Lirussi Darío, Weissmann Sebastian Felix, Ebensen Thomas, Nitsche-Gloy Ursula, Franz Heiko B G, Guzmán Carlos A
Department of Vaccinology and Applied Microbiology, Helmholtz Centre for Infection Research, Inhoffenstrasse 7, 38124 Braunschweig, Germany.
Women's Clinic, Hospital Marienstift GmbH, Helmstedter Strasse 35, 38102 Braunschweig, Germany.
Pharmaceutics. 2021 Feb 1;13(2):188. doi: 10.3390/pharmaceutics13020188.
Underdeveloped immunity during the neonatal age makes this period one of the most dangerous during the human lifespan, with infection-related mortality being one of the highest of all age groups. It is also discussed that vaccination during this time window may result in tolerance rather than in productive immunity, thus raising concerns about the overall vaccine-mediated protective efficacy. Cyclic di-nucleotides (CDN) are bacterial second messengers that are rapidly sensed by the immune system as a danger signal, allowing the utilization of these molecules as potent activators of the immune response. We have previously shown that cyclic di-adenosine monophosphate (CDA) is a potent and versatile adjuvant capable of promoting humoral and cellular immunity. We characterize here the cytokine profiles elicited by CDA in neonatal cord blood in comparison with other promising neonatal adjuvants, such as the imidazoquinoline resiquimod (R848), which is a synthetic dual TLR7 and TLR8 agonist. We observed superior activity of CDA in eliciting T helper 1 (Th1) and T follicular helper (TfH) cytokines in cells from human cord blood when compared to R848. Additional in vivo studies in mice showed that neonatal priming in a three-dose vaccination schedule is beneficial when CDA is used as a vaccine adjuvant. Humoral antibody titers were significantly higher in mice that received a neonatal prime as compared to those that did not. This effect was absent when using other adjuvants that were reported as suitable for neonatal vaccination. The biological significance of this immune response was assessed by a challenge with a genetically modified influenza H1N1 PR8 virus. The obtained results confirmed that CDA performed better than any other adjuvant tested. Altogether, our results suggest that CDA is a potent adjuvant in vitro on human cord blood, and in vivo in newborn mice, and thus a suitable candidate for the development of neonatal vaccines.
新生儿期免疫力发育不全，使这一时期成为人类生命中最危险的时期之一，与感染相关的死亡率在所有年龄组中位居前列。也有人讨论过，在此时间窗内接种疫苗可能导致免疫耐受而非产生有效的免疫力，从而引发对疫苗介导的总体保护效力的担忧。环二核苷酸（CDN）是细菌的第二信使，可被免疫系统迅速识别为危险信号，从而使这些分子能够用作免疫反应的有效激活剂。我们之前已经表明，环二磷酸腺苷（CDA）是一种强大且多功能的佐剂，能够促进体液免疫和细胞免疫。在此，我们将CDA与其他有前景的新生儿佐剂（如咪唑喹啉类的瑞喹莫德（R848），它是一种合成的TLR7和TLR8双重激动剂）进行比较，表征CDA在新生儿脐带血中引发的细胞因子谱。我们观察到，与R848相比，CDA在诱导人脐带血细胞中的辅助性T细胞1（Th1）和滤泡辅助性T细胞（TfH）细胞因子方面具有更强的活性。在小鼠中进行的额外体内研究表明，当将CDA用作疫苗佐剂时，按三剂接种程序进行新生儿初次免疫是有益的。与未接受新生儿初次免疫的小鼠相比，接受新生儿初次免疫的小鼠体内的体液抗体滴度显著更高。使用其他据报道适用于新生儿疫苗接种的佐剂时则没有这种效果。通过用基因改造的甲型H1N1流感PR8病毒进行攻毒来评估这种免疫反应的生物学意义。所得结果证实，CDA的表现优于所测试的任何其他佐剂。总之，我们的结果表明，CDA在体外对人脐带血以及在新生小鼠体内均是一种有效的佐剂，因此是开发新生儿疫苗的合适候选物。
