Yanik Sean, Venkatesh Varsha, Gordy James T, Gabriel-Alameh Mohamad, Meza Jacob, Li Yangchen, Glass Elizabeth, Flores-Garcia Yevel, Tam Ying, Chaiyawong Nattawat, Sarkar Deepti, Weissman Drew, Markham Richard, Srinivasan Prakash
Department of Molecular Microbiology and Immunology, Johns Hopkins School of Public Health, Baltimore, MD, 21205, USA.
The Johns Hopkins Malaria Research Institute, Baltimore, MD, 21205, USA.
Res Sq. 2024 Jul 9:rs.3.rs-4656309. doi: 10.21203/rs.3.rs-4656309/v1.
Resurgence in malaria has been noted in 2022 with 249 million clinical cases resulting in 608,000 deaths, mostly in children under five. Two vaccines, RTS, S, and more recently R21, targeting the circumsporozoite protein (CSP) are recommended by the WHO but are not yet widely available. Strong humoral responses to neutralize sporozoites before they can infect the hepatocytes are important for vaccine-mediated protection. Suboptimal protection conferred by these first-generation vaccines highlight the need for approaches to improve vaccine-induced immune responses. With the recent success of mRNA-LNP vaccines against COVID-19, there is growing interest in leveraging this approach to enhance malaria vaccines. Here, we present the development of a novel chemokine fusion mRNA vaccine aimed at boosting immune responses to PfCSP by targeting the immunogen to immature dendritic cells (iDC). Vaccination of mice with mRNA encoding full-length CSP fused to macrophage inflammatory protein 3 alpha (MIP3α) encapsulated within lipid nanoparticles (LNP) elicited robust CD4+ T cell responses and enhanced antibody titers against NANP repeat epitopes compared to a conventional CSP mRNA-LNP vaccine. Importantly, the CSP-MIP3α fusion vaccine provided significantly greater protection against liver infection upon challenge with PfCSP transgenic sporozoites. This enhanced protection was associated with multifunctional CD4+ T cells levels and anti-NANP repeat titers. This study highlights the potential to augment immune responses to PfCSP through iDC targeting and bolster protection against malaria liver infection.
2022年疟疾出现了卷土重来的情况，临床病例达2.49亿例，导致60.8万人死亡，其中大多数是五岁以下儿童。世界卫生组织推荐了两种针对环子孢子蛋白（CSP）的疫苗，即RTS,S和最近的R21，但尚未广泛供应。在子孢子感染肝细胞之前对其进行中和的强烈体液反应对于疫苗介导的保护作用很重要。这些第一代疫苗提供的保护效果欠佳，凸显了改进疫苗诱导免疫反应方法的必要性。随着mRNA-LNP疫苗在抗击新冠病毒方面最近取得成功，利用这种方法增强疟疾疫苗的兴趣与日俱增。在此，我们展示了一种新型趋化因子融合mRNA疫苗的研发情况，该疫苗旨在通过将免疫原靶向未成熟树突状细胞（iDC）来增强对恶性疟原虫CSP的免疫反应。与传统的CSP mRNA-LNP疫苗相比，用编码与巨噬细胞炎性蛋白3α（MIP3α）融合的全长CSP的mRNA进行小鼠疫苗接种，脂质纳米颗粒（LNP）包裹，引发了强烈的CD4+T细胞反应，并提高了针对NANP重复表位的抗体滴度。重要的是，CSP-MIP3α融合疫苗在用恶性疟原虫CSP转基因子孢子攻击后，对肝脏感染提供了显著更强的保护。这种增强的保护作用与多功能CD4+T细胞水平和抗NANP重复滴度相关。这项研究凸显了通过靶向iDC增强对恶性疟原虫CSP的免疫反应以及加强对疟疾肝脏感染保护的潜力。
