Department Of Virology, Institute Of Experimental Medicine, Saint Petersburg, Russia.
Expert Rev Vaccines. 2021 Sep;20(9):1097-1112. doi: 10.1080/14760584.2021.1964961. Epub 2021 Aug 17.
The licensed seasonal influenza vaccines predominantly induce neutralizing antibodies against immunodominant hypervariable epitopes of viral surface proteins, with limited protection against antigenically distant influenza viruses. Strategies have been developed to improve vaccines' performance in terms of broadly reactive and long-lasting immune response induction.
We have summarized the advancements in the development of cross-protective influenza vaccines and discussed the challenges in evaluating them in preclinical and clinical trials. Here, the literature regarding the current stage of development of universal influenza vaccine candidates was reviewed.
Although various strategies aim to redirect adaptive immune responses from variable immunodominant to immunosubdominant antigens, more conserved epitopes are being investigated. Approaches that improve antibody responses to conserved B cell epitopes have increased the protective efficacy of vaccines within a subtype or phylogenetic group of influenza viruses. Vaccines that elicit significant levels of T cells recognizing highly conserved viral epitopes possess a high cross-protective potential and may cover most circulating influenza viruses. However, the development of T cell-based universal influenza vaccines is challenging owing to the diversity of MHCs in the population, unpredictable degree of immunodominance, lack of adequate animal models, and difficulty in establishing T cell immunity in humans.
cHA: chimeric HA; HBc: hepatitis B virus core protein; HA: hemagglutinin; HLA: human leucocyte antigen; IIV: inactivated influenza vaccine; KLH: keyhole limpet hemocyanin; LAH: long alpha helix; LAIV: live attenuated influenza vaccine; M2e: extracellular domain of matrix 2 protein; MHC: major histocompatibility complex; mRNA: messenger ribonucleic acid; NA: neuraminidase; NS1: non-structural protein 1; qNIV: quadrivalent nanoparticle influenza vaccine; T: tissue-resident memory T cells; VE: vaccine effectiveness; VLP: virus-like particles; VSV: vesicular stomatitis virus.
已获许可的季节性流感疫苗主要诱导针对病毒表面蛋白免疫优势超变表位的中和抗体，对抗原差异较大的流感病毒的保护作用有限。为了提高疫苗产生广泛反应和持久免疫应答的能力，已经开发了各种策略。
我们总结了开发具有交叉保护作用的流感疫苗的进展，并讨论了在临床前和临床试验中评估这些疫苗所面临的挑战。在此，我们回顾了通用流感疫苗候选物当前开发阶段的相关文献。
虽然各种策略旨在将适应性免疫反应从可变免疫优势转向免疫亚优势抗原，但人们仍在研究更保守的表位。提高针对保守 B 细胞表位的抗体反应的方法提高了疫苗在流感病毒亚型或系统发生群内的保护效力。能够诱导大量识别高度保守病毒表位的 T 细胞的疫苗具有很高的交叉保护潜力，可能覆盖大多数流行的流感病毒。然而，由于人群中 MHC 的多样性、免疫优势的不可预测程度、缺乏足够的动物模型以及难以在人体中建立 T 细胞免疫，开发基于 T 细胞的通用流感疫苗具有挑战性。
cHA：嵌合 HA；HBc：乙型肝炎病毒核心蛋白；HA：血凝素；HLA：人类白细胞抗原；IIV：灭活流感疫苗；KLH：血蓝蛋白；LAH：长α螺旋；LAIV：减毒活流感疫苗；M2e：基质 2 蛋白的细胞外结构域；MHC：主要组织相容性复合体；mRNA：信使核糖核酸；NA：神经氨酸酶；NS1：非结构蛋白 1；qNIV：四价纳米颗粒流感疫苗；T：组织驻留记忆 T 细胞；VE：疫苗效力；VLP：病毒样颗粒；VSV：水疱性口炎病毒。
