Influenza A H5N1 and H7N9 in China: A spatial risk analysis

abstract: Background Zoonotic avian influenza poses a major risk to China, and other parts of the world. H5N1 has remained endemic in China and globally for nearly two decades, and in 2013, a novel zoonotic influenza A subtype H7N9 emerged in China. This study aimed to improve upon our current understanding of the spreading mechanisms of H7N9 and H5N1 by generating spatial risk profiles for each of the two virus subtypes across mainland China. Methods and findings In this study, we (i) developed a refined data set of H5N1 and H7N9 locations with consideration of animal/animal environment case data, as well as spatial accuracy and precision; (ii) used this data set along with environmental variables to build species distribution models (SDMs) for each virus subtype in high resolution spatial units of 1km[superscript 2] cells using Maxent; (iii) developed a risk modelling framework which integrated the results from the SDMs with human and chicken population variables, which was done to quantify the risk of zoonotic transmission; and (iv) identified areas at high risk of H5N1 and H7N9 transmission. We produced high performing SDMs (6 of 8 models with AUC > 0.9) for both H5N1 and H7N9. In all our SDMs, H7N9 consistently showed higher AUC results compared to H5N1, suggesting H7N9 suitability could be better explained by environmental variables. For both subtypes, high risk areas were primarily located in south-eastern China, with H5N1 distributions found to be more diffuse and extending more inland compared to H7N9. Conclusions We provide projections of our risk models to public health policy makers so that specific high risk areas can be targeted for control measures. We recommend comparing H5N1 and H7N9 prevalence rates and survivability in the natural environment to better understand the role of animal and environmental transmission in human infections.The article is published at http://journals.plos.org/plosone/article?id=10.1371/journal.pone.017498

Fogarty International Center collaborative networks in infectious disease modeling:Lessons learnt in research and capacity building

Due to a combination of ecological, political, and demographic factors, the emergence of novel pathogens has been increasingly observed in animals and humans in recent decades. Enhancing global capacity to study and interpret infectious disease surveillance data, and to develop data-driven computational models to guide policy, represents one of the most cost-effective, and yet overlooked, ways to prepare for the next pandemic. Epidemiological and behavioral data from recent pandemics and historic scourges have provided rich opportunities for validation of computational models, while new sequencing technologies and the ‘big data’ revolution present new tools for studying the epidemiology of outbreaks in real time. For the past two decades, the Division of International Epidemiology and Population Studies (DIEPS) of the NIH Fogarty International Center has spearheaded two synergistic programs to better understand and devise control strategies for global infectious disease threats. The Multinational Influenza Seasonal Mortality Study (MISMS) has strengthened global capacity to study the epidemiology and evolutionary dynamics of influenza viruses in 80 countries by organizing international research activities and training workshops. The Research and Policy in Infectious Disease Dynamics (RAPIDD) program and its precursor activities has established a network of global experts in infectious disease modeling operating at the research-policy interface, with collaborators in 78 countries. These activities have provided evidence-based recommendations for disease control, including during large-scale outbreaks of pandemic influenza, Ebola and Zika virus. Together, these programs have coordinated international collaborative networks to advance the study of emerging disease threats and the field of computational epidemic modeling. A global community of researchers and policy-makers have used the tools and trainings developed by these programs to interpret infectious disease patterns in their countries, understand modeling concepts, and inform control policies. Here we reflect on the scientific achievements and lessons learnt from these programs (h-index = 106 for RAPIDD and 79 for MISMS), including the identification of outstanding researchers and fellows; funding flexibility for timely research workshops and working groups (particularly relative to more traditional investigator-based grant programs); emphasis on group activities such as large-scale modeling reviews, model comparisons, forecasting challenges and special journal issues; strong quality control with a light touch on outputs; and prominence of training, data-sharing, and joint publications. Keywords: Infectious diseases, Transmission models, Computational models, Pathogen evolution, Capacity building, Emerging disease threats, Influenza, Control, Polic

The Socioeconomic and Ecological Drivers of Avian Influenza Risks in China and at the International Level

abstract: Avian influenzas are zoonoses, or pathogens borne by wildlife and livestock that can also infect people. In recent decades, and especially since the emergence of highly pathogenic avian influenza (HPAI) H5N1 in 1996, these diseases have become a significant threat to animal and public health across the world. HPAI H5N1 has caused severe damage to poultry populations, killing, or prompting the culling of, millions of birds in Asia, Africa, and Europe. It has also infected hundreds of people, with a mortality rate of approximately 50%. This dissertation focuses on the ecological and socioeconomic drivers of avian influenza risk, particularly in China, the most populous country to be infected. Among the most significant ecological risk factors are landscapes that serve as “mixing zones” for wild waterfowl and poultry, such as rice paddy, and nearby lakes and wetlands that are important breeding and wintering habitats for wild birds. Poultry outbreaks often involve cross infections between wild and domesticated birds. At the international level, trade in live poultry can spread the disease, especially if the imports are from countries not party to trade agreements with well-developed biosecurity standards. However, these risks can be mitigated in a number of ways. Protected habitats, such as Ramsar wetlands, can segregate wild bird and poultry populations, thereby lowering the chance of interspecies transmission. The industrialization of poultry production, while not without ethical and public health problems, can also be risk-reducing by causing wild-domestic segregation and allowing for the more efficient application of surveillance, vaccination, and other biosecurity measures. Disease surveillance is effective at preventing the spread of avian influenza, including across international borders. Economic modernization in general, as reflected in rising per-capita GDP, appears to mitigate avian influenza risks at both the national and sub-national levels. Poultry vaccination has been effective in many cases, but is an incomplete solution because of the practical difficulties of sustained and widespread implementation. The other popular approach to avian influenza control is culling, which can be highly expensive and raise ethical concerns about large-scale animal slaughter. Therefore, it is more economically efficient, and may even be more ethical, to target the socio-ecological drivers of avian influenza risks, including by implementing the policies discussed here.Dissertation/ThesisDoctoral Dissertation Biology 201

VIRAL RESPIRATORY INFECTIONS IN SINGAPORE

Master'sMASTER OF SCIENC

Economic, epidemiological, and social analyses of H7N9 influenza control strategies for yellow broilers in Guangxi, China

The emergence of H7N9 influenza and its zoonotic transmission in China since March 2013 highlighted the continued threat from emerging avian influenza with pandemic potential. A series of policies and interventions were implemented nationwide; however, critical reviews of the effectiveness of these control strategies are lacking. This research conducted in Guangxi, a province with a significant yellow broiler industry, was designed to provide economic, epidemiological, and social evidence to inform future H7N9 control strategies in China. A value chain study was conducted to examine the yellow broiler production and trading system in Guangxi. Stakeholders of the yellow broiler industry, their interactions, governance structure and risk practices were investigated. Yellow broiler grower companies were the dominant stakeholders. Trading platforms were key premises, linking farms and live bird markets, to be included in H7N9 influenza control programs. Poor biosecurity practices present in different premises along the value chain, pose significant challenges for the control of H7N9 influenza. Spatio-temporal patterns of the movement of live broilers within and from Guangxi were also assessed. The most central broiler populations in the movement network were identified. The results showed that targeting areas based on movement characteristics would enable controlling H7N9 influenza more effectively compared to applying the same policy throughout Guangxi. The yellow broiler industry stakeholders’ practices, attitudes and motivations regarding H7N9 vaccination were investigated using a mixed-methods design. There was a strong willingness for the industry to continue vaccination even without government support. The economic values of the H7N9 vaccination program were also assessed using a benefit-cost analysis. It demonstrated that the current vaccination program was economically profitable compared to not vaccinating. However, the economic returns of vaccination relied heavily on industry profits. In summary, these research findings can help strengthen the control of H7N9 influenza in Guangxi and provide support for future avian influenza control strategies throughout China

Economic factors influencing zoonotic disease dynamics: demand for poultry meat and seasonal transmission of avian influenza in Vietnam

While climate is often presented as a key factor influencing the seasonality of diseases, the importance of anthropogenic factors is less commonly evaluated. Using a combination of methods-wavelet analysis, economic analysis, statistical and disease transmission modelling-we aimed to explore the influence of climatic and economic factors on the seasonality of H5N1 Highly Pathogenic Avian Influenza in the domestic poultry population of Vietnam. We found that while climatic variables are associated with seasonal variation in the incidence of avian influenza outbreaks in the North of the country, this is not the case in the Centre and the South. In contrast, temporal patterns of H5N1 incidence are similar across these 3 regions: periods of high H5N1 incidence coincide with Lunar New Year festival, occurring in January-February, in the 3 climatic regions for 5 out of the 8 study years. Yet, daily poultry meat consumption drastically increases during Lunar New Year festival throughout the country. To meet this rise in demand, poultry production and trade are expected to peak around the festival period, promoting viral spread, which we demonstrated using a stochastic disease transmission model. This study illustrates the way in which economic factors may influence the dynamics of livestock pathogens

Humoral immune response after seasonal influenza vaccination

Introduction: Seasonal vaccination provides short-lasting and strain specific protection. Different factors influence efficacy and effectiveness and are related to the vaccine and the receptor. Those include adjuvants and strains contained, and age and sex of the receptor. The major target of antibodies after vaccination and infection is the hemagglutinin(HA) head with a limited number of immunodominant classically defined antigenic sites(Sb, Sa, Cb, Ca1 and Ca2) leading to strain-specific protection. In contrast, the HA stalk is subdominant and more conserved, and anti-stalk antibodies are cross-reactive among strains of the same phylogenetic group. Objective: To evaluate the humoral response after seasonal influenza vaccination considering vaccine composition, age and sex; and determine specific humoral responses against classically defined antigenic sites of the HA head and the stalk domain of influenza A virus. Methods: A total of 4,818 patients were recruited yearly during 28 seasons(1990-2018) from the Sentinel Surveillance Network of Castile and Leon (Spain). Three retrospective and two prospective designs were used. Serological analyses were conducted in samples obtained before and 28 days after seasonal vaccination by the National Influenza Centre of Valladolid (Spain) and the Mount Sinai Hospital of New York(US). Antibody levels against the HA head and stalk were measured by hemagglutination inhibition assay(HAI) and ELISAs. This research was approved by an Ethics Committee(PI 21-2314). Statistical analysis was performed taking significance at p<0.05. Results: Manuscript 1: Higher humoral response was found in the elderly against the A(H3N2) subtype with the adjuvanted influenza vaccine(FI 3.4, SCR 46%) compared to non-adjuvanted vaccine(FI 2.7,SCR 38.8%). However, the non-adjuvanted vaccine induced a better response against A(H1N1)pdm09(FI 4.5, SCR 57.3%) compared to the adjuvanted one(FI 3.2, SCR 45.8%) in the same group. Manuscript 2: Higher humoral response in terms of SCR against classical influenza A (H1N1), A(H1N1)pdm09 subtype and B/Victoria lineage(40.6%, 52.4% and 23.2%) were found in elderly women compared to elderly men(30.2%, 42.0% and 18.9%); and in FI(3.7 vs. 3.0) against A(H1N1)pdm09 in the same comparison. Manuscript 3: Significant heterotypic humoral responses were found between both influenza B lineages, but always lower than the homotypic response. Young adults showed higher homotypic(GMTi 3.2, SCR 41.6%) and heterotypic responses(GMTi 1.7, SCR 18.6%) with B/Victoria vaccine compared to the elderly while similar responses were found with B/Yamagata vaccine. Manuscript 4: Antibodies before vaccination were significantly reduced against all antigenic sites in the elderly and only against Sb and Ca2 in young adults compared to the Wt. Response to vaccination was reduced against all viruses compared to the Wt for the adjuvanted vaccine and only against Sb and Ca2 for the non-adjuvanted vaccine. The strongest reduction was observed against Sb followed by Ca2. Manuscript 5: All age groups elicited a significant increase of anti-stalk antibodies after seasonal influenza vaccination except for &#8805; 80-year-old cohort. Additionally, < 65-year-old vaccinees had higher titers against phylogenetic group 1 HAs vs. group 2. Similarly, <50-year-old showed higher increase of anti-stalk antibody titers(GMFR 1.69) compared to &#8805; 80-year-old(GMFR 1.08) for group 1. Conclusions: Age and sex play a role in vaccine responses with higher responses in elderly women compared to men against A(H1N1)pdm09. Better responses against this subtype were found with non-adjuvanted vaccines, while adjuvanted vaccines responded better against the A(H3N2) subtype in the elderly. However, seasonal vaccination can boost the induction of cross-reactive anti-stalk antibodies against phylogenetic groups 1 and 2 of HAs, with higher responses in younger populations. The immunodominance hierarchy of antigenic sites of HA head of the A(H1)pdm09 viruses is dominated by Sb followed by Ca2, but age and adjuvants can broaden responses towards subdominant epitopes. Finally, vaccination with a trivalent influenza vaccine provides cross-reactive protection against the B/lineage not contained.Introducción: La protección tras la vacunación antigripal es limitada y específica de cepa. Diferentes factores influyen en la eficacia y efectividad relacionados con la vacuna y con el receptor incluyendo: adyuvantes y composición; y edad y sexo. La principal diana de los anticuerpos tras la vacunación es la cabeza de la hemaglutinina (HA), inmunodominante y con capacidad de unión a un número limitado de sitios antigénicos(Sb, Sa, Cb, Ca1 y Ca2). En cambio, los anticuerpos frente al tallo de la HA, mucho más conservado y subdominante, presentan reactividad cruzada entre diferentes cepas del mismo grupo filogenético. Objetivo:Evaluar la respuesta humoral antigripal tras la vacunación considerando la composición de la vacuna, la edad y el sexo de los receptores; y, determinar las respuestas específicas frente a los sitios antigénicos clásicos de la cabeza y al tallo de la HA del virus de la gripe A. Métodos:Se reclutaron 4.818 pacientes durante 28 temporadas de gripe(1990-2018) por la Red Centinela de Vigilancia de Castilla y León(España). Se utilizaron tres diseños retrospectivos y dos prospectivos. Los análisis serológicos fueron realizados por el Centro Nacional de Gripe de Valladolid(España) y el Hospital Mount Sinai de Nueva York(EE.UU.), en muestras obtenidas antes y 28 días post-vacunación. Se detectaron anticuerpos frente a la cabeza y frente al tallo de la HA mediante ensayos de inhibición de la hemaglutinación (RIH) y ELISAs. Esta investigación fue aprobada por un Comité ético(PI 21-2314). Se realizó el análisis estadístico considerando significante p<0,05. Resultados Manuscrito 1: Se observó mayor respuesta en ancianos frente a A(H3N2) con vacuna adyuvada (RIC 3,4; 46%) en comparación con vacuna no adyuvada (RIC 2,7; TSC 38,8%). Sin embargo, la no adyuvada indujo una mejor respuesta frente a A(H1N1)pdm09 (RIC 4,5;TSC 57,3%) que la adyuvada (RIC 3,2;TSC 45,8%) en el mismo grupo etario. Manuscrito 2: Se encontró mayor respuesta frente a A(H1N1) clásico, A(H1N1)pdm09 y el linaje B/Victoria (TSC: 40,6%, 52,4% y 23,2%) en mujeres ancianas comparadas con hombres ancianos(TSC: 30,2%, 42,0% y 18,9%).También frente a A(H1N1)pdm09 en la misma comparación(RIC:3,7 vs. 3,0). Manuscrito 3: Se encontraron respuestas humorales heterotípicas frente a ambos linajes de gripe B, pero siempre inferiores a la homóloga. Los adultos mostraron respuestas homólogas(RIC:3,2;TSC:41,6%) y heterotípicas(RIC:1,7;TSC:18,6%) mayores con la vacuna de B/Victoria que los ancianos y similares con la vacuna B/Yamagata. Manuscrito 4: Los anticuerpos pre-vacunales se redujeron frente a todos los epítopos en ancianos y frente a Sb y Ca2 en adultos vs. Wt. La respuesta a la vacunación adyuvada se redujo frente a todos virus vs. Wt y sólo frente a Sb y Ca2 con vacuna no adyuvada. La mayor reducción se observó frente a Sb>Ca2. Manuscrito 5: Todos los grupos etarios aumentaron los anticuerpos frente al tallo tras la vacunación, excepto &#8805;80años. Además, los <65años presentaron títulos mayores frente al grupo filogenético 1 que al 2. Igualmente, los <50años mostraron un aumento mayor de anticuerpos frente al tallo del grupo 1 (RIC:1,69) en comparación con los &#8805;80años (RIC:1,08). Conclusiones: La edad y el sexo juegan un papel clave en las respuestas vacunales, siendo mayores en mujeres>65años que en hombres de la misma edad frente a A(H1N1)pdm09. Se observaron mejores respuestas a este subtipo con vacunas no adyuvadas, y frente a A(H3N2) con vacunas adyuvadas en ancianos . Sin embargo, la vacuna estacional puede inducir anticuerpos anti-tallo de los grupos filogenéticos 1 y ,2 con mayores respuestas en jóvenes. La inmunodominancia de los epítopos de la cabeza de la HA de los virus A(H1)pdm09 está dominada por Sb>Ca2; pudiendo ampliarse hacia epítopos subdominantes por la edad y los adyuvantes. Por último, la vacunación con una vacuna trivalente proporciona protección cruzada contra el linaje B no contenido en ella.Escuela de DoctoradoDoctorado en Investigación en Ciencias de la Salu

Emerg Infect Dis

PMC4550154611