Duncombe Caroline J, Sen Nilasha, Watson Felicia N, Poehlman Alen S, Layton Erik D, Boey Kenneth, Conrad Ethan N, Kalata Anya C, Seilie A Mariko, Dill-McFarland Kimberly A, Seshadri Chetan, Shears Melanie J, Murphy Sean C
Graduate Program in Pathobiology, Department of Global Health, University of Washington, Seattle, WA, 98195, USA.
Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA, 98195, USA.
Nat Commun. 2025 Jun 4;16(1):5172. doi: 10.1038/s41467-025-60193-7.
Attenuated whole organism vaccines targeting the malaria liver stage reliably confer sterile immunity. These vaccines completely protect female mice from infection, but protection in male mice remains unproven. We discover that male mice vaccinated with prime-and-trap, a whole organism-based vaccine strategy, exhibit poorer protection against Plasmodium sporozoite challenge than females. We investigate this sex difference, and identify vaccinated males have fewer hepatic memory CD8 T cells than females when scaling for liver biomass, and reduced inflammatory responses post-vaccination. Surgical hormone manipulation clarifies that the presence of testicular hormones hinders protection in male mice. The presence of androgens does not affect memory CD8 T cell quantity nor quality, but reduces recruitment of CD8 T cells in male liver tissues via a restricted inflammatory response. Here, we show both males and females form functional memory responses following prime-and-trap vaccination, but the presence of androgens during sporozoite challenge impair protection in male mice.
针对疟疾肝脏期的减毒全生物体疫苗能可靠地赋予无菌免疫力。这些疫苗能完全保护雌性小鼠免受感染，但对雄性小鼠的保护作用尚未得到证实。我们发现，接种初免-捕获（一种基于全生物体的疫苗策略）的雄性小鼠，在抵御疟原虫子孢子攻击方面的保护作用比雌性小鼠差。我们研究了这种性别差异，发现按肝脏生物量进行换算时，接种疫苗的雄性小鼠的肝脏记忆性CD8 T细胞比雌性小鼠少，且接种疫苗后的炎症反应减弱。手术激素处理表明，睾丸激素的存在会阻碍雄性小鼠的保护作用。雄激素的存在不影响记忆性CD8 T细胞的数量和质量，但会通过限制炎症反应减少雄性肝脏组织中CD8 T细胞的募集。在此，我们表明，雄性和雌性在接种初免-捕获疫苗后均形成功能性记忆反应，但在子孢子攻击期间雄激素的存在会损害雄性小鼠的保护作用。
