González-Domínguez Irene, Puente-Massaguer Eduard, Abdeljawad Adam, Lai Tsoi Ying, Liu Yonghong, Loganathan Madhumathi, Francis Benjamin, Lemus Nicholas, Dolange Victoria, Boza Marta, Slamanig Stefan, Martínez-Guevara Jose Luis, Krammer Florian, Palese Peter, Sun Weina
Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
Center for Vaccine Research and Pandemic Preparedness (C-VaRPP), Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
NPJ Vaccines. 2024 Nov 17;9(1):222. doi: 10.1038/s41541-024-01014-8.
We have developed a new universal influenza B vaccination strategy based on inactivated influenza B viruses displaying mosaic hemagglutinins (mHAs). Recombinant mHA viruses were constructed by replacing the four major antigenic sites of influenza B virus HAs, with those from exotic avian influenza A virus HAs. Sequential vaccination of naïve mice with mHA-based vaccines elicited higher immune responses towards the immuno-subdominant conserved epitopes of the HA than vaccination with wildtype viruses. Among the different preparations tested, mHA split vaccines were less immunogenic than their whole inactivated virus counterparts. This lower immunogenicity was overcome by the combination with adjuvants. mHA split vaccines adjuvanted with a Toll-like receptor-9 agonist (CpG 1018) increased Th1 immunity and in vivo cross-protection, whereas adjuvanting with an MF59-like oil-in-water nano-emulsion (AddaVax) enhanced and broadened humoral immune responses and antibody-mediated cross-protection. The mHA vaccines with or without adjuvant were subsequently evaluated in mice that were previously immunized to closely mimic human pre-existing immunity to influenza B viruses and the contribution of innate and cellular immunity was evaluated in this model. We believe these preclinical studies using the mHA strategy represent a major step toward the evaluation of a universal influenza B virus vaccine in clinical trials.
我们基于展示镶嵌血凝素（mHA）的灭活乙型流感病毒，开发了一种新的通用乙型流感疫苗接种策略。通过用外来甲型禽流感病毒血凝素的四个主要抗原位点替换乙型流感病毒血凝素的四个主要抗原位点，构建了重组mHA病毒。用基于mHA的疫苗对未免疫小鼠进行序贯接种，与用野生型病毒接种相比，引发了针对血凝素免疫亚优势保守表位的更高免疫反应。在测试的不同制剂中，mHA裂解疫苗的免疫原性低于其全灭活病毒对应物。通过与佐剂联合使用克服了这种较低的免疫原性。用Toll样受体9激动剂（CpG 1018）佐剂的mHA裂解疫苗增强了Th1免疫和体内交叉保护，而用MF59样水包油纳米乳剂（AddaVax）佐剂增强并拓宽了体液免疫反应和抗体介导的交叉保护。随后在先前免疫过的小鼠中评估了有或没有佐剂的mHA疫苗，以密切模拟人类对乙型流感病毒的预先存在的免疫力，并在该模型中评估了先天免疫和细胞免疫的作用。我们相信，使用mHA策略的这些临床前研究代表了朝着在临床试验中评估通用乙型流感病毒疫苗迈出的重要一步。
