Abstract
Interactions with receptors for the Fc region of IgG (FcγRs) have been shown to contribute to the in vivo protection against influenza A viruses provided by broadly neutralizing antibodies (bnAbs) that bind to the viral hemagglutinin (HA) stem. In particular, Fc-mediated antibody-dependent cellular cytotoxicity (ADCC) has been shown to contribute to protection by stem-binding bnAbs. Fc-mediated effector functions appear not to contribute to protection provided by strain-specific HA head-binding antibodies. We used a panel of anti-stem and anti-head influenza A and B monoclonal antibodies with identical human IgG1 Fc domains and investigated their ability to mediate ADCC-associated FcγRIIIa activation. Antibodies which do not interfere with sialic acid binding of HA can mediate FcγRIIIa activation. However, the FcγRIIIa activation was inhibited when a mutant HA, unable to bind sialic acids, was used. Antibodies which block sialic acid receptor interactions of HA interfered with FcγRIIIa activation. The inhibition of FcγRIIIa activation by HA head-binding and sialic acid receptor-blocking antibodies was confirmed in plasma samples of H5N1 vaccinated human subjects. Together, these results suggest that in addition to Fc–FcγR binding, interactions between HA and sialic acids on immune cells are required for optimal Fc-mediated effector functions by anti-HA antibodies.
Highlights
Influenza viruses cause annual epidemics that affect 5–15% of the global population, resulting in approximately 3–5 million cases of severe illness and up to 500,000 deaths worldwide, among the very young, the elderly, and the chronically ill [1,2,3]
We have previously described broadly reactive antibodies that were protective in vivo against group 1 influenza A viruses (CR6261) [12, 13], antigenically diverse influenza B viruses (CR8033 and CR8071), and both group 1 and group 2 influenza A viruses as well as influenza B viruses (CR9114) [20]
The identification and structural characterization of human antibodies with broad neutralizing activity against influenza viruses has raised hopes for the development of broad-spectrum antibody-based therapy and universal vaccines [33,34,35,36,37]. Functional characterization of such broadly neutralizing antibodies (bnAbs) has revealed that depending on where they bind the HA molecule, they can directly interfere with the viral life cycle by blocking the binding of HA to its sialic acid receptors on the host cell, by preventing the low pH-induced conformational changes of HA required for membrane fusion, by inhibiting the cleavage of the HA0 precursor protein, or by inhibiting viral egress [5,6,7, 11, 13, 19, 20]
Summary
Influenza viruses cause annual epidemics that affect 5–15% of the global population, resulting in approximately 3–5 million cases of severe illness and up to 500,000 deaths worldwide, among the very young, the elderly, and the chronically ill [1,2,3]. The structural characterization of several of these antibodies [5,6,7, 10,11,12,13,14,15] has revealed epitopes in the head and stem regions of the HA, where functional constraints appear to restrict the potential for the virus to mutate These epitopes are of great interest as vaccine targets, and several strategies are being employed to generate vaccines that induce broadly reactive antibodies [16,17,18]. We demonstrate that in particular, anti-head antibodies that inhibit the interactions between the HA receptor-binding site and sialic acids on immune cells fail to induce strong FcγRIIIa activation. The addition of such anti-head antibodies that block receptor binding can interfere with FcγRIIIa activation in human plasma. We propose a model that describes that optimal HA antibody-mediated FcγRIIIa activity is dependent on the interaction between HA on host cells and sialic acid receptors on immune cells
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
