Abstract

Mechanistic modeling can be used to describe the time course of vaccine-induced humoral immunity and to identify key biological drivers in antibody production. We utilized a six-compartment mechanistic model to describe a 20-week time course of humoral immune responses in 56 non-human primates (NHPs) elicited by vaccination with Ad26.COV2.S according to either a single-dose regimen (1 × 10¹¹ or 5 × 10¹⁰ viral particles [vp]) or a two-dose homologous regimen (5 × 10¹⁰ vp) given in an interval of 4 or 8 weeks. Humoral immune responses were quantified by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike-specific binding antibody concentrations as determined by spike protein-enzyme-linked immunosorbent assay (S-ELISA). The mechanistic model adequately described the central tendency and variability of binding antibody concentrations through 20 weeks in all vaccination arms. The estimation of mechanistic modeling parameters revealed greater contribution of the antibody production mediated by short-lived cells as compared to long-lived cells in driving the peak response, especially post second dose when a more rapid peak response was observed. The antibody production mediated by long-lived cells was identified as relevant for generating the first peak and for contributing to the long-term time course of sustained antibody concentrations in all vaccination arms. The findings contribute evidence on the key biological components responsible for the observed time course of vaccine-induced humoral immunity in NHPs and constitute a step toward defining immune biomarkers of protection against SARS-CoV-2 that might translate across species.

Significance Statement We demonstrate the adequacy of a mechanistic modeling approach describing the time course of binding antibody concentrations in non-human primates (NHPs) elicited by different dose levels and regimens of Ad26.COV2.S. The findings are relevant for informing the mechanism-based accounts of vaccine-induced humoral immunity in NHPs and translational research efforts aimed at identifying immune biomarkers of protection against SARS-CoV-2 infection.