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Highlights d ''Re-epitoping'' of an existing antibody by in silico design d Engineering a functional antibody to IL-17A d Crystal structure of the antibody-antigen complex confirms the targeted epitope

The spillover of animal coronaviruses (aCoVs) to humans has caused SARS, MERS, and COVID-19. While antibody responses displaying cross-reactivity between SARS-CoV-2 and seasonal/common cold human coronaviruses (hCoVs) have been reported, potential cross-reactivity with aCoVs and the diagnostic implications are incompletely understood. Here, we probed for antibody binding against all seven hCoVs and 49 aCoVs represented as 12,924 peptides within a phage-displayed antigen library. Antibody repertoires of 269 recovered COVID-19 patients showed distinct changes compared to 260 unexposed pre-pandemic controls, not limited to binding of SARS-CoV-2 antigens but including binding to antigens from hCoVs and aCoVs with shared motifs to SARS-CoV-2. We isolated broadly reactive monoclonal antibodies from recovered COVID-19 patients that bind a shared motif of SARS-CoV-2, hCoV-OC43, hCoV-HKU1, and several aCoVs, demonstrating that interspecies cross-reactivity can be mediated by a single immunoglobulin. Employing antibody binding data against the entire CoV antigen library allowed accurate discrimination of recovered COVID-19 patients from unexposed individuals by machine learning. Leaving out SARS-CoV-2 antigens and relying solely on antibody binding to other hCoVs and aCoVs achieved equally accurate detection of SARS-CoV-2 infection. The ability to detect SARS-CoV-2 infection without knowledge of its unique antigens solely from cross-reactive antibody responses against other hCoVs and aCoVs suggests a potential diagnostic strategy for the early stage of future pandemics. Creating regularly updated antigen libraries representing the animal coronavirome can provide the basis for a serological assay already poised to identify infected individuals following a future zoonotic transmission event.

While cross-reactive T cells epitopes of SARS-CoV-2 and seasonal/common cold human coronaviruses (hCoVs) have been reported in individuals unexposed to SARS-CoV-2, potential antibody-based cross-reactivity is incompletely understood. Here, we have probed for high resolution antibody binding against all hCoVs represented as 1,539 peptides with a phage-displayed antigen library. We detected broad serum antibody responses against peptides of seasonal hCoVs in up to 75% of individuals. Recovered COVID-19 patients exhibited distinct antibody repertoires targeting variable SARS-CoV-2 epitopes, and could be accurately classified from unexposed individuals (AUC=0.96). Up to 50% of recovered patients also mounted antibody responses against unique epitopes of seasonal hCoV-OC43, that were not detectable in unexposed individuals. These results indicate substantial interindividual variability and antibody cross-reactivity between hCoVs from the direction of SARS-CoV-2 infections towards seasonal hCoVs. Our accurate high throughput assay allows profiling preexisting antibody responses against seasonal hCoVs cost-effectively and could inform on their protective nature against SARS-CoV-2.

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Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating disease with an unclear etiology and pathogenesis. Both an involvement of the immune system and gut microbiota dysbiosis have been implicated in its pathophysiology. However, potential interactions between adaptive immune responses and the microbiota in ME/CFS have been incompletely characterized. Here, we profiled antibody responses of patients with severe ME/CFS and healthy controls against microbiota and viral antigens represented as a phage-displayed 244,000 variant library. Patients with severe ME/CFS exhibited distinct serum antibody epitope repertoires against flagellins of Lachnospiraceae bacteria. Training machine learning algorithms on this antibody-binding data demonstrated that immune responses against gut microbiota represent a unique layer of information beyond standard blood tests, providing improved molecular diagnostics for ME/CFS. Together, our results point toward an involvement of the microbiota-immune axis in ME/CFS and lay the foundation for comparative studies with inflammatory bowel diseases and illnesses characterized by long-term fatigue symptoms, including post–COVID-19 syndrome.