ChAdOx1 nCoV-19 (AZD1222) vaccine-induced Fc receptor binding tracks with differential susceptibility to COVID-19

Abstract

Despite the success of COVID-19 vaccines, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern have emerged that can cause breakthrough infections. Although protection against severe disease has been largely preserved, the immunological mediators of protection in humans remain undefined. We performed a substudy on the ChAdOx1 nCoV-19 (AZD1222) vaccinees enrolled in a South African clinical trial. At peak immunogenicity, before infection, no differences were observed in immunoglobulin (Ig)G1-binding antibody titers; however, the vaccine induced different Fc-receptor-binding antibodies across groups. Vaccinees who resisted COVID-19 exclusively mounted FcγR3B-binding antibodies. In contrast, enhanced IgA and IgG3, linked to enriched FcγR2B binding, was observed in individuals who experienced breakthrough. Antibodies unable to bind to FcγR3B led to immune complex clearance and resulted in inflammatory cascades. Differential antibody binding to FcγR3B was linked to Fc-glycosylation differences in SARS-CoV-2-specific antibodies. These data potentially point to specific FcγR3B-mediated antibody functional profiles as critical markers of immunity against COVID-19.

Impact of SARS-CoV-2 vaccination on FcγRIIIA/CD16 dynamics in Natural Killer cells: relevance for antibody-dependent functions

“…In the context of the growing appreciation of the Fc-dependent protective functions of vaccinal antibodies ( 3 – 9 , 51 ), NK cells may play a special role. Indeed, the capability of polyfunctional Abs to trigger ADCC has been correlated with protection against SARS-CoV-2 variants of concern, across different vaccine platforms ( 3 – 9 ).…”

Dissecting the properties of circulating IgG against Group A Streptococcus through a combined systems antigenomics-serology workflow

“…Advances in Omics technologies have also sparked the field of systems serology, a collection of integrative approaches to analyze various antibody features and functions, coupled to advanced computational and statistical methods(14–17). Systems serology has been useful to deconvolute immune correlates of protection and vaccine efficacy for the Human Immunodeficiency Virus (HIV)(18), Mycobacterium tuberculosis (MTB)(19), and SARS-CoV-2(20, 21). However, the starting point of systems serology is typically one or a few preselected antigen(s), a choice that often relies on previously acquired knowledge.…”

Distinct effector functions mediated by Fc regions of bovine IgG subclasses and their interaction with Fc gamma receptors

“…Complement-dependent cytotoxicity (CDC) is mediated by IgG binding to antigen on a target cell triggering the classical complement pathway via C1q, and is an important mechanism via which antibodies can kill tumor or virally infected cells (8). In certain viral infections, such as HIV and SARS-CoV-2, the Fc-mediated functions of IgG are of significant clinical importance (9,10). The ability of certain IgG subclasses to enhance cellular phagocytosis (ADCP) is key to the use of therapeutic mAbs in cancer treatment (11).…”