Protective antiviral antibodies that lack neutralizing activity: precedents and evolution of concepts

Antibody-mediated resistance to viral disease is often attributed solely to neutralizing antibodies (NAbs) despite a body of evidence -- more than 30 years in the making -- to show that other populations of antibodies (protective non-neutralizing antibodies, PnNAbs) can also contribute and are sometimes pivotal in host resistance to viruses. Recently, interest in varieties of PnNAbs has been restored and elevated by an HIV vaccine trial in which virus-specific nNAbs have been highlighted as a positive correlate of immunity. Here, I briefly review some of the historical precedents with many viruses other than HIV, along with the emergence of data over the course of some four decades, pointing emphatically to the importance of subsets of antiviral antibodies that operate by mechanisms other than classical virus neutralization. Foremost among suspected mechanisms of protection by PnNAbs is antibody-dependent cellular cytotoxicty (ADCC), but additional mechanisms have sometimes been incriminated or not experimentally excluded. Examples are given for the diversity of proteins and cognate epitopes bound by PnNAbs. Some such epitopes are restricted to virus-infected cell surfaces or found on secreted proteins; others may be associated with virions but unavailable to antibodies during much of the viral cycle; these are epitopes variously described as cryptic, transitional, dynamic, or reversibly masked.