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Neonatal herpes simplex virus (HSV) infections often result in significant mortality and neurological morbidity despite antiviral drug therapy. Maternally-transferred HSV-specific antibodies reduce the risk of clinically-overt neonatal HSV (nHSV), but this observation has not been translationally applied. Using a neonatal mouse model, we tested the hypothesis that passive transfer of HSV-specific human monoclonal antibodies (mAbs) can prevent mortality and morbidity associated with nHSV. The mAbs were expressedin vivoby vectored immunoprophylaxis, or administeredin vivofollowing recombinant expressionin vitro. Through these maternally-derived routes or through direct administration to pups, diverse mAbs to HSV glycoprotein D protected against neonatal HSV-1 and HSV-2 infection. Usingin vivobioluminescent imaging, both pre- and post-exposure mAb treatment significantly reduced viral load. Administration of mAb also reduced nHSV-induced behavioral morbidity, as measured by anxiety-like behavior. Together these studies support the notion that HSV-specific mAb-based therapies may prevent or improve HSV infection outcomes in neonates.Graphical AbstractDifferent antibody sources were used to maternally-transfer or directly administer HSV-specific mAbs to mouse pups. Neonatal mice were challenged with wild type or bioluminescent virus before or after mAb acquisition. Following infection, pups were assessed for survival, virus-induced bioluminescence and anxiety-like behavior as a measure of neurological morbidity. Efficacy was time and mAb dependent. Notably, all HSV-specific mAbs prevented nHSV-associated mortality.

Antibody functions such as neutralization require recognition of antigen by the Fab region, while effector functions are additionally mediated by interactions of the Fc region with soluble factors and cellular receptors. The efficacy of individual antibodies varies based on Fab domain characteristics, such as affinity for antigen and epitope-specificity, and on Fc domain characteristics that include isotype, subclass, and glycosylation profile. Here, a series of HIV-specific antibody subclass and hinge variants were constructed and tested to define those properties associated with differential effector function. In the context of the broadly neutralizing CD4 binding site-specific antibody VRC01 and the variable loop (V3) binding antibody 447-52D, hinge truncation and extension had a considerable impact on the magnitude of phagocytic activity of both IgG1 and IgG3 subclasses. The improvement in phagocytic potency of antibodies with extended hinges could not be attributed to changes in either intrinsic antigen or antibody receptor affinity. This effect was specific to phagocytosis and was generalizable to different phagocytes, at different effector cell to target ratios, for target particles of different size and composition, and occurred across a range of antibody concentrations. Antibody dependent cellular cytotoxicity and neutralization were generally independent of hinge length, and complement deposition displayed variable local optima. In vivo stability testing showed that IgG molecules with altered hinges can exhibit similar biodistribution and pharmacokinetic profiles as IgG1. Overall, these results suggest that when high phagocytic activity is desirable, therapeutic antibodies may benefit from being formatted as human IgG3 or engineered IgG1 forms with elongated hinges., Author summary Target binding and receptor binding domains of antibodies are separated by a hinge region that differs among IgG subclasses. Among these, IgG3 has a uniquely elongated hinge, whose role in an immunoglobulin’s ability to facilitate different immune functions is incompletely understood. We evaluated the effect of varied hinge length and composition on diverse antibody activities and found that extended hinges enhance phagocytosis, a process through which the immune system can clear potentially harmful particles such as viruses. This enhancement was observed across diverse effector cell types, target particles, and for multiple HIV-specific antibodies. Antibodies with extended hinges showed in vivo persistence and localization in a mouse model similar to those with natural hinges. Consequently, immune responses or antibody therapies expected to benefit from a strong phagocytic response, such as viral sequestration, may be enhanced naturally by the IgG3 subclass or artificially by hinge extension. This work expands knowledge of the role that IgG3 plays in immunity and provides a framework for hinge engineering to improve antibodies.

Neonatal herpes simplex virus (nHSV) infections cause devastating morbidity and mortality in infants. Most nHSV cases are associated with primary maternal infection, consistent with the hypothesis that maternal immunity is protective. In humans, we found HSV-specific neutralizing antibodies in newborns of immune mothers, indicating that placentally transferred HSV-specific antibody is protective. Using a murine model, we showed that passive administration of HSV-specific antibody to dams prevented disseminated infection and mortality in pups. Maternal immunization with an HSV-2 replication-defective vaccine candidate, dl5-29, led to transfer of HSV-specific antibodies into neonatal circulation that protected against nHSV neurological disease and death. Furthermore, we observed considerable anxiety-like behavior in adult mice that had been infected with low doses of HSV as neonates, despite a notable lack of signs of infection. This phenotype suggests that nHSV infection can have an unsuspected and permanent impact on behavior. These behavioral sequelae of nHSV were prevented by maternal immunization with dl5-29, demonstrating an unexpected benefit of immunization. These findings also support the general concept that maternal immunization can prevent neurotropic neonatal infections and associated morbidity and mortality., SCOPUS: ar.j, info:eu-repo/semantics/published