Mechanistic Modeling Projections of Antibody Persistence After Homologous Booster Regimens of COVID-19 Vaccine Ad26.COV2.S in Humans
(1) Anna Dari, (2) Philippe Jacqmin, (3) Yuki Iwaki, (1) Martine Neyens, (4) Mathieu Le Gars, (4) Jerald Sadoff, (1) Karin Hardt, (1) Javier Ruiz-Guiñazú, (1) Juan José Pérez Ruixo
(1) Janssen Research & Development, Beerse, Belgium; (2) MnS Modeling and Simulation, Dinant, Belgium; (3) Janssen Pharmaceutical K.K., Tokyo, Japan; (4) Janssen Vaccines & Prevention, Leiden, the Netherlands.
Objectives: To project the percentages of SARS-CoV-2–seronegative participants at baseline with quantifiable antibodies at 24 months (antibody persistence) following vaccination with the Ad26-based COVID-19 vaccine Ad26.COV2.S1 (5 × 1010 vp) given either as a single-dose or homologous booster regimen at an interval of 2, 3 or 6 months.
Methods: This analysis was based on SARS-CoV-2 specific antibody response data collected up to 15 months in baseline SARS-CoV-2-seronegative participants, enrolled into 3 phase I–IIa and 2 phase III clinical trials of Ad26.COV2.S. Response was assessed through the Wuhan Spike (S)-ELISA assay (binding antibody) and the wtVNA assay (reference strain: Victoria/1/2020)2 (neutralizing antibody). Vaccination regimens included a single dose, and boosters at either 2, 3 and 6 months. Data from participants with both S-ELISA and wtVNA measurements collected at the same time were used to explore the underlying relationship and inform model building. A unique model was used to fit data from both assays through a K-PD approach and described the key elements of humoral immune response3,4: the antigen, B cells, short-lived plasma cells (SLPC), long-lived plasma cells (LLPC), serum and peripheral sites antibody. The antigen dynamic was described by an exponential decay. The time course of B cell responses was assumed to be characterized by 2 major players: memory B cell and germinal center (GC) pathways.5 The memory B cell pathway was assumed to mediate the vaccine-induced production of SLPC.5 The GC pathway was assumed to predominantly mediate the production of LLPC.5 The antibody time course was described by both bi-phasic production and disposition.6 Due to the availability of only serum antibody concentrations, the mechanistic models were expected to be overparameterized. Consequently, some parameters were fixed following reparameterization or based on literature data. The effect of covariates (age and sex) was evaluated. The final model was used to explore the persistence of antibody response defined as the time up to which S-ELISA and wtVNA measurements are above the lower limit of quantification (LLOQ), after any of the 4 injection regimens of 5x1010 vp of Ad26.COV2.S available in the dataset, by simulating the time course of S-ELISA and wtVNA concentrations every 4 weeks up to two years after first vaccination in a cohort of 250,000 participants. Uncertainty in the estimates of the fixed effect, random effects on model parameters and residual variability were considered in conducting the simulations.
Results: A total of 5,608 S-ELISA samples from 978 participants and 1,882 wtVNA samples from a subset of 375 participants were collected and included in the analysis. The relationship between log-transformed S-ELISA and wtVNA data was linear, with an estimated slope (α) of 0.732 (log10(IC50)/log10(EU/mL)) (95% CI, 0.691–0.773). The relationship deviated from the identity line, indicating that the wtVNA signal is less than proportional to the S-ELISA signal. The mechanistic model adequately described the time course of binding and neutralizing antibodies through 15 months following primary vaccination with Ad26.COV2.S. The projected antibody persistence through 24 months was 70.5% following a single dose and ≥89.9% following any booster dose for S-ELISA, and 55.2% following a single dose and ≥80.0% following any booster dose for wtVNA. No difference in the overall antibody persistence at 24 months was observed between different boosting regimens. According to the estimated model parameters, the antibody production rate mediated by both LLPC and SLPC decreased with increasing age. The antibody production rate attributed to LLPC was higher in women relative to men. Boosting at 6 months vs. 2 or 3 months was associated with predicted higher loss of male participants aged ≥60 years with quantifiable neutralizing antibodies before the booster dose administration.
Conclusions: These findings suggest that a single dose of Ad26.COV2.S elicits persistent antibody responses and that homologous boosting is a viable strategy for maintaining long-term (for ≥2 years) protective effects of Ad26.COV2.S vaccination in different subgroups of vaccine recipients and in a context where SARS-CoV-2 variants with increased infectivity are circulating. However, in the absence of a correlate of protection no prediction on duration of protection can be made.
References:
[1] Bos et al., Ad26 vector-based COVID-19 vaccine encoding a prefusion-stabilized SARS-CoV-2 Spike immunogen induces potent humoral and cellular immune responses. npj Vaccines. 2020 Sep 28;5(1):1-1
[2] Sadoff et al., Interim results of a phase 1–2a trial of Ad26. COV2. S Covid-19 vaccine. New England Journal of Medicine. 2021 May 13;384(19):1824-35
[3] Balelli et al., A model for establishment, maintenance and reactivation of the immune response after vaccination against Ebola virus. Journal of Theor. Biol., 2020;495:110254
[4] Dari, A. et al. Quantifying antibody persistence after a single dose of COVID-19 vaccine Ad26.COV2.S in humans using a mechanistic modeling and simulation approach. Clin. Pharmacol. Ther. 113, 380-389 (2022).
[5] McNamara, H.A. et al. Antibody feedback limits the expansion of B cell responses to malaria vaccination but drives diversification of the humoral response. Cell Host Microbe 28, 572-585.e577 (2020).
[6] Davda et al., A model-based meta-analysis of monoclonal antibody pharmacokinetics to guide optimal first-in-human study design. mAbs, 2014; 6(4):1094-102