Pre-Clinical Evaluation of a Novel Nanoemulsion-Based Hepatitis B Mucosal Vaccine
Pre-Clinical Evaluation of a Novel Nanoemulsion-Based Hepatitis B Mucosal Vaccine
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DOI：
10.1371/journal.pone.0002954
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发表时间：
2008-08-13
期刊：
影响因子：
3.7
通讯作者：
Baker, James R., Jr.
中科院分区：
文献类型：
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作者：
Makidon, Paul E.;Bielinska, Anna U.;Baker, James R., Jr.
背景资料：尽管有安全有效的预防性疫苗，但B型肝炎病毒感染仍然是一个重要的全球健康问题。这些疫苗的局限性包括需要冷藏和三次免疫，从而限制了在发展中国家的使用。一种新的鼻用B型肝炎疫苗由重组B表面抗原（HBsAg）和一种新型纳米乳剂（NE）佐剂组成，这种新型疫苗可以在较少的给药次数下有效。方法和主要发现：物理特性表明，纳米Ag-NE由均匀的脂滴（349+/-17 nm）组成，通过静电和疏水相互作用与HBsAg结合。在小鼠、大鼠和豚鼠中评价了Ag-NE疫苗的免疫原性。鼻内免疫的动物产生了稳健和持续的全身IgG、粘膜伊加和强抗原特异性细胞免疫应答。血清IgG达到>= 10（6）滴度，并且与用明矾佐剂疫苗（Ag-Alu）的肌内接种相当。标准化表明，EPAg-NE疫苗接种与相当于或大于1000 IU/ml的保护性免疫相关。IFN-γ和TNF-α细胞因子的产生和IgG（2）亚类的IgG特异性抗体水平升高表明Th 1极化免疫应答。该疫苗在4 ℃下保持完全免疫原性一年，在25 ℃下保持6个月，在40 ℃下保持6周。结论：无针鼻内免疫法可作为一种安全有效的B肝炎疫苗，或为肠外免疫B肝炎疫苗提供一种可替代的加强免疫途径。该疫苗诱导Th 1相关的细胞免疫，并且还可以为缺乏细胞免疫应答以充分控制病毒复制的慢性B型肝炎感染患者提供治疗益处。该疫苗制剂在高温下的长期稳定性表明了该领域的直接优势，因为可以耐受冷链维持的潜在偏移而不损失治疗效果。
Background: Hepatitis B virus infection remains an important global health concern despite the availability of safe and effective prophylactic vaccines. Limitations to these vaccines include requirement for refrigeration and three immunizations thereby restricting use in the developing world. A new nasal hepatitis B vaccine composed of recombinant hepatitis B surface antigen (HBsAg) in a novel nanoemulsion (NE) adjuvant (HBsAg-NE) could be effective with fewer administrations.Methodology and Principal Findings: Physical characterization indicated that HBsAg-NE consists of uniform lipid droplets (349+/-17 nm) associated with HBsAg through electrostatic and hydrophobic interactions. Immunogenicity of HBsAg-NE vaccine was evaluated in mice, rats and guinea pigs. Animals immunized intranasally developed robust and sustained systemic IgG, mucosal IgA and strong antigen-specific cellular immune responses. Serum IgG reached >= 10(6) titers and was comparable to intramuscular vaccination with alum-adjuvanted vaccine (HBsAg-Alu). Normalization showed that HBsAg-NE vaccination correlates with a protective immunity equivalent or greater than 1000 IU/ml. Th1 polarized immune response was indicated by IFN-gamma and TNF-alpha cytokine production and elevated levels of IgG(2) subclass of HBsAg-specific antibodies. The vaccine retains full immunogenicity for a year at 4 degrees C, 6 months at 25 degrees C and 6 weeks at 40 degrees C. Comprehensive pre-clinical toxicology evaluation demonstrated that HBsAg-NE vaccine is safe and well tolerated in multiple animal models.Conclusions: Our results suggest that needle-free nasal immunization with HBsAg-NE could be a safe and effective hepatitis B vaccine, or provide an alternative booster administration for the parenteral hepatitis B vaccines. This vaccine induces a Th1 associated cellular immunity and also may provide therapeutic benefit to patients with chronic hepatitis B infection who lack cellular immune responses to adequately control viral replication. Long-term stability of this vaccine formulation at elevated temperatures suggests a direct advantage in the field, since potential excursions from cold chain maintenance could be tolerated without a loss in therapeutic efficacy.