Section for Molecular Biology and Immunology, Helminth-Immunology Group, Bernhard Nocht Institute for Tropical Medicine, Hamburg, Germany.
Research Department for Viral Zoonoses - One Health, Leibniz Institute for Experimental Virology Heinrich Pette Institute (HPI), Hamburg, Germany.
Front Immunol. 2021 Dec 21;12:784141. doi: 10.3389/fimmu.2021.784141. eCollection 2021.
Helminths still infect a quarter of the human population. They manage to establish chronic infections by downmodulating the immune system of their hosts. Consequently, the immune response of helminth-infected individuals to vaccinations may be impaired as well. Here we study the impact of helminth-induced immunomodulation on vaccination efficacy in the mouse system. We have previously shown that an underlying infection reduced the antibody (Ab) response to anti-influenza vaccination in the context of a systemic expansion of type 1 regulatory T cells (Tr1). Most important, vaccine-induced protection from a challenge infection with the 2009 pandemic H1N1 influenza A virus (2009 pH1N1) was impaired in vaccinated, infected mice. Here, we aim at the restoration of vaccination efficacy by drug-induced deworming. Treatment of mice with Flubendazole (FBZ) resulted in elimination of viable parasites in the thoracic cavity after two weeks. Simultaneous FBZ-treatment and vaccination did not restore Ab responses or protection in infected mice. Likewise, FBZ-treatment two weeks prior to vaccination did not significantly elevate the influenza-specific Ig response and did not protect mice from a challenge infection with 2009 pH1N1. Analysis of the regulatory T cell compartment revealed that infected and FBZ-treated mice still displayed expanded Tr1 cell populations that may contribute to the sustained suppression of vaccination responses in successfully dewormed mice. To outcompete this sustained immunomodulation in formerly helminth-infected mice, we finally combined the drug-induced deworming with an improved vaccination regimen. Two injections with the non-adjuvanted anti-influenza vaccine Begripal conferred 60% protection while MF59-adjuvanted Fluad conferred 100% protection from a 2009 pH1N1 infection in FBZ-treated, formerly infected mice. Of note, applying this improved prime-boost regimen did not restore protection in untreated infected mice. In summary our findings highlight the risk of failed vaccinations due to helminth infection.
蠕虫仍然感染了四分之一的人类。它们通过下调宿主的免疫系统来成功建立慢性感染。因此，蠕虫感染个体对疫苗的免疫反应也可能受损。在这里，我们研究了蠕虫诱导的免疫调节对小鼠系统中疫苗效力的影响。我们之前已经表明，基础感染会降低抗流感疫苗接种在 1 型调节性 T 细胞（Tr1）全身扩张的背景下的抗体（Ab）反应。最重要的是，在接种疫苗的感染小鼠中，疫苗诱导的对 2009 年大流行性 H1N1 流感 A 病毒（2009 pH1N1）的挑战感染的保护受损。在这里，我们旨在通过药物驱虫来恢复疫苗接种的效力。用氟苯达唑（FBZ）治疗两周后，胸腔内的活寄生虫被消除。在感染小鼠中，FBZ 治疗与疫苗接种同时进行并没有恢复 Ab 反应或保护作用。同样，疫苗接种前两周用 FBZ 治疗并没有显著提高流感特异性 Ig 反应，也不能保护小鼠免受 2009 pH1N1 的挑战感染。调节性 T 细胞区室的分析表明，感染和 FBZ 治疗的小鼠仍显示出扩展的 Tr1 细胞群体，这可能有助于在成功驱虫的小鼠中持续抑制疫苗反应。为了在以前感染过蠕虫的小鼠中竞争这种持续的免疫调节，我们最终将药物诱导的驱虫与改进的疫苗接种方案相结合。两次注射非佐剂抗流感疫苗 Begripal 可提供 60%的保护，而 MF59 佐剂 Fluad 可在 FBZ 治疗的以前感染的小鼠中提供 100%的 2009 pH1N1 感染保护。值得注意的是，在未治疗的感染小鼠中应用这种改进的初级加强方案并未恢复保护。总之，我们的研究结果强调了由于蠕虫感染而导致疫苗接种失败的风险。
