Modeling of waning immunity after SARS-CoV-2 vaccination and influencing factors

Abstract

SARS-CoV-2 vaccines are crucial in controlling COVID-19, but knowledge of which factors determine waning immunity is limited. We examined antibody levels and T-cell gamma-interferon release after two doses of BNT162b2 vaccine or a combination of ChAdOx1-nCoV19 and BNT162b2 vaccines for up to 230 days after the first dose. Generalized mixed models with and without natural cubic splines were used to determine immunity over time. Antibody responses were influenced by natural infection, sex, and age. IgA only became significant in naturally infected. A one-year IgG projection suggested an initial two-phase response in those given the second dose delayed (ChAdOx1/BNT162b2) followed by a more rapid decrease of antibody levels. T-cell responses correlated significantly with IgG antibody responses. Our results indicate that IgG levels will drop at different rates depending on prior infection, age, sex, T-cell response, and the interval between vaccine injections. Only natural infection mounted a significant and lasting IgA response.

Fig. 1. Dynamics and projection of circulating IgG levels against RBD after the first dose of the COVID-19 vaccination using a non-linear model.

Distribution of IgG levels, represented in log(AU/ml), over time (days from the first vaccine) in individuals with no prior infection vaccinated with BNT162b2 (top left) or with the combination ChAdOx1/BNT162b2 (bottom left), and in individuals previously infected and vaccinated with BNT162b2 (top right) or with the combination ChAdOx1/BNT162b2 (bottom right). Circles and triangles represent the observed levels of circulating IgG antibodies in females and males, respectively. Solid and dashed lines represent the predicted levels of circulating IgG antibodies calculated by the model in females and males, respectively. Black, yellow, and blue colors represent individuals with age <40, 40–60, and >60 years, respectively. Horizontal black dotted line represents the threshold for assay positivity. Vertical dash-dotted line indicates where the out-of-sample trend starts. Shadowed areas represent the 95% confidence interval. Center for the confidence interval is the predicted (mean) values.

Fig. 2. Dynamics and projection of circulating IgG levels against RBD after the second dose of the COVID-19 vaccination using a linear model.

Distribution of IgG levels, represented in log(AU/ml), over time (days from the second vaccine) in individuals with no prior infection vaccinated with BNT162b2 (top left) or with the combination ChAdOx1/BNT162b2 (bottom left), and in individuals previously infected and vaccinated with BNT162b2 (top right) or with the combination ChAdOx1/BNT162b2 (bottom right). Circles and triangles represent the observed levels of circulating IgG antibodies in females and males, respectively. Solid and dashed lines represent the predicted levels of circulating IgG antibodies calculated by the model in females and males, respectively. Black, yellow, and blue colors represent individuals with age <40, 40–60, and >60 years, respectively. Horizontal black dotted line represents the threshold for assay positivity. Vertical dash-dotted line indicates where the out-of-sample trend starts. Shadowed areas represent the 95% confidence interval. Center for the confidence interval is the predicted (mean) values.

Fig. 3. Observed and predicted probability of positive IgA responses against RBD after the first dose of the COVID-19 vaccination.

Distribution of positive IgA response (probability) over time (days from the first vaccine) in individuals with no prior infection vaccinated with BNT162b2 (top left) or with the combination ChAdOx1/BNT162b2 (bottom left), and in individuals previously infected and vaccinated with BNT162b2 (top right) or with the combination ChAdOx1/BNT162b2 (bottom right). Blue and pink backgrounds represent the conditional density estimation of positive and negative IgA responses, respectively. Solid and dashed lines represent the predicted probability of positive IgA responses calculated by the model in females and males, respectively. Black, yellow, and blue colors represent individuals with age <40, 40–60, and >60 years, respectively. Shadowed areas represent the 95% confidence interval. Center for the confidence interval is the predicted (mean) values.

Fig. 4. Observed and predicted the probability of neutralizing antibodies against RBD after the first dose of the COVID-19 vaccination.

Distribution of neutralizing antibodies (probability) over time (days from the first vaccine) in individuals with no prior infection vaccinated with BNT162b2 (top left) or with the combination ChAdOx1/BNT162b2 (bottom left), and in individuals previously infected and vaccinated with BNT162b2 (top right) or with the combination ChAdOx1/BNT162b2 (bottom right). Blue and pink backgrounds represent the conditional density estimation of neutralizing and non-neutralizing antibodies index, respectively. Solid and dashed lines across the graph represent the predicted probability of neutralizing antibodies index calculated by the model in females and males, respectively. Black, yellow, and blue colors represent individuals with age <40, 40–60, and >60 years, respectively. Shadowed areas represent the 95% confidence interval. Center for the confidence interval is the predicted (mean) values.

Fig. 5. Circulating IFN-γ levels modeled to circulating IgG levels against RBD in individuals vaccinated against SARS-CoV-2.

Distribution of circulating IgG levels, represented in log(AU/ml), over time (days from the first vaccine) in individuals vaccinated with BNT162b2 (left) or with the combination ChAdOx1/BNT162b2 (right). Circles and triangles represent the observed levels of circulating IgG levels for non-previously infected and infected individuals with SARS-CoV-2, respectively. Solid and dashed lines represent the predicted levels of circulating IgG levels for non-previously infected and infected individuals with SARS-CoV-2, respectively. Black, yellow, and blue colors represent low, intermediate, and high levels of IFN-γ released from stimulated T-cells against peptides derived from the S1 subunit of S protein. Black dotted line represents the threshold for assay positivity. Shadowed areas represent the 95% confidence interval. Center for the confidence interval is the predicted (mean) values.