Identifying correlates of protection from <i>Yersinia pestis</i> on a mouse model and assessing an opportunity for their use as markers of human vaccination efficiency

Abstract

In conditions when the assessment of changes in the incidence rate cannot be used as an indicator of the effectiveness of a live plague vaccine, there is a real need to search for other, in particular, immunological correlates of the vaccine's protection. Modern concepts of the patho- and immunogenesis of plague make it possible to narrow the search for possible correlates of protection, focusing on the assessment of cellular factors of the immune response. The aim of this work is to identify the immunological correlates of protection against plague in mice immunized with Yersinia pestis EV NIIEG, and to assess the dynamics of selected markers of immunological effectiveness of vaccination in people vaccinated against plague. Experimental model - BALB / c mice, 40 individuals in each group were immunized with Y. pestis EV at doses of 2 × 102, 1 × 103, 5 × 103, 2.5 × 104 CFU, and on the 21st day they were infected with Y. pestis 231 at a dose of 400 LD50. Control group - intact animals. Immunogenicity was determined by ImD50 and calculated by the Kerber method. Volunteers - 20 people who were first vaccinated with the live plague vaccine and 20 people who were not vaccinated against the plague (comparison group). The production of cytokines in the blood was determined on an enzyme-linked immunosorbent analyzer "LAZURIT" (Dynex Technologies, USA): in mice before infection with Y. pestis 231 on the 14th and 21st days after vaccination; in humans - before vaccination, 1, 6 and 12 months after vaccination. We used commercial kits in accordance with the instructions for their use. The immunized mice showed a significant increase (2.2 times) in the induced IFN-γ production and a moderate increase in the concentration of TNF-α, IL-10 and IL-17A on the 14th day of immunogenesis. A high correlation was found between the survival rate of animals and the level of antigen- / mitogen-induced production of IFN-γ (r = 0.94, p = 0.039), both on the 14th and 21st days, as well as a noticeable relationship with the level of production of IL-10 and IL-17A on the 14th day of immunogenesis. In volunteers one month after inoculation, an increase in the indicators of mitogen-induced production of all detectable cytokines was noted, but the levels of IFN-γ, TNF-α, IL-10, IL-17A significantly increased by the 6th month of observation (p &lt;0.05), although only for IFN-γ and IL-17A, the induced production of these cytokines remained at a sufficiently high level up to a year after inoculation. Thus, IFN-γ and IL-17A can be considered as possible informative correlates of protection of mice from Y. pestis on days 14 and 21, considering the increase in the induced production of these cytokines as adequate markers of the protective efficacy of immunization, and the assessment of the dynamics of these parameters in volunteers vaccinated with the plague live vaccine, an increase in the levels of IFN-γ and IL-17A can be considered a favorable prognostic marker of the immunological efficacy of the vaccine in the period from the 6th to the 12th month of observation.