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The genetic requirements for Influenza virus to infect and adapt to new species is largely unknown. To understand the evolutionary steps required by a virus to become virulent, a human virus (A/HK/1/68) (HK), avirulent in mice, was subjected to 20 and 21 serial lung-to-lung passages in mouse. Sequence analysis revealed the emergence of eleven mutations within the NS1 gene of the new virulent strains, many of which occurred in binding sites for transcriptional and translational cellular factors. In the present study we have rescued viruses containing each of the NS1 mouse adapted mutations onto A/PR/8/34 (PR8) backbone. We found 9 of 16 NS1 mutants were adaptive by inducing mortality, body weight loss in BALB/c mice and enhanced virus replication in MDCK cells with properties of host cell interferon transcription inhibition. Sequence comparisons with the highly pathogenic A/Hong Kong/156/1997 (H5N1) and the most severe pandemic A/Brevig Mission/1/1918 (H1N1) NS1 genes showed convergent evolution with some of the mouse adapted viruses for F103L plus M106I and V226I plus R227K mutations respectively. The F103L and M106I mutations in the HK NS1 gene were shown to be adaptive by assessment with respect to replication, early viral protein synthesis, interferon-β antagonism and tropism in the mouse lung. We extended the study and proved increased virulence associated with F103L+M106I mutations in their respective H5N1 NS1 gene on the PR8 and HK backbones, as well as the PR8 NS1 gene and the H9N2 (A/Ck/Bj/1/95) gene in the PR8 and A/WSN/33 backbones respectively. However the V226I and R227K mutations in their respective HK and 1918 NS1 genes slightly enhanced virulence and viral growth at later stages of infection. This study demonstrates that NS1 is a virulence factor; involved in multiple viral processes including interferon antagonism and viral protein synthesis. Furthermore, NS1 mutations acquired during mouse adaptation are proven to be adaptive in human, mouse and avian NS1 genes.

The capacity of zoonotic pathogens to infect multiple hosts creates surveillance challenges but also provides opportunities to gather data from animal species that can be used to understand risks to human health. This thesis presents a conceptual and practical assessment of the utility of domestic dog serosurveillance for the detection and surveillance of two pathogens, influenza A and Leptospira spp. The first chapter gives a theoretical framework that can be used to explore the attributes of animal sentinels and assess their utility in different contexts. In subsequent chapters, this framework is applied in a practical assessment of the utility of a domestic dog serosurveillance approach for the detection and surveillance influenza A and Leptospira spp. at two sites in Africa. Two cross-sectional surveys of the avian and mammal populations at a site in Northern Cameroon were conducted in early 2006 to determine if H5N1 influenza A viruses had circulated in this area and in which species that presence could be detected. Serological and molecular evidence of extensive H5 virus circulation in the domestic duck population was identified. 47% of domestic ducks at the Maga site were cELISA positive for anti-influenza A antibodies and 20% were HI test positive against an H5N1 antigen. There was also evidence of exposure to H5 subtype viruses in the local dog and pig populations. At the Kibera site in Nairobi, a cohort study was established to carry out surveillance of influenza A and Leptospira spp. in the domestic dog population and cross-sectional surveys of the domestic poultry and rodent populations were completed. There was no indication of influenza A circulation in any of the animal species surveyed, indicating low risk of zoonotic influenza A infection in the human population of Kibera. In contrast, there was extensive molecular and serological evidence of the presence of Leptospira spp. in both the rodent and dog populations. 18% of 236 trapped rodents were PCR positive for kidney carriage of pathogenic leptospires and the estimated seroprevalence of anti- Leptospira antibodies in the dog population ranged from 5-36% during the course of the study, indicating high potential risk of leptospirosis infection in the human population. The results indicate that dog serosurveillance can be used as useful tool for the determination of broad-scale patterns of pathogen presence and relative levels of population exposure. However, there are limitations of the data that can be gathered from animal sentinels and the complexities introduced particularly by incomplete understanding of diagnostic test performance must be recognized. Animal sentinel surveillance may be of most use for addressing fundamental questions of what pathogens are present where. In the developing world particularly where disease burden data are still lacking, dog sentinel serosurveillance can provide essential baseline data that can be used to target future research and resource allocation.

Objetivos: Determinar las variables respiratorias asociadas a mortalidad en pacientes que ingresaron a la Unidad de Cuidados Intensivos de adultos del Hospital Alberto Sabogal Sologuren, Callao – Perú, ingresados desde el 1 de julio al 31 de setiembre del 2009 con síndrome de distrés respiratorio agudo debido a infección confirmada por virus de la Influenza A (H1N1). Materiales y métodos: Se realizó un estudio de serie de casos, registrándose mediciones diarias de cada una de las variables respiratorias durante los primeros 10 días que recibieron ventilación mecánica invasiva, se estableció el promedio y desviación estándar de los grupos de pacientes sobrevivientes y no sobrevivientes, luego se buscó si esta diferencia es estadísticamente significativa. Resultados: De los 10 pacientes del estudio, sobrevivieron 4; en el transcurso de los días el agravamiento de las variables que mostraron diferencia estadísticamente significativa fueron: la Presión Pico (en los días 4, 5, 6, 7, 8, 9 y 10), la Presión Plateau (en los días 4, 5, 6, 8, 9 y 10) y la Gradiente Alveolo Arterial (en los días 4, 5, 8, 9 y 10), no habiendo diferencia estadística y secuencial en las demás variables: Compliance, Pa/FiO2, pH arterial, PaO2, PaCO2, volumen tidal, volumen minuto ni con el PEEP. Conclusión: Hay diferencia significativa a partir del cuarto día y de forma secuencial en las variables Presión Pico, Presión Plateau y el Gradiente Alveolo Arterial. Recomendaciones: Al estar inmersos en una pandemia, se debe valorar la evolución de la Presión Plateau, Presión Pico y la Gradiente Alveolo Arterial para trabajar en base al pronóstico del paciente.

Influenza A virus (AIV) has an extremely high rate of mutation. Frequent exchanges of gene segments between different AIV (reassortment) have been responsible for major pandemics in recent human history. The presence of a wild bird reservoir maintains the threat of incursion of AIV into domestic birds, humans and other animals. In this thesis, I addressed unanswered questions of how diverse AIV subtypes (classified according to antigenicity of the two surface proteins, haemagglutinin and neuraminidase) evolve and interact among different bird populations in different parts of the world, using Bayesian phylogenetic methods with large datasets of full genome sequences. Firstly, I explored the reassortment patterns of AIV internal segments among different subtypes by quantifying evolutionary parameters including reassortment rate, evolutionary rate and selective constraint in time-resolved Bayesian tree phylogenies. A major conclusion was that reassortment rate is negatively associated with selective constraint and that infection of wild rather than domestic birds was associated with a higher reassortment rate. Secondly, I described the spatial transmission pattern of AIV in China. Clustering of related viruses in particular geographic areas and economic zones was identified from the viral phylogeographic diffusion networks. The results indicated that Central China and the Pearl River Delta are two main sources of viral out flow; while the East Coast, especially the Yangtze River delta, is the major recipient area. Simultaneously, by applying a general linear model, the predictors that have the strongest impact on viral spatial diffusion were identified, including economic (agricultural) activity, climate, and ecology. Thirdly, I determined the genetic and phylogeographic origin of a recent H7N3 highly pathogenic avian influenza outbreak in Mexico. Location, subtype, avian host species and pathogenicity were modelled as discrete traits and jointly analysed using all eight viral gene segments. The results indicated that the outbreak AIV is a novel reassortant carried by wild waterfowl from different migration flyways in North America during the time period studied. Importantly, I concluded that Mexico, and Central America in general, might be a potential hotspot for AIV reassortment events, a possibility which to date has not attracted widespread attention. Overall, the work carried out in this thesis described the evolutionary dynamics of AIV from which important conclusions regarding its epidemiological impact in both Eurasia and North America can be drawn.

Influenza Aviar impacta en la salud pública debido a que representa un potencial riesgo zoonótico. Además, es una amenaza para la industria avícola debido a que puede causar una elevada morbilidad y mortalidad en las aves afectando la economía y el comercio. El virus de Influenza Aviar ha sido aislado de una amplia variedad de especies aviares como por ejemplo los patos domésticos que pueden ser posibles portadores silenciosos del virus. El objetivo del presente estudio fue evaluar la presencia del virus de Influenza Aviar en patos domésticos de crianza familiar en las provincias de Huaral y Huaura. Se colectaron 600 muestras de hisopado cloacal de patos domésticos de traspatio sin distinción de sexo o edad, las cuales fueron analizadas mediante aislamiento viral en huevos embrionados de pollo SPF. La presencia del virus de la Influenza Aviar fue determinada por la actividad hemaglutinante del fluido alantoideo, y confirmada mediante un kit de diagnóstico rápido, que utiliza anticuerpos monoclonales. El 100% (600/600) de las muestras analizadas fueron negativas al virus de Influenza Aviar en este estudio con una prevalencia determinística de 0%. Se concluyó que las aves incluidas en el muestreo no se encuentran infectadas con el virus de Influenza Aviar.

Master of Science / Department of Diagnostic Medicine/Pathobiology / Wenjun Ma / With introduction of the 2009 pandemic H1N1 virus (pH1N1) into swine herds, reassortment between the pH1N1 and endemic swine influenza viruses (SIVs) has been reported worldwide. Recently, reassortant H3N2 and H1N2 variant SIVs that contain the M gene from pH1N1 virus and the remaining seven genes from North American triple-reassortant (TR) SIVs have emerged. These variant viruses have caused more than 300 cases of human infections and one death in the USA, creating a major public health concern. To date, the pathogenicity and transmissibility of H1N2 variant viruses in pigs has not been investigated. Through passive surveillance, we have isolated two genotypes of reassortant H1N2 viruses with pH1N1 genes from diseased pigs in Kansas. Full genome sequence and phylogenetic analysis showed that one is a swine H1N2 variant virus (swH1N2v) with the M gene from pH1N1; the other is a reassortant H1N2 virus (2+6 rH1N2) with six internal genes from pH1N1 and the two surface genes from endemic North American TR H1N2 SIVs. Furthermore, we determined the pathogenicity and transmissibility of the swH1N2v, a human H1N2 variant (huH1N2v), and the 2+6 rH1N2 in pigs using an endemic TR H1N2 SIV (eH1N2) isolated in 2011 as a control. All four viruses were able to infect pigs and replicate in the lungs. Both H1N2 variant viruses caused more severe lung lesions in infected pigs when compared to the eH1N2 and 2+6 rH1N2 viruses. Although all four viruses are transmissible in pigs and were detected in the lungs of contact animals, the swH1N2v shed more efficiently than the other three viruses in the respective sentinel animals. The huH1N2v displayed delayed and inefficient nasal shedding in sentinel animals. Taken together, the human and swine H1N2 variant viruses are more pathogenic and the swH1N2v more transmissible in pigs and could pose a threat to public and animal health.

Influenza A virus (IAV) is one of the most common viruses circulating in the human population and is responsible for seasonal epidemics that affect millions of individuals worldwide. The need to develop new drugs and vaccines against IAVs led scientists to study the main IAV surface antigens hemagglutinin (HA) and neuraminidase (NA). In contrast to HA, which facilitates cell binding and entry of IAVs, NA plays a critical role in the release and spreading of the viral particles. The aim of this thesis was to study how the enzymatic head domain, the stalk and transmembrane domains have evolved to facilitate NA assembly into an enzymatically active homotetramer, and to determine how these regions have evolved together over time. Initially, we observed that the NA transmembrane domain (TMD) assists in the assembly of the head domain by tethering the stalk to the membrane in a tetrameric conformation. Upon examination of the available sequences for NA, we found that the subtype 1 (N1) TMDs have become more polar since 1918 while the subtype 2 (N2) TMDs have consistently retained the expected hydrophobicity of a TMD. Further analysis of the amino-acid sequences revealed a characteristic indicative of an amphipathic assembly for the N1 TMDs that were absent in the TMDs from N2. The function of the amphipathic assembly was examined by creating two viral chimeras, where the original TMD was replaced by another more polar or an engineered hydrophobic TMD. In both cases the viruses carrying the NA TMD chimeras showed reduced growth indicating that the TMD changes created an incompatibility with the head domain of NA. After prolonged passaging of these viruses, natural occurring mutations were observed in the TMD that were able to rescue the defects in viral growth, head domain folding and budding by creating a TMD with the appropriate polar or hydrophobic assembly properties. Interestingly, we observed that N1 and N2 have a great difference in the localization and length of amino-acid deletions occurring in the stalk region. In line with this observation, our data suggests that N1 supports large stalk deletions due to its strong TMD association, whereas N2 requires the presence of a strong oligomerizing stalk region to compensate for its weak TMD interaction. These results have demonstrated how important the NA TMD is for viral infectivity and how the three different domains have evolved in a cooperative manner to promote proper NA assembly / Influensa är en av de mest smittsamma sjukdomarna som drabbar människor och de flesta kan räkna med att bli infekterade många gånger under sin livstid. Influensaviruset attackerar främst luftvägarna, men kan även leda till t.ex. lunginflammation. De enskilda viruspartiklarna (virionerna) kan komma i olika former, men den vanligaste formen som används för att beskriva viruset är den sfäriska. På en virions yta så finns det två olika typer av membranproteiner, som kan liknas med två olika sorters spikar som sticker ut från viruset. Den ena ”spiken” kallas neuraminidas, eller bara kort för NA, och den andra för hemagglutinin (HA). När man har andats in ett influensavirus så kan viruset ta sig till de övre luftvägarna och vidare ner i luftstrupen för att där använda sig av HA för att ta sig in i en cell. Viruset använder sig sedan av cellen för att skapa många nya virioner, som tar sig ut ur cellen för att infektera fler celler. NA är det protein som virionerna använder sig av för att klyva sig loss från modercellen. Målet för avhandlingen var att studera NA och beskriva hur proteinet måste vara ihopsatt för att vara aktivt. NA har en uppbyggnad liknande en trädklunga, där fyra stycken identiska träd (med tillhörande rötter, stammar och trädkronor) går ihop och bildar en enda aktiv enhet, en s.k. tetramer. ”Rötterna” hos NA är den transmembrana domänen (TMD), den del av proteinet som sitter fast i influenaviruskroppen. ”Stammen”, eller stjälkdelen av NA, binder samman TMD med den största delen, huvuddomänen som motsvarar ”trädkronan”. Det är just huvuddomänen som är ansvarig för att klyva loss viruspartiklar från en modercell. Vi har i våra studier sett att det kan vara väldigt viktigt att TMD-domänerna går ihop i grupper om fyra för att hela NA ska kunna gå ihop i en tetramer och aktivt kunna klyva loss viruspartiklarna. När vi studerade TMD från olika influensavirus så märkte vi att vissa egenskaper hos TMD krävs för att de skulle kunna gå ihop, men också att dessa egenskaper inte fanns hos alla influensavirus. Virusen har evolverat över lång tid och har anpassat sig efter värdorganismerna (inklusive människan) och har hittat olika lösningar på problemet med att behöva bilda en tetramer. När vi gjorde ändringar i en TMD som vanligtvis gick ihop till en tetramer, och därmed förhindrade detta, så noterade vi att huvuddomänens funktion påverkades vilket ledde till att influensaviruset hade svårt att spridas. Vidare så har våra pågående studier på stjälkdelen visat att även denna del kan ha stor betydelse för tetrameriseringen av NA, speciellt i de fall där TM-domänen saknar egenskaper för att gå ihop. Avhandlingen tillför inte bara ny och viktig information till influensaforskningen, utan även potentiellt för framställandet av nya influensavacciner/-mediciner. / <p>At the time of the doctoral defense, the following paper was unpublished and had a status as follows: Paper 4: Manuscript.</p>

Tesis para optar al Grado de Magíster en Ciencias Animales y Veterinarias / El presente trabajo tuvo por objetivo caracterizar la evolución de la situación sanitaria global de influenza aviar y evaluar indicadores de gestión de los Servicios Veterinarios Oficiales (SVO), específicamente la velocidad de confirmación de eventos sanitarios y la velocidad de su notificación a la Organización Mundial de Sanidad Animal (OIE), analizando posibles factores asociados a su variación. Para ello se crearon dos bases de datos que consistieron en notificaciones inmediatas de influenza aviar publicadas en la plataforma WAHIS de la OIE: una más general, desde 2005 a 2016, que se utilizó para caracterizar la evolución de la situación sanitaria global; y otra más específica, desde 2014 a 2016, que se utilizó para evaluar indicadores de gestión de los SVO. Mediante el programa R se aplicó un análisis estadístico descriptivo para caracterizar la evolución de la situación sanitaria global, un análisis de regresión lineal para analizar la asociación de variables categóricas con la velocidad de confirmación de eventos, y un análisis de regresión logística para analizar la asociación de variables categóricas con la notificación de eventos a la OIE en un período de tiempo mayor a 24 horas. Se observó una variación en la evolución de la situación sanitaria global de influenza aviar según año para el período 2005-2016, con un aumento importante en las notificaciones enviadas a la OIE entre 2005 y 2006 (2,3% y 12,6% de las notificaciones, respectivamente), una disminución en las notificaciones entre 2007 y 2012 (8,4%, 7,6%, 5,6%, 6,2%, 5,8%, y 5,3% de las notificaciones en orden cronológico) y un aumento sostenido entre 2013 y 2016 (6,4%, 9,3%, 13,5% y 17,1% de las notificaciones en orden cronológico). Sin embargo, se comprobó que la variación anual no fue significativa estadísticamente. Se demostró que el laboratorio de confirmación (nacional o de referencia de la OIE), está asociado a la variación de la velocidad de confirmación de los eventos. Además, se comprobó que el motivo de notificación, la temporada en que se inicia un evento y la región geográfica que notifica, están asociados a la variación tanto 6 de la velocidad de confirmación como de la velocidad de notificación de eventos. No obstante, la región geográfica sería la variable más fuertemente asociada a la presentación de una velocidad de confirmación más lenta y al riesgo de presentar una velocidad de notificación fuera del tiempo límite de hasta 24 horas. Este resultado se relaciona con las diferentes capacidades de los SVO para confirmar eventos y con la voluntad política de notificar oportunamente a la OIE. Se evidenció que, durante el período 2014-2016, el valor máximo para la velocidad de confirmación fue de 133 días; mientras que el valor máximo para la velocidad de notificación fue de 351 días. Por otro lado, el 59,5% de las notificaciones fueron enviadas a la OIE en más de 24 horas después la confirmación de los eventos, no cumpliendo con lo establecido en el Código Sanitario de la OIE. Este último hallazgo podría tener importantes consecuencias en la sanidad animal global, puesto que el retraso de un SVO en comunicar al mundo la detección de una enfermedad de alto impacto comercial impediría una respuesta temprana por parte de otros SVO, lo que es clave para proteger la sanidad animal dentro de sus países y así evitar o disminuir su diseminación transfronteriza. Por lo tanto, se recomienda continuar fortaleciendo las capacidades de los SVO para enfrentar exitosamente los eventos de notificación inmediata a la OIE, poniendo especial énfasis en la misión de la OIE de garantizar la transparencia de la información zoosanitaria, y empoderando a la OIE para ejercer sanciones, si fuera necesario, en casos de incumplimiento de lo establecido en el Código Sanitario. / The objective of the present work was to characterize the evolution of the global health situation of avian influenza and to evaluate management indicators of the Official Veterinary Services (OVS), specifically the speed of confirmation of health events and the speed of its notification to the World Organization for Animal Health (OIE), analyzing possible factors associated with their variation. To this end, two databases were created consisting of immediate reports of avian influenza published on the OIE WAHIS interface: one more general, from 2005 to 2016, which was used to characterize the evolution of the global health situation; and another one, more specific, from 2014 to 2016, which was used to evaluate management indicators of the OVS. Through the use of R software, a descriptive statistical analysis was applied to characterize the evolution of the global health situation, a linear regression analysis was carried out to analyze the association of categorical variables with the speed of confirmation of events, and a logistic regression analysis was executed to analyze the association of categorical variables with notification of events to the OIE in a time period greater than 24 hours. A variation in the global health status of avian influenza per year was observed for the period 2005-2016, with a significant increase in notifications sent to the OIE between 2005 and 2006 (2.3% and 12.6% of the notifications, respectively), a decline in notifications between 2007 and 2012 (8.4%, 7.6%, 5.6%, 6.2%, 5.8%, and 5.3% of the notifications in chronological order) and a sustained increase between 2013 and 2016 (6.4%, 9.3%, 13.5% and 17.1% of the notifications in chronological order). However, it was found that the annual variation was not statistically significant. It was demonstrated that the type of confirmatory laboratory (national or OIE reference) is associated with the variation of the speed of confirmation of events. In addition, it was found that the reason for notification, the season in which an event starts and the reporting geographical region, are associated with the variation of 8 both the speed of confirmation and the speed of notification of events. However, the geographic region would be the variable most strongly associated with the presentation of a slower speed of confirmation and with the risk of presenting a speed of notification outside the time limit of up to 24 hours. This result is related to the different capacities of the SVO to confirm events and with the political will to timely notify to the OIE. It was evidenced that during the period 2014-2016, the maximum value for the speed of confirmation was 133 days; while the maximum value for the speed of notification was 351 days. On the other hand, 59.5% of the notifications were sent to the OIE in more than 24 hours after the confirmation of events, not complying with the provisions of the OIE Animal Health Code. This latest finding could have important implications for global animal health as the delay of an OVS in communicating to the world the detection of a disease with high-impact in trade would prevent an early response by other OVS, which is the key to protect animal health within their countries and to avoid or decrease cross-border dissemination. Therefore, it is recommended to continue strengthening the OVS capacities to successfully address events of immediate notification to the OIE, with particular emphasis on the OIE's mission to ensure the transparency of animal health information, and empowering the OIE to impose sanctions, if necessary, in cases of non-compliance with the provisions of the Animal Health Code

INTRODUÇÃO: Influenza é uma doença potencialmente grave após o transplante de células tronco hematopoiéticas (TCTH). A vacinação é a principal estratégia profilática, mas a resposta imune é menor do que em indivíduos saudáveis. Em geral os pacientes não respondem a vacinação nos primeiros seis meses após transplante, o que torna o período de maior vulnerabilidade. OBJETIVOS: Neste estudo avaliaram-se diferentes esquemas de vacinação contra influenza em TCTH alogênico relacionado, com imunização do doador e/ou do receptor no pré transplante. Determinou-se a resposta a vacina comparando-se as taxas de soroconversão entre os grupos de intervenção. Foram avaliados também os níveis de anticorpos considerados soroprotetores alcançados. MÉTODOS: Realizou-se ensaio clinico randomizado não cego, em população de candidatos ao TCTH e seus doadores do Hospital das Clínicas da Faculdade de Medicina da Universidade Federal de Minas Gerais/BH-MG e Hospital Amaral Carvalho/Jaú-SP. Quatro grupos de pares receptor-doador receberam diferentes esquemas de imunização de influenza no pré transplante: 1- sem vacinação, 2 - vacinação do doador; 3 - vacinação do receptor e 4 - vacinação de doador e receptor. Todos os pacientes receberam vacina a partir do 6º mês após transplante. Acompanhamento sorológico do par foi realizado no pré e no dia do transplante, e nos dias 30, 60, 100, 180 e após vacina apenas para os receptores. Títulos dos anticorpos sorotipo - específicos foram determinados pela reação de inibição de hemaglutinação. Níveis 1:40 foram considerados protetores e < 1:10 negativos. Soroconversão foi definida como aumento de quatro vezes ou mais dos títulos ou aumento de <1:10 para 1:40. RESULTADOS: De 08/2007 a 02/2010 131 pares receptor-doador foram incluídos e randomizados: 38 no grupo 1, 44 no grupo 2, 40 no grupo 3 e 9 no grupo 4. Não houve diferença estatística entre os grupos com relação às características clínicas. As taxas de soroproteção basal dos receptores foram de 18%, 32,8% e 63,3% para influenza A/H1N1, A/H3N2 e B, respectivamente. A condição sorológica pré transplante dos doadores foi semelhante. As taxas de soroconversão dos doadores foram de 30,1%, 41,5% e 30,9%, respectivamente para os A/H1N1, A/H3N2 e B. Nos receptores soroconversão até o dia 30 após transplante ocorreu em 16,3% dos pacientes para o A/H1N, 14,7% para A/H3N2 e 28,7%. As médias geométricas dos títulos de anticorpos neutralizantes foram calculadas para todos os subtipos virais ao longo do tempo. Para o A/H1N1 não houve diferença dos títulos até o D180 para nenhum dos grupos. Para o A/H3N2 houve diferença nos títulos no momento do transplante (p=0,019), com maiores títulos nos grupos 2 e 3 em relação ao grupo 1 e no dia 30 (p=0,018) com menores títulos para o grupo 4 que os demais. Para o subtipo B, as diferenças entre os grupos ocorreram no dia do transplante (p=0,020) e nos dias 30 (p= 0,018) e 60 (p=0,026) com menores títulos do grupo 4 em relação aos demais. As taxas de soroconversão após a vacina do dia 180 foram de 19,7% para o A/H1N1, 18% para o A/H3N2 e 8,2% para o B. Não houve diferença estatisticamente significante entre os grupos. CONCLUSÃO: A imunogenicidade da vacina de influenza em receptores de TCTH foi baixa. A estratégia de vacinação do doador e do receptor no pré transplante aumentou a média geométrica dos títulos protetores apenas para o subtipo A/H3N2 até o 30º pós transplante, em relação ao grupo sem vacinação / INTRODUCTION: Influenza is a potentially severe illness after hematopoietic stem cell transplantation (HSCT). Vaccination is the main prophylactic strategy, but the immune response is limited in the compromised host. Existing data support the recommendation of influenza vaccination after the 6th month of HSCT. OBJECTIVES: The study evaluated different schedules of influenza vaccination in HSCT. Recipient and/or their donors were randomized to receive influenza vaccine before transplant. The primary outcome was the comparison of serotype response between groups at baseline, 30 days and 6 months after transplantation. METHODS: A randomized, non-blind trial was conducted in patients undergoing HSCT and respective donors at Hospital das Clínicas, Universidade Federal de Minas Gerais /BH-MG and at Hospital Amaral Carvalho/Jaú-SP. Four groups of donor and recipient pairs received different influenza immunization at least 7 days before HSCT: group 1 no vaccination, group 2 donor received a single dose of influenza vaccine; group 3 recipients received a single dose of influenza vaccine and group 4 recipients and donor received influenza vaccine. Following transplantation, all study patients were immunized with influenza vaccine at 6 months. Donor serum samples were collected at baseline (pre transplantation) and in the day of transplantation. Recipients serum samples were taken at baseline, 30, 60, 100, 180 days after transplantation, and at least 2 weeks after 6-month vaccination. The hemagglutination inhibition assay (HIA) was performed to evaluate immune response. HI antibodies titers 1:40 were considered protective. Titers < 1:10 were considered negative. Antibody response (seroresponse) was defined as the appearance or 4-fold rise in HI antibody titers after vaccination. RESULTS: From August 2007 to February 2010 131 donor and recipient pairs were included in the study: 38 pairs in group 1, 44 in the group 2 , 40 in 3 group and 9 in group 4.There were no statistically difference between the 4 groups regarding to the clinical characteristics. At baseline 18% of recipients had protective antibody levels to A/H1N1, 32.8% to A/H3N2 and 63.3% to B. Donor serological condition was similar to recipients. Seroresponse occurred in 30,1% of donors to A/H1N1, 41,5% to A/H3N2 and 30,9% to B. Seroresponse until day 30 after transplant were detected in only 16,3% of the patients for the A/H1N, 14.7% for A/H3N2 and 28.7% for B. Comparisons of geometric mean antibody concentrations was performed at baseline and day of transplantation, and also at 30, 60, 100, 180 days after HSCT e after 6 months influenza vaccine. For the A/H1N1 there was no statistically difference between groups until 180 days after HSCT. For the A/H3N2 a significant increase in geometric mean titers in the day of transplantation (p=0,019) was observed in groups 2 and 3 in relation to group 1 and lower geometric mean titers (p=0,018) at day 30 for patients in group 4. For subtype B, the differences between groups occurred in the day of the transplantation (p=0,020) and at 30 (p= 0,018) and 60 (p=0,026) day. The geometric mean titers were lower in group 4 in relation to the others. Seroresponse after 6-month vaccination occurred in 19,7% to A/H1N1, 18% to A/H3N2 and 8.2% to B. There was no significant difference between the groups. CONCLUSION: Immunogenicity to influenza vaccine was poor in HSCT recipients. Donor or recipient vaccination strategy prior to transplantation increased the geometric mean titers only for subtype A/H3N2 at day 30 after transplant. No impact was observed in seroresponse rates after 6-month vaccination