Complement contributes to antibody-mediated protection against repeated SHIV challenge

Abstract

The first clinical efficacy trials of a broadly neutralizing antibody (bNAb) resulted in less benefit than expected and suggested that improvements are needed to prevent HIV infection. While considerable effort has focused on optimizing neutralization breadth and potency, it remains unclear whether augmenting the effector functions elicited by broadly neutralizing antibodies (bNAbs) may also improve their clinical potential. Among these effector functions, complement-mediated activities, which can culminate in the lysis of virions or infected cells, have been the least well studied. Here, functionally modified variants of the second-generation bNAb 10-1074 with ablated and enhanced complement activation profiles were used to examine the role of complement-associated effector functions. When administered prophylactically against simian-HIV challenge in rhesus macaques, more bNAb was required to prevent plasma viremia when complement activity was eliminated. Conversely, less bNAb was required to protect animals from plasma viremia when complement activity was enhanced. These results suggest that complement-mediated effector functions contribute to in vivo antiviral activity, and that their engineering may contribute to the further improvements in the efficacy of antibody-mediated prevention strategies.

Effector functions are required for broad and potent protection of neonatal mice with antibodies targeting HSV glycoprotein D

“… 35 Evidence in support of this hypothesis has been seen for other viruses. At subneutralizing Ab doses, mAb effector functions can be associated with improved resistance to infection, 38 , 39 control of viremia, 40 , 41 and clearance of virions 42 during simian-human immunodeficiency virus (SHIV) infection in non-human primates. Additionally, optimal mAb-mediated protection against severe acute respiratory syndrome coronavirus 2 infection required effector functions in addition to viral neutralization, particularly when neutralization potency was compromised.…”

Sex- and species-associated differences in complement-mediated immunity in humans and rhesus macaques

“…S4). The broadly neutralizing antibodies 10-1074 ( 56 ), VRC01 ( 57 ), and 10e8v4 ( 60 ), which are known to exhibit complement-mediated lytic activity ( 61 – 63 ), were tested. Among the mutations in the antibodies, LALA and KA substitutions are known to reduce complement activity, and EFTAE and EG have been reported to enhance complement activity ( 64 – 68 ).…”

Antibody effector functions are required for broad and potent protection of neonates from herpes simplex virus infection

“…Evidence in support of this hypothesis has been seen for other viruses. At sub-neutralizing antibody doses, mAb effector functions can be associated with improved resistance to infection 37,38 , control of viremia 39,40 , and clearance of virions 41 during SHIV infection in non-human primates. Additionally, optimal mAb-mediated protection against SARS-CoV-2 infection required effector functions in addition to viral neutralization, particularly when neutralization potency was compromised [42][43][44] .…”