Neutralizing antibodies against Mayaro virus require Fc effector functions for protective activity

Abstract

Despite causing outbreaks of fever and arthritis in multiple countries, no countermeasures exist against Mayaro virus (MAYV), an emerging mosquito-transmitted alphavirus. We generated 18 neutralizing mAbs against MAYV, 11 of which had “elite” activity that inhibited infection with EC50 values of <10 ng/ml. Antibodies with the greatest inhibitory capacity in cell culture mapped to epitopes near the fusion peptide of E1 and in domain B of the E2 glycoproteins. Unexpectedly, many of the elite neutralizing mAbs failed to prevent MAYV infection and disease in vivo. Instead, the most protective mAbs bound viral antigen on the cell surface with high avidity and promoted specific Fc effector functions, including phagocytosis by neutrophils and monocytes. In subclass switching studies, murine IgG2a and humanized IgG1 mAb variants controlled infection better than murine IgG1 and humanized IgG1-N297Q variants. An optimally protective antibody response to MAYV and possibly other alphaviruses may require tandem virus neutralization by the Fab moiety and effector functions of the Fc region.

Antibody barriers to going viral

“…What is the effector function involved? Earnest et al (2019) showed that several of the protective nAbs promoted neutrophil and monocyte-dependent phagocytosis of E2-coated beads, as might be expected. Of note, the protective activities of IgG2a nAbs with similar neutralizing titers varied widely, suggesting a potentially rich area for further research to understand the underlying mechanisms involved.…”

“…In conclusion, Earnest et al (2019) describe a thorough study of Ab protection against an alphavirus in a mouse model (note that several different aspects of the study are not covered in this overview). It will be interesting to see the next stages of the work in terms of understanding the molecular origins of the observations made.…”

“…For vaccines, enhancement may Ab linking infected cell and effector cell: interactions in a tight space. Earnest et al (2019) show that nAb protection against MAYV requires Ab interaction with an effector function, most likely an Fc receptor-bearing cell. The type of interaction probably involved is modeled here using available structures and known interaction sites.…”

Mayaro Virus Pathogenesis and Transmission Mechanisms

“…Interestingly, a study by Santiago et al shows that neutralizing antibodies alone are not sufficient to prevent the occurrence of chronic arthritis [50]. Earnest and collaborators generated a series of neutralizing broad-spectrum mouse antibodies by the use of recombinant MAYV E2 protein [68] and showed their therapeutic utility against MAYV, thereby underscoring the importance that should be given to IgG subclasses and their effector functions. Diagram showing the probable dissemination of MAYV in humans, based on animal experiments and clinical data for similar alphaviruses.…”

Differential and sequential immunomodulatory role of neutrophils and Ly6Chiinflammatory monocytes during antiviral antibody therapy

“…ADCC, ADCP, ….) have been shown to be required for antibody-mediated antiviral protection (Bournazos et al, 2014, 2019; Earnest et al, 2019; Fox et al, 2019; Gunn et al, 2018; Liu et al, 2017) whether and how FcγR engagement by antiviral mAbs affects the immunomodulatory properties of different FcγR-expressing cells (i.e. cytokines/chemokines secretion, activation markers expression, …) has been little studied.…”