Enhanced Protection against Ebola Virus Mediated by an Improved Adenovirus-Based Vaccine

Jason S. Richardson is with the Public Health Agency of Canada, Michel K. Yao is with the Public Health Agency of Canada, Kaylie N. Tran is with the Public Health Agency of Canada and University of Manitoba, Maria A. Croyle is with UT Austin, James E. Strong is with the Public Health Agency of Canada and University of Manitoba, Heinz Feldmann is with the Public Health Agency of Canada and University of Manitoba, Gary P. Kobinger is with the Public Health Agency of Canada and University of Manitoba.Background -- The Ebola virus is transmitted by direct contact with bodily fluids of infected individuals, eliciting death rates as high as 90% among infected humans. Currently, replication defective adenovirus-based Ebola vaccine is being studied in a phase I clinical trial. Another Ebola vaccine, based on an attenuated vesicular stomatitis virus has shown efficacy in post-exposure treatment of nonhuman primates to Ebola infection. In this report, we modified the common recombinant adenovirus serotype 5-based Ebola vaccine expressing the wild-type ZEBOV glycoprotein sequence from a CMV promoter (Ad-CMVZGP). The immune response elicited by this improved expression cassette vector (Ad-CAGoptZGP) and its ability to afford protection against lethal ZEBOV challenge in mice was compared to the standard Ad-CMVZGP vector. Methodology/Principal Findings -- Ad-CMVZGP was previously shown to protect mice, guinea pigs and nonhuman primates from an otherwise lethal challenge of Zaire ebolavirus. The antigenic expression cassette of this vector was improved through codon optimization, inclusion of a consensus Kozak sequence and reconfiguration of a CAG promoter (Ad-CAGoptZGP). Expression of GP from Ad-CAGoptZGP was substantially higher than from Ad-CMVZGP. Ad-CAGoptZGP significantly improved T and B cell responses at doses 10 to 100-fold lower than that needed with Ad-CMVZGP. Additionally, Ad-CAGoptZGP afforded full protections in mice against lethal challenge at a dose 100 times lower than the dose required for Ad-CMVZGP. Finally, Ad-CAGoptZGP induced full protection to mice when given 30 minutes post-challenge. Conclusions/Significance -- We describe an improved adenovirus-based Ebola vaccine capable of affording post-exposure protection against lethal challenge in mice. The molecular modifications of the new improved vaccine also translated in the induction of significantly enhanced immune responses and complete protection at a dose 100 times lower than with the previous generation adenovirus-based Ebola vaccine. Understanding and improving the molecular components of adenovirus-based vaccines can produce potent, optimized product, useful for vaccination and post-exposure therapy.Financial support was received from the following sources: The Public Health Agency of Canada and the Chemical, Biological, Radiological or Nuclear Research and Technology Initiative (grant #CRTI-06-0218RD awarded to GPK). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.Pharmac

Pandemic Influenza (H1N1) 2009 Is Associated with Severe Disease in India

Background: Pandemic influenza A (H1N1) 2009 has posed a serious public health challenge world-wide. In absence of reliable information on severity of the disease, the nations are unable to decide on the appropriate response against this disease. Methods: Based on the results of laboratory investigations, attendance in outpatient department, hospital admissions and mortality from the cases of influenza like illness from 1 August to 31 October 2009 in Pune urban agglomeration, risk of hospitalization and case fatality ratio were assessed to determine the severity of pandemic H1N1 and seasonal influenza-A infections. Results: Prevalence of pandemic H1N1 as well as seasonal-A cases were high in Pune urban agglomeration during the study period. The cases positive for pandemic H1N1 virus had significantly higher risk of hospitalization than those positive for seasonal influenza-A viruses (OR: 1.7). Of 93 influenza related deaths, 57 and 8 deaths from Pune (urban) and 27 and 1 death from Pune (rural) were from pandemic H1N1 positive and seasonal-A positive cases respectively. The case fatality ratio 0.86 % for pandemic H1N1 was significantly higher than that of seasonal-A (0.13%) and it was in category 3 of the pandemic severity index of CDC, USA. The data on the cumulative fatality of rural and urban Pune revealed that with time the epidemic is spreading to rural areas

The asthma epidemic and our artificial habitats

BACKGROUND: The recent increase in childhood asthma has been a puzzling one. Recent views focus on the role of infection in the education of the immune system of young children. However, this so called hygiene hypothesis fails to answer some important questions about the current trends in asthma or to account for environmental influences that bear little relation to infection. DISCUSSION: The multi-factorial nature of asthma, reflecting the different ways we tend to interact with our environment, mandates that we look at the asthma epidemic from a broader perspective. Seemingly modern affluent lifestyles are placing us increasingly in static, artificial, microenvironments very different from the conditions prevailed for most part of our evolution and shaped our organisms. Changes that occurred during the second half of the 20th century in industrialized nations with the spread of central heating/conditioning, building insulation, hygiene, TV/PC/games, manufactured food, indoor entertainment, cars, medical care, and sedentary lifestyles all seem to be depriving our children from the essential inputs needed to develop normal airway function (resistance). Asthma according to this view is a manifestation of our respiratory maladaptation to modern lifestyles, or in other words to our increasingly artificial habitats. The basis of the artificial habitat notion may lie in reduced exposure of innate immunity to a variety of environmental stimuli, infectious and non-infectious, leading to reduced formulation of regulatory cells/cytokines as well as inscribed regulatory pathways. This could contribute to a faulty checking mechanism of non-functional Th2 (and likely Th1) responses, resulting in asthma and other immuno-dysregulation disorders. SUMMARY: In this piece I discuss the artificial habitat concept, its correspondence with epidemiological data of asthma and allergy, and provide possible immunological underpinning for it from an evolutionary perspective of health and disease

Advancing brain barriers RNA sequencing: guidelines from experimental design to publication

Background: RNA sequencing (RNA-Seq) in its varied forms has become an indispensable tool for analyzing differential gene expression and thus characterization of specific tissues. Aiming to understand the brain barriers genetic signature, RNA seq has also been introduced in brain barriers research. This has led to availability of both, bulk and single-cell RNA-Seq datasets over the last few years. If appropriately performed, the RNA-Seq studies provide powerful datasets that allow for significant deepening of knowledge on the molecular mechanisms that establish the brain barriers. However, RNA-Seq studies comprise complex workflows that require to consider many options and variables before, during and after the proper sequencing process.Main body: In the current manuscript, we build on the interdisciplinary experience of the European PhD Training Network BtRAIN (https://www.btrain-2020.eu/) where bioinformaticians and brain barriers researchers collaborated to analyze and establish RNA-Seq datasets on vertebrate brain barriers. The obstacles BtRAIN has identified in this process have been integrated into the present manuscript. It provides guidelines along the entire workflow of brain barriers RNA-Seq studies starting from the overall experimental design to interpretation of results. Focusing on the vertebrate endothelial blood–brain barrier (BBB) and epithelial blood-cerebrospinal-fluid barrier (BCSFB) of the choroid plexus, we provide a step-by-step description of the workflow, highlighting the decisions to be made at each step of the workflow and explaining the strengths and weaknesses of individual choices made. Finally, we propose recommendations for accurate data interpretation and on the information to be included into a publication to ensure appropriate accessibility of the data and reproducibility of the observations by the scientific community.Conclusion: Next generation transcriptomic profiling of the brain barriers provides a novel resource for understanding the development, function and pathology of these barrier cells, which is essential for understanding CNS homeostasis and disease. Continuous advancement and sophistication of RNA-Seq will require interdisciplinary approaches between brain barrier researchers and bioinformaticians as successfully performed in BtRAIN. The present guidelines are built on the BtRAIN interdisciplinary experience and aim to facilitate collaboration of brain barriers researchers with bioinformaticians to advance RNA-Seq study design in the brain barriers community

Promoting community socio-ecological sustainability through technology: A case study from Chile

The importance of community learning in effecting social change towards ecological sustainability has been recognised for some time. More recently, the use of Information and Communication Technology (ICT) tools to promote socio-ecological sustainability has been shown to have potential in community education for sustainable development (ESD). The effective design and use of technology for community learning implies an understanding of a range of cross- dimensional factors including: socio-cultural characteristics and needs of the target audience; considerations of available and culturally responsive types of technology; and non-formal pedagogical ESD strategies for community empowerment. In addition, both technology itself and social communities are dynamically evolving and complex entities. This article presents a case study which evaluated the potential of ICT for promoting ecological literacy and action competence amongst community members in southern Chile. The case study addressed the ecological deterioration of a lake, which is having deep social, economic, recreational and cultural implications locally. The authors’ research involved developing a theoret- ical framework for the design, implementation and use of ICT for community learning for sustainability. The framework was based on key ideas from ESD, ICT and community education, and was underpinned by a systems thinking approach to account for the dynamism and complexity of such settings. Activity theory provided a frame to address overarching socio-cultural elements when using technology as a mediating tool for community learning. The authors’ findings suggest that the use of an ICT tool, such as a website, can enhance ecological literacy in relation to a local socio-ecological issue

Past, Present, and Future X-Ray and Gamma-Ray Missions

X- and -ray astronomy began in the early sixties of the last century with balloons flights, sounding rocket experiment and satellites. Long before space satellite detected X- and -rays emitted by cosmic sources, scientists had known that the Universe should be producing these photons. In this chapter we provided an overview of past and present missions that has made the X- and -ray astronomy an integral part of astronomical research, and prospects of future developments