Antiviral Neutralizing Antibodies: From in Vitro to in Vivo Activity

2023-09-25 Hits(172)

Neutralizing antibodies (nAbs) are being increasingly used as passive antiviral reagents in prophylactic and therapeutic modalities and to guide viral vaccine design. In vivo, nAbs can mediate antiviral functions through several mechanisms, including neutralization, which is defined by in vitro assays in which nAbs block viral entry to target cells, and antibody effector functions, which are defined by in vitro assays that evaluate nAbs against viruses and infected cells in the presence of effector systems. Interpreting in vivo results in terms of these in vitro assays is challenging but important in choosing optimal passive antibody and vaccine strategies. Here, I review findings from many different viruses and conclude that, although some generalizations are possible, deciphering the relative contributions of different antiviral mechanisms to the in vivo efficacy of antibodies currently requires consideration of individual antibody–virus interactions.

There are several definitions of neutralization, two of which are widely accepted. One is “the loss of infectivity which ensues when antibody molecule(s) bind to a virus particle, and usually occurs without the involvement of any other agency”. The phrase “without the involvement of any other agency” (although, rarely, complement is included) indicates that neutralization is typically measured in vitro by incubating antibodies, virus particles and target cells together and demonstrating reduced infection. A second definition of neutralization is “the reduction in viral infectivity by the binding of antibodies to the surface of viral particles (virions), thereby blocking a step in the viral replication cycle that precedes virally encoded transcription or synthesis”. For enveloped viruses, this block occurs before virus entry into a host cell but for non-enveloped viruses, it can occur after entry. In both cases, neutralization according to these definitions can be measured in in vitro assays. However, the term ‘neutralization’ can also be used to describe antiviral activities of antibodies such as protection in vivo, which may or may not involve neutralization in terms of blocking viral entry. This has created considerable confusion in the literature when antiviral (‘neutralizing’) activity in vivo is mediated by antibodies that do not block viral entry in typical neutralization assays in vitro — in other words, non-neutralizing antibodies (nnAbs). For the most part, the field has chosen to avoid confusion by defining neutralization so that it can be assessed by typical in vitro assays, involving antibody, virus and target cells alone.

The ability of nAbs to block viral entry by enveloped viruses in vitro requires that the antibodies bind to functional entry molecules on the surface of infectious virions, typically envelope (Env) protein spikes. Binding to these functional structures also endows nAbs with many other potential antiviral activities that could be manifested in vivo but are not present in neutralization assays in vitro. Thus, for example, virions coated with nAbs could be taken up in vivo by phagocytic cells via receptors for the antibody Fc (crystallizable fragment) domain (FcRs) or trapped on FcR-bearing cells and prevented from accessing target cells. Alternatively, functional viral structures that are recognized by nAbs can be expressed on infected cells, rendering them potential targets for antibody-dependent cellular cytotoxicity (ADCC). Again, recognition of functional structures will enhance the ability of antibodies to inhibit cell–cell spread of a viral infection.

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