Structural basis for the synergistic neutralization of coxsackievirus B1 by a triple-antibody cocktail

Coxsackievirus B1 (CVB1) is an emerging pathogen associated with severe neonatal diseases including aseptic meningitis, myocarditis, and pancreatitis and also with the development of type 1 diabetes. We characterize the binding and therapeutic efficacies of three CVB1-specific neutralizing antibodies (nAbs) identified for their ability to inhibit host receptor engagement. High-resolution cryo-EM structures showed that these antibodies recognize different epitopes but with an overlapping region in the capsid VP2 protein and specifically the highly variable EF loop. Moreover, they perturb capsid-receptor interactions by binding various viral particle forms. Antibody combinations achieve synergetic neutralization via a stepwise capsid transition and virion disruption, indicating dynamic changes in the virion in response to multiple nAbs targeting the receptor-binding site. Furthermore, this three-antibody cocktail protects against lethal challenge in neonatal mice and limits pancreatitis and viral replication in a non-obese diabetic mouse model. These results illustrate the utility of nAbs for rational design of therapeutics against picornaviruses such as CVB. [Display omitted] •Three CVB1 nAbs independently confer protection against lethal challenge•Triple-antibody cocktail offers synergistic neutralization and enhanced protection•nAbs perturb virion-receptor interactions via receptor mimicry•Triple-antibody cocktail triggers capsid rearrangement and disrupts CVB1 virion Zheng et al. report a therapeutic triple-antibody cocktail that confers receptor mimicry, multifunctional and synergistic neutralization, and infection protection, as tested with lethal challenge and a non-obese diabetic mice model. Structural analysis shows that the combination of three neutralizing antibodies achieves synergistic virus neutralization via stepwise capsid transition and uncoating.