PROJECT SUMMARY Influenza virus is a significant pathogen in adult solid organ transplant (SOT) recipients. However, these individuals respond poorly to standard-dose (SD) inactivated influenza vaccine (IIV). Recent studies have investigated two strategies to overcome poor immune responses in SOT recipients: (1) administration of high- dose (HD)-IIV compared to SD-IIV and (2) two doses of SD-IIV compared to one dose of SD-IIV in the same influenza season. The first study compared HD-IIV vs.SD-IIV in adult SOT recipients and noted that HD-IIV was safe and reported higher immunogenicity; however, the median post-transplant period was 38 months. In another phase II trial of adult SOT recipients, two doses of SD-IIV a month apart compared to one-dose of SD- IIV revealed increased immunogenicity, with a median post-transplant period of 18 months. Therefore, these studies lack evaluation in the early post-transplant period in this vulnerable population. Additionally, the administration of two-doses of HD-IIV in the same influenza season has not been evaluated in SOT recipients. Thus, the optimal immunization strategy for SOT recipients less than 12 months post-transplant is unknown. In addition, the immunologic predictors and correlates of influenza vaccine immunogenicity in SOT recipients have not been well-defined. The central hypothesis of our proposal is that adult SOT recipients that are 1-11 months out from transplant and are receiving two doses of HD-IIV will have higher hemagglutination inhibition geometric mean titers (GMT) to influenza A antigens compared to adult SOT recipients receiving two doses of SD-IIV over one influenza season. To test this hypothesis and address the critical knowledge gaps outlined above, we propose to conduct a phase II, multi-center, randomized-controlled immunogenicity and safety trial comparing either one dose of HD-IIV, two doses of SD- IIV, or two doses of HD-IIV in adult kidney, heart, and/or liver SOT recipients 1-11 months post-transplant. The results of this study will address significant knowledge gaps regarding influenza vaccine strategies and immune responses in adult SOT recipients and will guide vaccine recommendations in the early post- transplant period.