Anna Dari (1), Muriel Boulton (1), Matthieu Le Gars (2), Martine Neyens (1), Belén Valenzuela (1), Richard Hoetelmans (1), Juan José Pérez Ruixo (1)
(1) Janssen Research & Development, Antwerp, Belgium; (2) Janssen Vaccines and Prevention, Leiden, the Netherlands
Objective: To quantify the persistence of humoral immunity after a single injection of 5×1010 viral particles (vp) of the Janssen Ad26 vector-based COVID-19 vaccine, Ad26.COV2.S,1 in seronegative volunteers using mechanistic modelling-based simulations.
Methods: The current analysis was based on SARS-CoV-2 specific antibody response data collected up to 8 months (Day 239) in SARS-CoV-2-seronegative volunteers, enrolled in two Phase 1/2a studies. A total of 442 wtVNA (reference strain: Victoria/1/2020)2 and 1185 Wuhan Spike (S)-ELISA serum concentrations were collected from 82 and 220 participants, respectively, and included in the analysis. A mechanistic model was built to characterize the persistence of the antibody responses to Ad26.COV2.S. Several biological hypotheses were tested to best describe the time course of the SARS-CoV-2 neutralizing and Spike-specific binding antibodies measured by the wtVNA and S-ELISA assays, respectively. The models included the main components responsible of the antibody dynamic3,5-9: the antigen, the memory B-cells, the short-lived and long-lived plasma cells, and the antibodies in serum. The antigen dynamic was described by an exponential decay. The memory B cell time course was considered to present two proliferation terms, antigen-dependent and antigen-independent. Short and long-lived cells, resulting from memory B cell differentiation, were directly responsible for the antibody production. The antibody time course was described by both bi-phasic production and disposition.4 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 wtVNA and S-ELISA models were used to explore the persistence of immunogenicity defined as the time up to which wtVNA and S-ELISA measurements are above the lower limit of quantification (LLOQ), after a single injection of 5×1010 vp of Ad26.COV2.S by simulating the time course of wtVNA and S-ELISA concentrations every 4 weeks up to two years after 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: The open, 6-compartment mechanistic models successfully described wtVNA and S-ELISA data. All parameters that were estimated showed an adequate precision for the wtVNA and S-ELISA models. The covariate analysis revealed that the younger population (age < 60y) showed a 44% (95% CI: 27-61%) increase in the memory B cell production rate (antigen-independent) relative to older adults (age ≥ 60y). Female participants showed a 67% (95%CI: 14-120%) increase in the antibody production by the short-lived cells relative to male participants. The models developed with data up to day 85 were also able to predict the immune response at later time-points (Day 169 and Day 239) as evidenced by Visual Predictive Check (VPC). Finally, model-based simulations showed that 76.3% and 82.5% of seronegative participants older or younger than 60y, respectively, were predicted to have measurable wtVNA 24 months after vaccination. A proportion of 69.4% seronegative males and 91.4% seronegative female at baseline were predicted to have measurable wtVNA 24 months after vaccination. Similar frequencies were predicted for S-ELISA.
Conclusions: According to the mechanistic model-based simulations, a single dose of 5×1010 vp of Ad26.COV2.S in seronegative individuals would elicit durable SARS-CoV-2 binding and neutralizing antibodies responses against the wild type beyond 8 months and up to 24 months. Given the SARS-CoV-2 virus’ ability to adapt rapidly to the immune pressure and the rapid emergence of novel variants with increased infectivity (higher basic reproductive ratio), booster dose(s) have shown to increase antibodies responses and protection. A mechanistic modeling describing the persistence of immunogenicity after different booster regimens is ongoing.
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] 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
[5] Goel et al., Longitudinal analysis reveals distinct antibody and memory b cell responses in sars-cov2 naïve and recovered individuals following mRNA vaccination. medRxiv preprint doi: https://doi.org/10.1101/2021.03.03.21252872
[6] Yman et al., Antibody responses to merozoite antigens after natural Plasmodium falciparum infection: kinetics and longevity in absence of re-exposure. BMC Medicine, 2019; 17(1):1-4
[7] Jacqmin P, et al., Modelling response time profiles in the absence of drug concentrations: definition and performance evaluation of the K–PD model. Journal of pharmacokinetics and pharmacodynamics. 2007 Feb;34(1):57-85
[8] Pasin et al., Dynamics of the humoral immune response to a prime-boost Ebola vaccine: quantification and sources of variation. J Virol, 2019;93(18):e00579-19
[9] Wilson et al., Mathematical model of the antibody response to hepatitis B vaccines: Implications for reduced schedules. Vaccine, 2007; 25(18):3705-12
Reference: PAGE 30 (2022) Abstr 10040 [www.page-meeting.org/?abstract=10040]
Poster: Drug/Disease Modelling - Other Topics