Targeting SARS-CoV-2 receptor-binding domain to cells expressing CD40 improves protection to infection in convalescent macaques

Marlin, Romain; Godot, Veronique; Cardinaud, Sylvain; Galhaut, Mathilde; Coleon, Severin; Zurawski, Sandra; Dereuddre-Bosquet, Nathalie; Cavarelli, Mariangela; Gallouët, Anne-Sophie; Maisonnasse, Pauline; Dupaty, Léa; Fenwick, Craig; Naninck, Thibaut; Lemaitre, Julien; Gomez-Pacheco, Mario; Kahlaoui, Nidhal; Contreras, Vanessa; Relouzat, Francis; Fang, Raphaël Ho Tsong; Wang, Zhiqing; Ellis, Jerome; Chapon, Catherine; Centlivre, Mireille; Wiedemann, Aurelie; Lacabaratz, Christine; Surenaud, Mathieu; Szurgot, Inga; Liljeström, Peter; Planas, Delphine; Bruel, Timothée; Schwartz, Olivier; Werf, Sylvie van der; Pantaleo, Giuseppe; Prague, Mélanie; Thiébaut, Rodolphe; Zurawski, Gerard; Lévy, Yves; Grand, Roger Le

Achieving sufficient worldwide vaccination coverage against SARS-CoV-2 will require additional approaches to currently approved viral vector and mRNA vaccines. Subunit vaccines may have distinct advantages when immunizing vulnerable individuals, children and pregnant women. Here, we present a new generation of subunit vaccines targeting viral antigens to CD40-expressing antigen-presenting cells. We demonstrate that targeting the receptor-binding domain (RBD) of the SARS-CoV-2 spike protein to CD40 (αCD40.RBD) induces significant levels of specific T and B cells, with long-term memory phenotypes, in a humanized mouse model. Additionally, we demonstrate that a single dose of the αCD40.RBD vaccine, injected without adjuvant, is sufficient to boost a rapid increase in neutralizing antibodies in convalescent non-human primates (NHPs) exposed six months previously to SARS-CoV-2. Vaccine-elicited antibodies cross-neutralize different SARS-CoV-2 variants, including D614G, B1.1.7 and to a lesser extent B1.351. Such vaccination significantly improves protection against a new high-dose virulent challenge versus that in non-vaccinated convalescent animals.