Spike-Dependent Opsonization Indicates Both Dose-Dependent Inhibition of Phagocytosis and That Non-Neutralizing Antibodies Can Confer Protection to SARS-CoV-2

Abstract

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 correlate with 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 phagocytosis.

COVID‐19 and plasma cells: Is there long‐lived protection?*

“…In vivo animal models of SARS‐CoV‐2 infection have revealed that Fc‐mediated Ab function improves disease outcomes and reduces viral replication. Consistent results have been seen in mice, 145 , 152 , 153 , 154 , 155 hamsters, 154 and macaques. 145 , 156 , 157 In humans, Fc patterns differentially correlate with disease outcomes.…”

Clinical Characteristics of COVID-19 Patients Infected by the Omicron Variant of SARS-CoV-2

“…Nevertheless, for a genetically labile RNA virus, such as influenza virus or human immunodeficiency virus (HIV), the non-neutralizing antibodies have been proven to contribute significantly to efficient viral clearance ( 33 , 34 ). So far, those functional non-neutralizing antibody responses have been demonstrated to render protection against SARS-CoV-2 infection in its wild-type, alpha, beta, epsilon, and gamma form ( 35 – 37 ). Whether this protection reoccurs against other highly mutated SARS-CoV-2 variants, including delta and omicron, awaits to be soon unraveled.…”

From a recombinant key antigen to an accurate, affordable serological test: Lessons learnt from COVID-19 for future pandemics

“…This might be related to the fact that non-neutralizing antibodies have been shown to also contribute to protection to SARS-CoV-2 infection, e.g. by mediating phagocytosis [5] . Other works have also shown that binding antibodies provide an adequate correlate of protection for COVID-19 vaccines [17] , [32] .…”