Institute for Immunity, Transplantation and Infection, School of Medicine, Stanford University, Stanford, CA 94305, USA.
Center for Human Systems Immunology, Department of Surgery, Duke University, Durham, NC 27701, USA.
Sci Transl Med. 2024 Jul 31;16(758):eadn6605. doi: 10.1126/scitranslmed.adn6605.
Authorization of the Matrix-M (MM)-adjuvanted R21 vaccine by three countries and its subsequent endorsement by the World Health Organization for malaria prevention in children are a milestone in the fight against malaria. Yet, our understanding of the innate and adaptive immune responses elicited by this vaccine remains limited. Here, we compared three clinically relevant adjuvants [3M-052 + aluminum hydroxide (Alum) (3M), a TLR7/8 agonist formulated in Alum; GLA-LSQ, a TLR4 agonist formulated in liposomes with QS-21; and MM, the now-approved adjuvant for R21] for their capacity to induce durable immune responses to R21 in macaques. R21 adjuvanted with 3M on a 0, 8, and 23-week schedule elicited anti-circumsporozoite antibody responses comparable in magnitude to the R21/MM vaccine administered using a 0-4-8-week regimen and persisted up to 72 weeks with a half-life of 337 days. A booster dose at 72 weeks induced a recall response similar to the R21/MM vaccination. In contrast, R21/GLA-LSQ immunization induced a lower, short-lived response at the dose used. Consistent with the durable serum antibody responses, MM and 3M induced long-lived plasma cells in the bone marrow and other tissues, including the spleen. Furthermore, whereas 3M stimulated potent and persistent antiviral transcriptional and cytokine signatures after primary and booster immunizations, MM induced enhanced expression of interferon- and T2-related signatures more highly after the booster vaccination. Collectively, these findings provide a resource on the immune responses of three clinically relevant adjuvants with R21 and highlight the promise of 3M as another adjuvant for malarial vaccines.
三个国家批准了 Matrix-M（MM）佐剂 R21 疫苗，世界卫生组织随后也将其用于儿童疟疾预防，这是抗击疟疾的一个里程碑。然而，我们对该疫苗引起的固有和适应性免疫反应的理解仍然有限。在这里，我们比较了三种临床相关的佐剂[3M-052+氢氧化铝（Alum）（3M），一种在 Alum 中配制的 TLR7/8 激动剂；GLA-LSQ，一种在含有 QS-21 的脂质体中配制的 TLR4 激动剂；以及现在批准用于 R21 的 MM]，以了解它们诱导恒河猴对 R21 产生持久免疫反应的能力。按照 0、8 和 23 周的时间表，用 3M 佐剂的 R21 引发的抗环子孢子蛋白抗体反应与 0-4-8 周方案的 R21/MM 疫苗相当，持续至 72 周，半衰期为 337 天。72 周时进行加强免疫可引起类似于 R21/MM 接种的回忆反应。相比之下，在使用的剂量下，R21/GLA-LSQ 免疫诱导出较低、短暂的反应。与持久的血清抗体反应一致，MM 和 3M 在骨髓和其他组织中诱导了长寿的浆细胞，包括脾脏。此外，3M 在初次和加强免疫后刺激强烈且持久的抗病毒转录和细胞因子特征，而 MM 在加强免疫后诱导干扰素和 T2 相关特征的表达增强更为显著。总的来说，这些发现为 R21 与三种临床相关佐剂的免疫反应提供了资源，并突出了 3M 作为疟疾疫苗另一种佐剂的潜力。
