TLR7配体脂质体多次鼻腔强化的异种初补方案增强疫苗免疫原性。

IF 4.5 3区医学 Q2 IMMUNOLOGY

Vaccine Pub Date : 2025-10-08 DOI:10.1016/j.vaccine.2025.127778

Tomoko Hayashi, Shiyin Yao, Fumi Sato-Kaneko, Renna Cozza, Hiroyuki Baba, Jasmine Jin, Ian Mclaughlin, Fernando Gil, Paola Anguiano Quiroz, Nikunj M. Shukla, Michael Chan, Howard B. Cottam, Dennis A. Carson

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引用次数: 0

摘要

目的：尽管目前的肌肉注射流感疫苗在降低季节性感染的严重程度方面具有临床疗效，但它们对粘膜免疫的诱导有限，而粘膜免疫对预防病毒传播至关重要。此外，鼻内疫苗接种可诱导良好的粘膜免疫，提高临床疗效并减少传播，其自我增强潜力可能提高老年人和行动受限人群的覆盖率。方法：我们开发了lipoo -1V270，这是一种利用1,2-二油基- sc -甘油-3-磷脂胆碱（DOPC）和胆固醇合成的TLR7激动剂1V270的脂质体纳米颗粒制剂，用于粘膜疫苗递送。体外免疫刺激和体内免疫原性在小鼠模型中通过肌内和鼻内途径进行了评估，包括用灭活甲型流感病毒[IIAV， a/ California/04/2009 (H1N1)pdm09]佐剂单磷脂酰脂a （MPLA）启动的异源启动-增强方案。结果：体外分析显示，与未配制的1V270相比，lipoo -1V270表现出减弱的先天免疫效力。然而，lipoo - 1v270与IIAV在体内共给药可显著增强抗原特异性IgG1和IgG2a应答。随后，在经fda批准的疫苗中含有MPLA（一种成分）佐剂的IIAV肌肉灌注后，用lipop - 1v270鼻内增强，在鼻腔冲洗中引起了流感血凝素（HA）特异性粘膜IgA和IgG的强烈反应。在免疫小鼠增强免疫后7天内，这种异种的初始增强方案也诱导了强烈的脾t细胞反应和ha特异性IgG和IgA抗体。结论：在异源初补型疫苗接种方案中鼻内给药lipop - 1v270可有效增强黏膜对流感病毒感染的免疫力，并具有可接受的先天免疫介导的不良反应。这一战略可能适用于针对其他呼吸道传染病的疫苗。

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Enhancing vaccine immunogenicity through heterologous prime-boost regimen with multiple nasal boosting with liposomal TLR7 ligand

Objectives

Despite the clinical efficacy of current intramuscular influenza vaccines in reducing the severity of seasonal infection, they exhibit limited induction of mucosal immunity, which is essential for preventing viral transmission. In addition, intranasal vaccination can induce superior mucosal immunity, enhancing clinical efficacy and reducing transmission, and its self-boosting potential may improve coverage in older adults and those with mobility limitations.

Methods

We developed Lipo-1V270, a liposomal nanoparticle formulation of the synthetic TLR7 agonist 1V270 using 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC) and cholesterol for mucosal vaccine delivery. In vitro immune stimulation and in vivo immunogenicity were evaluated using intramuscular and intranasal routes in mouse models, including a heterologous prime-boost regimen with inactivated influenza A virus [IIAV, A/California/04/2009 (H1N1)pdm09] adjuvanted monophosphoryl lipid A (MPLA) priming.

Results

In vitro analysis showed that Lipo-1V270 exhibited attenuated innate immune potency compared to unformulated 1V270. However, in vivo co-administration of Lipo-1V270 with IIAV significantly enhanced antigen-specific IgG1 and IgG2a responses. Subsequently, intranasal boosting with Lipo-1V270, following intramuscular priming with IIAV adjuvanted with MPLA - a component included in FDA-approved vaccines - elicited robust influenza-hemagglutinin (HA)-specific mucosal IgA and IgG responses in nasal wash. This heterologous prime-boost regimen also induced strong splenic T-cell responses and HA-specific IgG and IgA antibodies in nasal wash without causing significant weight loss for 7 days post-boost in immunized mice.

Conclusions

Intranasal administration of Lipo-1V270 in a heterologous prime-boost vaccination regimen effectively enhances mucosal immunity against influenza virus infection, with an acceptable innate immune-mediated adverse effects profile. This strategy may be applicable to vaccines against other respiratory infectious diseases.

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来源期刊

Vaccine 医学-免疫学

CiteScore

8.70

自引率

5.50%

发文量

992

审稿时长

131 days

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