Requirement for Fc effector function is overcome by binding potency for broadly reactive anti-alphavirus antibodies.

Area of Science:

• Virology
• Immunology
• Vaccinology

Background:

• Alphaviruses pose significant public health risks, necessitating effective countermeasures.
• Broadly reactive anti-alphavirus monoclonal antibodies (mAbs) demonstrate protective potential in preclinical models.
• The precise mechanisms underlying Fc-dependent and Fc-independent protection by mAbs in vivo require further elucidation.

Purpose of the Study:

• To investigate the correlates of monoclonal antibody (mAb)-mediated protection against Venezuelan equine encephalitis virus (VEEV) challenge.
• To delineate the roles of Fc effector functions and antibody avidity in mAb efficacy.
• To inform the therapeutic development of broadly reactive anti-alphavirus mAbs.

Main Methods:

• Utilized two vaccine-elicited, broadly reactive anti-alphavirus mAbs, SKT05 and SKT20, in VEEV challenge models.
• Assessed mAb efficacy in preventing lethality and controlling viral replication and spread.
• Investigated the requirement of Fc effector functions and the impact of antibody dose and avidity.

Main Results:

• SKT20-mediated protection against VEEV lethality was dependent on Fc effector functions.
• SKT05-mediated survival was initially Fc-independent, linked to potent egress inhibition, but viral control became Fc-dependent.
• Fc effector function requirements varied with mAb dose and binding avidity, with higher avidity (SKT05) potentially overcoming Fc dependence.

Conclusions:

• Antibody avidity is a critical correlate for in vivo efficacy against alphaviruses.
• Fc-dependent mechanisms play a significant role in mAb-mediated control of alphavirus replication and spread.
• Findings provide a basis for leveraging antibody avidity and Fc functions in the development of therapeutic mAbs for alphavirus infections.