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Content archived on 2024-05-29

Immune response to respiratory virus infections and vaccination in elderly

Final Report Summary - RESPVIRUSES (Immune response to respiratory virus infections and vaccination in elderly)

Since its start the RESPVIRUSES project focussed on novel emerging or old re-emerging viral pathogens that infect the human respiratory tract and bear the risk of severe infections in the elderly. It is assumed that severe infections occur mainly due to immunosenescence factors, but so far this problem was not sufficiently investigated with respect to the challenge of respiratory viruses other than influenza. In the RESPVIRUSES project, hitherto major attention was paid to Human metapneumovirus (HMPV), the Respiratory syncytial virus (RSV), human coronavirus NL63, Epstein Barr virus, and the human bocavirus.

In a clinical study, it was shown by our consortium that severe infections with RSV in the elderly may be caused by the lack of neutralising antibodies against this pathogen. Previous studies have shown that virtually all adults have antibodies against RSV thus the data of our consortium are surprising as it remains unclear why the elderly suffer from life threatening RSV infections. The data lead to the hypothesis that either immunosenescence effects or viral evolution followed by immune escape or a combination of both occurs in the severe cases of RSV infections in the elderly. This concept is not really new, but so far has solely been hypothesized for influenza viruses and has been observed also in the Severe acute respiratory syndrome (SARS) epidemics.

With respect to novel diagnostic tools, we were able to develop new assays for testing the RSV serum status that were successfully tested with a clinical set of patients specimens (Sastre et al., submitted). In this context, the database application developed in the RESPVIRUSES project was converted into a safe online tool that is actually in use and will approximately cover more than 2 000 datasets on clinical respiratory infections or immune status against HMPV and other respiratory viruses.

In an ageing murine model of HMPV infections previously published from our consortium, we have started to test the efficacy of DsiRNA that are active against HMPV. We have identified six candidate DsiRNAs that were highly active against HMPV in a novel high throughput assay that allows identification of potent antivirals. Our data were independently verified by another (non-European) group of scientist working in the same field of research, but this group stopped further development as intellectual property rights are with one of our consortium partners. Preliminary data are highly promising and hopefully by the end of the project will result in candidate molecule available for subsequent clinical testing and application.

Major progress was made by our consortium with respect to the role of human bocavirus as a pathogen in airway infections. So far, less was known about human bocavirus and most information on its molecular biology were drawn from sequence alignments and the assumption that human bocavirus behaves like other parvoviruses despite of the lack of experimental evidence.

The RESPVIRUSES consortium was able to contribute with new information to this field. It was shown that the polarity of the packaged viral deoxyribonucleic acid (DNA) that is covered by the viral particle in the majority is of a negative strand polarity. Thereby, the polarity is not influence by the virus subtype. This information is useful for the development of novel diagnostic tools and antiviral drugs that target the viral nucleic acid, like e.g. siRNAs. Additionally, and even more exciting, we managed to culture human bocavirus for the very first time in cell culture. Thereby, both replication kinetics and the viral transcriptome were analysed and splicing variants were identified.