Introduction: An increase in epizootic activity has been registered in a number of plague foci in the Russian Federation over the past few years. As part of securing sanitary and epidemiologic wellbeing of the population living in the natural foci of the disease, a mass immunization with a live plague vaccine based of the Yersinia pestis EV line NIIEG vaccine strain was carried out. Objectives: The purpose of the study was to assess the influence of a complex of factors including age, gender, health status, the number of previous vaccinations against plague, blood groups, and HLA gene polymorphism on the state of the cellular and humoral immune response in people vaccinated with the live plague vaccine. Materials and methods: The analysis of venous blood of 347 volunteers included determination of the concentration of specific antibodies to the capsular antigen (F1) of plague microbe, spontaneous and induced production of marker cytokines (IFN-γ, TNF-α, and IL-4) by ELISA, and genes of the main histocompatibility complex (HLA) class II by real-time PCR. We also analyzed medical documentation (Form 025/u) and the results of a questionnaire-based survey of the vaccinated people. Results and discussion: We established the influence of various factors, including genetic ones, on marker indicators of the humoral and cellular immune response in persons vaccinated with the live plague vaccine. We also characterized the relationship between the level of specific antibodies to plague microbe F1 production and some cytokines and the age and the number of previous vaccinations in our volunteers. The most common gene variants of the main histocompatibility complex of class II (HLA-DQA1, HLA-DQB1 and HLA-DRB1) in the cohort were identified and possible relationships between the production of IFN-γ, TNF-α, IL-4 and allelic polymorphism of HLA class II genes were determined. Conclusions: Immunologic reactivity in people vaccinated with the live plague vaccine is mainly determined by age, the number of previous vaccinations against this infection, and individual characteristics of HLA gene polymorphism.