Cross-Neutralizing and Protective Human Antibody Specificities to Poxvirus Infections

Monkeypox (MPXV) and cowpox (CPXV) are emerging agents that cause severe human infections on an intermittent basis, and variola virus (VARV) has potential for use as an agent of bioterror. Vaccinia immune globulin (VIG) has been used therapeutically to treat severe orthopoxvirus infections but is in short supply. We generated a large panel of orthopoxvirus-specific human monoclonal antibodies (Abs) from immune subjects to investigate the molecular basis of broadly neutralizing antibody responses for diverse orthopoxviruses. Detailed analysis revealed the principal neutralizing antibody specificities that are cross-reactive for VACV, CPXV, MPXV, and VARV and that are determinants of protection in murine challenge models. Optimal protection following respiratory or systemic infection required a mixture of Abs that targeted several membrane proteins, including proteins on enveloped and mature virion forms of virus. This work reveals orthopoxvirus targets for human Abs that mediate cross-protective immunity and identifies new candidate Ab therapeutic mixtures to replace VIG. [Display omitted] •Orthopoxviruses elicit a complex B cell immune response reactive to diverse antigens•A large fraction of orthopoxvirus neutralizing mAbs possess cross-neutralizing activity•Six principal mAb specificities participate in cross-neutralization and protection•Most efficient protection is achieved by mixture of diverse mAbs specificities Protective immunity against smallpox and other members of the orthopoxvirus family requires the cooperation of antibodies that target different viral proteins at distinct stages of maturation of the virus.