sitio de origen de cada imagen, simplemente haga clic en ella. La mayoría de estos dignos sitios fuente, pertenecen a gobiernos locales y estatales, universidades, jardines botánicos, organizaciones sin fines de lucro o fotógrafos individuales. Están llenos de documentación interesante y vale la pena navegar para obtener información adicional sobre la botánica, las malas hierbas, las plantas y otros temas relacionados. (Algunos de los sitios de Canadá, Francia, Bélgica, Noruega, Alemania, Checa, Polonia, Japón y etc. desafortunadamente no tienen sus páginas disponibles en inglés.) Especies invasoras son consideradas como cualquier especie de insectos, animales, plantas y Patógenos, incluyendo sus semillas, huevos, esporas u otros materiales biológicos capaces de propagar esa especie, que no es nativa de ese ecosistema y cuya introducción causa o es probable que cause daño económico o ambiental o daño a la salud humana. Tenga en cuenta que su definición se aplica tanto a las especies nativas como a las introducidas. Curiosamente, algunas de las especies de malezas que se consideran nocivas en Colorado son muy admirado por sus flores de belleza, uso medicinal, e incluso valor de los alimentos (sí, algunos son comestibles) en otras partes del mundo. Por supuesto, muchos son muy venenosos para los seres humanos y / o los animales domésticos. Lista A: rue de África (Peganum harmala) Camelthorn (Alhagi pseudalhagi) Crupina Común (Crupina vulgaris) Cypress lechetrezna (Euphorbia cyparissias) glasto Tintoreros (Isatis tinctoria) salvinia gigante (Salvinia molesta) Hidrilla (Hydrilla verticillata) centaurea Meadow (Centaurea pratensis) mediterránea salvia (salvia aethiopis) Medusahead (Taeniatherum caput-medusae) tártago Myrtle (myrsinites Euphorbia) hawkweed anaranjado (Hieracium) salicaria (Lythrum salicaria) punta skeletonweed (Chondrilla juncea) Sericea lespedeza (lespedeza cuneata) centaurea squarrose (virgata Centaurea) chilca Tansy (jacobaea Senecio) abrepuño amarillo (Centaurea solstitialis) Lista B (Parte 1): ajenjo ajenjo (Artemisia absinthium) beleño Negro (Hyoscyamus niger) Bouncingbet (Saponaria officinalis) cardo Bull (Cirsium vulgare) cardo de Canadá (Cirsium arvense) clemátides chino (Clematis orientalis ) tanaceto común (Tanacetum vulgare) del cardo común (Dipsacus fullonum) maíz manzanilla (Anthemis arvensis) Cutleaf cardón (dipsacus laciniatus) toadflax dálmata, de hoja ancha (Linaria dalmática) toadflax dálmata, de hoja estrecha (cohete Linaria genistifolia) Dames (Hesperis matronalis ) centaurea difusa (Centaurea diffusa) watermilfoil eurasiático (Myriophyllum spicatum) berros canoso (Cardaria draba) cinoglosa (Cynoglossum officinale) Hojas lechetrezna (Euphorbia esula) Lista B (Parte 2): manzanilla mayweed (Anthemis cotula) polilla de gordolobo (Verbascum blattaria) cardo de almizcle (Carduus nutans) de ojo de buey margarita (Chrysanthemum leucanthemum) perenne pepperweed (Lepidium latifolium) Plumeless cardo (Carduus acanthoides) qUACKGRASS (Elytrigia repens) alfilerillo alfilerillo (Erodium cicutarium) centaurea de Rusia (repens Acroptilon) ruso-oliva (Elaeagnus angustifolia) El pino salado (Tamarix chinensis, T. parviflora, y T. ramosissima) manzanilla Scentless (Matricaria perforata) cardo borriquero (Onopordum acanthium) cardo borriquero (Onopordum tauricum) Centaurea manchada (maculosa Centaurea) Estimulado anoda (Anoda cristata) Sulfur cinquefoil (Potentilla recta) malva de Venecia ( Hibiscus trionum) Alcaravia salvaje (Carum carvi) Cenoura amarilla (Cyperus esculentus) Llanura amarilla (Linaria vulgaris) Lista C: Chicoría (Cicorium intybus) Bardana común (Arctium minus) Mullein común (Verbascum thapsus) bromo (Bromus tectorum) enredadera de campo (Convolvulus arvensis) halogeton (halogeton glomeratus) sorgo de alepo (Sorghum halepense) goatgrass articulado (Aegilops cylindrica) perenne sowthistle (Sonchus arvensis) cicuta (Conium maculatum) Puncturevine (Tribulus terrestris) Malva (Abutilon theophrasti) Wild Antecedentes Las infecciones generalizadas de las especies aviares con el virus H5N1 de la gripe aviar y su limitada propagación a los seres humanos sugieren que el virus tiene el potencial de causar una pandemia de gripe humana (H1N1, por sus siglas en inglés) . Existe una necesidad urgente de una vacuna H5N1 que sea eficaz contra cepas divergentes del virus H5N1. Métodos En un estudio aleatorizado, escalado de dosis, fase 1 y 2 de seis subgrupos, se investigó la seguridad de una vacuna H5N1 de virus completo producido en cultivos de células Vero y determinó su capacidad para inducir anticuerpos capaces de neutralizar varias cepas H5N1. En dos visitas con 21 días de diferencia, 275 voluntarios entre las edades de 18 y 45 años recibieron dos dosis de vacuna que contenían 3,75 g, 7,5 g, 15 g o 30 g de antígeno de hemaglutinina con adyuvante de alumbre o 7,5 g o 15 g de Antígeno de hemaglutinina sin adyuvante. Resultados La vacuna indujo una respuesta inmune neutralizante no sólo contra la cepa del virus del clado 1 (A / Vietnam / 1203/2004) sino también contra las cepas del clado 2 y 3. El uso de adyuvantes no mejoró la respuesta de anticuerpos. Se obtuvieron respuestas máximas a la cepa vacunal con formulaciones que contenían 7,5 gy 15 g de antígeno de hemaglutinina sin adyuvante. El dolor leve en el lugar de la inyección (en 9 a 27 de los sujetos) y el dolor de cabeza (en 6 a 31 de los sujetos) fueron los eventos adversos más comunes identificados para todas las formulaciones de la vacuna. Conclusiones Un régimen de vacunas de dos dosis de 7,5 g o 15 g de antígeno de hemaglutinina sin adyuvante indujo anticuerpos neutralizantes contra diversas cepas del virus H5N1 en un alto porcentaje de sujetos, lo que sugiere que esta puede ser una vacuna H5N1 útil. (Número de ClinicalTrials. gov, NCT00349141.) Medios en este artículo Figura 1 Matrícula y resultados. Figura 2 Curvas de distribución acumulativa inversa para títulos de anticuerpos neutralizantes en seis grupos de estudio después de la primera y segunda dosis de vacuna contra tres cepas de influenza aviar. Artículo Actividad La aparición de una nueva pandemia de gripe humana causada por una cepa de virus aviar es posible. La vacunación contra la gripe pandémica se considera la opción más eficaz para limitar su propagación. Sin embargo, los enfoques convencionales para la fabricación de vacunas contra la influenza tienen una serie de desventajas y suscitan preocupación acerca de si se pueden disponer suficientes cantidades de una vacuna eficaz con suficiente antelación al comienzo de una pandemia para tener un efecto importante en la salud pública. Además, los estudios clínicos de las formulaciones convencionales de vacunas divididas sin adyuvante han mostrado una inmunogenicidad deficiente. Se ha sugerido que las vacunas de virus completos tienen el potencial de ser más inmunogénicas que las vacunas con virus divididos o subunidades en poblaciones previamente no vacunadas. El primer estudio clínico de una vacuna de virus entero contra el virus H5N1 de la influenza aviar mostró que una dosis de antígeno sustancialmente reducida (10 g) con una formulación de alumbre indujo seroconversión en casi 100 de los sujetos. 6 Todos estos estudios se llevaron a cabo con vacunas fabricadas por métodos convencionales (es decir, con el uso de huevos de pollo embrionados y virus reasortantes modificados, atenuados producidos por genética inversa). 7 Hemos ideado una estrategia para el desarrollo de una vacuna H5N1 que implica el uso de un virus de tipo salvaje (es decir, la cepa que circula en la naturaleza) cultivado en un cultivo de células Vero. Esta estrategia tiene la ventaja de que se puede reducir el tiempo de espera para la producción de vacunas pandémicas, ya que no se requiere la generación de reasentamientos atenuados, aunque el requisito para el uso de instalaciones mejoradas de bioseguridad de nivel 3 (BSL-3) es una Relativo inconveniente. Además, el cultivo celular proporciona una robusta plataforma de fabricación que elimina la dependencia de huevos embrionados de pollo, lo que sería una ventaja en caso de disponibilidad limitada de estos huevos durante una pandemia causada por un virus aviar altamente patógeno. Esta técnica se utilizó para desarrollar una vacuna de virus entero que era altamente inmunogénica en modelos animales. 8 Presentamos un informe sobre la seguridad e inmunogenicidad de esta vacuna, usando formulaciones con y sin adyuvante de alumbre. Métodos Diseño del Estudio y Objetivo Desde junio de 2006 hasta septiembre de 2006, se inscribió un total de 284 hombres y mujeres entre las edades de 18 y 45 años en un ensayo clínico aleatorizado, parcialmente ciego (entre grupos) en tres sitios: uno en Austria y dos En Singapur. El estudio fue diseñado por su patrocinador, Baxter. Los datos fueron recogidos por los investigadores y fueron retenidos y analizados por Baxter. El manuscrito fue escrito por un subgrupo de la industria y los autores académicos de todos los autores contribuyeron a los contenidos, tenía pleno acceso a los datos, y atestiguar la integridad y exactitud de los datos y análisis de datos. Las juntas locales de revisión y los comités de ética aprobaron el protocolo para el estudio, que se llevó a cabo de conformidad con las directrices de buenas prácticas clínicas y las disposiciones de la Declaración de Helsinki. Los investigadores del estudio desconocían las asignaciones a los grupos de estudio. El objetivo era identificar la inmunogenicidad y seguridad de varias dosis de la vacuna de virus entero H5N1 inactivada en formulaciones con y Sin adyuvante. El resultado de la inmunogenicidad primaria fue el número de sujetos con anticuerpos de inhibición de la hemaglutinación y neutralización de la cepa vacunal (A / Vietnam / 1203/2004) 21 días después de la primera y segunda dosis de la vacuna. El resultado primario de seguridad fue cualquier reacción sistémica después de la primera y segunda dosis. Vacuna Se produjo la vacuna monovalente contra el virus de la gripe aviar H5N1 (Baxter) con la cepa de tipo salvaje A / Vietnam / 1203/2004, obtenida de los Centros para el Control y la Prevención de Enfermedades y se inactivó con formalina y luz ultravioleta. La vacuna se fabricó en cultivo de células Vero en una instalación BSL-3 mejorada (según se requiera para el virus H5N1 de tipo salvaje), como se describió anteriormente. 9 Asignación al azar y seguimiento Los sujetos eran elegibles para participar si estaban clínicamente sanos, comprendían los procedimientos del estudio, proporcionaron su consentimiento informado por escrito y acordaron mantener un registro diario de los síntomas. Se requería que las mujeres tuvieran una prueba de embarazo negativa en el cribado y antes de cada vacunación. Los sujetos fueron reclutados en tres cohortes de estudio de una manera escalonada de dosis y fueron asignados aleatoriamente para recibir dos inyecciones de 0,5 ml en el músculo deltoides a un intervalo de 21 días (rango 19 a 23) con una formulación de virus completo H5N1 que contenía 3,75 G, 7,5 g, 15 g o 30 g de antígeno de hemaglutinina con un adyuvante de alumbre de 0,2 o 7,5 g o 15 g de antígeno de hemaglutinina sin adyuvante. No hubo grupo placebo. Los sujetos y los investigadores no tenían conocimiento de la dosis de la vacuna administrada dentro de los subgrupos (Figura 1 Figura 1 Matrícula y Resultados y el Apéndice Suplementario). Se tomaron muestras de sangre para pruebas serológicas antes de la primera dosis de vacuna y el día 21 después de la primera y segunda dosis. Utilizando un diario proporcionado por los investigadores, se pidió a los sujetos que registraran la temperatura corporal oral diaria (usando termómetros digitales emitidos en el estudio), reacciones locales y eventos adversos sistémicos durante 7 días después de cada vacunación. Los días 7 y 21 después de cada vacunación, se pidió a los sujetos que regresaran para una revisión del diario y la evaluación de cualquier evento adverso. Ensayos Se evaluaron todos los resultados de inmunogenicidad frente a la cepa de virus influenza utilizada en la vacuna (A / Vietnam / 1203/2004) según ensayos de inhibición de la hemaglutinación y neutralización del virus. Para evaluar la reactividad cruzada de los anticuerpos, se realizaron también todos los ensayos con cepas de influenza relacionadas conocidas, por ejemplo, una cepa clade 3 original prototipo (A / Hong Kong / 156/1997) y una cepa clade 2 (A / Indonesia / 05/2005 ). Utilizando un ensayo de inhibición de hemaglutinación o neutralización de virus, se investigaron los resultados de inmunogenicidad secundaria analizando la respuesta de anticuerpos 21 días después de la primera y segunda dosis de vacuna el aumento en la respuesta de anticuerpos 21 días después de la primera y segunda dosis, en comparación con la línea base Y el número de sujetos con seroconversión (que se definió como un aumento mínimo en un factor de 4 en el título) 21 días después de la primera y segunda dosis, en comparación con la línea de base. El ensayo de hemaglutinación-inhibición es la prueba estándar para la detección de anticuerpos contra la gripe después de la infección o la vacunación. Sin embargo, este ensayo puede ser insensible para la detección de anticuerpos anti-H5. 10,11 Por esta razón, los análisis de inmunogenicidad se centraron en la determinación de las respuestas neutralizantes-anticuerpos funcionales. Dado que la mayoría de las autoridades encargadas de la concesión de licencias suelen solicitar datos relativos a los ensayos de inhibición de la hemaglutinación oa la hemólisis radial única, también se notifican estas determinaciones, pero sólo para la cepa A / Vietnam / 1203/2004 del virus de la vacuna. (Para detalles sobre los ensayos de inhibición de la hemaglutinación y de neutralización del virus y la hemólisis radial simple, véase el Apéndice Suplementario, 12-14.) Análisis estadístico El protocolo recomendaba la contratación de 45 sujetos por grupo de estudio. Con este número de sujetos, el intervalo de confianza de 95 para el porcentaje de sujetos con una respuesta de anticuerpos que se asoció con protección no se extendió más de 15 de la tasa observada, suponiendo una tasa de seroprotección de aproximadamente 80. Se utilizó la razón de verosimilitud chi Para comparar el número de sujetos con reacciones locales o sistémicas dentro de los 7 días después de la vacunación entre las diversas formulaciones de la vacuna. Para variables binarias (es decir, seroprotección y seroconversión), se calcularon tasas de respuesta y 95 intervalos de confianza para cada cepa y punto de tiempo. Los intervalos de confianza se interpretaron de una manera descriptiva, y no se hizo ningún ajuste para la multiplicidad. 15 Además, para los valores log-transformados de los títulos de neutralización del virus y la hemólisis radial simple, se realizó un análisis longitudinal dentro de un marco repetido de modelo mixto de análisis de covarianza. Se analizaron los cambios desde la línea de base, que representaban los efectos fijos de la formulación de la vacuna, el día, el sexo, la edad, el título basal, la interacción entre la formulación de la vacuna y el día y los efectos aleatorios para los sujetos. Las formulaciones de vacunas sin adyuvante se compararon con formulaciones con adyuvante dentro de este modelo. También se hicieron comparaciones entre grupos que recibieron 7,5 gy 15 g de antígeno de hemaglutinina sin adyuvante. Se calculó la proporción de sujetos con un título de neutralización de virus de 1:20 o más y la de sujetos con resultados de 25 mm 2 o más en hemólisis radial única, utilizando un modelo lineal generalizado con medidas repetidas y las ecuaciones de estimación general (Véase el apéndice suplementario). Resultados Población del estudio Un total de 275 sujetos entre las edades de 18 y 45 años recibieron la primera dosis de la vacuna, y 257 recibieron la segunda dosis. Todos los sujetos vacunados se incluyeron en el análisis de seguridad. Dos sujetos que inicialmente dieron su consentimiento se retiraron del estudio debido a eventos adversos no serios, incluyendo cuatro eventos en un sujeto (escalofríos, fatiga, malestar e insomnio) y un evento en el segundo sujeto (erupción papular) la mayoría de estos síntomas disminuyeron en 24 horas. Los datos de inmunogenicidad estaban disponibles para 258 sujetos para la primera dosis de vacuna y para 249 sujetos para la segunda dosis de vacuna. Seguridad Las tasas de aparición de reacciones sistémicas y de sitio de inyección durante los primeros 7 días después de cada dosis de vacuna se presentan en la Tabla 1. Tabla 1 Proporción de sujetos con reacciones sistémicas y de sitio de inyección dentro de los 7 días después de la primera y segunda dosis de vacuna . No se registraron eventos adversos graves relacionados con la vacuna. Hubo dos eventos adversos graves registrados en dos sujetos: hospitalización por contusión del pie izquierdo y hospitalización por un aborto electivo. La reacción del sitio de inyección más frecuente después de la vacunación fue el dolor, que ocurrió en 9 a 27 de los sujetos, la reacción sistémica más frecuentemente reportada fue el dolor de cabeza, que ocurrió en 6 a 31 de los sujetos. No hubo diferencias significativas entre las formulaciones de la vacuna con respecto a las reacciones locales después de la primera dosis y la segunda dosis de la vacuna (P0.32 y P0.97, respectivamente, para todas las comparaciones). Con respecto a las reacciones sistémicas, se observó una ligera diferencia entre las formulaciones vacunales después de la primera dosis de vacuna (P0.01), un hallazgo que se debió en gran medida a una tasa inesperadamente baja de cefalea observada en el grupo que recibió la formulación de 30 g Con adyuvante. No se observó ninguna diferencia con respecto a las reacciones sistémicas después de la segunda dosis de vacuna (P0.15). Respuesta inmunitaria A los 21 días después de la primera y segunda dosis, se detectaron anticuerpos neutralizantes funcionales contra la cepa A / Vietnam / 1203/2004 en pacientes que recibieron cualquiera de las seis formulaciones. Tabla 2 Tabla 2 Proporción de sujetos con un anticuerpo de neutralización de virus Título de 1:20 o más. Muestra las tasas de respuesta en sujetos con un título de neutralización del virus de 1:20 o más y la proporción de los pacientes con seroconversión. Muestra el aumento geométrico de la media (GMI) del título desde la línea de base y el porcentaje de seroconversión. Numéricamente, las formulaciones sin adyuvante indujeron las tasas más altas de un título de neutralización de virus de 1:20 o más después de la primera dosis (40,5 y 39,5 para 7,5 gy 15 g sin adyuvante, respectivamente) y la segunda dosis (76,2 y 70,7 para 7,5 gy 15 g sin adyuvante, respectivamente) (Tabla 2). Se obtuvieron resultados similares con respecto a GMI (Tabla 3), ya que se obtuvieron las GMI más altas para las formulaciones sin adyuvante (5,3 y 5,7 para 7,5 gy 15 g sin adyuvante, respectivamente) (Tabla 3). Entre los sujetos con seroconversión (aumento del título por un factor de al menos 4 después de la inmunización), se observaron de nuevo las tasas más altas de respuesta en sujetos que recibieron una formulación de 7,5 g o 15 g sin adyuvante (69,0 y 68,3, respectivamente ) (Tabla 3 ). El análisis estadístico con el uso de un modelo mixto sobre valores de neutralización de virus transformados logarítmicamente confirmó que las formulaciones sin adyuvante indujeron respuestas inmunitarias significativamente más altas que las formulaciones con adyuvante (Plt0.001). No hubo diferencias significativas entre las dos formulaciones sin adyuvante o entre las cuatro formulaciones con adyuvante. Todas las formulaciones vacunales mostraron una proporción similar de aumento en el título de anticuerpos entre el día 21 y el día 42, como se muestra por la interacción no significativa entre la formulación de la vacuna y el día (Tabla 4) Análisis en Múltiple Modelo de Valores Transformados en Registro de Títulos de Neutralización de Virus. Y la Tabla 4 en el Apéndice Suplementario). Tabla 5 Tabla 5 Respuesta de anticuerpos a la cepa homóloga de virus después de la primera y segunda dosis de vacuna. Compara las tasas presumidas de seroprotección, medida por el ensayo de inhibición de la hemaglutinación (es decir, la proporción de sujetos con un título 40) y una hemólisis radial única (es decir, la proporción de sujetos con un área de 25 m 2 en hemólisis radial única). Numéricamente, las formulaciones sin adyuvante fueron de nuevo más inmunogénicas que aquellas con adyuvante. En la hemólisis radial única, el porcentaje de seroprotección 21 días después de la segunda dosis de vacuna sin adyuvante fue 78,6 para la dosis de 7,5 g y 61,0 para la dosis de 15 g. La hemólisis radial única para los anticuerpos H5N1 parecía ser más sensible que el ensayo de inhibición de la hemaglutinación, ya que los valores equivalentes para el ensayo de inhibición de la hemaglutinación fueron 47,6 y 26,8, respectivamente. También analizamos los cambios de los resultados basados en la hemólisis radial simple utilizando un análisis de covarianza mixta para los valores log-transformados y los resultados fueron similares a los obtenidos para los títulos de neutralización del virus. Nuevamente, se observó un efecto significativo de las formulaciones vacunales, con formulaciones sin adyuvante que mostraron tasas de respuesta más altas que aquellas con adyuvante. No hubo diferencia significativa entre las dos formulaciones sin adyuvante o entre las formulaciones con adyuvante (Tabla 4 y Tabla 5 en el Apéndice Suplementario). Neutralización cruzada Las formulaciones de 7,5 g y 15 g sin adyuvante mostraron altos niveles de reactividad cruzada frente a la cepa A / Hong Kong (76,2 y 78,0, respectivamente, con un título neutralizador de 1:20) (Tabla 2). Las respuestas frente a la cepa del clado 2 fueron algo más bajas (con tasas de un título de neutralización del virus de 1:20 de 45,2 y 36,6 para las formulaciones de 7,5 g y 15 g sin adyuvante, respectivamente) (Tabla 2). También se analizó la respuesta de neutralización del virus a las cepas heterólogas utilizando el modelo mixto. Los resultados fueron similares a los de la cepa homóloga. Las formulaciones sin adyuvante provocaron respuestas inmunitarias significativamente mayores que aquellas con adyuvante. Los títulos de anticuerpos aumentaron significativamente desde la línea de base, independientemente de la dosis de vacuna (Tabla 4 y Tablas 3 y 4 en el Apéndice Suplementario). Las curvas de distribución acumulativas inversas para los títulos de anticuerpos después de la primera y segunda dosis de la vacuna contra las tres cepas apoyan el hallazgo de mayor inmunogenicidad de las formulaciones sin adyuvante (Figura 2) Figura 2 Curvas de distribución acumulativa inversa para los títulos de anticuerpos neutralizantes en seis grupos de estudio después La primera y segunda dosis de vacuna contra tres cepas de influenza aviar. El análisis de las tasas de seroprotección con respuestas inmunes homólogas y heterólogas mostró resultados que eran consistentes con los obtenidos mediante análisis directo de valores de títulos de neutralización de virus y hemólisis radial única (Tablas 6 y 7 en el Apéndice Suplementario). Discusión Se ha informado de que las vacunas contra la gripe trivalente de virus enteros son más inmunogénicas que las vacunas subviriónicas, pero también son más propensas a causar reacciones adversas. En nuestro estudio, una vacuna monovalente de virus entero H5N1 tenía un perfil de efectos secundarios similar al de las formulaciones de subvirion H5N1 descritas anteriormente. Lo más importante es que la baja tasa de fiebre entre los sujetos en nuestro estudio (2 a 7) se compara favorablemente con la reportada tanto para vacunas de subvirión H5N1 como para una vacuna H5N1 de virus completo derivado de huevo con adyuvante. 2,3,6,16 Sin embargo, cabe señalar que los sistemas de notificación y las características de los sujetos difieren entre los diversos estudios. Con respecto a la inmunogenicidad, se obtuvo la respuesta más alta de anticuerpos neutralizantes después de la segunda dosis de la vacuna (76.2) con la formulación de 7.5 g sin adyuvante, lo que equivalía a una tasa de seroconversión de 69.0 y representaba un aumento de un factor de 4 O más en el título de neutralización después de dos dosis de vacuna (Tabla 2 y Tabla 3). Estos datos son también similares a los niveles de inmunogenicidad informados en un estudio de una vacuna H5N1 de virus entero derivada de huevo, en la que 96 de los sujetos que recibieron dos dosis de formulaciones de 5 g o 10 g tenían un título de neutralización de 1: 20 o más 6, aunque las diferencias en los sistemas de ensayo deben tenerse en cuenta al hacer tales comparaciones directas. Se obtuvieron tasas más bajas de seroprotección y seroconversión (según se definen en las directrices del Comité de Especialidades Farmacéuticas 17) con el ensayo de hemaglutinación-inhibición que con el ensayo de neutralización del virus, lo que apoya el hallazgo de que el ensayo de inhibición de la hemaglutinación es menos sensible Para la detección de anticuerpos anti-H5, como se informó anteriormente. 10,11 En nuestro estudio, la hemólisis radial única, que se considera que tiene una sensibilidad equivalente a la del ensayo de hemaglutinación-inhibición para cepas estacionales de influenza18, mostró ser más sensible que el ensayo de inhibición de la hemaglutinación para el H5N1. La falta de mejora de la inmunogenicidad de la vacuna mediante el uso de coadyuvante de alumbre a las dosis estudiadas aquí fue consistente con los datos de un estudio previo, que mostró que no se observó efecto del adyuvante de alumbre con una dosis de 15 g de vacuna subvirion, G de formulación sin alumbre era más inmunogénica que la formulación con adyuvante. En el estudio anterior, se observó una respuesta inmune mejorada con el uso de alumbre sólo con la formulación de 30 g. No investigamos esta dosis sin alumbre en nuestro estudio. Sin embargo, otros estudios han descrito efectos positivos sustanciales de otros coadyuvantes sobre la inmunogenicidad de H5N1. El uso de una emulsión basada en aceite en agua en una dosis de 3,8 g de vacuna de virus dividido dio como resultado 82 seroconversión, en comparación con la seroconversión 4 sin adyuvante. 16 La adición de otro adyuvante a base de aceite en agua (MF-59) a una vacuna H5N3 también se asoció con un aumento sustancial en la respuesta de anticuerpos. 19 Nuestros datos también mostraron que la vacuna basada en el clado 1 de virus completo puede inducir una respuesta sustancial de neutralización cruzada frente a cepas de clado 2 y clado 3. Los resultados descritos en la Tabla 2 son alentadores: después de dos dosis de 7,5 g de la formulación sin adyuvante, las proporciones de sujetos con títulos neutralizantes de 1:20 o más fueron 45 de las inmunizadas contra la cepa india de clado 2 y 76 de aquellas Inmunizados contra la cepa Hong Kong del clado 3. Sin embargo, no hay evidencia disponible que indique qué título neutralizador es suficiente para conferir protección. La mayoría de los estudios de vacunas H5N1 de virus dividido y de virus completos no han descrito intentos de determinar la reactividad cruzada de anticuerpos frente a otras cepas del virus H5N1. Sin embargo, un estudio reciente de una nueva vacuna de virus dividido con adyuvante también mostró altos niveles de neutralización cruzada contra una cepa de clado 2. Además, en un estudio con 15 sujetos, dos dosis de una vacuna H5N3 con MF-59 como adyuvante indujeron niveles intermedios de reactividad cruzada a cepas antigénicamente distintas de H5N1 y tres dosis indujeron altos niveles de reactividad cruzada. La aparente ausencia de una relación dosis-respuesta en nuestro estudio puede ser sorprendente. Sin embargo, está de acuerdo con una serie de estudios de la vacuna para la gripe pandémica. Leroux-Roels et al. No informaron relación entre la dosis de antígeno y la respuesta de anticuerpo neutralizante para formulaciones de H5N1 con adyuvante 16, y parecía haber una relación de respuesta de dosis inversa con respecto a las respuestas a la cepa de clado 2. Un número de otros estudios que implican otras vacunas de cepa pandémica H9N2, 21 H5N3, 19 y H2N2 22 no han demostrado relación dosis-respuesta o incluso una respuesta reducida en dosis más altas. Las razones de estos hallazgos no son claras, pero al menos con respecto a las vacunas con adyuvante, se ha especulado que la relación de adyuvante frente al antígeno puede ser crítica para determinar el efecto de mejora inmune en lugar de la concentración de antígeno solo. Para otras vacunas virales, particularmente aquellas con proteínas solubles, se ha reportado que hay relaciones de dosis-respuesta distintas para la inducción de diversas citoquinas. En muchos estudios, se han obtenido respuestas similares a las mediadas por células T auxiliares de tipo 2 en dosis bajas de vacuna, y se han obtenido respuestas similares a las mediadas por células T auxiliares de tipo 1 en dosis más altas. Se requerirán más estudios centrados en las respuestas de las células T para investigar este fenómeno. Además, estos estudios se extenderán mediante el uso de dosis de antígenos inferiores a 3,75 g para confirmar y ampliar los resultados obtenidos en nuestro estudio. Nuestro estudio proporciona información inicial de seguridad e inmunogenicidad para una vacuna H5N1 de virus entero producida en el cultivo de células Vero. También muestra que se puede obtener una respuesta inmune ampliamente reactiva al clado 2 y al clado 3 del virus H5N1 con el uso de una vacuna de clade 1 de dosis baja sin adyuvante. Dado que no se observó ninguna relación de doserespuesta significativa, la formulación de 7,5 g sin adyuvante ha sido elegida para un desarrollo posterior. Con el apoyo de Baxter. Los Dres. Ehrlich, Berezuk, Fritsch, Lw-Baselli, Vartian, Bobrovsky, Pavlova, Pllabauer, Kistner, y Barrett informan haber sido contratados por Baxter y tener una participación en la empresa Drs. Kistner y Barrett, titulares de patentes sobre vacunas contra la influenza derivadas de cultivos celulares de Vero. Dr. Mller, recibiendo honorarios de consultoría y conferencias y apoyo de donaciones (a la Universidad Médica de Viena) de Baxter Dr. Tambyah, como miembro del Comité Asesor AsiaPacífico sobre Baxter, Merlion Pharmaceuticals y Janssen-Cilag, honorarios de conferencia de Pfizer, Wyeth e IBC Asia, y el apoyo de Baxter e Interimmune y el Dr. Montomoli, recibiendo honorarios de conferencias y apoyo a las donaciones (a la Universidad de Siena ) De Baxter. No se informó ningún otro conflicto de interés potencial relacionado con este artículo. Los Dres. Ehrlich y Mller contribuyeron igualmente a este artículo. Este estudio está dedicado a la memoria del Dr. Michel Canavaggio, jefe de investigación y desarrollo de biosciencia de Baxter y gran partidario de este proyecto, fallecido en julio de 2006, unas 6 semanas después del inicio del estudio. Agradecemos a los siguientes miembros del equipo de investigación y desarrollo de Baxter por su papel crítico en este estudio: L. Grillberger, K. Howard, W. Mundt, M. Reiter, H. Savidis-Dacho, C. Tauer y W. Wodal N. Cox y S. Klimov de los Centros para el Control y Prevención de Enfermedades por proporcionar el virus H5N1 y J. Wood del Instituto Nacional de Patrones y Control Biológicos por proporcionar los estándares de referencia. Baxter BioScience (HJEGBSFAL-BNVRBBGPEMPOKPNB) y el Departamento de Farmacología Clínica de la Universidad Médica de Viena, el Hospital General de Viena (MMCJ), tanto en el Hospital General Changi de Viena (HMLO) como en la Universidad Nacional De Singapur y el Hospital Universitario Nacional (PATDF), todos en Singapur y la Universidad de Siena, Siena, Italia (EM). Dirija las solicitudes de reimpresión al Dr. Mller en el Departamento de Farmacología Clínica, Universidad Médica de Viena, Hospital General de Viena (AKH), Whillinger Grtel 18-20, 1090 Viena, Austria, o en markus. muellermeduniwien. ac. at. Apéndice Además de los autores, los siguientes investigadores contribuyeron al ensayo: Junta de vigilancia y seguridad de datos: E. Marth, R. Konior, F. Sonnenburg Baxter Equipo de estudio clínico: K. Birthistle, T. Dvorak, S. Geyer, M. Kraft, MC Leitgeb, F. Maritsch, L. Phillipson, E. Robotka. Viena: A. Abrahim, M. Bauer, M. Brunner, A. Cornea, C. Drucker, Z. Erdogan, J. Griss, B. Heinisch, F. Kovar, E. Lackner, C. Lambers, O. Langer, I. Leitner, C. Marsik, W. Poeppl, M. Popovic, R. Sauermann, R. Schaberl, G. Sodeck, C. Thallinger, F. Traunmueller, C. Wagner, M. Zeitlinger Singapur: Hospital General Changi (Dirección del Centro de Estudios): SK Chua, S. Chuin, R. Fong, A. S. Foo, A. G. Koh, P. K. Lim, S. Y. Yap, L. H. Yew National University Hospital (Dirección del Centro de Estudios): J. W.L. Goh, LY. Hsu, C. W.P. Loke, J. Y.C. Ng, E. L. Toh, P. Weatherill, Y. P. Zhou. Referencias Wood JM. Selección de cepas de la vacuna contra la gripe y el desarrollo de vacunas pandémicas. Vaccine 200220: Suppl 5: 40-44 CrossRef Web de la Ciencia Treanor JJ. Campbell JD. Zangwill KM. Rowe T. Wolff M. Seguridad e inmunogenicidad de una vacuna inactivada subvirion influenza A (H5N1). N Engl J Med 2006354: 1343-1351 Texto completo gratuito Web of Science Medline Bresson JL. Perronne C. Launay O. et al. Seguridad e inmunogenicidad de una vacuna inactivada de virus de gripe dividida virión A / Vietnam / 1194/2004 (H5N1): ensayo clínico aleatorizado de fase I. Lancet 2006367: 1657-1664 CrossRef Web de la ciencia Medline Wood JM. Desarrollo de vacunas contra la gripe pandémica. Philos Trans R Soc Lond B Biol Sci 2001356: 1953 - 1960 CrossRef Web de Ciencias Medline Nicholson KG. Tyrrell DAJ. Harrison P. et al. Estudios clínicos de la vacuna monovalente inactivada de virus enteros y subunidad A / URSS / 77 (H1N1): respuestas serológicas y reacciones clínicas. J Biol Stand 19797: 123 - 136 CrossRef Medline Lin J. Zhang, J. Dong X. et al. Safety and immunogenicity of an inactivated adjuvanted whole-virion influenza A (H5N1) vaccine: phase 1 randomised controlled trial. Lancet 2006368:991-997 CrossRef Web of Science Medline Nicolson C. Major D. Wood JM. Robertson JS. Generation of influenza vaccine viruses on Vero cells by reverse genetics: an H5N1 candidate vaccine strain produced under a quality system. Vaccine 200523:2943-2952 CrossRef Web of Science Medline Kistner O. Howard K. Spruth M. et al. Cell culture (Vero) derived whole-virus (H5N1) vaccine based on wild-type virus strain induces cross-protective immune responses. Vaccine 200725:6028-6036 CrossRef Web of Science Medline Kistner O. Barrett PN. Mundt W. Reiter M. Schober-Bendixen S. Dorner F. Development of a mammalian cell (Vero)-derived candidate influenza virus vaccine. Vaccine 199816:960-968 CrossRef Web of Science Medline Rowe T. Abernathy RA. Hu-Primmer J. et al. Detection of antibody to avian influenza A (H5N1) virus in human serum by using a combination of serologic assays. J Clin Microbiol 199937:937-943 Web of Science Medline Lu BL. Webster RG. Hinshaw VS. Failure to detect hemagglutination-inhibiting antibodies with intact avian influenza virions. Infect Immun 198238:530-535 Web of Science Medline Stephenson I. Wood JM. Nicholson KG. Charlett A. Zambon MC. Detection of anti-H5 responses in human sera by HI using horse erythrocytes following MF59-adjuvanted influenza A/Duck/Singapore/97 vaccine. Virus Res 2004103:91-95 CrossRef Web of Science Medline Reed LJ. Muench H. A simple method of estimating fifty percent endpoints. Am J Hyg 193827:493-497 Schild GC. Pereira MS. Chakraverty P. Single-radial-hemolysis: a new method for the assay of antibody to influenza haemagglutinin: applications for diagnosis and seroepidemiologic surveillance of influenza. Bull World Health Organ 197552:43-50 Web of Science Medline Fitting a model that contains a random effect. In: Collett D. Modeling binary data. Boca Raton, FL: Chapman amp Hall/CRC Press, 1991:202-12. Leroux-Roels I. Borkowski A. Vanwolleghem T. et al. Antigen sparing and cross-reactive immunity with an adjuvanted rH5N1 prototype pandemic influenza vaccine: a randomised controlled trial. Lancet 2007370:580-589 CrossRef Web of Science Medline Committee for Proprietary Medicinal Products. Note for guidance on harmonisation of requirements for influenza vaccines. London: European Agency for the Evaluation of Medicinal Products, 1997. (Publication no. CPMP/BWP/214/96.) Wood JM. Gaines-Das RE. Taylor J. Charkraverty P. Comparison of influenza serological techniques by international collaborative study. Vaccine 199412:167-174 CrossRef Web of Science Medline Nicholson KG. Colegate AE. Podda A. et al. Safety and antigenicity of non-adjuvanted and MF59-adjuvanted influenza A/Duck/Singapore/97 (H5N3) vaccine: a randomised trial of two potential vaccines against H5N1 influenza. Lancet 2001357:1937-1943 CrossRef Web of Science Medline Stephenson I. Bugarini R. Nicholson KG. Et al. Cross-reactivity to highly pathogenic avian influenza H5N1 viruses after vaccination with nonadjuvanted and MF59-adjuvanted influenza A/Duck/Singapore/97 (H5N3) vaccine: a potential priming strategy. J Infect Dis 2005191:1210-1215 CrossRef Web of Science Medline Stephenson I. Nicholson KG. Gluck R. et al. Safety and antigenicity of whole virus and subunit influenza A/Hong Kong/1073/99 (H9N2) vaccine in healthy adults: phase I randomised trial. Lancet 2003362:1959-1966 CrossRef Web of Science Medline Hehme N. Engelmann H. Kuenzel W. Neumeier E. Saenger R. Immunogenicity of a monovalent, aluminum-adjuvanted influenza whole virus vaccine for pandemic use. Virus Res 2004103:163-171 CrossRef Web of Science Medline Constant SL. Bottomly K. Induction of TH1 and TH2 CD4 T cell responses: the alternative approaches. Annu Rev Immunol 199715:297-322 CrossRef Web of Science Medline Citing Articles A. Roldo, A. C. Silva, M. C.M. Mellado, P. M. Alves, M. J.T. Carrondo. 2017. Viruses and Virus-Like Particles in Biotechnology: Fundamentals and Applications. Reference Module in Life Sciences. CrossRef Weiping Cao, William G. Davis, Jin Hyang Kim, Juan A. De La Cruz, Andrew Taylor, Grant R. Hendrickson, Amrita Kumar, Priya Ranjan, L. Andrew Lyon, Jacqueline M. Katz, Shivaprakash Gangappa, Suryaprakash Sambhara. (2016) An oil-in-water nanoemulsion enhances immunogenicity of H5N1 vaccine in mice. Nanomedicine: Nanotechnology, Biology and Medicine 12 :7, 1909-1917. CrossRef Claudia Maria Trombetta, Emanuele Montomoli. (2016) Influenza immunology evaluation and correlates of protection: a focus on vaccines. Expert Review of Vaccines 15 :8, 967-976. CrossRef Takeshi Naruse, Tadashi Fukuda, Tetsuro Tanabe, Munetaka Ichikawa, Yoshiaki Oda, Shinji Tochihara, Kazuhiko Kimachi, Yoichiro Kino, Kohji Ueda. (2017) A clinical phase I study of an EB66 cell-derived H5N1 pandemic vaccine adjuvanted with AS03. Vaccine 33 . 6078-6084. CrossRef Rita Czako, Kanta Subbarao. (2017) Refining the approach to vaccines against influenza A viruses with pandemic potential. Future Virology 10 :9, 1033-1047. CrossRef Barnaby E Young, Sapna P Sadarangani, Yee Sin Leo. (2017) The avian influenza vaccine Emerflu. Why did it fail. Expert Review of Vaccines 14 . 1125-1134. CrossRef Duckhyang Shin, Kuk Jin Park, Hyeon Lee, Eun Young Cho, Mi Suk Kim, Mi Hui Hwang, Soo In Kim, Dong Ho Ahn. (2017) Comparison of immunogenicity of cell-and egg-passaged viruses for manufacturing MDCK cell culture-based influenza vaccines. Virus Research 204 . 40-46. CrossRef Nagendra R. Hegde. (2017) Cell culture-based influenza vaccines: a necessary and indispensable investment for the future. Human Vaccines amp Immunotherapeutics . 00-00. CrossRef M. Trondsen, L. A. Aqrawi, F. Zhou, G. Pedersen, M. C. Trieu, P. Zhou, R. J. Cox. (2017) Induction of Local Secretory IgA and Multifunctional CD4 T-helper Cells Following Intranasal Immunization with a H5N1 Whole Inactivated Influenza Virus Vaccine in BALB/c Mice. Scandinavian Journal of Immunology 81 :10.1111/sji.2017.81.issue-5, 305-317. CrossRef Gerald Aichinger, Barbara Grohmann-Izay, Maikel V. W. van der Velden, Sandor Fritsch, Manuela Koska, Daniel Portsmouth, Mary Kate Hart, Wael El-Amin, Otfried Kistner, P. Noel Barrett, S. A. Plotkin. (2017) Phase I/II Randomized Double-Blind Study of the Safety and Immunogenicity of a Nonadjuvanted Vero Cell Culture-Derived Whole-Virus H9N2 Influenza Vaccine in Healthy Adults. Clinical and Vaccine Immunology 22 . 46-55. CrossRef Joanne M. Langley, Louise Frenette, Robert Jeanfreau, Scott A. Halperin, Michael Kyle, Laurence Chu, Shelly McNeil, Mamadou Dram, Philippe Moris, Louis Fries, David W. Vaughn. (2017) Immunogenicity of heterologous H5N1 influenza booster vaccination 6 or 18 months after primary vaccination in adults: A randomized controlled clinical trial. Vaccine 33 . 559-567. CrossRef Claudia Trombetta, Daniele Perini, Stuart Mather, Nigel Temperton, Emanuele Montomoli. (2014) Overview of Serological Techniques for Influenza Vaccine Evaluation: Past, Present and Future. Vaccines 2 . 707-734. CrossRef Zhongpeng Zhao, Chuanbo Fan, Yueqiang Duan, Liangyan Zhang, Min Li, Xiaolan Yang, Ruisheng Li, Penghui Yang, Xiliang Wang. (2014) Protection from infection with influenza A H7N9 virus in a mouse model by equine neutralizing F(ab)2. International Immunopharmacology 23 . 134-138. CrossRef Brendon Y Chua, Lorena E Brown, David C Jackson. (2014) Considerations for the rapid deployment of vaccines against H7N9 influenza. Expert Review of Vaccines 13 . 1327-1337. CrossRef Calvin C. Willhite, Nataliya A. Karyakina, Robert A. Yokel, Nagarajkumar Yenugadhati, Thomas M. Wisniewski, Ian M. F. Arnold, Franco Momoli, Daniel Krewski. (2014) Systematic review of potential health risks posed by pharmaceutical, occupational and consumer exposures to metallic and nanoscale aluminum, aluminum oxides, aluminum hydroxide and its soluble salts. Critical Reviews in Toxicology 44 . 1-80. CrossRef Jenny G. H. Low, Lawrence S. Lee, Eng Eong Ooi, Kantharaj Ethirajulu, Pauline Yeo, Alex Matter, John E. Connolly, David A. G. Skibinski, Philippe Saudan, Martin Bachmann, Brendon J. Hanson, Qingshu Lu, Sebastian Maurer-Stroh, Sam Lim, Veronica Novotny-Diermayr. (2014) Safety and immunogenicity of a virus-like particle pandemic influenza A (H1N1) 2009 vaccine: Results from a double-blinded, randomized Phase I clinical trial in healthy Asian volunteers. Vaccine 32 . 5041-5048. CrossRef R. Fritz, N. Hetzelt, R. Ilk, C. Hohenadl, M. V. W. van der Velden, G. Aichinger, D. Portsmouth, O. Kistner, M. K. Howard, P. N. Barrett, T. R. Kreil. (2014) Neuraminidase-Inhibiting Antibody Response to H5N1 Virus Vaccination in Chronically Ill and Immunocompromised Patients. Open Forum Infectious Diseases 1 . ofu072-ofu072. CrossRef Catherine J Luke, Kanta Subbarao. (2014) Improving pandemic H5N1 influenza vaccines by combining different vaccine platforms. Expert Review of Vaccines 13 . 873-883. CrossRef Anna-Karin Maltais, Koert J. Stittelaar, Edwin J. B. Veldhuis Kroeze, Geert van Amerongen, Marcel L. Dijkshoorn, Gabriel P. Krestin, Jorma Hinkula, Hans Arwidsson, Alf Lindberg, Albert D. M.E. Osterhaus. (2014) Intranasally administered Endocine formulated 2009 pandemic influenza H1N1 vaccine induces broad specific antibody responses and confers protection in ferrets. Vaccine 32 . 3307-3315. CrossRef Sabine Nakowitsch, Andrea M. Waltenberger, Nina Wressnigg, Nicole Ferstl, Andrea Triendl, Bettina Kiefmann, Emanuele Montomoli, Giulia Lapini, Maria Sergeeva, Thomas Muster, Julia R. Romanova. (2014) Egg - or cell culture-derived hemagglutinin mutations impair virus stability and antigen content of inactivated influenza vaccines. Biotechnology Journal 9 :10.1002/biot. v9.3, 405-414. CrossRef M. V. W. van der Velden, R. Fritz, E. M. Pollabauer, D. Portsmouth, M. K. Howard, T. R. Kreil, T. Dvorak, S. Fritsch, T. Vesikari, J. Diez-Domingo, P. Richmond, B. W. Lee, O. Kistner, H. J. Ehrlich, P. N. Barrett, G. Aichinger. (2014) Safety and Immunogenicity of a Vero Cell Culture-Derived Whole-Virus Influenza A(H5N1) Vaccine in a Pediatric Population. Journal of Infectious Diseases 209 . 12-23. CrossRef Eun Hye Park, Jung Yum, Keun Bon Ku, Heui Man Kim, Young Myong Kang, Jeong Cheol Kim, Ji An Kim, Yoo Kyung Kang, Sang Heui Seo. (2014) Red Ginseng-containing diet helps to protect mice and ferrets from the lethal infection by highly pathogenic H5N1 influenza virus. Journal of Ginseng Research 38 . 40-46. CrossRef Mariana Baz, Catherine J. Luke, Xing Cheng, Hong Jin, Kanta Subbarao. (2013) H5N1 vaccines in humans. Virus Research 178 . 78-98. CrossRef Sung-Ching Pan, Hsiang-Chi Kung, Tsui-Mai Kao, Hsio Wu, Shao-Xing Dong, Mei-Hua Hu, Ai-Hsiang Chou, Pele Chong, Szu-Min Hsieh, Shan-Chwen Chang. (2013) The Madin-Darby canine kidney cell culture derived influenza A/H5N1 vaccine: A Phase I trial in Taiwan. Journal of Microbiology, Immunology and Infection 46 . 448-455. CrossRef James F. Cummings, Melanie L. Guerrero, James E. Moon, Paige Waterman, Robin K. Nielsen, Stacie Jefferson, F. Liaini Gross, Kathy Hancock, Jacqueline M. Katz, Vidadi Yusibov. (2013) Safety and immunogenicity of a plant-produced recombinant monomer hemagglutinin-based influenza vaccine derived from influenza A (H1N1)pdm09 virus: A Phase 1 dose-escalation study in healthy adults. Vaccine . CrossRef Nina Wressnigg, Eva-Maria Pllabauer, Gerald Aichinger, Daniel Portsmouth, Alexandra Lw-Baselli, Sandor Fritsch, Ian Livey, Brian A Crowe, Michael Schwendinger, Peter Brhl, Andreas Pilz, Thomas Dvorak, Julia Singer, Clair Firth, Benjamin Luft, Bernhard Schmitt, Markus Zeitlinger, Markus Mller, Herwig Kollaritsch, Maria Paulke-Korinek, Meral Esen, Peter G Kremsner, Hartmut J Ehrlich, P Noel Barrett. (2013) Safety and immunogenicity of a novel multivalent OspA vaccine against Lyme borreliosis in healthy adults: a double-blind, randomised, dose-escalation phase 1/2 trial. The Lancet Infectious Diseases 13 . 680-689. CrossRef Marc P. Girard, John S. Tam, Yuri Pervikov, Jacqueline M. Katz. (2013) Report on the first WHO integrated meeting on development and clinical trials of influenza vaccines that induce broadly protective and long-lasting immune responses. Vaccine 31 :37, 3766-3771. CrossRef Larry R. Smith, Walter Wodal, Brian A. Crowe, Astrid Kerschbaum, Peter Bruehl, Michael G. Schwendinger, Helga Savidis-Dacho, Sean M. Sullivan, Mark Shlapobersky, Jukka Hartikka, Alain Rolland, P. Noel Barrett, Otfried Kistner. (2013) Preclinical evaluation of Vaxfectin-adjuvanted Vero cell-derived seasonal split and pandemic whole virus influenza vaccines. Human vaccines amp immunotherapeutics 9 . 1333-1345. CrossRef Ling Tao, JianJun Chen, Jin Meng, Yao Chen, Hongxia Li, Yan Liu, Zhenhua Zheng, Hanzhong Wang. (2013) Enhanced protective efficacy of H5 subtype influenza vaccine with modification of the multibasic cleavage site of hemagglutinin in retroviral pseudotypes. Virologica Sinica . CrossRef P. Noel Barrett, Daniel Portsmouth, Hartmut J. Ehrlich. 2013. Accelerated Biopharmaceutical Development: Vero Cell Technology and Pandemic Influenza Vaccine Production. Modern Biopharmaceuticals, 349-386. CrossRef P Noel Barrett, Daniel Portsmouth, Hartmut J Ehrlich. (2013) Vero cell culture-derived pandemic influenza vaccines: preclinical and clinical development. Expert Review of Vaccines 12 . 395-413. CrossRef Marc Gurwith, Michael Lock, Eve M Taylor, Glenn Ishioka, Jeff Alexander, Tim Mayall, John E Ervin, Richard N Greenberg, Cynthia Strout, John J Treanor, Richard Webby, Peter F Wright. (2013) Safety and immunogenicity of an oral, replicating adenovirus serotype 4 vector vaccine for H5N1 influenza: a randomised, double-blind, placebo-controlled, phase 1 study. The Lancet Infectious Diseases 13 :3, 238-250. CrossRef Ilseob Lee, Jin Il Kim, Man-Seong Park. (2013) Cell Culture-based Influenza Vaccines as Alternatives to Egg-based Vaccines. Journal of Bacteriology and Virology 43 . 9. CrossRef Gillian M. Keating, Greg L. Plosker, Katherine A. Lyseng-Williamson. (2012) A/H5N1 Prepandemic Influenza Vaccine (Vepacel): A Guide to Its Use. BioDrugs 26 . 425-430. CrossRef Jessica Chichester, R. Jones, Brian Green, Mark Stow, Fudu Miao, George Moonsammy, Stephen Streatfield, Vidadi Yusibov. (2012) Safety and Immunogenicity of a Plant-Produced Recombinant Hemagglutinin-Based Influenza Vaccine (HAI-05) Derived from A/Indonesia/05/2005 (H5N1) Influenza Virus: A Phase 1 Randomized, Double-Blind, Placebo-Controlled, Dose-Escalation Study in Healthy Adults. Viruses 4 . 3227-3244. CrossRef Kohhei Tetsutani, Ken J. Ishii. (2012) Adjuvants in influenza vaccines. Vaccine 30 . 7658-7661. CrossRef Felix Geeraedts, Wouter ter Veer, Jan Wilschut, Anke Huckriede, Aalzen de Haan. (2012) Effect of viral membrane fusion activity on antibody induction by influenza H5N1 whole inactivated virus vaccine. Vaccine 30 . 6501-6507. CrossRef X. Hu, K. Hong, C. Zhao, Y. Zheng, L. Ma, Y. Ruan, H. Gao, K. Greene, M. Sarzotti-Kelsoe, D. C. Montefiori, Y. Shao. (2012) Profiles of neutralizing antibody response in chronically human immunodeficiency virus type 1 clade B-infected former plasma donors from China naive to antiretroviral therapy. Journal of General Virology 93 . 2267-2278. CrossRef Kelvin KW To, Kenneth HL Ng, Tak-Lun Que, Jacky MC Chan, Kay-Yan Tsang, Alan KL Tsang, Honglin Chen, Kwok-Yung Yuen. (2012) Avian influenza A H5N1 virus: a continuous threat to humans. Emerging Microbes amp Infections 1 . e25. CrossRef Maikel V. W. van der Velden, Gerald Aichinger, Eva Maria Pllabauer, Alexandra Lw-Baselli, Sandor Fritsch, Karima Benamara, Otfried Kistner, Markus Mller, Markus Zeitlinger, Herwig Kollaritsch, Timo Vesikari, Hartmut J. Ehrlich, P. Noel Barrett. (2012) Cell culture (Vero cell) derived whole-virus non-adjuvanted H5N1 influenza vaccine induces long-lasting cross-reactive memory immune response: Homologous or heterologous booster response following two dose or single dose priming. Vaccine 30 . 6127-6135. CrossRef Alexandra Loew-Baselli, Borislava G. Pavlova, Sandor Fritsch, Eva Maria Poellabauer, Wolfgang Draxler, Otfried. Kistner, Ulrich Behre, Rudolf Angermayr, Johannes Neugebauer, Karola Kirsten, Elisabeth Frster-Waldl, Ralph Koellges, Hartmut J. Ehrlich, P. Noel Barrett. (2012) A non-adjuvanted whole-virus H1N1 pandemic vaccine is well tolerated and highly immunogenic in children and adolescents and induces substantial immunological memory. Vaccine 30 . 5956-5966. CrossRef Nicolas Sabarth, Helga Savidis-Dacho, Michael G. Schwendinger, Peter Brhl, Daniel Portsmouth, Brian A. Crowe, Otfried Kistner, P. Noel Barrett, Thomas R. Kreil, M. Keith Howard. (2012) A cell culture-derived whole-virus H5N1 vaccine induces long-lasting cross-clade protective immunity in mice which is augmented by a homologous or heterologous booster vaccination. Vaccine 30 . 5533-5540. CrossRef Michael Schotsaert, Xavier Saelens, Geert Leroux-Roels. (2012) Influenza vaccines: T-cell responses deserve more attention. Expert Review of Vaccines 11 . 949-962. CrossRef Ali Rowhani-Rahbar, Nicola P Klein, Roger Baxter. (2012) Assessing the safety of influenza vaccination in specific populations: children and the elderly. Expert Review of Vaccines 11 . 973-984. CrossRef Greg L. Plosker. (2012) A/H5N1 Prepandemic Influenza Vaccine (Whole Virion, Vero Cell-Derived, Inactivated) Vepacel. Drugs 72 . 1543-1557. CrossRef Candice Yuen-Yue Chan, Paul Anantharajah Tambyah. (2012) Preflucel: a Vero-cell culture-derived trivalent influenza vaccine. Expert Review of Vaccines 11 . 759-773. CrossRef Walter Wodal, Falko G. Falkner, Astrid Kerschbaum, Claudia Gaiswinkler, Richard Fritz, Stefan Kiermayr, Daniel Portsmouth, Helga Savidis-Dacho, Sogue Coulibaly, Christina Piskernik, Christine Hohenadl, M. Keith Howard, Otfried Kistner, P. Noel Barrett, Thomas R. Kreil. (2012) A cell culture-derived whole-virus H9N2 vaccine induces high titer antibodies against hemagglutinin and neuraminidase and protects mice from severe lung pathology and weight loss after challenge with a highly virulent H9N2 isolate. Vaccine 30 . 4625-4631. CrossRef Hartmut J. Ehrlich, Gregory Berezuk, Sandor Fritsch, Gerald Aichinger, Julia Singer, Daniel Portsmouth, Mary Kate Hart, Wael El-Amin, Otfried Kistner, P. Noel Barrett. (2012) Clinical development of a Vero cell culture-derived seasonal influenza vaccine. Vaccine 30 . 4377-4386. CrossRef Hartmut J. Ehrlich, Markus Mller, Herwig Kollaritsch, Fritz Pinl, Bernhard Schmitt, Markus Zeitlinger, Alexandra Loew-Baselli, Thomas R. Kreil, Otfried Kistner, Daniel Portsmouth, Sandor Fritsch, Friedrich Maritsch, Gerald Aichinger, Borislava G. Pavlova, P. Noel Barrett. (2012) Pre-vaccination immunity and immune responses to a cell culture-derived whole-virus H1N1 vaccine are similar to a seasonal influenza vaccine. Vaccine 30 . 4543-4551. CrossRef Fangye Zhou, Jian Zhou, Lei Ma, Shaohui Song, Xinwen Zhang, Weidong Li, Shude Jiang, Yue Wang, Guoyang Liao. (2012) High-yield production of a stable Vero cell-based vaccine candidate against the highly pathogenic avian influenza virus H5N1. Biochemical and Biophysical Research Communications 421 . 850-854. CrossRef Emanuele Montomoli, Baharak Khadang, Simona Piccirella, Claudia Trombetta, Elisa Mennitto, Ilaria Manini, Valerio Stanzani, Giulia Lapini. (2012) Cell culture-derived influenza vaccines from Vero cells: a new horizon for vaccine production. Expert Review of Vaccines 11 . 587-594. CrossRef Nathalie Garon, David W Vaughn, Arnaud M Didierlaurent. (2012) Development and evaluation of AS03, an Adjuvant System containing - tocopherol and squalene in an oil-in-water emulsion. Expert Review of Vaccines 11 . 349-366. CrossRef Philip Dormitzer, Theodore Tsai, Giuseppe Del Giudice. (2012) New technologies for influenza vaccines. Human Vaccines amp Immunotherapeutics 8 . 45-58. CrossRef Paul A. Tambyah, Annelies Wilder-Smith, Borislava G. Pavlova, P. Noel Barrett, Helen M. L. Oh, David S. Hui, Kwok-yung Yuen, Sandor Fritsch, Gerald Aichinger, Alexandra Loew-Baselli, Maikel van der Velden, Friedrich Maritsch, Otfried Kistner, Hartmut J. Ehrlich. (2012) Safety and immunogenicity of two different doses of a Vero cell-derived, whole virus clade 2 H5N1 (A/Indonesia/05/2005) influenza vaccine. Vaccine 30 . 329-335. CrossRef Qunfeng Wu, Shaobo Xiao, Huiying Fan, Yang Li, Jinfang Xu, Zhen Li, Wei Lu, Xiaoyue Su, Wei Zou, Meilin Jin, Huanchun Chen, Liurong Fang. (2011) Protective immunity elicited by a pseudotyped baculovirus-mediated bivalent H5N1 influenza vaccine. Antiviral Research 92 . 493-496. CrossRef Jessica A. Belser, Cynthia B. Snider, Nancy J. Cox, Frederick G. Hayden. (2011) XIth International Symposium on Respiratory Viral Infections. Influenza and Other Respiratory Viruses 5 :10.1111/irv.2011.5.issue-6, 443-e457. CrossRef Thomas R. Kreil, John K. Mc Vey, Laura Shau-Ping Lei, Laureano Camacho, Walter Wodal, Astrid Kerschbaum, Edy Segura, Etienne Vandamme, Patrick Gavit, Hartmut J. Ehrlich, P. Noel Barrett, Donald A. Baker. (2011) Preparation of commercial quantities of a hyperimmune human intravenous immunoglobulin preparation against an emerging infectious disease: the example of pandemic H1N1 influenza. Transfusion . no-no. CrossRef Gerald Aichinger, Hartmut J. Ehrlich, John G. Aaskov, Sandor Fritsch, Christiane Thomasser, Wolfgang Draxler, Michael Wolzt, Markus Mller, Fritz Pinl, Pierre Van Damme, Annick Hens, Jack Levy, Daniel Portsmouth, Georg Holzer, Otfried Kistner, Thomas R. Kreil, P. Noel Barrett. (2011) Safety and immunogenicity of an inactivated whole virus Vero cell-derived Ross River virus vaccine: A randomized trial. Vaccine 29 . 9376-9384. CrossRef John Steel. (2011) New Strategies for the Development of H5N1 Subtype Influenza Vaccines. BioDrugs 25 . 285-298. CrossRef Rebecca J. Cox, Gabriel Pedersen, Abdullah S. Madhun, Signe Svindland, Marianne Svik, Lucy Breakwell, Katja Hoschler, Marieke Willemsen, Laura Campitelli, Jane Kristin Nstbakken, Gerrit Jan Weverling, Jaco Klap, Kenneth C. McCullough, Maria Zambon, Ronald Kompier, Haakon Sjursen. (2011) Evaluation of a virosomal H5N1 vaccine formulated with Matrix M adjuvant in a phase I clinical trial. Vaccine 29 . 8049-8059. CrossRef Jeremy C. Jones, Erik W. Settles, Curtis R. Brandt, Stacey Schultz-Cherry. (2011) Virus aggregating peptide enhances the cell-mediated response to influenza virus vaccine. Vaccine 29 . 7696-7703. CrossRef Chunyan He, Zhiqiang Yang, Kuitang Tong. (2011) Downstream processing of Vero cell-derived human influenza A virus (H1N1) grown in serum-free medium. Journal of Chromatography A 1218 . 5279-5285. CrossRef Michael L Perdue, Frank Arnold, Sheng Li, Armen Donabedian, Vittoria Cioce, Thomas Warf, Robert Huebner. (2011) The future of cell culture-based influenza vaccine production. Expert Review of Vaccines 10 . 1183-1194. CrossRef K. K. Orlinger, Y. Hofmeister, R. Fritz, G. W. Holzer, F. G. Falkner, B. Unger, A. Loew-Baselli, E.-M. Poellabauer, H. J. Ehrlich, P. N. Barrett, T. R. Kreil. (2011) A Tick-borne Encephalitis Virus Vaccine Based on the European Prototype Strain Induces Broadly Reactive Cross-neutralizing Antibodies in Humans. Journal of Infectious Diseases 203 . 1556-1564. CrossRef Derek T OHagan, Rino Rappuoli, Ennio De Gregorio, Theodore Tsai, Giuseppe Del Giudice. (2011) MF59 adjuvant: the best insurance against influenza strain diversity. Expert Review of Vaccines 10 . 447-462. CrossRef Heng Liu, Laura Bungener, Wouter ter Veer, Beth-Ann Coller, Jan Wilschut, Anke Huckriede. (2011) Preclinical evaluation of the saponin derivative GPI-0100 as an immunostimulating and dose-sparing adjuvant for pandemic influenza vaccines. Vaccine 29 . 2037-2043. CrossRef P Noel Barrett, Gregory Berezuk, Sandor Fritsch, Gerald Aichinger, Mary Kate Hart, Wael El-Amin, Otfried Kistner, Hartmut J Ehrlich. (2011) Efficacy, safety, and immunogenicity of a Vero-cell-culture-derived trivalent influenza vaccine: a multicentre, double-blind, randomised, placebo-controlled trial. The Lancet 377 . 751-759. CrossRef Shao-Zhen Feng, Pei-Rong Jiao, Wen-Bao Qi, Hui-Ying Fan, Ming Liao. (2011) Development and strategies of cell-culture technology for influenza vaccine. Applied Microbiology and Biotechnology 89 . 893-902. CrossRef Atika Abelin, Tony Colegate, Stephen Gardner, Norbert Hehme, Abraham Palache. (2011) Lessons from pandemic influenza A(H1N1): The research-based vaccine industrys perspective. Vaccine 29 . 1135-1138. CrossRef Yoichi Furuya. (2011) Return of inactivated whole-virus vaccine for superior efficacy. Immunology and Cell Biology 90 :6, 571. CrossRef R. Fritz, N. Sabarth, S. Kiermayr, C. Hohenadl, M. K. Howard, R. Ilk, O. Kistner, H. J. Ehrlich, P. N. Barrett, T. R. Kreil. (2011) A Vero Cell-Derived Whole-Virus H5N1 Vaccine Effectively Induces Neuraminidase-Inhibiting Antibodies. Journal of Infectious Diseases 205 :1, 28. CrossRef A. Roldo, A. C. Silva, M. C.M. Mellado, P. M. Alves, M. J.T. Carrondo. 2011. Viruses and Virus-Like Particles in Biotechnology. Comprehensive Biotechnology, 625-649. CrossRef Brian A. Crowe, Peter Brhl, Marijan Gerencer, Michael G. Schwendinger, Andreas Pilz, Otfried Kistner, Katrin Koelling-Schlebusch, Gerald Aichinger, Julia Singer, Markus Zeitlinger, Markus Mller, Hartmut Ehrlich, P. Noel Barrett. (2010) Evaluation of the cellular immune responses induced by a non-adjuvanted inactivated whole virus A/H5N1/VN/1203 pandemic influenza vaccine in humans. Vaccine 29 :2, 166-173. CrossRef Penghui Yang, Chong Tang, Deyan Luo, Zhongpeng Zhan, Li Xing, Yueqiang Duan, Weihong Jia, Daxin Peng, Xiufan Liu, Xiliang Wang. (2010) Cross-clade protection against HPAI H5N1 influenza virus challenge in BALB/c mice intranasally administered adjuvant-combined influenza vaccine. Veterinary Microbiology 146 :1-2, 17-23. CrossRef Jiang Wu, Shu-Zhen Liu, Shan-Shan Dong, Xiao-Ping Dong, Wu-Li Zhang, Min Lu, Chang-Gui Li, Ji-Chen Zhou, Han-Hua Fang, Yan Liu, Li-Ying Liu, Yuan-Zheng Qiu, Qiang Gao, Xiao-Mei Zhang, Jiang-Ting Chen, Xiang Zhong, Wei-Dong Yin, Zi-Jian Feng. (2010) Safety and immunogenicity of adjuvanted inactivated split-virion and whole-virion influenza A (H5N1) vaccines in children: A phase III randomized trial. Vaccine 28 . 6221-6227. CrossRef Felix Geeraedts, Vinay Saluja, Wouter Veer, Jean-Pierre Amorij, Henderik W. Frijlink, Jan Wilschut, Wouter L. J. Hinrichs, Anke Huckriede. (2010) Preservation of the Immunogenicity of Dry-powder Influenza H5N1 Whole Inactivated Virus Vaccine at Elevated Storage Temperatures. The AAPS Journal 12 . 215-222. CrossRef Neetu Singh, Aseem Pandey, Suresh K. Mittal. (2010) Avian influenza pandemic preparedness: developing prepandemic and pandemic vaccines against a moving target. Expert Reviews in Molecular Medicine 12 . CrossRef Wei Lu, Paul A Tambyah. (2010) Safety and immunogenicity of influenza A H1N1 vaccines. Expert Review of Vaccines 9 . 365-369. CrossRef S. Koyama, T. Aoshi, T. Tanimoto, Y. Kumagai, K. Kobiyama, T. Tougan, K. Sakurai, C. Coban, T. Horii, S. Akira, K. J. Ishii. (2010) Plasmacytoid Dendritic Cells Delineate Immunogenicity of Influenza Vaccine Subtypes. Science Translational Medicine 2 . 25ra24-25ra24. CrossRef Michael J. Loeffelholz. (2010) Avian Influenza A H5N1 Virus. Clinics in Laboratory Medicine 30 . 1-20. CrossRef Larry R. Smith, Mary K. Wloch, Ming Ye, Luane R. Reyes, Souphaphone Boutsaboualoy, Casey E. Dunne, Jennifer A. Chaplin, Denis Rusalov, Alain P. Rolland, Cindy L. Fisher, Mohamed S. Al-Ibrahim, Martin L. Kabongo, Roy Steigbigel, Robert B. Belshe, Ernest R. Kitt, Alice H. Chu, Ronald B. Moss. (2010) Phase 1 clinical trials of the safety and immunogenicity of adjuvanted plasmid DNA vaccines encoding influenza A virus H5 hemagglutinin. Vaccine 28 :13, 2565-2572. CrossRef Cosue Miyaki, Wagner Quintilio, Eliane N. Miyaji, Viviane F. Botosso, Flavia S. Kubrusly, Fernanda L. Santos, Dmitri Iourtov, Hisako G. Higashi, Isaias Raw. (2010) Production of H5N1 (NIBRG-14) inactivated whole virus and split virion influenza vaccines and analysis of immunogenicity in mice using different adjuvant formulations. Vaccine 28 :13, 2505-2509. CrossRef Andr van Maurik, Nicolas Sabarth, Helga Savidis Dacho, Peter Brhl, Michael Schwendinger, Brian A. Crowe, P. Noel Barrett, Otfried Kistner, M. Keith Howard. (2010) Seasonal influenza vaccine elicits heterosubtypic immunity against H5N1 that can be further boosted by H5N1 vaccination. Vaccine 28 . 1778-1785. CrossRef Daisuke Ikeno, Kazuhiko Kimachi, Yoichiro Kino, Seiichi Harada, Kayo Yoshida, Shinji Tochihara, Shigeyuki Itamura, Takato Odagiri, Masato Tashiro, Kenji Okada, Chiaki Miyazaki, Kohji Ueda. (2010) Immunogenicity of an inactivated adjuvanted whole-virion influenza A (H5N1, NIBRG-14) vaccine administered by intramuscular or subcutaneous injection. Microbiology and Immunology 54 :10.1111/mim.2010.54.issue-2, 81-88. CrossRef Suryaprakash Sambhara, Gregory A. Poland. (2010) H5N1 Avian Influenza: Preventive and Therapeutic Strategies Against a Pandemic. Annual Review of Medicine 61 :1, 187-198. CrossRef Jos M. Bayas Rodrguez, Alberto L. Garca-Basteiro, Guillermo Mena Pinilla. (2010) Problemtica de la vacunacin contra la gripe A en Espaa. Archivos de Bronconeumologa 46 . 32-38. CrossRef J. A. Stockman. (2010) A Clinical Trial of a Whole-Virus H5N1 Vaccine Derived from Cell Culture. Yearbook of Pediatrics 2010 . 219-221. CrossRef Nicolas Sabarth, M. Keith Howard, Helga Savidis-Dacho, Andr van Maurik, P. Noel Barrett, Otfried Kistner. (2010) Comparison of single, homologous prime-boost and heterologous prime-boost immunization strategies against H5N1 influenza virus in a mouse challenge model. Vaccine 28 . 650-656. CrossRef Zoltan Vajo, Ferenc Tamas, Laszlo Sinka, Istvan Jankovics. (2010) Safety and immunogenicity of a 2009 pandemic influenza A H1N1 vaccine when administered alone or simultaneously with the seasonal influenza vaccine for the 200910 influenza season: a multicentre, randomised controlled trial. The Lancet 375 . 49-55. CrossRef Xiao-Feng Liang, Hua-Qing Wang, Jun-Zhi Wang, Han-Hua Fang, Jiang Wu, Feng-Cai Zhu, Rong-Cheng Li, Sheng-Li Xia, Yu-Liang Zhao, Fang-Jun Li, Shao-Hong Yan, Wei-Dong Yin, Kang An, Duo-Jia Feng, Xuan-Lin Cui, Feng-Chun Qi, Chang-Jun Ju, Yu-Hui Zhang, Zhi-Jun Guo, Ping-Yu Chen, Ze Chen, Kun-Ming Yan, Yu Wang. (2010) Safety and immunogenicity of 2009 pandemic influenza A H1N1 vaccines in China: a multicentre, double-blind, randomised, placebo-controlled trial. The Lancet 375 . 56-66. CrossRef Stacey Schultz-Cherry, Jeremy C. Jones. 2010. Influenza Vaccines. Advances in Virus Research, 63-84. CrossRef Wendy Keitel, Nicola Groth, Maria Lattanzi, Michaela Praus, Anne Katrin Hilbert, Astrid Borkowski, Ted F. Tsai. (2010) Dose ranging of adjuvant and antigen in a cell culture H5N1 influenza vaccine: Safety and immunogenicity of a phase 1/2 clinical trial. Vaccine 28 . 840-848. CrossRef Arash Hassantoufighi, Henry Zhang, Matthew Sandbulte, Jin Gao, Jody Manischewitz, Lisa King, Hana Golding, Timothy M. Straight, Maryna C. Eichelberger. (2010) A practical influenza neutralization assay to simultaneously quantify hemagglutinin and neuraminidase-inhibiting antibody responses. Vaccine 28 . 790-797. CrossRef Maria R. Farcet, Christina B. Planitzer, Oliver Stein, Jens Modrof, Thomas R. Kreil. (2010) Hepatitis A virus antibodies in immunoglobulin preparations. Journal of Allergy and Clinical Immunology 125 . 198-202. CrossRef Zhu. Feng-Cai. Wang. Hua. Fang. Han-Hua. Yang. Jian Guo. Lin. Xiao Jun. Liang. Xiao-Feng. Zhang. Xue-Feng. Pan. Hong-Xing. Meng. Fan-Yue. Hu. Yue Mei. Liu. Wen-Dong. Li. Chang-Gui. Li. Wei. Zhang. Xiang. Hu. Jin Mei. Peng. Wei Bing. Yang. Bao Ping. Xi. Pei. Wang. Hua-Qing. Zheng. Jing-Shan. (2009) A Novel Influenza A (H1N1) Vaccine in Various Age Groups. New England Journal of Medicine 361 :25, 2414-2423. Free Full Text Lars R. Haaheim, Abdullah S. Madhun, Rebecca Cox. (2009) Pandemic Influenza Vaccines The Challenges. Viruses 1 . 1089-1109. CrossRef Karl G. Nicholson, Catherine I. Thompson, Jaco M. Klap, John M. Wood, Sally Batham, Robert W. Newman, Robert Mischler, Maria C. Zambon, Iain Stephenson. (2009) Safety and immunogenicity of whole-virus, alum-adjuvanted whole-virus, virosomal, and whole-virus intradermal influenza A/H9N2 vaccine formulations. Vaccine 28 . 171-178. CrossRef Markus Mller. (2009) Zur Medienberichterstattung ber den in sterreich verfgbaren Impfstoff gegen pandemische Influenza A/H1N1. Wiener klinische Wochenschrift 121 . 663-664. CrossRef Shan Lu, Shixia Wang. (2009) Technical transformation of biodefense vaccines. Vaccine 27 . D8-D15. CrossRef Wendy A. Keitel, Cornelia L. Dekker, ChrisAnna Mink, James D. Campbell, Kathryn M. Edwards, Shital M. Patel, Dora Y. Ho, Helen K. Talbot, Kuo Guo, Diana L. Noah, Heather Hill. (2009) Safety and immunogenicity of inactivated, Vero cell culture-derived whole virus influenza A/H5N1 vaccine given alone or with aluminum hydroxide adjuvant in healthy adults. Vaccine 27 . 6642-6648. CrossRef R. Rappuoli, G. Del Giudice, G. J. Nabel, A. D. M. E. Osterhaus, R. Robinson, D. Salisbury, K. Stohr, J. J. Treanor. (2009) Rethinking Influenza. Science 326 . 50-50. CrossRef Christina B. Planitzer, Jens Modrof, Mei-ying W. Yu, Thomas R. Kreil. (2009) West Nile Virus Infection in Plasma of Blood and Plasma Donors, United States. Emerging Infectious Diseases 15 . 1668-1670. CrossRef Tino F. Schwarz, Thomas Horacek, Markus Knuf, Hanns-Gerd Damman, Franois Roman, Mamadou Dram, Paul Gillard, Wolfgang Jilg. (2009) Single dose vaccination with AS03-adjuvanted H5N1 vaccines in a randomized trial induces strong and broad immune responsiveness to booster vaccination in adults. Vaccine 27 . 6284-6290. CrossRef Liisa Lehtoranta, Anja Villberg, Riitta Santanen, Thedi Ziegler. (2009) A novel, colorimetric neutralization assay for measuring antibodies to influenza viruses. Journal of Virological Methods 159 . 271-276. CrossRef Lamberto Manzoli, Georgia Salanti, Corrado De Vito, Antonio Boccia, John PA Ioannidis, Paolo Villari. (2009) Immunogenicity and adverse events of avian influenza A H5N1 vaccine in healthy adults: multiple-treatments meta-analysis. The Lancet Infectious Diseases 9 . 482-492. CrossRef Ruth A. Karron, Kawsar Talaat, Catherine Luke, Karen Callahan, Bhagvanji Thumar, Susan DiLorenzo, Josephine McAuliffe, Elizabeth Schappell, Amorsolo Suguitan, Kimberly Mills, Grace Chen, Elaine Lamirande, Kathleen Coelingh, Hong Jin, Brian R. Murphy, George Kemble, Kanta Subbarao. (2009) Evaluation of two live attenuated cold-adapted H5N1 influenza virus vaccines in healthy adults. Vaccine 27 . 4953-4960. CrossRef Luc Hessel. (2009) Pandemic influenza vaccines: meeting the supply, distribution and deployment challenges. Influenza and Other Respiratory Viruses 3 :10.1111/irv.2009.3.issue-4, 165-170. CrossRef Tristan Clark, Iain Stephenson. (2009) Influenza A/H1N1 in 2009: a pandemic in evolution. Expert Review of Vaccines 8 . 819-822. CrossRef Frederick G. Hayden, Wendy A. Howard, Laszlo Palkonyay, Marie Paule Kieny. (2009) Report of the 5th meeting on the evaluation of pandemic influenza prototype vaccines in clinical trials. Vaccine 27 . 4079-4089. CrossRef Alexander Doroshenko, Scott A Halperin. (2009) Trivalent MDCK cell culture-derived influenza vaccine Optaflu (Novartis Vaccines). Expert Review of Vaccines 8 . 679-688. CrossRef Rebecca J. Cox, Diane Major, Solveig Hauge, Abdullah S. Madhun, Karl A. Brokstad, Mirjam Kuhne, Jon Smith, Frederick R. Vogel, Maria Zambon, Lars R. Haaheim, John Wood. (2009) A cell-based H7N1 split influenza virion vaccine confers protection in mouse and ferret challenge models. Influenza and Other Respiratory Viruses 3 :10.1111/irv.2009.3.issue-3, 107-117. CrossRef P Noel Barrett, Wolfgang Mundt, Otfried Kistner, M Keith Howard. (2009) Vero cell platform in vaccine production: moving towards cell culture-based viral vaccines. Expert Review of Vaccines 8 . 607-618. CrossRef Zoltan Vajo. (2009) Influenza A (H5N1) pandemic prototype vaccine Fluval . Expert Review of Vaccines 8 . 619-624. CrossRef Arnold S Monto, Suzanne E Ohmit. (2009) Seasonal influenza vaccines: evolutions and future trends. Expert Review of Vaccines 8 . 383-389. CrossRef Bram Palache, Ryoko Krause. (2009) Progress with human H5N1 vaccines: a perspective from industry. Expert Review of Vaccines 8 . 391-400. CrossRef Isabel Leroux-Roels, Geert Leroux-Roels. (2009) Current status and progress of prepandemic and pandemic influenza vaccine development. Expert Review of Vaccines 8 . 401-423. CrossRef Jessica A Chichester, Lars R Haaheim, Vidadi Yusibov. (2009) Using plant cells as influenza vaccine substrates. Expert Review of Vaccines 8 . 493-498. CrossRef Rebecca J. Cox, Abdullah S. Madhun, Solveig Hauge, Haakon Sjursen, Diane Major, Mirjam Kuhne, Katja Hschler, Melanie Saville, Frederick R. Vogel, Wendy Barclay, Isabella Donatelli, Maria Zambon, John Wood, Lars R. Haaheim. (2009) A phase I clinical trial of a PER. C6 cell grown influenza H7 virus vaccine. Vaccine 27 . 1889-1897. CrossRef (2009) Vaccin contre la grippe aviaire. premiers essais concluants. Revue Francophone des Laboratoires 2009 :410, 17. CrossRef Arnt-Ove Hovden, Karl A. Brokstad, Diane Major, John Wood, Lars R. Haaheim, Rebecca J. Cox. (2009) A pilot study of the immune response to whole inactivated avian influenza H7N1 virus vaccine in mice. Influenza and Other Respiratory Viruses 3 :10.1111/irv.2009.3.issue-1, 21-28. CrossRef ampNA. (2008) Update your vaccination protocol. Journal of the American Academy of Physician Assistants 21 . 16-17. CrossRef Mary Elizabeth Wilson. (2008) Preface. Medical Clinics of North America 92 . xiii-xviii. CrossRef Julian W. Tang, Karry L. K. Ngai, Paul K. S. Chan. (2008) Lack of cross-immune reactivity against influenza H5N1 from seasonal influenza vaccine in humans. Journal of Medical Virology 80 :10.1002/jmv. v80:11, 1992-1996. CrossRef Mary Hoelscher, Shivaprakash Gangappa, Weimin Zhong, Lakshmi Jayashankar, Suryaprakash Sambhara. (2008) Vaccines against epidemic and pandemic influenza. Expert Opinion on Drug Delivery 5 . 1139-1157. CrossRef Ophlie Marais. (2008) Un vaccin contre le virus H5N1 driv de cultures cellulaires. Option/Bio 19 :406, 4. CrossRef Barrett R. Crowther, Troy D. Schmeling, Mary S. Hayney. (2008) Influenza vaccination: Outlook for 2008-09 season. Journal of the American Pharmacists Association 48 :5, 686-687. CrossRef Daniel A. Hussar. (2008) New drugs: Methylnaltrexone bromide, alvimopan, and rilonacept. Journal of the American Pharmacists Association 48 :5, 688-691. CrossRef (2008) News in brief. Nature Medicine 14 . 702-703. CrossRef Wright. Peter F. (2008) Vaccine Preparedness Are We Ready for the Next Influenza Pandemic. New England Journal of Medicine 358 :24, 2540-2543. Free Full TextA Clinical Trial of a Whole-Virus H5N1 Vaccine Derived from Cell Culture Background Widespread infections of avian species with avian influenza H5N1 virus and its limited spread to humans suggest that the virus has the potential to cause a human influenza pandemic. An urgent need exists for an H5N1 vaccine that is effective against divergent strains of H5N1 virus. Methods In a randomized, dose-escalation, phase 1 and 2 study involving six subgroups, we investigated the safety of an H5N1 whole-virus vaccine produced on Vero cell cultures and determined its ability to induce antibodies capable of neutralizing various H5N1 strains. In two visits 21 days apart, 275 volunteers between the ages of 18 and 45 years received two doses of vaccine that each contained 3.75 g, 7.5 g, 15 g, or 30 g of hemagglutinin antigen with alum adjuvant or 7.5 g or 15 g of hemagglutinin antigen without adjuvant. Serologic analysis was performed at baseline and on days 21 and 42. Results The vaccine induced a neutralizing immune response not only against the clade 1 (A/Vietnam/1203/2004) virus strain but also against the clade 2 and 3 strains. The use of adjuvants did not improve the antibody response. Maximum responses to the vaccine strain were obtained with formulations containing 7.5 g and 15 g of hemagglutinin antigen without adjuvant. Mild pain at the injection site (in 9 to 27 of subjects) and headache (in 6 to 31 of subjects) were the most common adverse events identified for all vaccine formulations. Conclusions A two-dose vaccine regimen of either 7.5 g or 15 g of hemagglutinin antigen without adjuvant induced neutralizing antibodies against diverse H5N1 virus strains in a high percentage of subjects, suggesting that this may be a useful H5N1 vaccine. (ClinicalTrials. gov number, NCT00349141 .) Media in This Article Figure 1 Enrollment and Outcomes. Figure 2 Reverse Cumulative Distribution Curves for Titers of Neutralizing Antibodies in Six Study Groups after the First and Second Doses of Vaccine against Three Strains of Avian Influenza. Article Activity The emergence of a new human influenza pandemic caused by an avian virus strain is possible. Vaccination against pandemic influenza is considered to be the most effective option to limit its spread. However, the conventional approaches to the manufacture of influenza vaccines have a number of disadvantages and raise concern about whether sufficient quantities of an effective vaccine can be made available early enough at the onset of a pandemic to have a major effect on public health. 1 In addition, clinical studies of conventional split-vaccine formulations without adjuvant have shown poor immunogenicity. 2,3 It has been suggested that whole-virus vaccines have the potential to be more immunogenic than split-virus or subunit vaccines in previously unvaccinated populations. 4,5 The first clinical study of a whole-virus vaccine against avian influenza H5N1 virus showed that a substantially reduced antigen dosage (10 g) with an alum formulation induced seroconversion in nearly 100 of subjects. 6 All these studies were carried out with vaccines manufactured by conventional methods (i. e. with the use of embryonated chicken eggs and modified, attenuated reassortant viruses produced by reverse genetics). 7 We have devised a strategy for the development of an H5N1 vaccine that involves the use of a wild-type virus (i. e. the strain circulating in nature) grown in a Vero cell culture. This strategy has the advantage that the lead time for pandemic vaccine production can be reduced, since the generation of attenuated reassortants is not required, although the requirement for the use of enhanced biosafety level 3 (BSL-3) facilities for such a strategy is a relative drawback. In addition, cell culture provides a robust manufacturing platform that eliminates dependence on embryonated chicken eggs, which would be an advantage in the event of limited availability of such eggs during a pandemic caused by a highly pathogenic avian virus. This technique was used to develop a whole-virus vaccine that was highly immunogenic in animal models. 8 We report on the safety and immunogenicity of this vaccine, using formulations with and without alum adjuvant. Methods Study Design and Objective From June 2006 through September 2006, we enrolled a total of 284 men and women between the ages of 18 and 45 years in a randomized, partially blinded (between groups) clinical trial at three sites: one in Austria and two in Singapore. The study was designed by its sponsor, Baxter. Data were collected by the investigators and were held and analyzed by Baxter. The manuscript was written by a subgroup of industry and academic authors all authors contributed to the content, had full access to the data, and vouch for the completeness and accuracy of the data and data analysis. The appropriate local review boards and ethics committees approved the protocol for the study, which was conducted in compliance with Good Clinical Practice guidelines and the provisions of the Declaration of Helsinki. The study investigators were unaware of assignments to study groups. (For details of the study design, see the Supplementary Appendix. available with the full text of this article at nejm. org.) The objective was to identify the immunogenicity and safety of various doses of inactivated H5N1 whole-virus vaccine in formulations with and without adjuvant. The primary immunogenicity outcome was the number of subjects with hemagglutination-inhibition and neutralizing antibodies to the vaccine strain (A/Vietnam/1203/2004) 21 days after the first and second doses of vaccine. The primary safety outcome was any systemic reaction after the first and second doses. Vaccine The monovalent avian influenza H5N1 whole-virus vaccine (Baxter) was produced with the wild-type strain A/Vietnam/1203/2004, which was obtained from the Centers for Disease Control and Prevention and was inactivated with formalin and ultraviolet light. The vaccine was manufactured in Vero cell culture in an enhanced BSL-3 facility (as required for wild-type H5N1 virus), as described previously. 9 Randomization and Follow-up Subjects were eligible to participate if they were clinically healthy, understood the study procedures, provided written informed consent, and agreed to keep a daily record of symptoms. Women were required to have a negative pregnancy test at screening and before each vaccination. Subjects were recruited in three study cohorts in a dose-escalating manner and were randomly assigned to receive two 0.5-ml injections into the deltoid muscle at an interval of 21 days (range, 19 to 23) with an H5N1 whole-virus formulation containing 3.75 g, 7.5 g, 15 g, or 30 g of hemagglutinin antigen with a 0.2 alum adjuvant or 7.5 g or 15 g of hemagglutinin antigen without adjuvant. There was no placebo group. Subjects and investigators were unaware of the dose of vaccine administered within the subgroups (Figure 1 Figure 1 Enrollment and Outcomes. and the Supplementary Appendix ). Blood samples were taken for serologic testing before the first dose of vaccine and on day 21 after the first and second doses. Using a diary provided by the investigators, subjects were asked to record daily oral body temperature (using study-issued digital thermometers), local reactions, and systemic adverse events for 7 days after each vaccination. On days 7 and 21 after each vaccination, subjects were asked to return for a review of the diary and assessment for any adverse events. Assays We evaluated all immunogenicity outcomes against the influenza-virus strain used in the vaccine (A/Vietnam/1203/2004) according to hemagglutination-inhibition and virus-neutralization assays. To assess cross-reactivity of antibodies, all assays were also conducted with known related influenza strains for example, an original prototype clade 3 strain (A/Hong Kong/156/1997) and a clade 2 strain (A/Indonesia/05/2005). Using a hemagglutination-inhibition or virus-neutralization assay, we investigated secondary immunogenicity outcomes by analyzing the antibody response 21 days after the first and second doses of vaccine the increase in the antibody response 21 days after the first and second doses, as compared with baseline and the number of subjects with seroconversion (which we defined as a minimum increase by a factor of 4 in the titer) 21 days after the first and second doses, as compared with baseline. The hemagglutination-inhibition assay is the standard test for detection of antibodies against influenza after infection or vaccination. However, this assay may be insensitive for the detection of anti-H5 antibodies. 10,11 For this reason, immunogenicity analyses focused on a determination of functional neutralizing-antibody responses. Since most licensing authorities typically request data regarding hemagglutination-inhibition assays or single radial hemolysis, these determinations are also reported but only for the vaccine virus strain A/Vietnam/1203/2004. (For details on hemagglutination-inhibition and virus-neutralization assays and single radial hemolysis, 12-14 see the Supplementary Appendix .) Statistical Analysis The protocol called for the recruitment of 45 subjects per study group. With this number of subjects, the 95 confidence interval for the percentage of subjects with an antibody response that was associated with protection did not extend more than 15 from the observed rate, assuming a seroprotection rate of approximately 80. We used the likelihood-ratio chi-square test to compare the number of subjects with local or systemic reactions within 7 days after vaccination among the various vaccine formulations. For binary variables (i. e. seroprotection and seroconversion), response rates and 95 confidence intervals were computed for each strain and time point. The confidence intervals were interpreted in a descriptive manner, and no adjustment for multiplicity was made. 15 In addition, for the log-transformed values of virus-neutralization titers and single radial hemolysis, a longitudinal analysis was performed within a repeated mixed-model framework of analysis of covariance. Changes from baseline were analyzed, accounting for the fixed effects of vaccine formulation, day, sex, age, baseline titer, interaction between the vaccine formulation and day, and random effects for subjects. Vaccine formulations without adjuvant were compared with formulations with adjuvant within this model. Comparisons were also made between groups receiving 7.5 g and 15 g of hemagglutinin antigen without adjuvant. We calculated the proportion of subjects with a virus-neutralization titer of 1:20 or more and that of subjects with results of 25 mm 2 or more on single radial hemolysis, using a generalized linear model with repeated measurements and the general-estimating-equations method (see the Supplementary Appendix ). Results Study Population A total of 275 subjects between the ages of 18 and 45 years received the first dose of vaccine, and 257 received the second dose. All vaccinated subjects were included in the safety analysis. Two subjects who initially gave their consent withdrew from the study because of nonserious adverse events, including four events in one subject (chills, fatigue, malaise, and insomnia) and one event in the second subject (papular rash) the majority of these symptoms abated within 24 hours. Immunogenicity data were available for 258 subjects for the first dose of vaccine and for 249 subjects for the second dose of vaccine. Safety The rates of occurrence of injection-site and systemic reactions during the first 7 days after each dose of vaccine are presented in Table 1 Table 1 Proportion of Subjects with Injection-Site and Systemic Reactions within 7 Days after the First and Second Doses of Vaccine. No serious, vaccine-related adverse events were recorded. There were two serious adverse events recorded in two subjects: hospitalization due to a contusion of the left foot and hospitalization for an elective abortion. The most commonly occurring injection-site reaction after vaccination was pain, which occurred in 9 to 27 of subjects the most frequently reported systemic reaction was headache, which occurred in 6 to 31 of subjects. There were no significant differences between the vaccine formulations with respect to local reactions after the first dose and the second dose of vaccine (P0.32 and P0.97, respectively, for all comparisons). With respect to systemic reactions, a slight difference was observed between the vaccine formulations after the first dose of vaccine (P0.01), a finding that was largely due to an unexpectedly low rate of headache observed in the group receiving the 30-g formulation with adjuvant. No difference was shown regarding systemic reactions after the second dose of vaccine (P0.15). Immune Response At 21 days after the first and second doses, functional neutralizing antibodies against strain A/Vietnam/1203/2004 were detected in patients receiving any of the six formulations. Table 2 Table 2 Proportion of Subjects with a Virus-Neutralization Antibody Titer of 1:20 or More. shows the rates of response in subjects with a virus-neutralization titer of 1:20 or more, and Table 3 Table 3 Geometric Mean of the Increase from Baseline (GMI) and Proportion of Subjects with Seroconversion. shows the geometric mean increase (GMI) of the titer from baseline and the percentage of seroconversion. Numerically, the formulations without adjuvant induced the highest rates of a virus-neutralization titer of 1:20 or more after the first dose (40.5 and 39.5 for 7.5 g and 15 g without adjuvant, respectively) and the second dose (76.2 and 70.7 for 7.5 g and 15 g without adjuvant, respectively) (Table 2 ). Similar results were obtained with respect to GMI (Table 3 ), since the highest GMIs were obtained for the formulations without adjuvant (5.3 and 5.7 for 7.5 g and 15 g without adjuvant, respectively) (Table 3 ). Among subjects with seroconversion (an increase in the titer by a factor of at least 4 after immunization), the highest rates of response were again seen in subjects who received a 7.5-g or 15-g formulation without adjuvant (69.0 and 68.3, respectively) (Table 3 ). Statistical analysis with the use of a mixed model on log-transformed virus-neutralization values confirmed that the formulations without adjuvant induced significantly higher immune responses than did the formulations with adjuvant (Plt0.001). There were no significant differences between the two formulations without adjuvant or among the four formulations with adjuvant. All vaccine formulations showed a similar ratio of increase in antibody titer between day 21 and day 42, as shown by the nonsignificant interaction between vaccine formulation and day (Table 4 Table 4 Mixed-Model Analysis of Log-Transformed Values of Virus-Neutralization Titer. and Table 4 in the Supplementary Appendix ). Table 5 Table 5 Antibody Response to the Homologous Virus Strain after the First and Second Doses of Vaccine. compares the presumed rates of seroprotection, as measured by hemagglutination-inhibition assay (i. e. the proportion of subjects with a titer 40) and single radial hemolysis (i. e. the proportion of subjects with an area of 25 m 2 on single radial hemolysis). Numerically, the formulations without adjuvant again were more immunogenic than those with adjuvant. On single radial hemolysis, the percentage of seroprotection 21 days after the second dose of vaccine without adjuvant was 78.6 for the 7.5-g dose and 61.0 for the 15-g dose. Single radial hemolysis for H5N1 antibodies appeared to be more sensitive than hemagglutination-inhibition assay, since the equivalent values for hemagglutination-inhibition assay were 47.6 and 26.8, respectively. We also analyzed changes from baseline in results on single radial hemolysis using a mixed-model analysis of covariance for the log-transformed values, and the results were similar to those obtained for the virus-neutralization titers. Again, we observed a significant effect of the vaccine formulations, with formulations without adjuvant showing higher response rates than those with adjuvant. There was no significant difference between the two formulations without adjuvant or among the formulations with adjuvant (Table 4. and Table 5 in the Supplementary Appendix ). Cross-Neutralization The 7.5-g and 15-g formulations without adjuvant showed high levels of cross-reactivity against the A/Hong Kong strain (76.2 and 78.0, respectively, with a neutralizing titer of 1:20) (Table 2 ). The responses against the clade 2 strain were somewhat lower (with rates of a virus-neutralization titer of 1:20 of 45.2 and 36.6 for the 7.5-g and 15-g formulations without adjuvant, respectively) (Table 2 ). We also analyzed the virus-neutralization response to the heterologous strains using the mixed model. Results were similar to those for the homologous strain. Formulations without adjuvant elicited significantly higher immune responses than those with adjuvant. Antibody titers increased significantly from baseline, independently of the vaccine dose (Table 4. and Tables 3 and 4 in the Supplementary Appendix ). The reverse cumulative distribution curves for antibody titers after the first and second doses of vaccine against all three strains support the finding of higher immunogenicity from the formulations without adjuvant (Figure 2 Figure 2 Reverse Cumulative Distribution Curves for Titers of Neutralizing Antibodies in Six Study Groups after the First and Second Doses of Vaccine against Three Strains of Avian Influenza. ). Analysis of rates of seroprotection with homologous and heterologous immune responses showed results that were consistent with those obtained by direct analysis of values of virus-neutralization titers and single radial hemolysis (Tables 6 and 7 in the Supplementary Appendix ). Discussion It has been reported that whole-virus trivalent influenza vaccines are more immunogenic than subvirion vaccines but are also more prone to cause adverse reactions. 5 In our study, a monovalent whole-virus H5N1 vaccine had a side-effect profile similar to that of subvirion H5N1 formulations described previously. 2,3,16 Most important, the low rate of fever among subjects in our study (2 to 7) compares favorably with that reported both for subvirion H5N1 vaccines and for an egg-derived whole-virus H5N1 vaccine with adjuvant. 2,3,6,16 However, it should be noted that reporting systems and characteristics of the subjects differ among the various studies. With respect to immunogenicity, the highest neutralizing-antibody response after the second dose of vaccine (76.2) was obtained with the 7.5-g formulation without adjuvant, which was equivalent to a rate of seroconversion of 69.0 and represented an increase by a factor of 4 or more in the neutralization titer after two doses of vaccine (Table 2 and Table 3 ). These data are also similar to the levels of immunogenicity reported in a study of an egg-derived whole-virus H5N1 vaccine, in which 96 of subjects who received two doses of 5-g or 10-g formulations had a neutralization titer of 1:20 or more, 6 although differences in assay systems must be taken into account in making such direct comparisons. Lower rates of seroprotection and seroconversion (as defined in the guidelines of the Committee for Proprietary Medicinal Products 17 ) were obtained with the hemagglutination-inhibition assay than with the virus-neutralization assay, which supports the finding that the hemagglutination-inhibition assay is less sensitive for detection of anti-H5 antibodies, as reported previously. 10,11 In our study, single radial hemolysis, which is considered to have a sensitivity equivalent to that of the hemagglutination-inhibition assay for seasonal influenza strains, 18 was shown to be more sensitive than the hemagglutination-inhibition assay for H5N1. The lack of enhancement of vaccine immunogenicity by the use of alum adjuvant at the doses studied here was consistent with data from a previous study, which showed that no effect of alum adjuvant was seen with a 15-g dose of subvirion vaccine, and a 7.5-g formulation without alum was more immunogenic than the formulation with adjuvant. 3 In the previous study, an enhanced immune response with the use of alum was seen only with the 30-g formulation. We did not investigate this dose without alum in our study. However, other studies have described substantial positive effects of other adjuvants on H5N1 immunogenicity. The use of an oil-in-waterbased emulsion in a 3.8-g dose of split-virus vaccine resulted in 82 seroconversion, as compared with 4 seroconversion without adjuvant. 16 The addition of another oil-in-waterbased adjuvant (MF-59) to an H5N3 vaccine was also associated with a substantial increase in antibody response. 19 Our data also showed that the whole-virus clade 1based vaccine can induce a substantial cross-neutralizing response against clade 2 and clade 3 strains. The results described in Table 2 are encouraging: after two doses of 7.5-g of the formulation without adjuvant, the proportions of subjects with neutralizing titers of 1:20 or more were 45 of those immunized against the clade 2 Indonesia strain and 76 of those immunized against the clade 3 Hong Kong strain. However, there is no available evidence to indicate which neutralizing titer is sufficient to confer protection. Most studies of H5N1 split-virus and whole-virus vaccines have not described attempts to determine the cross-reactivity of antibodies to other H5N1 virus strains. However, a recent study of a novel split-virus vaccine with adjuvant also showed high levels of cross-neutralization against a clade 2 strain. 16 In addition, in a study involving 15 subjects, two doses of an H5N3 vaccine with MF-59 as adjuvant induced intermediate levels of cross-reactivity to antigenically distinct H5N1 strains, and three doses induced high levels of cross-reactivity. 20 The apparent absence of a doseresponse relationship in our study may be surprising. However, it is in agreement with a number of studies of vaccine for pandemic influenza. Leroux-Roels et al. reported no relationship between the dose of antigen and the neutralizing-antibody response for H5N1 formulations with adjuvant, 16 and there appeared to be an inverse doseresponse relationship with respect to responses to the clade 2 strain. A number of other studies involving other pandemic-strain vaccines H9N2, 21 H5N3, 19 and H2N2 22 have shown no doseresponse relationship or even a reduced response at higher doses. The reasons for these findings are unclear, but at least with respect to vaccines with adjuvant, it has been speculated that the ratio of adjuvant to antigen may be critical in determining the immune-enhancing effect rather than the antigen concentration alone. 19 For other viral vaccines, particularly those with soluble proteins, it has been reported that there are distinct doseresponse relationships for induction of various cytokines. In many studies, responses similar to those mediated by type 2 helper T cells have been elicited at low doses of vaccine, and responses similar to those mediated by type 1 helper T cells have been elicited at higher doses. 23 Further studies focusing on T-cell responses will be required to investigate this phenomenon. In addition, these studies will be extended by the use of antigen doses lower than 3.75 g to confirm and extend the results obtained in our study. Our study provides initial safety and immunogenicity data for a whole-virus H5N1 vaccine produced on Vero cell culture. It also shows that a broadly reactive immune response to clade 2 and clade 3 of H5N1 virus can be obtained with the use of a low-dose clade 1 vaccine without adjuvant. Since we observed no significant doseresponse relationship, the 7.5-g formulation without adjuvant has been chosen for further development. Supported by Baxter. Drs. Ehrlich, Berezuk, Fritsch, Lw-Baselli, Vartian, Bobrovsky, Pavlova, Pllabauer, Kistner, and Barrett report being employed by Baxter and having an equity interest in the company Drs. Kistner and Barrett, holding patents on influenza vaccines derived from Vero cell cultures Dr. Mller, receiving consulting and lecture fees and grant support (to the Medical University of Vienna) from Baxter Dr. Tambyah, serving as a member of the AsiaPacific Advisory Committee on Influenza and receiving consulting fees from Baxter, Merlion Pharmaceuticals, and Janssen-Cilag, lecture fees from Pfizer, Wyeth and IBC Asia, and grant support from Baxter and Interimmune and Dr. Montomoli, receiving lecture fees and grant support (to the University of Siena) from Baxter. No other potential conflict of interest relevant to this article was reported. Drs. Ehrlich and Mller contributed equally to this article. This study is dedicated to the memory of Dr. Michel Canavaggio, head of bioscience research and development at Baxter and a great supporter of this project, who died in July 2006, about 6 weeks after the initiation of the study. We thank the following members of the Baxter research and development team for their critical role in this study: L. Grillberger, K. Howard, W. Mundt, M. Reiter, H. Savidis-Dacho, C. Tauer, and W. Wodal N. Cox and S. Klimov of the Centers for Disease Control and Prevention for providing the H5N1 viruses and J. Wood of the National Institute for Biological Standards and Control for providing the reference standards. Source Information From the Department of Global Research and Development, Baxter BioScience (H. J.E. G. B. S. F. A. L.-B. N. V. R. B. B. G.P. E. M.P. O. K. P. N.B.), and the Department of Clinical Pharmacology, Medical University of Vienna, Vienna General Hospital (M. M. C. J.) both in Vienna Changi General Hospital (H. M.L. O.) and the National University of Singapore and National University Hospital (P. A.T. D. F.) all in Singapore and the University of Siena, Siena, Italy (E. M.). Address reprint requests to Dr. Mller at the Department of Clinical Pharmacology, Medical University of Vienna, Vienna General Hospital (AKH), Whringer Grtel 18-20, 1090 Vienna, Austria, or at markus. muellermeduniwien. ac. at . Appendix In addition to the authors, the following investigators contributed to the trial: Data Monitoring and Safety Board: E. Marth, R. Konior, F. Sonnenburg Baxter Clinical Study Team: K. Birthistle, T. Dvorak, S. Geyer, M. Kraft, M. C. Leitgeb, F. Maritsch, L. Phillipson, E. Robotka. Austria: Medical University of Vienna, Vienna General Hospital (Study Center Management), Vienna: A. Abrahim, M. Bauer, M. Brunner, A. Cornea, C. Drucker, Z. Erdogan, J. Griss, B. Heinisch, F. Kovar, E. Lackner, C. Lambers, O. Langer, I. Leitner, C. Marsik, W. Poeppl, M. Popovic, R. Sauermann, R. Schaberl, G. Sodeck, C. Thallinger, F. Traunmueller, C. Wagner, M. Zeitlinger Singapore: Changi General Hospital (Study Center Management): S. K. Chua, S. Chuin, R. Fong, A. S. Foo, A. G. Koh, P. K. Lim, S. Y. Yap, L. H. Yew National University Hospital (Study Center Management): J. W.L. Goh, L. Y. Hsu, C. W.P. Loke, J. Y.C. Ng, E. L. Toh, P. Weatherill, Y. P. Zhou. References Wood JM. Selection of influenza vaccine strains and developing pandemic vaccines. Vaccine 200220:Suppl 5:40-44 CrossRef Web of Science Treanor JJ. Campbell JD. Zangwill KM. Rowe T. Wolff M. Safety and immunogenicity of an inactivated subvirion influenza A (H5N1) vaccine. N Engl J Med 2006354:1343-1351 Free Full Text Web of Science Medline Bresson JL. Perronne C. Launay O. et al. Safety and immunogenicity of an inactivated split-virion influenza A/Vietnam/1194/2004 (H5N1) vaccine: phase I randomised trial. Lancet 2006367:1657-1664 CrossRef Web of Science Medline Wood JM. Developing vaccines against pandemic influenza. Philos Trans R Soc Lond B Biol Sci 2001356:1953-1960 CrossRef Web of Science Medline Nicholson KG. Tyrrell DAJ. Harrison P. et al. Clinical studies of monovalent inactivated whole virus and subunit A/USSR/77 (H1N1) vaccine: serological responses and clinical reactions. J Biol Stand 19797:123-136 CrossRef Medline Lin J. Zhang J. Dong X. et al. Safety and immunogenicity of an inactivated adjuvanted whole-virion influenza A (H5N1) vaccine: phase 1 randomised controlled trial. Lancet 2006368:991-997 CrossRef Web of Science Medline Nicolson C. Major D. Wood JM. Robertson JS. Generation of influenza vaccine viruses on Vero cells by reverse genetics: an H5N1 candidate vaccine strain produced under a quality system. Vaccine 200523:2943-2952 CrossRef Web of Science Medline Kistner O. Howard K. Spruth M. et al. Cell culture (Vero) derived whole-virus (H5N1) vaccine based on wild-type virus strain induces cross-protective immune responses. Vaccine 200725:6028-6036 CrossRef Web of Science Medline Kistner O. Barrett PN. Mundt W. Reiter M. Schober-Bendixen S. Dorner F. Development of a mammalian cell (Vero)-derived candidate influenza virus vaccine. Vaccine 199816:960-968 CrossRef Web of Science Medline Rowe T. Abernathy RA. Hu-Primmer J. et al. Detection of antibody to avian influenza A (H5N1) virus in human serum by using a combination of serologic assays. J Clin Microbiol 199937:937-943 Web of Science Medline Lu BL. Webster RG. Hinshaw VS. Failure to detect hemagglutination-inhibiting antibodies with intact avian influenza virions. Infect Immun 198238:530-535 Web of Science Medline Stephenson I. Wood JM. Nicholson KG. Charlett A. Zambon MC. Detection of anti-H5 responses in human sera by HI using horse erythrocytes following MF59-adjuvanted influenza A/Duck/Singapore/97 vaccine. Virus Res 2004103:91-95 CrossRef Web of Science Medline Reed LJ. Muench H. A simple method of estimating fifty percent endpoints. Am J Hyg 193827:493-497 Schild GC. Pereira MS. Chakraverty P. Single-radial-hemolysis: a new method for the assay of antibody to influenza haemagglutinin: applications for diagnosis and seroepidemiologic surveillance of influenza. Bull World Health Organ 197552:43-50 Web of Science Medline Fitting a model that contains a random effect. In: Collett D. Modeling binary data. Boca Raton, FL: Chapman amp Hall/CRC Press, 1991:202-12. Leroux-Roels I. Borkowski A. Vanwolleghem T. et al. Antigen sparing and cross-reactive immunity with an adjuvanted rH5N1 prototype pandemic influenza vaccine: a randomised controlled trial. Lancet 2007370:580-589 CrossRef Web of Science Medline Committee for Proprietary Medicinal Products. Note for guidance on harmonisation of requirements for influenza vaccines. London: European Agency for the Evaluation of Medicinal Products, 1997. (Publication no. CPMP/BWP/214/96.) Wood JM. Gaines-Das RE. Taylor J. Charkraverty P. Comparison of influenza serological techniques by international collaborative study. Vaccine 199412:167-174 CrossRef Web of Science Medline Nicholson KG. Colegate AE. Podda A. et al. Safety and antigenicity of non-adjuvanted and MF59-adjuvanted influenza A/Duck/Singapore/97 (H5N3) vaccine: a randomised trial of two potential vaccines against H5N1 influenza. Lancet 2001357:1937-1943 CrossRef Web of Science Medline Stephenson I. Bugarini R. Nicholson KG. Et al. Cross-reactivity to highly pathogenic avian influenza H5N1 viruses after vaccination with nonadjuvanted and MF59-adjuvanted influenza A/Duck/Singapore/97 (H5N3) vaccine: a potential priming strategy. J Infect Dis 2005191:1210-1215 CrossRef Web of Science Medline Stephenson I. Nicholson KG. Gluck R. et al. Safety and antigenicity of whole virus and subunit influenza A/Hong Kong/1073/99 (H9N2) vaccine in healthy adults: phase I randomised trial. Lancet 2003362:1959-1966 CrossRef Web of Science Medline Hehme N. Engelmann H. Kuenzel W. Neumeier E. Saenger R. Immunogenicity of a monovalent, aluminum-adjuvanted influenza whole virus vaccine for pandemic use. Virus Res 2004103:163-171 CrossRef Web of Science Medline Constant SL. Bottomly K. Induction of TH1 and TH2 CD4 T cell responses: the alternative approaches. Annu Rev Immunol 199715:297-322 CrossRef Web of Science Medline Citing Articles A. Roldo, A. C. Silva, M. C.M. Mellado, P. M. Alves, M. J.T. Carrondo. 2017. Viruses and Virus-Like Particles in Biotechnology: Fundamentals and Applications. Reference Module in Life Sciences. CrossRef Weiping Cao, William G. Davis, Jin Hyang Kim, Juan A. De La Cruz, Andrew Taylor, Grant R. Hendrickson, Amrita Kumar, Priya Ranjan, L. Andrew Lyon, Jacqueline M. Katz, Shivaprakash Gangappa, Suryaprakash Sambhara. (2016) An oil-in-water nanoemulsion enhances immunogenicity of H5N1 vaccine in mice. Nanomedicine: Nanotechnology, Biology and Medicine 12 :7, 1909-1917. CrossRef Claudia Maria Trombetta, Emanuele Montomoli. (2016) Influenza immunology evaluation and correlates of protection: a focus on vaccines. Expert Review of Vaccines 15 :8, 967-976. CrossRef Takeshi Naruse, Tadashi Fukuda, Tetsuro Tanabe, Munetaka Ichikawa, Yoshiaki Oda, Shinji Tochihara, Kazuhiko Kimachi, Yoichiro Kino, Kohji Ueda. (2017) A clinical phase I study of an EB66 cell-derived H5N1 pandemic vaccine adjuvanted with AS03. Vaccine 33 . 6078-6084. CrossRef Rita Czako, Kanta Subbarao. (2017) Refining the approach to vaccines against influenza A viruses with pandemic potential. Future Virology 10 :9, 1033-1047. CrossRef Barnaby E Young, Sapna P Sadarangani, Yee Sin Leo. (2017) The avian influenza vaccine Emerflu. Why did it fail. Expert Review of Vaccines 14 . 1125-1134. CrossRef Duckhyang Shin, Kuk Jin Park, Hyeon Lee, Eun Young Cho, Mi Suk Kim, Mi Hui Hwang, Soo In Kim, Dong Ho Ahn. (2017) Comparison of immunogenicity of cell-and egg-passaged viruses for manufacturing MDCK cell culture-based influenza vaccines. Virus Research 204 . 40-46. CrossRef Nagendra R. Hegde. (2017) Cell culture-based influenza vaccines: a necessary and indispensable investment for the future. Human Vaccines amp Immunotherapeutics . 00-00. CrossRef M. Trondsen, L. A. Aqrawi, F. Zhou, G. Pedersen, M. C. Trieu, P. Zhou, R. J. Cox. (2017) Induction of Local Secretory IgA and Multifunctional CD4 T-helper Cells Following Intranasal Immunization with a H5N1 Whole Inactivated Influenza Virus Vaccine in BALB/c Mice. Scandinavian Journal of Immunology 81 :10.1111/sji.2017.81.issue-5, 305-317. CrossRef Gerald Aichinger, Barbara Grohmann-Izay, Maikel V. W. van der Velden, Sandor Fritsch, Manuela Koska, Daniel Portsmouth, Mary Kate Hart, Wael El-Amin, Otfried Kistner, P. Noel Barrett, S. A. Plotkin. (2017) Phase I/II Randomized Double-Blind Study of the Safety and Immunogenicity of a Nonadjuvanted Vero Cell Culture-Derived Whole-Virus H9N2 Influenza Vaccine in Healthy Adults. Clinical and Vaccine Immunology 22 . 46-55. CrossRef Joanne M. Langley, Louise Frenette, Robert Jeanfreau, Scott A. Halperin, Michael Kyle, Laurence Chu, Shelly McNeil, Mamadou Dram, Philippe Moris, Louis Fries, David W. Vaughn. (2017) Immunogenicity of heterologous H5N1 influenza booster vaccination 6 or 18 months after primary vaccination in adults: A randomized controlled clinical trial. Vaccine 33 . 559-567. CrossRef Claudia Trombetta, Daniele Perini, Stuart Mather, Nigel Temperton, Emanuele Montomoli. (2014) Overview of Serological Techniques for Influenza Vaccine Evaluation: Past, Present and Future. Vaccines 2 . 707-734. CrossRef Zhongpeng Zhao, Chuanbo Fan, Yueqiang Duan, Liangyan Zhang, Min Li, Xiaolan Yang, Ruisheng Li, Penghui Yang, Xiliang Wang. (2014) Protection from infection with influenza A H7N9 virus in a mouse model by equine neutralizing F(ab)2. International Immunopharmacology 23 . 134-138. CrossRef Brendon Y Chua, Lorena E Brown, David C Jackson. (2014) Considerations for the rapid deployment of vaccines against H7N9 influenza. Expert Review of Vaccines 13 . 1327-1337. CrossRef Calvin C. Willhite, Nataliya A. Karyakina, Robert A. Yokel, Nagarajkumar Yenugadhati, Thomas M. Wisniewski, Ian M. F. Arnold, Franco Momoli, Daniel Krewski. (2014) Systematic review of potential health risks posed by pharmaceutical, occupational and consumer exposures to metallic and nanoscale aluminum, aluminum oxides, aluminum hydroxide and its soluble salts. Critical Reviews in Toxicology 44 . 1-80. CrossRef Jenny G. H. Low, Lawrence S. Lee, Eng Eong Ooi, Kantharaj Ethirajulu, Pauline Yeo, Alex Matter, John E. Connolly, David A. G. Skibinski, Philippe Saudan, Martin Bachmann, Brendon J. Hanson, Qingshu Lu, Sebastian Maurer-Stroh, Sam Lim, Veronica Novotny-Diermayr. (2014) Safety and immunogenicity of a virus-like particle pandemic influenza A (H1N1) 2009 vaccine: Results from a double-blinded, randomized Phase I clinical trial in healthy Asian volunteers. Vaccine 32 . 5041-5048. CrossRef R. Fritz, N. Hetzelt, R. Ilk, C. Hohenadl, M. V. W. van der Velden, G. Aichinger, D. Portsmouth, O. Kistner, M. K. Howard, P. N. Barrett, T. R. Kreil. (2014) Neuraminidase-Inhibiting Antibody Response to H5N1 Virus Vaccination in Chronically Ill and Immunocompromised Patients. Open Forum Infectious Diseases 1 . ofu072-ofu072. CrossRef Catherine J Luke, Kanta Subbarao. (2014) Improving pandemic H5N1 influenza vaccines by combining different vaccine platforms. Expert Review of Vaccines 13 . 873-883. CrossRef Anna-Karin Maltais, Koert J. Stittelaar, Edwin J. B. Veldhuis Kroeze, Geert van Amerongen, Marcel L. Dijkshoorn, Gabriel P. Krestin, Jorma Hinkula, Hans Arwidsson, Alf Lindberg, Albert D. M.E. Osterhaus. (2014) Intranasally administered Endocine formulated 2009 pandemic influenza H1N1 vaccine induces broad specific antibody responses and confers protection in ferrets. Vaccine 32 . 3307-3315. CrossRef Sabine Nakowitsch, Andrea M. Waltenberger, Nina Wressnigg, Nicole Ferstl, Andrea Triendl, Bettina Kiefmann, Emanuele Montomoli, Giulia Lapini, Maria Sergeeva, Thomas Muster, Julia R. Romanova. (2014) Egg - or cell culture-derived hemagglutinin mutations impair virus stability and antigen content of inactivated influenza vaccines. Biotechnology Journal 9 :10.1002/biot. v9.3, 405-414. CrossRef M. V. W. van der Velden, R. Fritz, E. M. Pollabauer, D. Portsmouth, M. K. Howard, T. R. Kreil, T. Dvorak, S. Fritsch, T. Vesikari, J. Diez-Domingo, P. Richmond, B. W. Lee, O. Kistner, H. J. Ehrlich, P. N. Barrett, G. Aichinger. (2014) Safety and Immunogenicity of a Vero Cell Culture-Derived Whole-Virus Influenza A(H5N1) Vaccine in a Pediatric Population. Journal of Infectious Diseases 209 . 12-23. CrossRef Eun Hye Park, Jung Yum, Keun Bon Ku, Heui Man Kim, Young Myong Kang, Jeong Cheol Kim, Ji An Kim, Yoo Kyung Kang, Sang Heui Seo. (2014) Red Ginseng-containing diet helps to protect mice and ferrets from the lethal infection by highly pathogenic H5N1 influenza virus. Journal of Ginseng Research 38 . 40-46. CrossRef Mariana Baz, Catherine J. Luke, Xing Cheng, Hong Jin, Kanta Subbarao. (2013) H5N1 vaccines in humans. Virus Research 178 . 78-98. CrossRef Sung-Ching Pan, Hsiang-Chi Kung, Tsui-Mai Kao, Hsio Wu, Shao-Xing Dong, Mei-Hua Hu, Ai-Hsiang Chou, Pele Chong, Szu-Min Hsieh, Shan-Chwen Chang. (2013) The Madin-Darby canine kidney cell culture derived influenza A/H5N1 vaccine: A Phase I trial in Taiwan. Journal of Microbiology, Immunology and Infection 46 . 448-455. CrossRef James F. Cummings, Melanie L. Guerrero, James E. Moon, Paige Waterman, Robin K. Nielsen, Stacie Jefferson, F. Liaini Gross, Kathy Hancock, Jacqueline M. Katz, Vidadi Yusibov. (2013) Safety and immunogenicity of a plant-produced recombinant monomer hemagglutinin-based influenza vaccine derived from influenza A (H1N1)pdm09 virus: A Phase 1 dose-escalation study in healthy adults. Vaccine . CrossRef Nina Wressnigg, Eva-Maria Pllabauer, Gerald Aichinger, Daniel Portsmouth, Alexandra Lw-Baselli, Sandor Fritsch, Ian Livey, Brian A Crowe, Michael Schwendinger, Peter Brhl, Andreas Pilz, Thomas Dvorak, Julia Singer, Clair Firth, Benjamin Luft, Bernhard Schmitt, Markus Zeitlinger, Markus Mller, Herwig Kollaritsch, Maria Paulke-Korinek, Meral Esen, Peter G Kremsner, Hartmut J Ehrlich, P Noel Barrett. (2013) Safety and immunogenicity of a novel multivalent OspA vaccine against Lyme borreliosis in healthy adults: a double-blind, randomised, dose-escalation phase 1/2 trial. The Lancet Infectious Diseases 13 . 680-689. CrossRef Marc P. Girard, John S. Tam, Yuri Pervikov, Jacqueline M. Katz. (2013) Report on the first WHO integrated meeting on development and clinical trials of influenza vaccines that induce broadly protective and long-lasting immune responses. Vaccine 31 :37, 3766-3771. CrossRef Larry R. Smith, Walter Wodal, Brian A. Crowe, Astrid Kerschbaum, Peter Bruehl, Michael G. Schwendinger, Helga Savidis-Dacho, Sean M. Sullivan, Mark Shlapobersky, Jukka Hartikka, Alain Rolland, P. Noel Barrett, Otfried Kistner. (2013) Preclinical evaluation of Vaxfectin-adjuvanted Vero cell-derived seasonal split and pandemic whole virus influenza vaccines. Human vaccines amp immunotherapeutics 9 . 1333-1345. CrossRef Ling Tao, JianJun Chen, Jin Meng, Yao Chen, Hongxia Li, Yan Liu, Zhenhua Zheng, Hanzhong Wang. (2013) Enhanced protective efficacy of H5 subtype influenza vaccine with modification of the multibasic cleavage site of hemagglutinin in retroviral pseudotypes. Virologica Sinica . CrossRef P. Noel Barrett, Daniel Portsmouth, Hartmut J. Ehrlich. 2013. Accelerated Biopharmaceutical Development: Vero Cell Technology and Pandemic Influenza Vaccine Production. Modern Biopharmaceuticals, 349-386. CrossRef P Noel Barrett, Daniel Portsmouth, Hartmut J Ehrlich. (2013) Vero cell culture-derived pandemic influenza vaccines: preclinical and clinical development. Expert Review of Vaccines 12 . 395-413. CrossRef Marc Gurwith, Michael Lock, Eve M Taylor, Glenn Ishioka, Jeff Alexander, Tim Mayall, John E Ervin, Richard N Greenberg, Cynthia Strout, John J Treanor, Richard Webby, Peter F Wright. (2013) Safety and immunogenicity of an oral, replicating adenovirus serotype 4 vector vaccine for H5N1 influenza: a randomised, double-blind, placebo-controlled, phase 1 study. The Lancet Infectious Diseases 13 :3, 238-250. CrossRef Ilseob Lee, Jin Il Kim, Man-Seong Park. (2013) Cell Culture-based Influenza Vaccines as Alternatives to Egg-based Vaccines. Journal of Bacteriology and Virology 43 . 9. CrossRef Gillian M. Keating, Greg L. Plosker, Katherine A. Lyseng-Williamson. (2012) A/H5N1 Prepandemic Influenza Vaccine (Vepacel): A Guide to Its Use. BioDrugs 26 . 425-430. CrossRef Jessica Chichester, R. Jones, Brian Green, Mark Stow, Fudu Miao, George Moonsammy, Stephen Streatfield, Vidadi Yusibov. (2012) Safety and Immunogenicity of a Plant-Produced Recombinant Hemagglutinin-Based Influenza Vaccine (HAI-05) Derived from A/Indonesia/05/2005 (H5N1) Influenza Virus: A Phase 1 Randomized, Double-Blind, Placebo-Controlled, Dose-Escalation Study in Healthy Adults. Viruses 4 . 3227-3244. CrossRef Kohhei Tetsutani, Ken J. Ishii. (2012) Adjuvants in influenza vaccines. Vaccine 30 . 7658-7661. CrossRef Felix Geeraedts, Wouter ter Veer, Jan Wilschut, Anke Huckriede, Aalzen de Haan. (2012) Effect of viral membrane fusion activity on antibody induction by influenza H5N1 whole inactivated virus vaccine. Vaccine 30 . 6501-6507. CrossRef X. Hu, K. Hong, C. Zhao, Y. Zheng, L. Ma, Y. Ruan, H. Gao, K. Greene, M. Sarzotti-Kelsoe, D. C. Montefiori, Y. Shao. (2012) Profiles of neutralizing antibody response in chronically human immunodeficiency virus type 1 clade B-infected former plasma donors from China naive to antiretroviral therapy. Journal of General Virology 93 . 2267-2278. CrossRef Kelvin KW To, Kenneth HL Ng, Tak-Lun Que, Jacky MC Chan, Kay-Yan Tsang, Alan KL Tsang, Honglin Chen, Kwok-Yung Yuen. (2012) Avian influenza A H5N1 virus: a continuous threat to humans. Emerging Microbes amp Infections 1 . e25. CrossRef Maikel V. W. van der Velden, Gerald Aichinger, Eva Maria Pllabauer, Alexandra Lw-Baselli, Sandor Fritsch, Karima Benamara, Otfried Kistner, Markus Mller, Markus Zeitlinger, Herwig Kollaritsch, Timo Vesikari, Hartmut J. Ehrlich, P. Noel Barrett. (2012) Cell culture (Vero cell) derived whole-virus non-adjuvanted H5N1 influenza vaccine induces long-lasting cross-reactive memory immune response: Homologous or heterologous booster response following two dose or single dose priming. Vaccine 30 . 6127-6135. CrossRef Alexandra Loew-Baselli, Borislava G. Pavlova, Sandor Fritsch, Eva Maria Poellabauer, Wolfgang Draxler, Otfried. Kistner, Ulrich Behre, Rudolf Angermayr, Johannes Neugebauer, Karola Kirsten, Elisabeth Frster-Waldl, Ralph Koellges, Hartmut J. Ehrlich, P. Noel Barrett. (2012) A non-adjuvanted whole-virus H1N1 pandemic vaccine is well tolerated and highly immunogenic in children and adolescents and induces substantial immunological memory. Vaccine 30 . 5956-5966. CrossRef Nicolas Sabarth, Helga Savidis-Dacho, Michael G. Schwendinger, Peter Brhl, Daniel Portsmouth, Brian A. Crowe, Otfried Kistner, P. Noel Barrett, Thomas R. Kreil, M. Keith Howard. (2012) A cell culture-derived whole-virus H5N1 vaccine induces long-lasting cross-clade protective immunity in mice which is augmented by a homologous or heterologous booster vaccination. Vaccine 30 . 5533-5540. CrossRef Michael Schotsaert, Xavier Saelens, Geert Leroux-Roels. (2012) Influenza vaccines: T-cell responses deserve more attention. Expert Review of Vaccines 11 . 949-962. CrossRef Ali Rowhani-Rahbar, Nicola P Klein, Roger Baxter. (2012) Assessing the safety of influenza vaccination in specific populations: children and the elderly. Expert Review of Vaccines 11 . 973-984. CrossRef Greg L. Plosker. (2012) A/H5N1 Prepandemic Influenza Vaccine (Whole Virion, Vero Cell-Derived, Inactivated) Vepacel. Drugs 72 . 1543-1557. CrossRef Candice Yuen-Yue Chan, Paul Anantharajah Tambyah. (2012) Preflucel: a Vero-cell culture-derived trivalent influenza vaccine. Expert Review of Vaccines 11 . 759-773. CrossRef Walter Wodal, Falko G. Falkner, Astrid Kerschbaum, Claudia Gaiswinkler, Richard Fritz, Stefan Kiermayr, Daniel Portsmouth, Helga Savidis-Dacho, Sogue Coulibaly, Christina Piskernik, Christine Hohenadl, M. Keith Howard, Otfried Kistner, P. Noel Barrett, Thomas R. Kreil. (2012) A cell culture-derived whole-virus H9N2 vaccine induces high titer antibodies against hemagglutinin and neuraminidase and protects mice from severe lung pathology and weight loss after challenge with a highly virulent H9N2 isolate. Vaccine 30 . 4625-4631. CrossRef Hartmut J. Ehrlich, Gregory Berezuk, Sandor Fritsch, Gerald Aichinger, Julia Singer, Daniel Portsmouth, Mary Kate Hart, Wael El-Amin, Otfried Kistner, P. Noel Barrett. (2012) Clinical development of a Vero cell culture-derived seasonal influenza vaccine. Vaccine 30 . 4377-4386. CrossRef Hartmut J. Ehrlich, Markus Mller, Herwig Kollaritsch, Fritz Pinl, Bernhard Schmitt, Markus Zeitlinger, Alexandra Loew-Baselli, Thomas R. Kreil, Otfried Kistner, Daniel Portsmouth, Sandor Fritsch, Friedrich Maritsch, Gerald Aichinger, Borislava G. Pavlova, P. Noel Barrett. (2012) Pre-vaccination immunity and immune responses to a cell culture-derived whole-virus H1N1 vaccine are similar to a seasonal influenza vaccine. Vaccine 30 . 4543-4551. CrossRef Fangye Zhou, Jian Zhou, Lei Ma, Shaohui Song, Xinwen Zhang, Weidong Li, Shude Jiang, Yue Wang, Guoyang Liao. (2012) High-yield production of a stable Vero cell-based vaccine candidate against the highly pathogenic avian influenza virus H5N1. Biochemical and Biophysical Research Communications 421 . 850-854. CrossRef Emanuele Montomoli, Baharak Khadang, Simona Piccirella, Claudia Trombetta, Elisa Mennitto, Ilaria Manini, Valerio Stanzani, Giulia Lapini. (2012) Cell culture-derived influenza vaccines from Vero cells: a new horizon for vaccine production. Expert Review of Vaccines 11 . 587-594. CrossRef Nathalie Garon, David W Vaughn, Arnaud M Didierlaurent. (2012) Development and evaluation of AS03, an Adjuvant System containing - tocopherol and squalene in an oil-in-water emulsion. Expert Review of Vaccines 11 . 349-366. CrossRef Philip Dormitzer, Theodore Tsai, Giuseppe Del Giudice. (2012) New technologies for influenza vaccines. Human Vaccines amp Immunotherapeutics 8 . 45-58. CrossRef Paul A. Tambyah, Annelies Wilder-Smith, Borislava G. Pavlova, P. Noel Barrett, Helen M. L. Oh, David S. Hui, Kwok-yung Yuen, Sandor Fritsch, Gerald Aichinger, Alexandra Loew-Baselli, Maikel van der Velden, Friedrich Maritsch, Otfried Kistner, Hartmut J. Ehrlich. (2012) Safety and immunogenicity of two different doses of a Vero cell-derived, whole virus clade 2 H5N1 (A/Indonesia/05/2005) influenza vaccine. Vaccine 30 . 329-335. CrossRef Qunfeng Wu, Shaobo Xiao, Huiying Fan, Yang Li, Jinfang Xu, Zhen Li, Wei Lu, Xiaoyue Su, Wei Zou, Meilin Jin, Huanchun Chen, Liurong Fang. (2011) Protective immunity elicited by a pseudotyped baculovirus-mediated bivalent H5N1 influenza vaccine. Antiviral Research 92 . 493-496. CrossRef Jessica A. Belser, Cynthia B. Snider, Nancy J. Cox, Frederick G. Hayden. (2011) XIth International Symposium on Respiratory Viral Infections. Influenza and Other Respiratory Viruses 5 :10.1111/irv.2011.5.issue-6, 443-e457. CrossRef Thomas R. Kreil, John K. Mc Vey, Laura Shau-Ping Lei, Laureano Camacho, Walter Wodal, Astrid Kerschbaum, Edy Segura, Etienne Vandamme, Patrick Gavit, Hartmut J. Ehrlich, P. Noel Barrett, Donald A. Baker. (2011) Preparation of commercial quantities of a hyperimmune human intravenous immunoglobulin preparation against an emerging infectious disease: the example of pandemic H1N1 influenza. Transfusion . no-no. CrossRef Gerald Aichinger, Hartmut J. Ehrlich, John G. Aaskov, Sandor Fritsch, Christiane Thomasser, Wolfgang Draxler, Michael Wolzt, Markus Mller, Fritz Pinl, Pierre Van Damme, Annick Hens, Jack Levy, Daniel Portsmouth, Georg Holzer, Otfried Kistner, Thomas R. Kreil, P. Noel Barrett. (2011) Safety and immunogenicity of an inactivated whole virus Vero cell-derived Ross River virus vaccine: A randomized trial. Vaccine 29 . 9376-9384. CrossRef John Steel. (2011) New Strategies for the Development of H5N1 Subtype Influenza Vaccines. BioDrugs 25 . 285-298. CrossRef Rebecca J. Cox, Gabriel Pedersen, Abdullah S. Madhun, Signe Svindland, Marianne Svik, Lucy Breakwell, Katja Hoschler, Marieke Willemsen, Laura Campitelli, Jane Kristin Nstbakken, Gerrit Jan Weverling, Jaco Klap, Kenneth C. McCullough, Maria Zambon, Ronald Kompier, Haakon Sjursen. (2011) Evaluation of a virosomal H5N1 vaccine formulated with Matrix M adjuvant in a phase I clinical trial. Vaccine 29 . 8049-8059. CrossRef Jeremy C. Jones, Erik W. Settles, Curtis R. Brandt, Stacey Schultz-Cherry. (2011) Virus aggregating peptide enhances the cell-mediated response to influenza virus vaccine. Vaccine 29 . 7696-7703. CrossRef Chunyan He, Zhiqiang Yang, Kuitang Tong. (2011) Downstream processing of Vero cell-derived human influenza A virus (H1N1) grown in serum-free medium. Journal of Chromatography A 1218 . 5279-5285. CrossRef Michael L Perdue, Frank Arnold, Sheng Li, Armen Donabedian, Vittoria Cioce, Thomas Warf, Robert Huebner. (2011) The future of cell culture-based influenza vaccine production. Expert Review of Vaccines 10 . 1183-1194. CrossRef K. K. Orlinger, Y. Hofmeister, R. Fritz, G. W. Holzer, F. G. Falkner, B. Unger, A. Loew-Baselli, E.-M. Poellabauer, H. J. Ehrlich, P. N. Barrett, T. R. Kreil. (2011) A Tick-borne Encephalitis Virus Vaccine Based on the European Prototype Strain Induces Broadly Reactive Cross-neutralizing Antibodies in Humans. Journal of Infectious Diseases 203 . 1556-1564. CrossRef Derek T OHagan, Rino Rappuoli, Ennio De Gregorio, Theodore Tsai, Giuseppe Del Giudice. (2011) MF59 adjuvant: the best insurance against influenza strain diversity. Expert Review of Vaccines 10 . 447-462. CrossRef Heng Liu, Laura Bungener, Wouter ter Veer, Beth-Ann Coller, Jan Wilschut, Anke Huckriede. (2011) Preclinical evaluation of the saponin derivative GPI-0100 as an immunostimulating and dose-sparing adjuvant for pandemic influenza vaccines. Vaccine 29 . 2037-2043. CrossRef P Noel Barrett, Gregory Berezuk, Sandor Fritsch, Gerald Aichinger, Mary Kate Hart, Wael El-Amin, Otfried Kistner, Hartmut J Ehrlich. (2011) Efficacy, safety, and immunogenicity of a Vero-cell-culture-derived trivalent influenza vaccine: a multicentre, double-blind, randomised, placebo-controlled trial. The Lancet 377 . 751-759. CrossRef Shao-Zhen Feng, Pei-Rong Jiao, Wen-Bao Qi, Hui-Ying Fan, Ming Liao. (2011) Development and strategies of cell-culture technology for influenza vaccine. Applied Microbiology and Biotechnology 89 . 893-902. CrossRef Atika Abelin, Tony Colegate, Stephen Gardner, Norbert Hehme, Abraham Palache. (2011) Lessons from pandemic influenza A(H1N1): The research-based vaccine industrys perspective. Vaccine 29 . 1135-1138. CrossRef Yoichi Furuya. (2011) Return of inactivated whole-virus vaccine for superior efficacy. Immunology and Cell Biology 90 :6, 571. CrossRef R. Fritz, N. Sabarth, S. Kiermayr, C. Hohenadl, M. K. Howard, R. Ilk, O. Kistner, H. J. Ehrlich, P. N. Barrett, T. R. Kreil. (2011) A Vero Cell-Derived Whole-Virus H5N1 Vaccine Effectively Induces Neuraminidase-Inhibiting Antibodies. Journal of Infectious Diseases 205 :1, 28. CrossRef A. Roldo, A. C. Silva, M. C.M. Mellado, P. M. Alves, M. J.T. Carrondo. 2011. Viruses and Virus-Like Particles in Biotechnology. Comprehensive Biotechnology, 625-649. CrossRef Brian A. Crowe, Peter Brhl, Marijan Gerencer, Michael G. Schwendinger, Andreas Pilz, Otfried Kistner, Katrin Koelling-Schlebusch, Gerald Aichinger, Julia Singer, Markus Zeitlinger, Markus Mller, Hartmut Ehrlich, P. Noel Barrett. (2010) Evaluation of the cellular immune responses induced by a non-adjuvanted inactivated whole virus A/H5N1/VN/1203 pandemic influenza vaccine in humans. Vaccine 29 :2, 166-173. CrossRef Penghui Yang, Chong Tang, Deyan Luo, Zhongpeng Zhan, Li Xing, Yueqiang Duan, Weihong Jia, Daxin Peng, Xiufan Liu, Xiliang Wang. (2010) Cross-clade protection against HPAI H5N1 influenza virus challenge in BALB/c mice intranasally administered adjuvant-combined influenza vaccine. Veterinary Microbiology 146 :1-2, 17-23. CrossRef Jiang Wu, Shu-Zhen Liu, Shan-Shan Dong, Xiao-Ping Dong, Wu-Li Zhang, Min Lu, Chang-Gui Li, Ji-Chen Zhou, Han-Hua Fang, Yan Liu, Li-Ying Liu, Yuan-Zheng Qiu, Qiang Gao, Xiao-Mei Zhang, Jiang-Ting Chen, Xiang Zhong, Wei-Dong Yin, Zi-Jian Feng. (2010) Safety and immunogenicity of adjuvanted inactivated split-virion and whole-virion influenza A (H5N1) vaccines in children: A phase III randomized trial. Vaccine 28 . 6221-6227. CrossRef Felix Geeraedts, Vinay Saluja, Wouter Veer, Jean-Pierre Amorij, Henderik W. Frijlink, Jan Wilschut, Wouter L. J. Hinrichs, Anke Huckriede. (2010) Preservation of the Immunogenicity of Dry-powder Influenza H5N1 Whole Inactivated Virus Vaccine at Elevated Storage Temperatures. The AAPS Journal 12 . 215-222. CrossRef Neetu Singh, Aseem Pandey, Suresh K. Mittal. (2010) Avian influenza pandemic preparedness: developing prepandemic and pandemic vaccines against a moving target. Expert Reviews in Molecular Medicine 12 . CrossRef Wei Lu, Paul A Tambyah. (2010) Safety and immunogenicity of influenza A H1N1 vaccines. Expert Review of Vaccines 9 . 365-369. CrossRef S. Koyama, T. Aoshi, T. Tanimoto, Y. Kumagai, K. Kobiyama, T. Tougan, K. Sakurai, C. Coban, T. Horii, S. Akira, K. J. Ishii. (2010) Plasmacytoid Dendritic Cells Delineate Immunogenicity of Influenza Vaccine Subtypes. Science Translational Medicine 2 . 25ra24-25ra24. CrossRef Michael J. Loeffelholz. (2010) Avian Influenza A H5N1 Virus. Clinics in Laboratory Medicine 30 . 1-20. CrossRef Larry R. Smith, Mary K. Wloch, Ming Ye, Luane R. Reyes, Souphaphone Boutsaboualoy, Casey E. Dunne, Jennifer A. Chaplin, Denis Rusalov, Alain P. Rolland, Cindy L. Fisher, Mohamed S. Al-Ibrahim, Martin L. Kabongo, Roy Steigbigel, Robert B. Belshe, Ernest R. Kitt, Alice H. Chu, Ronald B. Moss. (2010) Phase 1 clinical trials of the safety and immunogenicity of adjuvanted plasmid DNA vaccines encoding influenza A virus H5 hemagglutinin. Vaccine 28 :13, 2565-2572. CrossRef Cosue Miyaki, Wagner Quintilio, Eliane N. Miyaji, Viviane F. Botosso, Flavia S. Kubrusly, Fernanda L. Santos, Dmitri Iourtov, Hisako G. Higashi, Isaias Raw. (2010) Production of H5N1 (NIBRG-14) inactivated whole virus and split virion influenza vaccines and analysis of immunogenicity in mice using different adjuvant formulations. Vaccine 28 :13, 2505-2509. CrossRef Andr van Maurik, Nicolas Sabarth, Helga Savidis Dacho, Peter Brhl, Michael Schwendinger, Brian A. Crowe, P. Noel Barrett, Otfried Kistner, M. Keith Howard. (2010) Seasonal influenza vaccine elicits heterosubtypic immunity against H5N1 that can be further boosted by H5N1 vaccination. Vaccine 28 . 1778-1785. CrossRef Daisuke Ikeno, Kazuhiko Kimachi, Yoichiro Kino, Seiichi Harada, Kayo Yoshida, Shinji Tochihara, Shigeyuki Itamura, Takato Odagiri, Masato Tashiro, Kenji Okada, Chiaki Miyazaki, Kohji Ueda. (2010) Immunogenicity of an inactivated adjuvanted whole-virion influenza A (H5N1, NIBRG-14) vaccine administered by intramuscular or subcutaneous injection. Microbiology and Immunology 54 :10.1111/mim.2010.54.issue-2, 81-88. CrossRef Suryaprakash Sambhara, Gregory A. Poland. (2010) H5N1 Avian Influenza: Preventive and Therapeutic Strategies Against a Pandemic. Annual Review of Medicine 61 :1, 187-198. CrossRef Jos M. Bayas Rodrguez, Alberto L. Garca-Basteiro, Guillermo Mena Pinilla. (2010) Problemtica de la vacunacin contra la gripe A en Espaa. Archivos de Bronconeumologa 46 . 32-38. CrossRef J. A. Stockman. (2010) A Clinical Trial of a Whole-Virus H5N1 Vaccine Derived from Cell Culture. Yearbook of Pediatrics 2010 . 219-221. CrossRef Nicolas Sabarth, M. Keith Howard, Helga Savidis-Dacho, Andr van Maurik, P. Noel Barrett, Otfried Kistner. (2010) Comparison of single, homologous prime-boost and heterologous prime-boost immunization strategies against H5N1 influenza virus in a mouse challenge model. Vaccine 28 . 650-656. CrossRef Zoltan Vajo, Ferenc Tamas, Laszlo Sinka, Istvan Jankovics. (2010) Safety and immunogenicity of a 2009 pandemic influenza A H1N1 vaccine when administered alone or simultaneously with the seasonal influenza vaccine for the 200910 influenza season: a multicentre, randomised controlled trial. The Lancet 375 . 49-55. CrossRef Xiao-Feng Liang, Hua-Qing Wang, Jun-Zhi Wang, Han-Hua Fang, Jiang Wu, Feng-Cai Zhu, Rong-Cheng Li, Sheng-Li Xia, Yu-Liang Zhao, Fang-Jun Li, Shao-Hong Yan, Wei-Dong Yin, Kang An, Duo-Jia Feng, Xuan-Lin Cui, Feng-Chun Qi, Chang-Jun Ju, Yu-Hui Zhang, Zhi-Jun Guo, Ping-Yu Chen, Ze Chen, Kun-Ming Yan, Yu Wang. (2010) Safety and immunogenicity of 2009 pandemic influenza A H1N1 vaccines in China: a multicentre, double-blind, randomised, placebo-controlled trial. The Lancet 375 . 56-66. CrossRef Stacey Schultz-Cherry, Jeremy C. Jones. 2010. Influenza Vaccines. Advances in Virus Research, 63-84. CrossRef Wendy Keitel, Nicola Groth, Maria Lattanzi, Michaela Praus, Anne Katrin Hilbert, Astrid Borkowski, Ted F. Tsai. (2010) Dose ranging of adjuvant and antigen in a cell culture H5N1 influenza vaccine: Safety and immunogenicity of a phase 1/2 clinical trial. Vaccine 28 . 840-848. CrossRef Arash Hassantoufighi, Henry Zhang, Matthew Sandbulte, Jin Gao, Jody Manischewitz, Lisa King, Hana Golding, Timothy M. Straight, Maryna C. Eichelberger. (2010) A practical influenza neutralization assay to simultaneously quantify hemagglutinin and neuraminidase-inhibiting antibody responses. Vaccine 28 . 790-797. CrossRef Maria R. Farcet, Christina B. Planitzer, Oliver Stein, Jens Modrof, Thomas R. Kreil. (2010) Hepatitis A virus antibodies in immunoglobulin preparations. Journal of Allergy and Clinical Immunology 125 . 198-202. CrossRef Zhu. Feng-Cai. Wang. Hua. Fang. Han-Hua. Yang. Jian Guo. Lin. Xiao Jun. Liang. Xiao-Feng. Zhang. Xue-Feng. Pan. Hong-Xing. Meng. Fan-Yue. Hu. Yue Mei. Liu. Wen-Dong. Li. Chang-Gui. Li. Wei. Zhang. Xiang. Hu. Jin Mei. Peng. Wei Bing. Yang. Bao Ping. Xi. Pei. Wang. Hua-Qing. Zheng. Jing-Shan. (2009) A Novel Influenza A (H1N1) Vaccine in Various Age Groups. New England Journal of Medicine 361 :25, 2414-2423. Free Full Text Lars R. Haaheim, Abdullah S. Madhun, Rebecca Cox. (2009) Pandemic Influenza Vaccines The Challenges. Viruses 1 . 1089-1109. CrossRef Karl G. Nicholson, Catherine I. Thompson, Jaco M. Klap, John M. Wood, Sally Batham, Robert W. Newman, Robert Mischler, Maria C. Zambon, Iain Stephenson. (2009) Safety and immunogenicity of whole-virus, alum-adjuvanted whole-virus, virosomal, and whole-virus intradermal influenza A/H9N2 vaccine formulations. Vaccine 28 . 171-178. CrossRef Markus Mller. (2009) Zur Medienberichterstattung ber den in sterreich verfgbaren Impfstoff gegen pandemische Influenza A/H1N1. Wiener klinische Wochenschrift 121 . 663-664. CrossRef Shan Lu, Shixia Wang. (2009) Technical transformation of biodefense vaccines. Vaccine 27 . D8-D15. CrossRef Wendy A. Keitel, Cornelia L. Dekker, ChrisAnna Mink, James D. Campbell, Kathryn M. Edwards, Shital M. Patel, Dora Y. Ho, Helen K. Talbot, Kuo Guo, Diana L. Noah, Heather Hill. (2009) Safety and immunogenicity of inactivated, Vero cell culture-derived whole virus influenza A/H5N1 vaccine given alone or with aluminum hydroxide adjuvant in healthy adults. Vaccine 27 . 6642-6648. CrossRef R. Rappuoli, G. Del Giudice, G. J. Nabel, A. D. M. E. Osterhaus, R. Robinson, D. Salisbury, K. Stohr, J. J. Treanor. (2009) Rethinking Influenza. Science 326 . 50-50. CrossRef Christina B. Planitzer, Jens Modrof, Mei-ying W. Yu, Thomas R. Kreil. (2009) West Nile Virus Infection in Plasma of Blood and Plasma Donors, United States. Emerging Infectious Diseases 15 . 1668-1670. CrossRef Tino F. Schwarz, Thomas Horacek, Markus Knuf, Hanns-Gerd Damman, Franois Roman, Mamadou Dram, Paul Gillard, Wolfgang Jilg. (2009) Single dose vaccination with AS03-adjuvanted H5N1 vaccines in a randomized trial induces strong and broad immune responsiveness to booster vaccination in adults. Vaccine 27 . 6284-6290. CrossRef Liisa Lehtoranta, Anja Villberg, Riitta Santanen, Thedi Ziegler. (2009) A novel, colorimetric neutralization assay for measuring antibodies to influenza viruses. Journal of Virological Methods 159 . 271-276. CrossRef Lamberto Manzoli, Georgia Salanti, Corrado De Vito, Antonio Boccia, John PA Ioannidis, Paolo Villari. (2009) Immunogenicity and adverse events of avian influenza A H5N1 vaccine in healthy adults: multiple-treatments meta-analysis. The Lancet Infectious Diseases 9 . 482-492. CrossRef Ruth A. Karron, Kawsar Talaat, Catherine Luke, Karen Callahan, Bhagvanji Thumar, Susan DiLorenzo, Josephine McAuliffe, Elizabeth Schappell, Amorsolo Suguitan, Kimberly Mills, Grace Chen, Elaine Lamirande, Kathleen Coelingh, Hong Jin, Brian R. Murphy, George Kemble, Kanta Subbarao. (2009) Evaluation of two live attenuated cold-adapted H5N1 influenza virus vaccines in healthy adults. Vaccine 27 . 4953-4960. CrossRef Luc Hessel. (2009) Pandemic influenza vaccines: meeting the supply, distribution and deployment challenges. Influenza and Other Respiratory Viruses 3 :10.1111/irv.2009.3.issue-4, 165-170. CrossRef Tristan Clark, Iain Stephenson. (2009) Influenza A/H1N1 in 2009: a pandemic in evolution. Expert Review of Vaccines 8 . 819-822. CrossRef Frederick G. Hayden, Wendy A. Howard, Laszlo Palkonyay, Marie Paule Kieny. (2009) Report of the 5th meeting on the evaluation of pandemic influenza prototype vaccines in clinical trials. Vaccine 27 . 4079-4089. CrossRef Alexander Doroshenko, Scott A Halperin. (2009) Trivalent MDCK cell culture-derived influenza vaccine Optaflu (Novartis Vaccines). Expert Review of Vaccines 8 . 679-688. CrossRef Rebecca J. Cox, Diane Major, Solveig Hauge, Abdullah S. Madhun, Karl A. Brokstad, Mirjam Kuhne, Jon Smith, Frederick R. Vogel, Maria Zambon, Lars R. Haaheim, John Wood. (2009) A cell-based H7N1 split influenza virion vaccine confers protection in mouse and ferret challenge models. Influenza and Other Respiratory Viruses 3 :10.1111/irv.2009.3.issue-3, 107-117. CrossRef P Noel Barrett, Wolfgang Mundt, Otfried Kistner, M Keith Howard. (2009) Vero cell platform in vaccine production: moving towards cell culture-based viral vaccines. Expert Review of Vaccines 8 . 607-618. CrossRef Zoltan Vajo. (2009) Influenza A (H5N1) pandemic prototype vaccine Fluval . Expert Review of Vaccines 8 . 619-624. CrossRef Arnold S Monto, Suzanne E Ohmit. (2009) Seasonal influenza vaccines: evolutions and future trends. Expert Review of Vaccines 8 . 383-389. CrossRef Bram Palache, Ryoko Krause. (2009) Progress with human H5N1 vaccines: a perspective from industry. Expert Review of Vaccines 8 . 391-400. CrossRef Isabel Leroux-Roels, Geert Leroux-Roels. (2009) Current status and progress of prepandemic and pandemic influenza vaccine development. Expert Review of Vaccines 8 . 401-423. CrossRef Jessica A Chichester, Lars R Haaheim, Vidadi Yusibov. (2009) Using plant cells as influenza vaccine substrates. Expert Review of Vaccines 8 . 493-498. CrossRef Rebecca J. Cox, Abdullah S. Madhun, Solveig Hauge, Haakon Sjursen, Diane Major, Mirjam Kuhne, Katja Hschler, Melanie Saville, Frederick R. Vogel, Wendy Barclay, Isabella Donatelli, Maria Zambon, John Wood, Lars R. Haaheim. (2009) A phase I clinical trial of a PER. C6 cell grown influenza H7 virus vaccine. Vaccine 27 . 1889-1897. CrossRef (2009) Vaccin contre la grippe aviaire. premiers essais concluants. Revue Francophone des Laboratoires 2009 :410, 17. CrossRef Arnt-Ove Hovden, Karl A. Brokstad, Diane Major, John Wood, Lars R. Haaheim, Rebecca J. Cox. (2009) A pilot study of the immune response to whole inactivated avian influenza H7N1 virus vaccine in mice. Influenza and Other Respiratory Viruses 3 :10.1111/irv.2009.3.issue-1, 21-28. CrossRef ampNA. (2008) Update your vaccination protocol. Journal of the American Academy of Physician Assistants 21 . 16-17. CrossRef Mary Elizabeth Wilson. (2008) Preface. Medical Clinics of North America 92 . xiii-xviii. CrossRef Julian W. Tang, Karry L. K. Ngai, Paul K. S. Chan. (2008) Lack of cross-immune reactivity against influenza H5N1 from seasonal influenza vaccine in humans. Journal of Medical Virology 80 :10.1002/jmv. v80:11, 1992-1996. CrossRef Mary Hoelscher, Shivaprakash Gangappa, Weimin Zhong, Lakshmi Jayashankar, Suryaprakash Sambhara. (2008) Vaccines against epidemic and pandemic influenza. Expert Opinion on Drug Delivery 5 . 1139-1157. CrossRef Ophlie Marais. (2008) Un vaccin contre le virus H5N1 driv de cultures cellulaires. Option/Bio 19 :406, 4. CrossRef Barrett R. Crowther, Troy D. Schmeling, Mary S. Hayney. (2008) Influenza vaccination: Outlook for 2008-09 season. Journal of the American Pharmacists Association 48 :5, 686-687. CrossRef Daniel A. Hussar. (2008) New drugs: Methylnaltrexone bromide, alvimopan, and rilonacept. Journal of the American Pharmacists Association 48 :5, 688-691. CrossRef (2008) News in brief. Nature Medicine 14 . 702-703. CrossRef Wright. Peter F. (2008) Vaccine Preparedness Are We Ready for the Next Influenza Pandemic. New England Journal of Medicine 358 :24, 2540-2543. Free Full Text
No comments:
Post a Comment