The Protective Effect of IL-17A in Pneumonic Plague Can Be Compensated by Effective Vaccines and Immunization Strategies in Mice

Plague, caused by <i>Yersinia pestis</i>, poses a public health threat not only due to sporadic outbreaks across the globe but also due to its potential as a biothreat agent. Ironically, among the seven deadliest pandemics in global history, three were caused by <i>Y. pestis</i>. Pneumonic plague, the more contagious and severe form of the disease, is difficult to contain, requiring either prophylactic antibiotic treatment or vaccination. However, no vaccine (live attenuated or subunit) is currently approved by the Food and Drug Administration, requiring rigorous preclinical studies in different animal models, thus forming the basis of this study. <b>Objectives</b>: The aim of this study was to evaluate the efficacy and immune responses of two live attenuated vaccines (LAVs), LMA and LMP, either alone or in combination with a trivalent adenoviral vector-based vaccine (Ad5-YFV), in IL-17A-depleted and IgG control mice by using an anti-IL-17A monoclonal antibody (mAb) or its matched isotype IgG, respectively. <b>Methods</b>: IL-17A mAb or IgG isotype control was administered to mice twice per week to their respective groups during the course of immunization. Serum, spleens, and broncho-alveolar lavage fluid (BALF) were collected for assessing immunological responses, and another cohort of mice was intranasally challenged with a lethal dose of parental <i>Y. pestis</i> CO92. <b>Results</b>: Robust humoral and cellular immune responses followed by complete protection were observed in all vaccinated animals against highly lethal intranasal challenge doses of parental <i>Y. pestis</i> CO92. Serum IgG titers to YscF and overall mucosal IgA titers to all three antigens of the Ad5-YFV vaccine were significantly lower, with slightly reduced serum LcrV-neutralizing antibodies when IL-17A was depleted compared to IgG control animals during the course of immunization. A remarkable reduction in Th1 (IFNγ or IL-2) and Th17 cell populations was observed in IL-17A-depleted mice compared to IgG controls in response to vaccination. On the other hand, B cell activities in germinal centers, overall activated antigen-specific T cells, and memory B and T cells remained at comparable levels in both vaccinated IL-17A-depleted and IgG control mice. <b>Conclusions</b>: These data demonstrated the effectiveness of our vaccines even under the reduced levels of both Th1 and Th17 responses and thus should be suitable for those individuals associated with certain immune deficiencies.