Opsonization by non-neutralizing antibodies can confer protection to SARS-CoV-2 despite Spike-dependent modulation of phagocytosis

Bahnan, Wael; Wrighton, Sebastian; Sundwall, Martin; Bläckberg, Anna; Höglund, Urban; Larsson, Olivia; Khakzad, Hamed; Godzwon, Magdalena; Walle, Maria; Elder, Elizabeth; Happonen, Lotta; André, Oscar; Ahnlide, Johannes Kumra; Hellmark, Thomas; Wendel-Hansen, Vidar; Wallin, Robert PA; Malmström, Johan; Malmström, Lars; Ohlin, Mats; Rasmussen, Magnus; Nordenfelt, Pontus

Spike-specific antibodies are central to effective COVID19 immunity. Research efforts have focused on antibodies that neutralize the ACE2-Spike interaction but not on non-neutralizing antibodies. Antibody-dependent phagocytosis is an immune mechanism enhanced by opsonization, where typically, more bound antibodies trigger a stronger phagocyte response. Here, we show that Spike-specific antibodies, dependent on concentration, can either enhance or reduce Spike-bead phagocytosis by monocytes independently of the antibody neutralization potential. Surprisingly, we find that both convalescent patient plasma and patient-derived monoclonal antibodies lead to maximum opsonization already at low levels of bound antibodies and is reduced as antibody binding to Spike protein increases. Moreover, we show that this Spike-dependent modulation of opsonization seems to affect the outcome in an experimental SARS-CoV-2 infection model. These results suggest that the levels of anti-Spike antibodies could influence monocyte-mediated immune functions and propose that non-neutralizing antibodies could confer protection to SARS-CoV-2 infection by mediating phago-cytosis.