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The coronavirus spike glycoprotein, located on the virion surface, is the key mediator of cell entry. As such, it is an attractive target for the development of protective antibodies and vaccines. Here we describe two human monoclonal antibodies, 1.6C7 and 28D9, that display a remarkable cross-reactivity against distinct species from three Betacoronavirus subgenera, capable of binding the spike proteins of SARS-CoV and SARS-CoV-2, MERS-CoV and the endemic human coronavirus HCoV-OC43. Both antibodies, derived from immunized transgenic mice carrying a human immunoglobulin repertoire, blocked MERS-CoV infection in cells, whereas 28D9 also showed weak cross-neutralizing potential against HCoV-OC43, SARS-CoV and SARS-CoV-2 in a neutralization-sensitive virus pseudotyping system, but not against authentic virus. Both cross-reactive monoclonal antibodies were found to target the stem helix in the spike protein S2 fusion subunit which, in the prefusion conformation of trimeric spike, forms a surface exposed membrane-proximal helical bundle, that is antibody-accessible. We demonstrate that administration of these antibodies in mice protects from a lethal MERS-CoV challenge in both prophylactic and/or therapeutic models. Collectively, these antibodies delineate a conserved, immunogenic and vulnerabe site on the spike protein which spurs the development of broad-range diagnostic, preventive and therapeutic measures against coronaviruses., The project was co-financed by a grant from the Zoonotic Anticipation and Preparedness Initiative [ZAPI project; Innovative Medicines Initiative (IMI) grant agreement no. 115760], with the assistance and financial support of IMI and the European Commission, and in-kind contributions from European Federation of Pharmaceutical Industries and Associations partners. The collaboration project is cofunded by the PPP Allowance made available by Health~Holland, Top Sector Life Sciences & Health, to stimulate public-private partnerships. This study was also partially financed by grants from the Ministry of Science and Innovation of Spain (BIO2016-75549-R AEI/FEDER, UE) and NIH (2PO1AIO6O699). The mice used to generate the mAbs produced in this study were provided by Harbour Antibodies BV, a daughter company of Harbour Biomed (http://www.harbourbiomed.com). Chunyan Wang was supported by a grant from the China Scholarship Council.

Background Thymic stromal lymphopoietin (TSLP) controls allergic T H 2 inflammatory responses through induction of distinct activation programs in dendritic cells (DCs). However, knowledge about TSLP receptor expression and functional consequences of receptor activation by DCs residing in the human respiratory tract is limited. Objective We wanted to identify TSLP-responding DC populations in the human upper airway mucosa and assess the TSLP-mediated effects on such DCs in allergic airway responses. Results We found that the TSLP receptor was constitutively and preferentially expressed by myeloid CD1c + DCs in the human airway mucosa and that the density of this DC subset in nasal mucosa increased significantly after in vivo allergen challenge of patients with allergic rhinitis. In vitro , TSLP strongly enhanced the capacity of CD1c + DCs to activate allergen-specific memory CD4 + T cells. Moreover, TSLP rapidly induced CCR7 expression on CD1c + DCs. However, T H 2 cytokines attenuated TSLP-mediated CCR7 induction, thus inhibiting the TSLP-induced DC migration potential to the draining lymph nodes. Conclusion Our results suggest that TSLP-mediated activation of human nasal mucosal CD1c + DCs triggers CCR7-dependent migration to the draining lymph nodes and enhances their capacity to initiate T H 2 responses. However, the observation that T H 2 cytokines abrogate the induction of CCR7 implies that during a T H 2-mediated inflammatory reaction, TLSP-activated CD1c + DCs are retained in the inflamed tissue to further exacerbate local inflammation by activating local antigen-specific memory T H 2 cells.