Quantifying Antibody Persistence After a Single Dose of COVID‐19 Vaccine Ad26.COV2.S in Humans Using a Mechanistic Modeling and Simulation Approach

Abstract

Understanding persistence of humoral immune responses elicited by vaccination against coronavirus disease 2019 (COVID-19) is critical for informing the duration of protection and appropriate booster timing. We developed a mechanistic model to characterize the time course of humoral immune responses in severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2)-seronegative adults after primary vaccination with the Janssen COVID-19 vaccine, Ad26. COV2.S. The persistence of antibody responses was quantified through mechanistic modeling-based simulations. Two biomarkers of humoral immune responses were examined: SARS-CoV-2 neutralizing antibodies determined by wild-type virus neutralization assay (wtVNA) and spike protein-binding antibodies determined by indirect spike protein enzyme-linked immunosorbent assay (S-ELISA). The persistence of antibody responses was defined as the period of time during which wtVNA and S-ELISA titers remained above the lower limit of quantification. A total of 442 wtVNA and 1,185 S-ELISA titers from 82 and 220 participants, respectively, were analyzed following administration of a single dose of Ad26.COV2.S (5 × 10 10 viral particles). The mechanistic model adequately described the time course of observed wtVNA and S-ELISA serum titers and its associated variability up to 8 months following vaccination. Mechanistic modelbased simulations show that single-dose Ad26.COV2.S elicits durable but waning antibody responses up to 24 months following immunization. Of the estimated model parameters, the production rate of memory B cells was decreased in older adults relative to younger adults, and the antibody production rate mediated by long-lived plasma cells was increased in women relative to men. A steeper waning of antibody responses was predicted in men and in older adults.

Mechanistic modeling projections of antibody persistence after homologous booster regimens of COVID‐19 vaccine Ad26.COV2.S in humans

“…Men aged greater than or equal to 60 years were predicted to show the most pronounced waning of antibody persistence, in line with the mechanistic modeling simulations stratified by age and sex in the context of single‐dose Ad26.COV2.S 13 . This subgroup was also projected to show the most pronounced reduction in waning following any booster.…”

“…The structural model (Figure 1) considered the key elements of humoral immune response 10–13,17 : the antigen (Ag, Spike [S]‐protein), the memory B cells (M 1 ), germinal centers (M 2 ), the short‐lived plasma cells (SLPCs), the long‐lived plasma cells (LLPCs), the antibody in serum (Ab), and the antibody in peripheral sites (P). The relationship between vaccine dosing and antigen effects on antibody response was described using a virtual antigen compartment based on a K‐PD (kinetics of drug action) model as follows 18 :where k Ag denotes the first‐order equilibration rate constant depicting the apparent nonspecific decay of S‐protein over time following vaccination 10 …”

“…The production of SLPCs and LLPCs is assumed to be a second‐order process determined by the amount of antigen, the memory B cells and GCs available, and the differentiation rates of memory B cells into SLPCs (k pS ) and GCs into LLPCs (k pL ) 10,13,22 :where k eS and k eL denote the first‐order elimination rate constants of SLPC and LLPC, respectively, assuming differential half‐life durations for SLPC (days) versus LLPC (months or years) 21–23 . The dynamics of serum antibody production was described as a linear combination of production due to the amount of SLPCs and LLPCs, and antibody disposition was characterized by a first‐order elimination and linear distribution to a nonspecific peripheral compartment:where k AbS and k AbL denote the first‐order production rate constants of antibodies from SLPCs and LLPCs, respectively; k eAb denotes the first‐order elimination rate constant of serum antibodies; k AbP denotes the nonspecific distribution to a peripheral compartment; and k PAb denotes the return of antibodies from the peripheral to the serum compartment.…”

“…We recently used mechanistic model‐based simulations to quantify antibody persistence over 24 months from clinical trial data curated through 8 months in SARS‐CoV‐2‐seronegative participants vaccinated with single‐dose Ad26.COV2.S (5 × 10 10 vp) 13 . The projected 24‐month persistence was 81.1% for binding antibodies and 80.4% for neutralizing antibodies 13 . Antibody responses were projected to decline over time, with the most pronounced waning projected in men and older adults 13 .…”

Quantitative mechanistic model reveals key determinants of placental IgG transfer and informs prenatal immunization strategies

“…To simulate maternal Tdap immunization, a model of plasma cell activation and IgG secretion in response to antigen stimulus was adapted from a previous study by White et al in the context of malaria (46). The model consisted of 8 parameters, of which 4 were fitted parameters determined by White et al , 1 was determined experimentally by Dari et al , and 3 were optimized in this study (50). Parameters were tuned to fit previously published dynamic data of the maternal IgG response to Tdap booster vaccination (47) (Table 3).…”