Woodworth Joshua S, Contreras Vanessa, Christensen Dennis, Naninck Thibaut, Kahlaoui Nidhal, Gallouët Anne-Sophie, Langlois Sébastien, Burban Emma, Joly Candie, Gros Wesley, Dereuddre-Bosquet Nathalie, Morin Julie, Olsen Ming Liu, Rosenkrands Ida, Stein Ann-Kathrin, Wood Grith Krøyer, Follmann Frank, Lindenstrøm Thomas, LeGrand Roger, Pedersen Gabriel Kristian, Mortensen Rasmus
Department of Infectious Disease Immunology, Statens Serum Institut; Artillerivej 5, 2300 Copenhagen, Denmark.
Université Paris-Saclay, Inserm, CEA, Immunologie des maladies virales, auto-immunes, hématologiques et bactériennes (IMVA-HB/IDMIT/UMR1184); 92265, Fontenay-aux-Roses & Kremlin Bicêtre, France.
bioRxiv. 2023 Feb 23:2023.02.23.529651. doi: 10.1101/2023.02.23.529651.
After clean drinking water, vaccination is the most impactful global health intervention. However, development of new vaccines against difficult-to-target diseases is hampered by the lack of diverse adjuvants for human use. Of particular interest, none of the currently available adjuvants induce Th17 cells. Here, we develop and test an improved liposomal adjuvant, termed CAF10b, that incorporates a TLR-9 agonist. In a head-to-head study in non-human primates (NHPs), immunization with antigen adjuvanted with CAF10b induced significantly increased antibody and cellular immune responses compared to previous CAF adjuvants, already in clinical trials. This was not seen in the mouse model, demonstrating that adjuvant effects can be highly species specific. Importantly, intramuscular immunization of NHPs with CAF10b induced robust Th17 responses that were observed in circulation half a year after vaccination. Furthermore, subsequent instillation of unadjuvanted antigen into the skin and lungs of these memory animals led to significant recall responses including transient local lung inflammation observed by Positron Emission Tomography-Computed Tomography (PET-CT), elevated antibody titers, and expanded systemic and local Th1 and Th17 responses, including >20% antigen-specific T cells in the bronchoalveolar lavage. Overall, CAF10b demonstrated an adjuvant able to drive true memory antibody, Th1 and Th17 vaccine-responses across rodent and primate species, supporting its translational potential.
除清洁饮用水外,疫苗接种是最具影响力的全球卫生干预措施。然而,针对难以攻克的疾病研发新型疫苗受到了缺乏适用于人类的多种佐剂的阻碍。特别值得关注的是,目前可用的佐剂均不能诱导Th17细胞。在此,我们研发并测试了一种改良的脂质体佐剂,称为CAF10b,它包含一种TLR-9激动剂。在一项针对非人类灵长类动物(NHP)的直接比较研究中,与已进入临床试验阶段的先前CAF佐剂相比,用CAF10b佐剂的抗原进行免疫接种可显著增强抗体和细胞免疫反应。在小鼠模型中未观察到这种情况,这表明佐剂效应可能具有高度的物种特异性。重要的是,用CAF10b对NHP进行肌肉注射免疫可诱导强烈的Th17反应,在接种疫苗半年后仍可在循环系统中观察到。此外,随后将无佐剂抗原滴注到这些记忆动物的皮肤和肺部会引发显著的回忆反应,包括通过正电子发射断层扫描-计算机断层扫描(PET-CT)观察到的短暂局部肺部炎症、抗体滴度升高以及全身和局部Th1及Th17反应增强,包括支气管肺泡灌洗中>20%的抗原特异性T细胞。总体而言,CAF10b证明是一种能够在啮齿动物和灵长类动物物种中驱动真正的记忆抗体、Th1和Th17疫苗反应的佐剂,支持其转化潜力。