A cross-reactive antibody protects against Ross River virus musculoskeletal disease despite rapid neutralization escape in mice

Arthritogenic alphaviruses cause debilitating musculoskeletal disease and historically have circulated in distinct regions. With the global spread of chikungunya virus (CHIKV), there now is more geographic overlap, which could result in heterologous immunity affecting natural infection or vaccination. Here, we evaluated the capacity of a cross-reactive anti-CHIKV monoclonal antibody (CHK-265) to protect against disease caused by the distantly related alphavirus, Ross River virus (RRV). Although CHK-265 only moderately neutralizes RRV infection in cell culture, it limited clinical disease in mice independently of Fc effector function activity. Despite this protective phenotype, RRV escaped from CHK-265 neutralization in vivo, with resistant variants retaining pathogenic potential. Near the inoculation site, CHK-265 reduced viral burden in a type I interferon signaling-dependent manner and limited immune cell infiltration into musculoskeletal tissue. In a parallel set of experiments, purified human CHIKV immune IgG also weakly neutralized RRV, yet when transferred to mice, resulted in improved clinical outcome during RRV infection despite the emergence of resistant viruses. Overall, this study suggests that weakly cross-neutralizing antibodies can protect against heterologous alphavirus disease, even if neutralization escape occurs, through an early viral control program that tempers inflammation.
Author summary The induction of broadly neutralizing antibodies is a goal of many antiviral vaccine programs. In this study, we show that cross-reactive monoclonal and polyclonal antibodies developed after CHIKV infection or immunization with relatively weak cross-neutralizing activity can protect against RRV-induced musculoskeletal disease in mice. Even though RRV rapidly escaped from neutralization, antibody therapy reduced inflammation in musculoskeletal tissues and decreased viral burden near the site of infection in a manner that required type I interferon signaling. These studies in mice show that broadly reactive antibodies with limited neutralizing activity still can confer protection against heterologous alphaviruses.