Systemic IL-15, IFN-γ, and IP-10/CXCL10 signature associated with effective immune response to SARS-CoV-2 in BNT162b2 mRNA vaccine recipients

Bergamaschi, Cristina; Terpos, Evangelos; Rosati, Margherita; Angel, Matthew; Bear, Jenifer; Stellas, Dimitris; Karaliota, Sevasti; Apostolakou, Filia; Bagratuni, Tina; Patseas, Dimitris; Gumeni, Sentiljana; Trougakos, Ioannis P.; Dimopoulos, Meletios A.; Felber, Barbara K.; Pavlakis, George N.

doi:10.1016/j.celrep.2021.109504

Cited by 177 publications

(243 citation statements)

References 84 publications

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“…[22], which begin on day ∼ 50 past dose one, an interval-censored data point was added to day 1 to guide the initial condition fit, where the allowable initial range of the fit is bounded within all the initial day 1 IgG values used in this work. Final clinical data points for IL-15 and IL-6 were gathered immediately after dose two where these quantities have peaked, such that the subsequent decay was not characterized [19]. To ensure the eventual decrease in these cytokines as a function of time in our modelled prediction, we added an interval-censored data point on day 200, which ensures the fit on this day is between 0 and the minimal value determined on day 1 for each respective concentration.…”

Section: Methodsmentioning

confidence: 99%

“…1a. Similarly we do the same for the BNT162b2 two-dose result, where we average the individual IgG fitted parameters from Tables S3 and S4 from Stankov et al [18], Bergamaschi et al [19], Camara et al [20], Wang et al [22], and Suthar et al [23]. The result is shown as the red points with corresponding average fit in Fig.…”

Section: Model Is Consistent With Clinically-observed Humoral Responsesmentioning

confidence: 97%

“…In comparison, two doses of mRNA-1273 and BNT162b2 have shown seroconversion in the short term that surpasses that of recovered patients: one month post second dose, antibody stimulation (IgG and IgM) is reported to be higher while neutralizing antibodies are shown to be similar to recovered patients for fully vaccinated individuals [12, 13, 14]. In vaccinated individuals, studies of antibodies responses are predominantly short- (less than 60 days) and mediumterm (less than 120 days) studies [11, 15, 16, 17, 18, 19, 20, 21, 22], with one recent study examining antibody response out to day 210 [23]. With the continued emergence of new variants of concern, there is now a key gap in the understanding of the long-term (beyond 120 days) robustness of the two-dose LNP-formulated mRNA vaccines adopted by health authorities.…”

Section: Introductionmentioning

confidence: 99%

“…To address this gap, we established an ODE-based mechanistic model that describes the humoral immune response of mRNA vaccines to predict long term immunity. We fit our model to reported antibody and cytokine levels to clinical trial data using two standard doses of mRNA-1273 (100 μ g) or BNT162b2 (30 μ g) [17, 18, 19, 20, 21, 22], as well as separately to two low doses of mRNA-1273 (25 μ g) [24]. Model results show significant decay in antibody a few months after dose-two inoculation, with the decay rate depending on the vaccine type, dose size, and age of the vaccine recipient.…”

Section: Introductionmentioning

confidence: 99%

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Long-term predictions of humoral immunity after two doses of BNT162b2 and mRNA-1273 vaccines based on dosage, age and sex

Korosec

Farhang‐Sardroodi

Dick

et al. 2021

Preprint

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Background. The lipid nanoparticle (LNP)-formulated mRNA vaccines are a widely adopted two-dose vaccination public health strategy to manage the COVID-19 pandemic. Clinical trial data has described the immunogeneicity of the vaccine, albeit within a limited study time frame. Our aims were to use a within-host mathematical model for LNP-formulated mRNA vaccines, informed by available clinical trial data, to project a longer term understanding of humoral immunity as a function of vaccine type, dosage amount, age, and sex. Methods. We developed a mathematical model describing the immunization process of LNP-formulated mRNA vaccines, and fit our model to twenty-two clinical humoral and cytokine BNT162b2 or mRNA-1273 human two-dose vaccination data sets. We incorporated multi-dose effects in our model to specify whether the dosage is standard or low-dose. We further specify the age groups 18-55, 56-70, and 70+ in our fits for two-standard doses of mRNA-1273, and sex in our fits for two-standard doses of BNT162b2. We used non-linear mixed effect models to fit to all similar data types (e.g. standard two-dose BNT162b2 or mRNA-1273, or two low-dose mRNA-1273). Therefore, in our fits all estimated parameters are statistically correlated, which allowed us to determine the underlying 'population-dynamics' structure common to a data type. We therefore made accurate long-term predictions informed by all clinical data used in this study. Findings. We estimate that two standard doses of either mRNA-1273 or BNT162b2, with dosage times separated by the company-mandated intervals, results in individuals loosing more than 99% humoral immunity relative to peak immunity by eight months following the second dose. We predict that within an eight month period following dose two (corresponding to the CDC time-frame for administration of a third dose), there exists a period of time longer than one month where an individual has less then 99% humoral immunity relative to peak immunity, regardless of which vaccine was administered. We further find that age has a strong influence in maintaining humoral immunity; by eight months following dose two we predict that individuals aged 18-55 have a four-fold humoral advantage compared to aged 56-70 and 70+ individuals. We find that sex has little effect on the vaccine uptake and long-term IgG counts. Finally, we find that humoral immunity generated from two low doses of mRNA-1273 decays substantially slower relative to peak immunity gained than compared to two standard doses of either mRNA-1273 or BNT162b2. Interpretation. For the two dose mRNA vaccines, our predictions highlight the importance of the recommended third booster dose in order to maintain elevated levels of antibodies. We further show that age plays a critical role in determining the antibody levels. Hence, a third booster dose may confer an immuno-protective advantage in older individuals.

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Section: Methodsmentioning

confidence: 99%

Section: Model Is Consistent With Clinically-observed Humoral Responsesmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Long-term predictions of humoral immunity after two doses of BNT162b2 and mRNA-1273 vaccines based on dosage, age and sex

Korosec

Farhang‐Sardroodi

Dick

et al. 2021

Preprint

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show abstract

“…An in-house ELISA measuring IgG was used to determine antibodies against the complete Spike protein, Spike-Receptor binding domain (Spike-RBD), complete Nucleocapsid protein (N), and Nucleocapsid-RNA binding domain (N-RBD), as previously described. The in-house assay measuring Spike shows excellent correlation with the ROCHE assay but has a larger range of detection and is more sensitive [ 22 , 23 ]. The cut-off values were determined using 17–23 healthy human plasma samples collected between 2015 and 2018 and tested against the different antigens, and the mean and standard deviation were calculated as previously described [ 22 ].…”

Section: Methodsmentioning

confidence: 99%

Kinetics of Nucleocapsid, Spike and Neutralizing Antibodies, and Viral Load in Patients with Severe COVID-19 Treated with Convalescent Plasma

Thomopoulos

Rosati

Terpos

et al. 2021

Viruses

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COVID-19 is an ongoing pandemic with high morbidity and mortality. Despite meticulous research, only dexamethasone has shown consistent mortality reduction. Convalescent plasma (CP) infusion might also develop into a safe and effective treatment modality on the basis of recent studies and meta-analyses; however, little is known regarding the kinetics of antibodies in CP recipients. To evaluate the kinetics, we followed 31 CP recipients longitudinally enrolled at a median of 3 days post symptom onset for changes in binding and neutralizing antibody titers and viral loads. Antibodies against the complete trimeric Spike protein and the receptor-binding domain (Spike-RBD), as well as against the complete Nucleocapsid protein and the RNA binding domain (N-RBD) were determined at baseline and weekly following CP infusion. Neutralizing antibody (pseudotype NAb) titers were determined at the same time points. Viral loads were determined semi-quantitatively by SARS-CoV-2 PCR. Patients with low humoral responses at entry showed a robust increase of antibodies to all SARS-CoV-2 proteins and Nab, reaching peak levels within 2 weeks. The rapid increase in binding and neutralizing antibodies was paralleled by a concomitant clearance of the virus within the same timeframe. Patients with high humoral responses at entry demonstrated low or no further increases; however, virus clearance followed the same trajectory as in patients with low antibody response at baseline. Together, the sequential immunological and virological analysis of this well-defined cohort of patients early in infection shows the presence of high levels of binding and neutralizing antibodies and potent clearance of the virus.

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Immune Responses to mRNA Vaccine

Exposito,

Monge,

Arruda

et al. 2024

Trends in mRNA Vaccine Research

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Systemic IL-15, IFN-γ, and IP-10/CXCL10 signature associated with effective immune response to SARS-CoV-2 in BNT162b2 mRNA vaccine recipients

Cited by 177 publications

References 84 publications

Long-term predictions of humoral immunity after two doses of BNT162b2 and mRNA-1273 vaccines based on dosage, age and sex

Long-term predictions of humoral immunity after two doses of BNT162b2 and mRNA-1273 vaccines based on dosage, age and sex

Kinetics of Nucleocapsid, Spike and Neutralizing Antibodies, and Viral Load in Patients with Severe COVID-19 Treated with Convalescent Plasma

Immune Responses to mRNA Vaccine

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