Effect of an Adenovirus-Vectored Universal Influenza Virus Vaccine on Pulmonary Pathophysiology in a Mouse Model.
Effect of an Adenovirus-Vectored Universal Influenza Virus Vaccine on Pulmonary Pathophysiology in a Mouse Model.
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DOI：
10.1128/jvi.02359-20
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发表时间：
2021-04-12
影响因子：
5.4
通讯作者：
Epstein SL
中科院分区：
文献类型：
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作者：
Dhakal S;Loube J;Misplon JA;Lo CY;Creisher PS;Mulka KR;Deshpande S;Mitzner W;Klein SL;Epstein SL
在疫苗问世之前，呼吸道病毒可能会迅速出现和传播。这将是一个巨大的进步，使用疫苗，以保护整个类别的病毒，如通用流感疫苗，而不需要预测哪种病毒将出现。目前的流感疫苗，无论是减毒活疫苗还是灭活疫苗，都不能预防具有大流行潜力的抗原性新型甲型流感病毒(IAV)，这引发了人们对开发通用流感疫苗的兴趣。针对IAV核蛋白(NP)高度保守抗原的通用流感疫苗候选有望成为诱导T细胞免疫的疫苗，但人们对在肺部诱导强大的CD8 T细胞反应的安全性提出了担忧。利用小鼠模型，系统评价了表达IAV NP(A/NP-Rad)或IBV NP(B/NP-Rad)的重组腺病毒载体(Rad)在免疫后和IAV活体攻击后对肺部炎症和功能的影响。在接种A/NP-Rad或B/NP-Rad疫苗后，雌性小鼠表现出强烈的全身和肺疫苗特异性B细胞和T细胞反应，并且没有出现发病率(例如体重下降)。体内肺功能测试和肺组织病理学评分均显示，与未接种的小鼠相比，鼻内接种Rad的不良反应最小。在IAV攻击后，接种A/NP-Rad疫苗的小鼠与未接种疫苗或B/NP-Rad疫苗的小鼠相比，发病率、肺部病毒滴度和肺部炎症发生率显著降低。根据对肺生理学的分析，使用以前没有应用于T细胞损伤问题的详细测试，接种疫苗保护的小鼠的肺功能也比对照组好。结果提供了证据，在这个模型中，腺病毒通用流感疫苗不会损害肺组织。此外，获得性免疫，特别是肺部的T细胞免疫，在重新刺激时不会造成损害，而是减轻IAV感染后的肺损害。重要性呼吸道病毒可以在疫苗可用之前迅速出现和传播。这将是一个巨大的进步，使用疫苗，以保护整个类别的病毒，如通用流感疫苗，而不需要预测哪种病毒将出现。流感病毒的核蛋白(NP)提供了一个在不同毒株之间保守的靶标，也是一个主要的T细胞靶标。在动物中，接种NP疫苗可以产生强大的T细胞免疫力，并对各种流感病毒株产生持久的保护作用。已经提出了一些担忧，但没有进行实验评估，即强大的局部T细胞反应可能会损害肺部。我们在这样的接种设置中对肺功能进行了详细的分析。尽管肺部有CD8 T细胞反应，但单独接种疫苗后，肺没有受到损害，功能正常，在随后的感染中得到保护。这一先例为基于T细胞介导保护的疫苗提供了重要支持，目前正在考虑将其用于流感疫苗和SARS-CoV-2疫苗。
Respiratory viruses can emerge and spread rapidly before vaccines are available. It would be a tremendous advance to use vaccines that protect against whole categories of viruses, such as universal influenza vaccines, without the need to predict which virus will emerge. Current influenza vaccines, live attenuated or inactivated, do not protect against antigenically novel influenza A viruses (IAVs) of pandemic potential, which has driven interest in the development of universal influenza vaccines. Universal influenza vaccine candidates targeting highly conserved antigens of IAV nucleoprotein (NP) are promising as vaccines that induce T cell immunity, but concerns have been raised about the safety of inducing robust CD8 T cell responses in the lungs. Using a mouse model, we systematically evaluated effects of recombinant adenovirus vectors (rAd) expressing IAV NP (A/NP-rAd) or influenza B virus (IBV) NP (B/NP-rAd) on pulmonary inflammation and function after vaccination and following live IAV challenge. After A/NP-rAd or B/NP-rAd vaccination, female mice exhibited robust systemic and pulmonary vaccine-specific B cell and T cell responses and experienced no morbidity (e.g., body mass loss). Both in vivo pulmonary function testing and lung histopathology scoring revealed minimal adverse effects of intranasal rAd vaccination compared with unvaccinated mice. After IAV challenge, A/NP-rAd-vaccinated mice experienced significantly less morbidity, had lower pulmonary virus titers, and developed less pulmonary inflammation than unvaccinated or B/NP-rAd-vaccinated mice. Based on analysis of pulmonary physiology using detailed testing not previously applied to the question of T cell damage, mice protected by vaccination also had better lung function than controls. Results provide evidence that, in this model, adenoviral universal influenza vaccine does not damage pulmonary tissue. In addition, adaptive immunity, in particular, T cell immunity in the lungs, does not cause damage when restimulated but instead mitigates pulmonary damage following IAV infection. IMPORTANCE Respiratory viruses can emerge and spread rapidly before vaccines are available. It would be a tremendous advance to use vaccines that protect against whole categories of viruses, such as universal influenza vaccines, without the need to predict which virus will emerge. The nucleoprotein (NP) of influenza virus provides a target conserved among strains and is a dominant T cell target. In animals, vaccination to NP generates powerful T cell immunity and long-lasting protection against diverse influenza strains. Concerns have been raised, but not evaluated experimentally, that potent local T cell responses might damage the lungs. We analyzed lung function in detail in the setting of such a vaccination. Despite CD8 T cell responses in the lungs, lungs were not damaged and functioned normally after vaccination alone and were protected upon subsequent infection. This precedent provides important support for vaccines based on T cell-mediated protection, currently being considered for both influenza and SARS-CoV-2 vaccines.