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BEHANDLING-God og treffsikker diagnostikk, behandling og rehabilitering

Defining the immune cells in COVID-19 that correlate with disease severity

Alternativ tittel: Undersøkelse av immunceller ved alvorlig covid-19-sykdom

Tildelt: kr 3,2 mill.

Prosjektet bruker avanserte multiparameteranalyser for å følge immunitet og sykdom hos COVID-19 pasienter og hos friske eller pasienter etter vaksinasjon. Vi har i løpet av 2021 publisert artikler som beskriver alvorlige bivirkninger av AstraZenecavaksinen publisert i NEJM og EHJ. Prosjektet har gjort det mulig for oss å sette i gang en rekke aktiviteter og få ytterligere midler, inkludert det første prosjektet fra den internasjonale vaksinealiansen CEPI til en norsk gruppe, en observasjonsstudie, en intervensjonsvaksinestudie (2021-003618-37) og videre oppfølging av pasienter med alvorlige venøs trombose etter covid-19-vaksinasjon i Norge. Vi vil publisere en rekke artikler som definerer cellulære responser mot koronavaksiner hos immunkompromitterte individer, vi overvåker nå immunresponser fra tredje og fjerde revaksinasjon av høyrisikogrupper. Vi sammenligner immunresponser mot villtype, alfa- og deltavariantene av koronaviruset. Vi analyserer også cellulære immunresponser til familiemedlemmer som deltar i husholdningsstudien der FHI-forskere rekrutterer deltakere fra familier der en eller flere har utviklet covid-19 sykdom. Vi måler nivåene av beskyttende cellulære immunresponser hos vaksinerte helsearbeidere og immunkompromitterte pasienter. Resultatene har blitt rapportert til Folkehelseinstituttet, Helsedirektoratet og har hjulpet regjeringen til å ta beslutninger. Prosjektet fortsetter i rammen av CEPI-prosjektet og annen finansiering.

The grant allowed us to start COVID-19 work, to establish regional and National networks and to secure the first Norwegian grant from the international coalition for preparedness against pandemics and for vaccine development, CEPI (The Coalition for Epidemic Preparedness Innovations). The CEPI grant was 3.1M USD and allowed us to establish research on vaccine efficacy and safety, with focus on immunosuppressed patient groups with highest risk of severe disease and mortality from COVID-19. We have also defined vaccine safety, severe adverse effects, mortality, breakthrough infections and COVID-19 in healthy and in immunosuppressed patients. We delivered a knowledge base for management of the pandemic for the Norwegian Corona Vaccination Program at NIPH, the Norwegian Medicines Agency and the Department of Health. A series of articles have been published in the best journals (such as N Engl J Med, Eur Heart J, Lancet Rheumatol, Am J Transplant, Arthritis Rheumatol, J Neurol Neurosurg Psychiatry). The RCN grant allowed us to recruit an international scientist that has been first-author on 2 of the papers and on several papers that are accepted or to be submitted. The research allowed an interventional trial and revaccination (3rd and 4th dose) of immunosuppressed patient cohorts. Results allowed Norwegian health authorities to evaluate and change the vaccination program in Norway for the benefit of the patients with the highest risk of severe disease and mortality. The mortality has been reduced by a factor of 5-10 in the highest risk groups. The knowledge base allows us to understand that the pandemic is far from over for patients with highest risk and that continued followup is mandatory. The vigilance has allowed new efforts to establish trials in Norway, these are expected to start-up in the summer of 2020. We have had a media presence and informed of the importance of continued vaccination and for social distancing, this has been in the National media.

The ongoing COVID-19 pandemic requires information that could stratify patient treatment and new treatment options for the minority that develop fatal lung injury of unclear pathogenesis. Very few studies have focused on defining SARS-CoV-2 viral interaction with the host immune system, natural history and the pathogenesis of severe disease. This project is designed to discover important pathogenesis principles that may guide triage and choice of therapy, allow an understanding if immune inhibition should play a role, facilitate clinical trials and suggest novel biomarkers that can point to patients that risk developing life threatening lung disease. We propose a multidisciplinary groundbreaking study of material from COVID-19 patients that develop acute lung injury. We will define the pathogenic disease course and biomarkers of disease with single cell mass cytometry and RNA sequencing. Cells from two international clinical trial launched in accordance with the “Proposed next steps” in the 2020 WHO Roadmap will be compared for inflammatory signature. We ask what exact types and subsets of inflammatory cells that secrete pro-inflammatory cytokines, a cytokine storm and inflammation that destroys lung tissue. We ask if there is too weak or too strong immune responses in fatal COVID-19. We ask if convalescent patient serum with neutralizing antibodies can reduce the inflammatory cells that cause lung injury. We also ask if cell therapy with immune inhibitory decidua stroma cells (DSC) can negate the cellular inflammatory responses and fatal lung injury in COVID-19, but this study is currently on hold due to few relevant patients. Results will suggest new biomarkers for risk stratification, and triage, test the effect of convalescent serum and immune inhibitory DSC, have importance for the use of cheap anti-inflammatory medication in low-income countries, and will be disseminated in a European lab network to allow improved laboratory prediction of severe lung disease.

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BEHANDLING-God og treffsikker diagnostikk, behandling og rehabilitering