The Jenner Institute Laboratories, University of Oxford, Old Road Campus Research Building, Oxford OX3 7DQ, UK.
Sci Rep. 2017 Apr 19;7:46621. doi: 10.1038/srep46621.
The leading malaria vaccine in development is the circumsporozoite protein (CSP)-based particle vaccine, RTS,S, which targets the pre-erythrocytic stage of Plasmodium falciparum infection. It induces modest levels of protective efficacy, thought to be mediated primarily by CSP-specific antibodies. We aimed to enhance vaccine efficacy by generating a more immunogenic CSP-based particle vaccine and therefore developed a next-generation RTS,S-like vaccine, called R21. The major improvement is that in contrast to RTS,S, R21 particles are formed from a single CSP-hepatitis B surface antigen (HBsAg) fusion protein, and this leads to a vaccine composed of a much higher proportion of CSP than in RTS,S. We demonstrate that in BALB/c mice R21 is immunogenic at very low doses and when administered with the adjuvants Abisco-100 and Matrix-M it elicits sterile protection against transgenic sporozoite challenge. Concurrent induction of potent cellular and humoral immune responses was also achieved by combining R21 with TRAP-based viral vectors and protective efficacy was significantly enhanced. In addition, in contrast to RTS,S, only a minimal antibody response to the HBsAg carrier was induced. These studies identify an anti-sporozoite vaccine component that may improve upon the current leading malaria vaccine RTS,S. R21 is now under evaluation in Phase 1/2a clinical trials.
正在开发的领先疟疾疫苗是基于环子孢子蛋白（CSP）的颗粒疫苗 RTS,S，该疫苗针对恶性疟原虫感染的红细胞前阶段。它诱导适度水平的保护效力，被认为主要由 CSP 特异性抗体介导。我们旨在通过生成更具免疫原性的基于 CSP 的颗粒疫苗来提高疫苗效力，因此开发了一种新一代的 RTS,S 样疫苗，称为 R21。主要的改进是，与 RTS,S 相比，R21 颗粒由单个 CSP-乙型肝炎表面抗原（HBsAg）融合蛋白形成，这导致疫苗中 CSP 的比例比 RTS,S 高得多。我们证明，在 BALB/c 小鼠中，R21 在非常低的剂量下具有免疫原性，并且当与佐剂 Abisco-100 和 Matrix-M 一起给药时，它可以针对转基因子孢子挑战产生无菌保护。通过将 R21 与基于 TRAP 的病毒载体结合使用，还可以同时诱导出强大的细胞和体液免疫反应，并显著增强了保护效力。此外，与 RTS,S 不同，仅诱导出对 HBsAg 载体的最小抗体反应。这些研究确定了一种抗子孢子疫苗成分，该成分可能优于目前领先的疟疾疫苗 RTS,S。R21 目前正在进行 1/2a 期临床试验评估。
