BACKGROUND: The emergence of new SARS-CoV-2 variants of concern B.1.1.7 (Alpha), B.1.351 (Beta), P.1 (Gamma) and B.1.617.2 (Delta) that harbor mutations in the viral S protein raised concern about activity of current vaccines and therapeutic antibodies. Independent studies have shown that mutant variants are partially or completely resistant against some of the therapeutic antibodies authorized for emergency use. METHODS: We employed hybridoma technology, ELISA-based and cell-based S-ACE2 interaction assays combined with authentic virus neutralization assays to develop second-generation antibodies, which were specifically selected for their ability to neutralize the new variants of SARS-CoV-2. FINDINGS: AX290 and AX677, two monoclonal antibodies with non-overlapping epitopes, exhibit subnanomolar or nanomolar affinities to the receptor binding domain of the viral Spike protein carrying amino acid substitutions N501Y, N439K, E484K, K417N, and a combination N501Y/E484K/K417N found in the circulating virus variants. The antibodies showed excellent neutralization of an authentic SARS-CoV-2 virus representing strains circulating in Europe in spring 2020 and also the variants of concern B.1.1.7 (Alpha), B.1.351 (Beta) and B.1.617.2 (Delta). In addition, AX677 is able to bind Omicron Spike protein just like the wild type Spike. The combination of the two antibodies prevented the appearance of escape mutations of the authentic SARS-CoV-2 virus. Prophylactic administration of AX290 and AX677, either individually or in combination, effectively reduced viral burden and inflammation in the lungs, and prevented disease in a mouse model of SARS-CoV-2 infection. INTERPRETATION: The virus-neutralizing properties were fully reproduced in chimeric mouse-human versions of the antibodies, which may represent a promising tool for COVID-19 therapy. FUNDING: The study was funded by AXON Neuroscience SE and AXON COVIDAX a.s.
- MeSH
- angiotensin konvertující enzym 2 chemie genetika metabolismus MeSH
- antigenní drift a shift MeSH
- COVID-19 virologie MeSH
- farmakoterapie COVID-19 MeSH
- glykoprotein S, koronavirus genetika imunologie metabolismus MeSH
- imunodominantní epitopy imunologie MeSH
- kinetika MeSH
- lidé MeSH
- modely nemocí na zvířatech MeSH
- monoklonální protilátky imunologie terapeutické užití MeSH
- mutace MeSH
- myši MeSH
- neutralizační testy MeSH
- plíce patologie MeSH
- protinádorové látky imunologicky aktivní imunologie terapeutické užití MeSH
- SARS-CoV-2 genetika imunologie izolace a purifikace MeSH
- vazba proteinů MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Akútne brušné klinické prejavy ako počiatočný prejav meningokokovej infekcie sú neobvyklé a často ich vyvolávajú hyperinvazívne izoláty meningokokov. Iba 10 % pacientov infikovaných meningokokovým kmeňom, ktorý je v Európe na vzostupe, trpí bolesťami brucha. V tejto práci prezentujeme prvý laboratórne potvrdený smrteľný prípad, inak zdravého dospelého muža, s akútnou bolesťou brucha počas prvých 24–48 hodín maskujúcim infekciu Neisseria meningitidis (N. meningitidis). V Národnom referenčnom centre pre meningokoky sme v krvi post mortem identifikovali N. meningitidis séroskupiny C pomocou polymerázovej reťazovej reakcie (PCR) v reálnom čase. Následne sa realizovalo masívne paralelné sekvenovanie (MPS) na izolovanej celkovej DNA pre potvrdenie patogénu a pre ďalšie jeho skúmanie.
Acute abdominal clinical presentations as initial manifestation of meningococcal infection are uncommon and frequently provoked by hyperinvasive isolates of meningococci. 10% of patients infected by the meningococcal strain, that is on the rise in Europe, suffer from abdominal pain. We hereby report the first laboratory confirmed fatal case of an otherwise healthy adult male presented with acute abdominal pain during first 24-48 hours, masking Neisseria meningitidis (N. meningitidis) infection. In the National Reference Center for meningococci, in the blood of a man post-mortem, we identified N. meningitidis serogroup C using real time polymerase chain reaction (PCR). Subsequently, massivelly-parallel sequencing (MPS) was performed on isolated total DNA for pathogen confirmation and further investigation.
- MeSH
- akutní bolest MeSH
- bolesti břicha * MeSH
- diferenciální diagnóza MeSH
- fatální výsledek MeSH
- lidé středního věku MeSH
- lidé MeSH
- meningokokové infekce * diagnóza MeSH
- Neisseria meningitidis séroskupiny C izolace a purifikace patogenita MeSH
- pitva MeSH
- polymerázová řetězová reakce MeSH
- Check Tag
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- Publikační typ
- kazuistiky MeSH
- práce podpořená grantem MeSH
- Geografické názvy
- Slovenská republika MeSH
