Human antibody specificities that confer protective immunity to poxvirus infections (VAC11P.1109)

Abstract Immunization with vaccinia virus (VACV) induces cross-protective immunity to variola, the causative agent of smallpox, and other clinically important poxviral species, such as cowpox and monkeypox viruses. Vaccine-mediated protection has been correlated with elicitation of broad neutralizing antibodies (Abs). However, the specificity and breadth of protective human Abs to poxviruses are largely unknown. We used a highly-optimized human hybridoma technology to generate a panel of 90 anti-VACV monoclonal Abs from vaccinia-immunized subjects or from subjects who had a history of naturally-acquired monkeypox infection. Then, we assessed the neutralizing and protective capabilities of the Abs in vitro and in a lethal respiratory VACV challenge in a mouse model. A large fraction of Abs from the panel (>40%) possessed neutralizing activity against VACV, cowpox and/or monkeypox viruses. Antibodies to a variety of envelope proteins in VACV extracellular virions (A33, B5) or mature virions (L1, A27, D8, H3) contributed substantially to neutralizing activity in vitro. For protective immunity in vivo, L1, A27, A33 and B5 antibodies conferred levels of protection that were comparable to those induced by live viral vaccination, especially when used in combination. Such antibody cocktails have promise for use in as immunotherapeutics in humans.