Evaluating anti-Orthopoxvirus antibodies in individuals from Brazilian rural areas prior to the bovine vaccinia era

Vaccinia virus naturally circulates in Brazil and is the causative agent of a zoonotic disease known as bovine vaccinia (BV). We retrospectively evaluated two populations from the Amazon and Southeast Regions. BV outbreaks had not been reported in these regions before sample collection. Neutralising antibodies were found in 13 individuals (n = 132) with titres ranging from 100 ≥ 6,400 neutralising units/mL. Univariate analysis identified age and vaccination as statistically significant risk factors in individuals from the Southeast Region. The absence of detectable antibodies in vaccinated individuals raises questions about the protection of smallpox vaccine years after vaccination and reinforces the need for surveillance of Orthopoxvirus in Brazilian populations without evidence of previous outbreaks.

Vaccinia immune globulin: current policies, preparedness, and product safety and efficacy.

In 1980 the World Health Organization declared that smallpox was eradicated from the world, and routine smallpox vaccination was discontinued. Nevertheless, samples of the smallpox virus (variola virus) were retained for research purposes, not least because of fears that terrorist groups or rogue states might also have kept samples in order to develop a bioweapon. Variola virus represents an effective bioweapon because it is associated with high morbidity and mortality and is highly contagious. Since September 11, 2001, countries around the world have begun to develop policies and preparedness programs to deal with a bioterror attack, including stockpiling of smallpox vaccine. Smallpox vaccine itself may be associated with a number of serious adverse events, which can often be managed with vaccinia immune globulin (VIG). VIG may also be needed as prophylaxis in patients for whom pre-exposure smallpox vaccine is contraindicated (such as those with eczema or pregnant women), although it is currently not licensed in these cases. Two intravenous formulations of VIG (VIGIV Cangene and VIGIV Dynport) have been licensed by the FDA for the management of patients with progressive vaccinia, eczema vaccinatum, severe generalized vaccinia, and extensive body surface involvement or periocular implantation following inadvertent inoculation.

Historico da vacinacao antivariolica no Brasil

A historical chronology of smallpox vaccination in Brazil is presented, with emphasis on the State of Sao Paulo. We also present the scientific and philosophical concepts that influenced the regulation and practice of vaccination in Sao Paulo based on the historiographic bibliography, legislation about vaccination, and the debates in the state legislative body. Discovered by Jenner in 1796, the vaccine reached in Brazil in 1804 and was only used in the colonial capital, the city of Rio de Janeiro. In the 1890 decade, smallpox, side by side with yellow fever, typhoid fever and other pestilential diseases, was the major health problem in the State of Sao Paulo. There was also the fear that the vaccine might transmit syphilis, an Unfounded attitude since the product used in Sao Paulo (the 'animal vaccine') was elaborated from bovine serum. The immediate necessity to fight a highly lethal disease that threatened the State population and the coffee-growing business led to the abandonment of the fears and of the liberal principles in favor of the sanitary needs. The vaccine became compulsory in 1891 in the State of Sao Paulo and its application met no resistance on the part of the population, in contrast to the so-called 'Vaccine Revolt' that would occur in Rio de Janeiro in 1904.

Das Interleukin-1Beta-Rezeptor-Homolog im Modifizierten Vakziniavirus Ankara (MVA) - Charakterisierung und möglicher Einfluss auf MVA-basierte Impfvektoren

MVA ist ein attenuiertes Vakziniavirus, das durch wiederholte Passagierung von Chorioallantoisvirus Ankara auf Hühnerembryofibroblasten gewonnen wurde. Es ist bis auf wenige Ausnahmen nicht mehr in der Lage, in Säugerzellen zu replizieren, zeigt aber dennoch eine vollständige virale Proteinexpression und induziert nach Immunisierung eine zu VACV vergleichbare Immunantwort. Aus diesem Grund wurde es bereits als Impfstoff gegen die menschliche Pockenerkrankung eingesetzt, ohne hierbei die bei den klassischen Impfviren beobachtbaren Nebenwirkungen hervorzurufen. Das Genom von MVA enthält jedoch noch Immunmodulatoren, deren Deletion Ansatzpunkt für die weitere Verbesserung des Impfstoffes sein kann. Im Rahmen der vorliegenden Arbeit wurde eine Deletionsmutante untersucht, bei der das Gen für den Interleukin-1β Rezeptor (IL-1βR) deletiert ist (MVA ΔIL-1βR). Es konnte nachgewiesen werden, dass der IL-1βR in murinen als auch in humanen Zellen exprimiertes IL-1β bindet und somit inaktiviert. Des Weiteren wurde gefunden, dass MVA in der Lage ist, IL-1β in antigenpräsentierenden Zellen zu induzieren, welches aber durch die Neutralisierung aufgrund des IL-1βR nur transient nachzuweisen war. Im Gegensatz dazu induzierte MVA ΔIL-1βR eine anhaltende und um ein Vielfaches erhöhte Sekretion an IL-1β. Untersuchungen in antigenpräsentierenden Zellen aus knock-out Mäusen, die verschiedene Defizienzen in den Signalwegen zur IL-1β-Induktion trugen, zeigten, dass die Sekretion von IL-1β von Caspase-1 abhängig war, welches wahrscheinlich aus der vorgeschalteten Aktivierung der NLRP3- und/oder AIM2-Inflammasomen resultierte. Interessanterweise wurden auch Caspase-1 unabhängige Mechanismen beobachtet, die auf eine Inflammasom-unabhängige IL-1β-Induktion hinweisen könnten. In Bezug auf die Immunaktivierung führte die vermehrte Sekretion von IL-1β durch MVA ΔIL-1βR vermutlich zu einer verbesserten Antigenpräsentation, die die nachfolgende T-Zellantwort beeinflusste. In Übereinstimmung mit bereits veröffentlichten Daten wurde nach Immunisierung mit MVA ΔIL-1βR eine effektivere Gedächtnis-T-Zellantwort festgestellt, deren Charakteristika und zu Grunde liegenden Mechanismen hier untersucht wurden. Jedoch konnten weder Unterschiede in weiteren pro-inflammatorischen Zytokinmustern noch im Verlauf insbesondere der CD8+ T-Zell-Aktivierung und -erhaltung zwischen MVA und MVA ΔIL-1βR beobachtet werden. Als mögliche weitere Ursache für die veränderte Gedächtnis-T-Zellantwort könnte daher eine vermehrte Stimulation durch antigenpräsentierende Zellen und eine IL-21-vermittelte bessere Unterstützungsfunktion der CD8+ Gedächtnis-T-Zellen durch CD4+ T-Zellen in Frage kommen. Zusammenfassend konnten hier neue molekulare Mechanismen, die zur Induktion von IL-1β nach einer MVA-Infektion führen, aufgedeckt werden. Darüber hinaus existieren bereits erste Hinweise auf einen Vorteil der Deletion des IL-1βR für MVA-basierte Vektorimpfstoffe. Die vorliegende Arbeit hat weitere Daten erhoben, die das Erzielen verbesserter Immunantworten nach Immunisierung mit MVA ΔIL-1βR unterstützen, woraus sich neue Ansätze für die Entwicklung MVA-basierter Impfstoffe ergeben könnten.

A mechanism for the inhibition of fever by a virus.

Poxviruses encode proteins that block the activity of cytokines. Here we show that the study of such virulence factors can contribute to our understanding of not only virus pathogenesis but also the physiological role of cytokines. Fever is a nonspecific response to infection that contributes to host defense. Several cytokines induce an elevation of body temperature when injected into animals, but in naturally occurring fever it has been difficult to show that any cytokine has a critical role. We describe the first example of the suppression of fever by a virus and the molecular mechanism leading to it. Several vaccinia virus strains including smallpox vaccines express soluble interleukin 1 (IL-1) receptors, which bind IL-1 beta but not IL-1 alpha. These viruses prevent the febrile response in infected mice, whereas strains that naturally or through genetic engineering lack the receptor induce fever. Repair of the defective IL-1 beta inhibitor in the smallpox vaccine Copenhagen, a more virulent virus than the widely used vaccine strains Wyeth and Lister, suppresses fever and attenuates the disease. The vaccinia-induced fever was inhibited with antibodies to IL-1 beta. These findings provide strong evidence that IL-1 beta, and not other cytokines, is the major endogenous pyrogen in a poxvirus infection.

La tardía emergencia mediática de la vacuna contra la viruela, cobertura de noticias en prensa española (1999-2004)

Introducción. Las discusiones sobre la necesidad de conservación del virus de la viruela en 1999 pusieron de actualidad una enfermedad erradicada veinte años atrás. El escenario de alarma internacional creado tras los incidentes del 11-S en EE.UU vino a resituar a la viruela como potencial candidata para ser utilizada como arma bioterrorista. La consecuencia directa fue la reactivación de una vacuna que permanecía en el olvido y cuyos destinatarios iniciales eran los cuerpos de seguridad estadounidenses. España también se interesó por adquirir la vacuna antivariólica. El objetivo de este estudio es valorar la cobertura mediática que la viruela obtuvo en nuestro país. Métodos. Revisión sistemática en la base documental Dow Jones Factiva de las noticias publicadas durante el periodo 1999-2004 en los cuatro diarios de mayor tirada nacional (ABC, El Mundo, El País y La Vanguardia), utilizando como palabra clave “viruela”. Se efectuó un análisis cuantitativo y cualitativo de los datos obtenidos. Resultados. Se analizaron 416 noticias. El Mundo, con un total de 158 (37.98%), fue el diario con más publicaciones. El mayor número de noticias (152, 36,5%) se editaron en 2003, coincidiendo con la adquisición de vacunas por España. El tipo de mensajes emitidos fue variable a lo largo del sexenio, predominando los relacionados con “diplomacia y política”, “riesgo epidemiológico”, “bioterrorismo” y “vacuna”, concentrados en años diferentes. Conclusiones. La alarma creada en torno a la vacunación antivariólica fue un fenómeno mediático que obedeció a cuestiones de estrategia política más que a un problema real de salud pública.

Los ensayos de Joaquín de Villalba (1752-1807) sobre la vacuna de la viruela en la Escuela de Veterinaria de Madrid

La rápida propagación del método empírico para combatir la viruela dado a conocer por Edward Jenner conllevó algunas dificultades. A la necesidad de obtener la máxima aceptación posible entre la población, se añadió la de ejecutar con rigor la técnica así como la de producir, transportar y conservar el fluido vacunal con garantías de calidad. Abastecerse de vacuna era una preocupación solventada en parte gracias a los envíos realizados desde instituciones radicadas en Londres o París. Tras su recepción se iniciaban cadenas de vacunaciones mediante la técnica del brazo a brazo. El temor a la extinción del fluido vacunal, no obstante, despertó el interés por la producción autóctona. Era necesario encontrar vacas afectadas por viruela vacuna o en su defecto aprender a conservar la materia vacunal en las propias vacas u otros animales. Varias iniciativas exploraron esta posibilidad. El fondo documental de la Biblioteca Nacional de España conserva un texto que refleja 2 de estos ensayos realizados en la Real Escuela Veterinaria de Madrid a cargo del médico Joaquín de Villalba y el albéitar Antonio Roura en 1802 y 1803. La tentativa no obtuvo el éxito deseado.

Un médico rural contra la viruela, la epidemia de 1891-92 en Huércanos (Logroño)

La práctica inconstante de la vacunación contra la viruela durante el siglo xix tuvo como consecuencia la aparición de varias oleadas epidémicas en España. La baja aceptación de la vacuna entre la población, unida a la incapacidad del estado para organizar campañas y suministrar vacuna, contribuyeron a perpetuar la enfermedad. Durante la segunda mitad del siglo se abrió un debate sobre la necesidad de hacer obligatoria la vacunación y revacunación, incorporándose, además, el uso de la vacuna animalizada. Un texto de Emilio Casas Arriola, médico de Huércanos (Logroño), describe el brote epidémico sufrido entre 1891 y 1892 en este municipio. La obra tiene la estructura de una topografía médica y fue redactada con la intención de concurrir a un premio de la Real Academia Médica de Madrid. Se analizan las dificultades, vicisitudes y medidas adoptadas para afrontar la epidemia en un entorno aislado y rural.

Una propuesta fallida para propagar la vacuna contra la viruela en Hispanoamérica (1802)

Tras la inicial propagación del método jenneriano por Inglaterra y el resto del continente europeo, se mostró un gran interés por difundirlo hacia Oriente y América. En el caso de España, los focos epidémicos que estaban ocurriendo en los territorios de ultramar movieron a las autoridades de los distintos virreinatos a solicitar a la Corona que enviara cuanto antes el nuevo remedio. La monarquía borbónica, que había introducido las expediciones científicas como elemento de progreso y dominio, aprobó el proyecto conocido como “Real Expedición Filantrópica de la Vacuna”, que partió hacia América al mando de Balmis en 1803. Relatamos una propuesta inédita anterior a esa, en la que un desconocido cirujano, Rafael de Malaguilla, se ofreció para llevar a cabo una iniciativa similar.

El viaje de la vacuna contra la viruela: una expedición, dos océanos, tres continentes y miles de niños

España fomentó durante el periodo de la ilustración borbónica la formación de expediciones científicas, entre las que se encuentra la Real Expedición Filantrópica de la Vacuna (REFV), un ejemplo de biopolítica aplicado por el Estado para proteger la salud. La expedición dio la vuelta al mundo utilizando niños como reservorio para transportar el fluido vacuno. Francisco Xavier Balmis estableció una cadena humana brazo a brazo que materializó el éxito de la misión. En este artículo se analizan las características y avatares por las que pasaron los niños que contribuyeron a la propagación de la vacuna antivariólica.

DNA/NYVAC Vaccine Regimen Induces HIV-Specific CD4 and CD8 T-Cell Responses in Intestinal Mucosa

Background: HIV vaccine-candidates based on rare adenovirus serotypes such as Ad26 and Ad35 vectors, and poxvirus vectors are important components of future promising vaccine regimens that in the near future hopefully will move into a number of efficacy clinical trials in combination with protein vaccines. For these reasons, it is important to comprehensively characterize the vaccine-induced immune responses in different anatomical compartments and particularly at mucosal sites which represent the primary port of entry for HIV.Methods: In the present study, we have investigated the anatomic distribution in blood and gut mucosal tissues (rectum and ileum) of memory poxvirus-specific CD4 and CD8 T cells in subjects vaccinated with smallpox and compared with vector (NYVAC)-specific and HIV insert-specific T-cell responses induced by an experimental DNA-C/NYVAC-C vaccine regimen.Results: Smallpox-specific CD4 T-cell responses were present in the blood of 52% of subject studied, while Smallpox-specific CD8 T cells were rarely detected (12%). With one exception, Smallpoxspecific T cells were not measurable in gut tissues. Interestingly, NYVAC vector-specific and HIV-specific CD4 and CD8 T-cell responses were detected in almost 100% of the subjects immunized with DNA-C/NYVAC-C in blood and gut tissues. The large majority (83%) of NYVAC-specific CD4 T cells expressed a4b7 integrins and the HIV co-receptor CCR5.Conclusion: These results demonstrate that the experimental DNA-C/NYVAC-C HIV vaccine regimen induces the homing of potentially protective HIV-specific CD4 and CD8 T cells in the gut, the port of entry of HIV and one of the major sites for HIV spreading and depletion of CD4 T cells.

DNA/NYVAC vaccine regimen induces HIV-specific CD4 and CD8 T-cell responses in intestinal mucosa.

In the present study, we have investigated the anatomic distribution in blood and gut mucosal tissues of memory poxvirus-specific CD4 and CD8 T cells in subjects vaccinated with smallpox and compared it with vector (NYVAC)-specific and HIV insert-specific T-cell responses induced by an experimental DNA-C/ NYVAC-C vaccine regimen. Smallpox-specific CD4 T-cell responses were present in the blood of 52% of the subjects studied, while smallpox-specific CD8 T cells were rarely detected (12%). With one exception, smallpox-specific T cells were not measurable in gut tissues. Interestingly, NYVAC vector-specific and HIV-specific CD4 and CD8 T-cell responses were detected in almost 100% of the subjects immunized with DNA-C/NYVAC-C in blood and gut tissues. The large majority (83%) of NYVAC-specific CD4 T cells expressed α4β7 integrins and the HIV coreceptor CCR5. These results demonstrate that the experimental DNA-C/NYVAC-C HIV vaccine regimen induces the homing of potentially protective HIV-specific CD4 and CD8 T cells in the gut, the port of entry of HIV and one of the major sites for HIV spreading and the depletion of CD4 T cells.

Post Hoc Analysis Of The Patricia Randomized Trial Of The Efficacy Of Human Papillomavirus Type 16 (hpv-16)/hpv-18 As04-adjuvanted Vaccine Against Incident And Persistent Infection With Nonvaccine Oncogenic Hpv Types Using An Alternative Multiplex Type-specific Pcr Assay For Hpv Dna.

The efficacy of the human papillomavirus type 16 (HPV-16)/HPV-18 AS04-adjuvanted vaccine against cervical infections with HPV in the Papilloma Trial against Cancer in Young Adults (PATRICIA) was evaluated using a combination of the broad-spectrum L1-based SPF10 PCR-DNA enzyme immunoassay (DEIA)/line probe assay (LiPA25) system with type-specific PCRs for HPV-16 and -18. Broad-spectrum PCR assays may underestimate the presence of HPV genotypes present at relatively low concentrations in multiple infections, due to competition between genotypes. Therefore, samples were retrospectively reanalyzed using a testing algorithm incorporating the SPF10 PCR-DEIA/LiPA25 plus a novel E6-based multiplex type-specific PCR and reverse hybridization assay (MPTS12 RHA), which permits detection of a panel of nine oncogenic HPV genotypes (types 16, 18, 31, 33, 35, 45, 52, 58, and 59). For the vaccine against HPV types 16 and 18, there was no major impact on estimates of vaccine efficacy (VE) for incident or 6-month or 12-month persistent infections when the MPTS12 RHA was included in the testing algorithm versus estimates with the protocol-specified algorithm. However, the alternative testing algorithm showed greater sensitivity than the protocol-specified algorithm for detection of some nonvaccine oncogenic HPV types. More cases were gained in the control group than in the vaccine group, leading to higher point estimates of VE for 6-month and 12-month persistent infections for the nonvaccine oncogenic types included in the MPTS12 RHA assay (types 31, 33, 35, 45, 52, 58, and 59). This post hoc analysis indicates that the per-protocol testing algorithm used in PATRICIA underestimated the VE against some nonvaccine oncogenic HPV types and that the choice of the HPV DNA testing methodology is important for the evaluation of VE in clinical trials. (This study has been registered at ClinicalTrials.gov under registration no. NCT00122681.).

Antibody responses elicited in mice immunized with Bacillus subtilis vaccine strains expressing Stx2B subunit of enterohaemorragic Escherichia coli O157:H7

No effective vaccine or immunotherapy is presently available for patients with the hemolytic uremic syndrome (HUS) induced by Shiga-like toxin (Stx) producedbyenterohaemorragic Escherichia coli (EHEC) strains, such as those belonging to the O157:H7 serotype. In this work we evaluated the performance of Bacillus subtilis strains, a harmless spore former gram-positive bacterium species, as a vaccine vehicle for the expression of Stx2B subunit (Stx2B). A recombinant B. subtilis vaccine strain expressing Stx2B under the control of a stress inducible promoter was delivered to BALB/c mice via oral, nasal or subcutaneous routes using both vegetative cells and spores. Mice immunized with vegetative cells by the oral route developed low but specific anti-Stx2B serum IgG and fecal IgA responses while mice immunized with recombinant spores developed anti-Stx2B responses only after administration via the parenteral route. Nonetheless, serum anti-Stx2B antibodies raised in mice immunized with the recombinant B. subtilis strain did not inhibit the toxic effects of the native toxin, both under in vitro and in vivo conditions, suggesting that either the quantity or the quality of the induced immune response did not support an effective neutralization of Stx2 produced by EHEC strains.