Cd4 T Cell-Mediated Immunopathology Of A Staphylococcus Aureus Whole Cell Vaccine During Systemic Infection

Abstract Staphylococcus aureus causes a wide array of diseases, ranging from superficial skin infections to life threatening diseases like sepsis. Treatment is difficult due to emerging multidrug-resistant strains and importantly, several approaches to develop an efficacious vaccine have either failed or augmented disease in clinical trials. In the present study, gamma-irradiated S. aureus USA300 (IRS) was used as a whole-cell vaccine to evaluate the immune response towards vaccination and subsequent infection. C57BL/6 mice were vaccinated thrice intramuscularly, adjuvanted with or without Al(OH)3, at two-week intervals and challenged with USA300 intravenously 2 weeks after the last vaccination. Vaccination enhanced mortality and failed to control bacterial growth in blood and organs when compared to PBS controls and was worse without Al(OH)3. USA300-specific antibodies were induced by vaccination but did not cause enhanced mortality when tested in serum transfer studies. Furthermore, B cell deficient and WT mice were similarly susceptible to infection after vaccination. Infection increased frequency of CD44hiTbet+ and CD44hiIFNg+ (Th1 effector) cells in spleens of both vaccinated groups but was higher in mice vaccinated without Al(OH)3. Frequency of CD44hiRORgt+ and CD44hiIL-17+ (Th17 effector) cells increased only in groups vaccinated with Al(OH)3. Depletion of CD4 T cells during infection reversed the lethal phenotype. Similarly, neutralization of IFNg but not IL-17 during infection improved survival and reduced organ pathology. Taken together, our findings show a detrimental role for IFNg+CD4 Teff cells generated by vaccination with IRS, and might shed some light on recent vaccine failures.