Evaluation of an inactivated Ross River virus vaccine in active and passive mouse immunization models and establishment of a correlate of protection

Ross River Virus has caused reported outbreaks of epidemic polyarthritis, a chronic debilitating disease associated with significant long-term morbidity in Australia and the Pacific region since the 1920s. To address this public health concern, a formalin- and UV-inactivated whole virus vaccine grown in animal protein-free cell culture was developed and tested in preclinical studies to evaluate immunogenicity and efficacy in animal models. After active immunizations, the vaccine dose-dependently induced antibodies and protected adult mice from viremia and interferon α/β receptor knock-out (IFN-α/βR(-/-)) mice from death and disease. In passive transfer studies, administration of human vaccinee sera followed by RRV challenge protected adult mice from viremia and young mice from development of arthritic signs similar to human RRV-induced disease. Based on the good correlation between antibody titers in human sera and protection of animals, a correlate of protection was defined. This is of particular importance for the evaluation of the vaccine because of the comparatively low annual incidence of RRV disease, which renders a classical efficacy trial impractical. Antibody-dependent enhancement of infection, did not occur in mice even at low to undetectable concentrations of vaccine-induced antibodies. Also, RRV vaccine-induced antibodies were partially cross-protective against infection with a related alphavirus, Chikungunya virus, and did not enhance infection. Based on these findings, the inactivated RRV vaccine is expected to be efficacious and protect humans from RRV disease

Persistence of multiple genetic lineages within intra-host populations of Ross River virus

We examined the structure and extent of genetic diversity in intrahost populations of Ross River virus (RRV) in samples from six human patients, focusing on the nonstructural (nsP3) and structural (E2) protein genes. Strikingly, although the samples were collected from contrasting ecological settings 3,000 kilometers apart in Australia, we observed multiple viral lineages in four of the six individuals, which is indicative of widespread mixed infections. In addition, a comparison with previously published RRV sequences revealed that these distinct lineages have been in circulation for at least 5 years, and we were able to document their long-term persistence over extensive geographical distances

Ross River virus evolution : implications for vaccine development

Ross River virus is a mosquito-borne alphavirus that causes approximately 5000 cases of epidemic polyarthritis in Australia each year and has direct medical-associated costs of approximately US$15 million annually. While mosquito control programs are able, at best, to contain rather than prevent this disease, natural infection with Ross River virus confers lifelong protection against subsequent clinical infection. A killed-virus vaccine has been developed, which is in Phase III clinical trials. Analyses of intra-host genetic diversity and of long-term evolutionary changes in Ross River virus populations suggest that antigenic variation is unlikely to pose a threat to the efficacy of this vaccine.

Ross River virus arthritis

“Epidemics” of a benign disease causing polyarthralgia and rash were first described in Australia in 1927.63 Following the recovery of the causative agent and the advent of serologic tests able to diagnose Ross River virus infection, epidemic polyarthritis has been recognized as endemic in Australia and has occurred as epidemics in numerous Pacific nations. Approximately 4000 cases of epidemic polyarthritis are reported in Australia each year, with a peak of 7800 cases in 1996. Some confusion has been generated recently by use of the term Ross River fever to describe clinical Ross River virus infections because fever does not develop in more than half of those with clinical disease.59 Additional confusion has been generated by efforts to describe any polyarthritis caused by an Australian arbovirus as epidemic polyarthritis. The term epidemic polyarthritis should be used to describe only clinical disease caused by Ross River virus.

Projecting the impact of climate change on the transmission of Ross River virus : methodological challenges and research needs

Ross River virus (RRV) is the most common vector-borne disease in Australia. It is vitally important to make appropriate projections on the future spread of RRV under various climate change scenarios because such information is essential for policy-makers to identify vulnerable communities and to better manage RRV epidemics. However, there are many methodological challenges in projecting the impact of climate change on the transmission of RRV disease. This study critically examined the methodological issues and proposed possible solutions. A literature search was conducted between January and October 2012, using the electronic databases Medline, Web of Science and PubMed. Nineteen relevant papers were identified. These studies demonstrate that key challenges for projecting future climate change on RRV disease include: (1) a complex ecology (e.g. many mosquito vectors, immunity, heterogeneous in both time and space); (2) unclear interactions between social and environmental factors; and (3) uncertainty in climate change modelling and socioeconomic development scenarios. Future risk assessments of climate change will ultimately need to better understand the ecology of RRV disease and to integrate climate change scenarios with local socioeconomic and environmental factors, in order to develop effective adaptation strategies to prevent or reduce RRV transmission.

Epidemiological patterns of Ross River virus disease in Queensland, Australia, 2001-2011

Ross River virus (RRV) infection is a debilitating disease which has a significant impact on population health, economic productivity and tourism in Australia. This study examined epidemiological patterns of the RRV disease in Queensland, Australia between January 2001 and December 2011 at a statistical local area level. Spatial-temporal analyses were used to identify the patterns of the disease distribution over time stratified by age, sex and space. The results show that the mean annual incidence was 54 per 100,000 people, with a male: female ratio of 1:1.1. Two space-time clusters were identified: the areas adjacent to Townsville, on the eastern coast of Queensland; and the south east areas. Thus, although public health intervention should be considered across all areas in which RRV occurs, it should specifically focus on these high risk regions, particularly during the summer and autumn to reduce the social and economic impacts of RRV.

Outbreak detection algorithms for seasonal disease data : a case study using Ross River virus disease

Background Detection of outbreaks is an important part of disease surveillance. Although many algorithms have been designed for detecting outbreaks, few have been specifically assessed against diseases that have distinct seasonal incidence patterns, such as those caused by vector-borne pathogens. Methods We applied five previously reported outbreak detection algorithms to Ross River virus (RRV) disease data (1991-2007) for the four local government areas (LGAs) of Brisbane, Emerald, Redland and Townsville in Queensland, Australia. The methods used were the Early Aberration Reporting System (EARS) C1, C2 and C3 methods, negative binomial cusum (NBC), historical limits method (HLM), Poisson outbreak detection (POD) method and the purely temporal SaTScan analysis. Seasonally-adjusted variants of the NBC and SaTScan methods were developed. Some of the algorithms were applied using a range of parameter values, resulting in 17 variants of the five algorithms. Results The 9,188 RRV disease notifications that occurred in the four selected regions over the study period showed marked seasonality, which adversely affected the performance of some of the outbreak detection algorithms. Most of the methods examined were able to detect the same major events. The exception was the seasonally-adjusted NBC methods that detected an excess of short signals. The NBC, POD and temporal SaTScan algorithms were the only methods that consistently had high true positive rates and low false positive and false negative rates across the four study areas. The timeliness of outbreak signals generated by each method was also compared but there was no consistency across outbreaks and LGAs. Conclusions This study has highlighted several issues associated with applying outbreak detection algorithms to seasonal disease data. In lieu of a true gold standard, a quantitative comparison is difficult and caution should be taken when interpreting the true positives, false positives, sensitivity and specificity.

Ross River virus disease activity associated with naturally occurring non-tidal flood events in Australia : A systematic review

Ross River virus (RRV) disease is the most common and widespread mosquito-borne disease in Australia, resulting in considerable health and economic cost to communities. While naturally occurring non-tidal flood events may enhance mosquito abundance, little is known about the impact of such events on RRV transmission. This paper critically reviews the existing evidence for an association between naturally occurring non-tidal flood events and RRV transmission. A systematic literature search was conducted on RRV transmission related to flooding and inundation from rain and riverine overflow. Overall, the evidence to support a positive association between flooding and RRV outbreaks is largely circumstantial, with the literature mostly reporting only coincidental occurrence between the two. However, for the Murray River, river flow and height (surrogates of flooding) were positively and significantly associated with RRV transmission. The association between non-tidal flooding and RRV transmission has not been studied comprehensively. More frequent flood events arising from climate change may result in increased outbreaks of RRV disease. Understanding the link between flood events and RRV transmission is necessary if resources for mosquito spraying and public health warnings are to be utilized more effectively and efficiently.

Characterization of epitopes for virus-neutralizing monoclonal antibodies to Ross River virus E2 using phage-displayed random peptide libraries

Ross River virus (RRV) is the predominant cause of epidemic polyarthritis in Australia, yet the antigenic determinants are not well defined. We aimed to characterize epitope(s) on RRV-E2 for a panel of monoclonal antibodies (MAbs) that recognize overlapping conformational epitopes on the E2 envelope protein of RRV and that neutralize virus infection of cells in vitro. Phage-displayed random peptide libraries were probed with the MAbs T1E7, NB3C4, and T10C9 using solution-phase and solid-phase biopanning methods. The peptides VSIFPPA and KTAISPT were selected 15 and 6 times, respectively, by all three of the MAbs using solution-phase biopanning. The peptide LRLPPAP was selected 8 times by NB3C4 using solid-phase biopanning; this peptide shares a trio of amino acids with the peptide VSIFPPA. Phage that expressed the peptides VSIFPPA and LRLPPAP were reactive with T1E7 and/or NB3C4, and phage that expressed the peptides VSIFPPA, LRLPPAP, and KTAISPT partially inhibited the reactivity of T1E7 with RRV. The selected peptides resemble regions of RRV-E2 adjacent to sites mutated in neutralization escape variants of RRV derived by culture in the presence of these MAbs (E2 210-219 and 238-245) and an additional region of E2 172-182. Together these sites represent a conformational epitope of E2 that is informative of cellular contact sites on RRV.

La modernización entre cafetales : San José, Costa Rica, 1880-1930

This work examines the urban modernization of San José, Costa Rica, between 1880 and 1930, using a cultural approach to trace the emergence of the bourgeois city in a small Central American capital, within the context of order and progress. As proposed by Henri Lefebvre, Manuel Castells and Edward Soja, space is given its rightful place as protagonist. The city, subject of this study, is explored as a seat of social power and as the embodiment of a cultural transformation that took shape in that space, a transformation spearheaded by the dominant social group, the Liberal elite. An analysis of the product built environment allows us to understand why the city grew in a determined manner: how the urban space became organized and how its infrastructure and services distributed. Although the emphasis is on the Liberal heyday from 1880-1930, this study also examines the history of the city since its origins in the late colonial period through its consolidation as a capital during the independent era, in order to characterize the nineteenth century colonial city that prevailed up to 1890 s. A diverse array of primary sources including official acts, memoirs, newspaper sources, maps and plans, photographs, and travelogues are used to study the initial phase of San Jose s urban growth. The investigation places the first period of modern urban growth at the turn of the nineteenth century within the prevailing ideological and political context of Positivism and Liberalism. The ideas of the city s elite regarding progress were translated into and reflected in the physical transformation of the city and in the social construction of space. Not only the transformations but also the limits and contradictions of the process of urban change are examined. At the same time, the reorganization of the city s physical space and the beginnings of the ensanche are studied. Hygiene as an engine of urban renovation is explored by studying the period s new public infrastructure (including pipelines, sewer systems, and the use of asphalt pavement) as part of the Saneamiento of San José. The modernization of public space is analyzed through a study of the first parks, boulevards and monuments and the emergence of a new urban culture prominently displayed in these green spaces. Parks and boulevards were new public and secular places of power within the modern city, used by the elite to display and educate the urban population into the new civic and secular traditions. The study goes on to explore the idealized image of the modern city through an analysis of European and North American travelogues and photography. The new esthetic of theatrical-spectacular representation of the modern city constructed a visual guide of how to understand and come to know the city. A partial and selective image of generalized urban change presented only the bourgeois facade and excluded everything that challenged the idea of progress. The enduring patterns of spatial and symbolic exclusion built into Costa Rica s capital city at the dawn of the twentieth century shed important light on the long-term political social and cultural processes that have created the troubled urban landscapes of contemporary Latin America.

Isänmaa ja Ranska : Suomalainen frankofilia 1880-1914

In Finland the period 1880 -1914 constituted an essential phase in the creation of the great national project as well as it was a golden time of Francophilia. With Francophilia, i.e. French-mindedness, is here understood a collectively upheld strong sympathy towards France and French culture. However, the Francophilia of late nineteenth century Finland was free from apparent political intentions and remained a chosen disposition. The strength of its drive was not only based on the older European admiration of everything French, but also on the growing fascination for a novelty emerging besides the traditional influences of the Germanic culture. In Finnish society Francophilia mostly worked as an opposite force to the most confined conceptions of what was considered national ; as a consequence France came to denote more than a country and Francophilia contained an important symbolical meaning in the construction of the Finnish nation. The main tasks of the study are to introduce as the first large historical presentation of the subject a covering examination of the many descriptions of Paris-phases of assorted artists, authors, and intellectuals, to clarify the mental relationship of the Finnish intelligentsia to France prior to national independence, and finally to provide these developments with case studies of certain life paths. However, the examination is not biographical, because the starting point remains within the rhetoric arguments of Francophilia and patriotism as these appeared within the public sphere. Historical persons have thus been dealt with primarily as reflectors of the then-current French-minded mentality. Such Francophiles in Finland were first and foremost Werner Söderhjelm, Juhani Aho, L. Onerva and V. A. Koskenniemi. The networks of the Finnish cultural field are mostly displayed through these examples. In previous research the intensive relationship of Finnish artists and authors with France has not been connected with actual concepts of nationalism. The respective periods of the intellectuals in Paris have simply been viewed as devoid of ideological links with the contemporary advancement of the fatherland, or even as opposites to the patriotic pursuits in Finland. From the viewpoint of this study these now canonized creators of a Finnish culture are primarily seen as patriots and fellow countrymen, and only secondly as artists and artist s colleagues. The dissertation is constructed as both a regional survey of the idealization of France and a study of Finnish history through the mirror of Francophilia. As such France only held an instrumental role for the receiving culture, i.e. for the construction of Finland, as no "objective truths" were sought for in France. Keywords: France, francophilia, Finnishness, national project, Paris

Studio portrait of Richard Molling, Margot Molling, Adolf Molling, Ilse Molling, Lena Molling nee Marx; Schoenau am Koenigssee, Germany.

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