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Analyzing cellular immunogenicity in vaccine clinical trials: a new statistical method including non-specific responses for accurate estimation of vaccine effect

Abstract : Evaluation of immunogenicity is a key step in the clinical development of novel vaccines. T-cell responses to vaccine candidates are typically assessed by intracellular cytokine staining (ICS) using multiparametric flow cytometry. A conventional statistical approach to analyze ICS data is to compare, between vaccine regimens or between baseline and post-vaccination of the same regimen depending on the trial design, the percentages of cells producing a cytokine of interest after ex vivo stimulation of peripheral blood mononuclear cells (PBMC) with vaccine antigens, after subtracting the non-specific response (of unstimulated cells) of each sample. Subtraction of the non-specific response is aimed at capturing the specific response to the antigen, but raises methodological issues related to measurement error and statistical power. We describe here a new statistical approach to analyze ICS data from vaccine trials. We propose a bivariate linear regression model for estimating the non-specific and antigen-specific ICS responses. We benchmarked the performance of the model in terms of both bias and control of type-I and -II errors in comparison with conventional approaches, and applied it to simulated data as well as real pre- and post-vaccination data from two recent HIV vaccine trials (ANRS VRI01 in healthy volunteers and therapeutic VRI02 ANRS 149 LIGHT in HIV-infected participants). The model was as good as the conventional approaches (with or without subtraction of the non-specific response) in all simulation scenarios in terms of statistical performance, whereas the conventional approaches did not provide robust results across all scenarios. The proposed model estimated the T-cell responses to the antigens without any effect of the non-specific response on the specific response, irrespective of the correlation between the non-specific and specific responses. This novel method of analyzing T-cell immunogenicity data based on bivariate modeling is more flexible than conventional methods, and so yields more detailed results and enables accurate interpretation of vaccine-induced response.
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Submitted on : Monday, March 8, 2021 - 10:53:50 AM
Last modification on : Thursday, April 8, 2021 - 3:56:02 PM

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Édouard Lhomme, Boris P. Hejblum, C. Lacabaratz, A. Wiedemann, J. D. Lelievre, et al.. Analyzing cellular immunogenicity in vaccine clinical trials: a new statistical method including non-specific responses for accurate estimation of vaccine effect. Journal of Immunological Methods, Elsevier, 2020, 477, pp.112711. ⟨10.1016/j.jim.2019.112711⟩. ⟨hal-03161945v1⟩

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