Dynamics of antibody binding and neutralization during viral infection

TL;DR

This paper develops mathematical models to understand antibody binding and neutralization during viral infection, highlighting how in vivo dynamics differ from traditional assays and proposing simplified models for practical use.

Contribution

It introduces a new infection analog of affinity (IAA) and demonstrates how in vivo viral dynamics affect antibody binding and neutralization, providing a theoretical framework for better interpretation.

Findings

Viral production alters the role of affinity in binding.

Koff has a limited effect on binding in vivo due to viral decay.

Simplified models are justified for practical analysis.

Abstract

In vivo in infection, virions are constantly produced and die rapidly. In contrast, most antibody binding assays do not include such features. Motivated by this, we considered virions with n=100 binding sites in simple mathematical models with and without the production of virions. In the absence of viral production, at steady state, the distribution of virions by the number of sites bound is given by a binomial distribution, with the proportion being a simple function of antibody affinity (Kon/Koff) and concentration; this generalizes to a multinomial distribution in the case of two or more kinds of antibodies. In the presence of viral production, the role of affinity is replaced by an infection analog of affinity (IAA), with IAA=Kon/(Koff+dv+r), where dv is the virus decaying rate and r is the infection growth rate. Because in vivo dv can be large, the amount of binding as well as the effect of Koff on binding are substantially reduced. When neutralization is added, the effect of Koff is similarly small which may help explain the relatively high Koff reported for many antibodies. We next show that the n+2-dimensional model used for neutralization can be simplified to a 2-dimensional model. This provides some justification for the simple models that have been used in practice. A corollary of our results is that an unexpectedly large effect of Koff in vivo may point to mechanisms of neutralization beyond stoichiometry. Our results suggest reporting Kon and Koff separately, rather than focusing on affinity, until the situation is better resolved both experimentally and theoretically.