de Menezes Maria N, Ge Zhengyu, Cozijnsen Anton, Gras Stephanie, Bertolino Patrick, Caminschi Irina, Lahoud Mireille H, Yui Katsuyuki, McFadden Geoffrey I, Beattie Lynette, Heath William R, Fernandez-Ruiz Daniel
Department of Microbiology and Immunology, The Doherty Institute for Infection and Immunity, The University of Melbourne, Melbourne, Victoria, Australia.
School of BioSciences, University of Melbourne, Parkville, Victoria, Australia.
PLoS Pathog. 2025 May 27;21(5):e1012731. doi: 10.1371/journal.ppat.1012731. eCollection 2025 May.
Vaccination with radiation-attenuated sporozoites (RAS) can provide highly effective protection against malaria in both humans and mice. To extend understanding of malaria immunity and inform the development of future vaccines, we studied the protective response elicited by this vaccine in C57BL/6 mice. We reveal that successive doses of Plasmodium berghei RAS favour the generation of liver CD8+ tissue-resident memory T cells (TRM cells) over circulating memory cells and markedly enhance their longevity. Importantly, RAS immunisation strongly skews the composition of the liver CD8+ TRM compartment towards cells specific for abundant sporozoite antigens, such as thrombospondin-related anonymous protein (TRAP) and circumsporozoite protein (CSP), which become major mediators of protection. The increased prevalence of sporozoite specificities is associated with limited intrahepatic attenuated parasite development and inhibition of naïve T cell responses to all parasite antigens, whether formerly encountered or not, in previously vaccinated mice. This leads to the exclusive expansion of effector T cells formed upon initial immunisation, ultimately reducing the diversity of the liver TRM pool later established. However, stronger responses to less abundant epitopes can be achieved with higher initial doses of RAS. These findings provide novel insights into the mechanisms governing malaria immunity induced by attenuated sporozoite vaccination and highlight the susceptibility of this vaccine to limitations imposed by strain-specific immunity associated with the abundant, yet highly variable sporozoite antigens CSP and TRAP.
用辐射减毒子孢子（RAS）进行疫苗接种可在人类和小鼠中提供针对疟疾的高效保护。为了扩展对疟疾免疫的理解并为未来疫苗的开发提供信息，我们研究了该疫苗在C57BL/6小鼠中引发的保护性反应。我们发现，连续剂量的伯氏疟原虫RAS相较于循环记忆细胞，更有利于肝脏CD8+组织驻留记忆T细胞（TRM细胞）的产生，并显著延长其寿命。重要的是，RAS免疫强烈地使肝脏CD8+ TRM区室的组成偏向于针对丰富子孢子抗原的细胞，如血小板反应蛋白相关无名蛋白（TRAP）和环子孢子蛋白（CSP），这些抗原成为主要的保护介质。子孢子特异性的增加与肝内减毒寄生虫发育受限以及在先前接种疫苗的小鼠中对所有寄生虫抗原（无论先前是否遇到）的幼稚T细胞反应受到抑制有关。这导致初次免疫时形成的效应T细胞的独家扩增，最终减少了后来建立的肝脏TRM库的多样性。然而，使用更高初始剂量的RAS可以实现对较少丰富表位的更强反应。这些发现为减毒子孢子疫苗接种诱导的疟疾免疫机制提供了新的见解，并突出了该疫苗对与丰富但高度可变的子孢子抗原CSP和TRAP相关的菌株特异性免疫所施加限制的敏感性。
