Modeling the kinetics of the neutralizing antibody response against SARS-CoV-2 variants after several administrations of Bnt162b2

Abstract

Because SARS-CoV-2 constantly mutates to escape from the immune response, there is a reduction of neutralizing capacity of antibodies initially targeting the historical strain against emerging Variants of Concern (VoC)s. That is why the measure of the protection conferred by vaccination cannot solely rely on the antibody levels, but also requires to measure their neutralization capacity. Here we used a mathematical model to follow the humoral response in 26 individuals that received up to three vaccination doses of Bnt162b2 vaccine, and for whom both anti-S IgG and neutralization capacity was measured longitudinally against all main VoCs. Our model could identify two independent mechanisms that led to a marked increase in measured humoral response over the successive vaccination doses. In addition to the already known increase in IgG levels after each dose, we identified that the neutralization capacity was significantly increased after the third vaccine administration against all VoCs, despite large inter-individual variability. Consequently, the model projects that the mean duration of detectable neutralizing capacity against non-Omicron VoC is between 348 days (Beta variant, 95% Prediction Intervals PI [307; 389]) and 587 days (Alpha variant, 95% PI [537; 636]). Despite the low neutralization levels after three doses, the mean duration of detectable neutralizing capacity against Omicron variants varies between 173 days (BA.5 variant, 95% PI [142; 200]) and 256 days (BA.1 variant, 95% PI [227; 286]). Our model shows the benefit of incorporating the neutralization capacity in the follow-up of patients to better inform on their level of protection against the different SARS-CoV-2 variants. Trial registration: This clinical trial is registered with ClinicalTrials.gov, Trial IDs NCT04750720 and NCT05315583.

Fig 1

A: longitudinal evolution of the binding antibody concentration of anti-S IgG. B-C-D: longitudinal evolution of the neutralizing activity against VoCs after the first (B, see S1 Fig for a zoomed version), second (C) and third (D) vaccination dose. Squares represent median values, and plain horizontal lines represent the minimal and maximal encountered values among subjects. The lower limit of detection (LOD) is equal to 6 BAU/mL for IgG and 30 for ED₅₀. Given the limited number of samples available, data were grouped, using a one week sliding window after the first dose, 20 days in the first 100 days following the second or third infection, and 50 days for the other data points.

Fig 2. Evolution of the predicted ratio ED50ν/BAU for each VoC after successive vaccine doses.

Each circle represents a ratio $E{D}_{50}^{\nu }/BAU$ computed when both measurements for $E{D}_{50}^{\nu }$ and BAU where available for a given patient at a given observation time. Most of patients contribute several times due to the repeated measurements made over time after each dose. All predictions below the limit of detection for $E{D}_{50}^{\nu }$ were removed to avoid overoptimistic $E{D}_{50}^{\nu }/BAU$ ratio when replacing $E{D}_{50}^{\nu }$ values by detection threshold. This explains why very few values are available for Beta and Delta and none for Omicron strains for one dose case. Comparison between vaccine dose was done using Wilcoxon test with Holm correction, p-values are given above the brackets.

Fig 3. Individual fits for four representative individuals.

The solid line is the subject-specific prediction and the shaded area is the 95% prediction interval. The plain dots and crosses represent the observed and censored data, respectively.

Fig 4

A: Predicted evolution of binding antibody concentration. The horizontal line corresponds to the value of 264 BAU/ml considered as a threshold against symptomatic infection. B: Predicted kinetics of $E{D}_{50}^{\nu }$. The horizontal line corresponds to the LOD. In all panels, the shaded area is the 95% prediction interval.

Fig 5

A: Predicted probability of having predicted antibody concentration (anti-S IgG) greater than 264 BAU/mL. B-C-D: Probability of having detectable neutralizing activity against VoCs after after the first (B), second (C) or third (D) vaccination dose. Simulations were performed assuming that the second and third vaccination doses occurred at day 27 and 269, respectively.