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Analysis of SARS-CoV-2 intra host evolution in immunocompromised individuals: A potential source of immune escape variants

Subject Area Virology
Term from 2021 to 2022
Project identifier Deutsche Forschungsgemeinschaft (DFG) - Project number 466171387
 
Final Report Year 2023

Final Report Abstract

Immunocompromised patients are at risk to develop severe COVID-19. These patients are also prone to develop persistent infection, which can last for weeks. During viral persistence, SARS-CoV-2 can acquire mutations that result in immune evasion or evasion from therapeutic monoclonal antibody treatments. To better understand intra-host evolution on a genomic scale, we established a next generation sequencing and bioinformatics approach to analyse persistent infection in immunocompromised patients. In collaboration with clinical partners, we set up a biobank which included patients with defined immunodeficiencies (respiratory tract, serum samples). Since the beginning of the pandemic, we were able to recruit more than 50 patients with persistent infection that lasted longer than four weeks. We used whole genome sequencing to characterize the SARS-CoV- 2 genome in a longitudinal fashion. In general, we were able to show that notable mutations occur after 4 weeks of ongoing infection. In addition, we used cell culture techniques to isolate virus and to analyse its replicative capacity and fitness. This was completed by in vivo experiments and by analysing the B and T cell response in these patients. In a case series of patients with primary antibody immunodeficiency who were treated with convalescent plasma, we demonstrated reduced viral loads in respiratory samples and improvement of clinical symptoms. No significant side effects upon treatment were noticed. In one patient, longitudinal full-genome sequencing revealed the emergence of mutations in the viral genome, potentially conferring an antibody escape. A similar mutational profile was observed in a kidney transplant patient with ongoing infection for more than 150 days. He developed mutations similar to those seen in variants of concern (VOC) from the UK and South Africa. A similar mutation pattern was observed in non-immunocompromised patients in late 2021. Moreover, during our screening, we observed a local emergence of the hitherto rarely detected A.27 variant. This variant most likely originated in Western Africa and spread globally but never reached dominance over other SARS-CoV-2 variants. However, the A.27 variant had a concerning pattern of mutations suggesting a potential to escape the adaptive immune system. This finding further highlights the importance of a molecular global SARS-CoV-2 surveillance. The last patient which we analysed in detail, was an immunocompromised individual receiving SARS-CoV2 monoclonal antibody therapy. However, the patient did not clear the virus after treatment due to the emergence of therapy escape variants. This was shown by neutralization and mouse protection analyses. The patient resolved the infection after modification of the immunosuppressive regimen resulting in an adaptive immune response. Taken together, our data underline the importance and relevance of immune escape of persistently SARS-Cov-2 infected and immunocompromised patients.

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