Invasive pulmonary aspergillosis caused by the ubiquitous mold Aspergillus fumigatus is a major threat to immunocompromised patients, causing unacceptably high mortality despite standard of care treatment, and costing an estimated $1.2 billion annually. Treatment for this disease has been complicated by the emergence of azole resistant strains of A. fumigatus, rendering first-line antifungal therapy ineffective. The difficulties in treating infected patients using currently available drugs make immunotherapeutic vaccination an attractive option. Here, we demonstrate the efficacy of VesiVax® adjuvant liposomes, consisting of a combination of two individual liposome preparations, to which two recombinant A. fumigatus surface antigens, Asp f 3 and Asp f 9 (VesiVax® Af3/9), have been chemically conjugated. Using a murine model, we demonstrate that VesiVax® Af3/9 is protective against infection by azole resistant strains of A. fumigatus in both steroid-suppressed and neutropenic mice as quantified by improved survival and reduced fungal burden in the lungs. This protection correlates with upregulation of IL-4 produced by splenocytes, and the presence of Asp f 3 and Asp f 9 specific IgG2a antibodies in the serum of mice given VesiVax® Af3/9. Furthermore, mice given VesiVax® Af3/9 with a subsequent course of liposomal amphotericin B (AmBisome®) had improved survival over those given either treatment alone, indicating a benefit to VesiVax® Af3/9 vaccination even in the case of infections that require follow-up antifungal treatment. These data demonstrate that prophylactic vaccination with VesiVax® Af3/9 is a promising method of protection against invasive pulmonary aspergillosis even as the changing face of the disease renders current therapies ineffective.

由普遍存在的霉菌烟曲霉引起的侵袭性肺曲霉病是免疫功能低下患者的主要威胁，尽管采用标准护理治疗，但死亡率仍高得令人无法接受，估计每年损失 12 亿美元。由于烟曲霉的唑类耐药菌株的出现，这种疾病的治疗变得复杂，导致一线抗真菌治疗无效。使用目前可用的药物治疗感染患者的困难使得免疫治疗疫苗成为一个有吸引力的选择。在这里，我们展示了 VesiVax® 佐剂脂质体的功效，该脂质体由两种单独的脂质体制剂组合而成，其中两种重组烟曲霉表面抗原 Asp f 3 和 Asp f 9 (VesiVax® Af3/9) 已化学偶联。使用鼠模型，我们证明 VesiVax® Af3/9 对烟曲霉抗唑类菌株的感染具有保护作用在类固醇抑制和中性粒细胞减少的小鼠中，通过提高存活率和减少肺部真菌负荷来量化。这种保护与脾细胞产生的 IL-4 的上调以及给予 VesiVax® Af3/9 的小鼠血清中 Asp f 3 和 Asp f 9 特异性 IgG2a 抗体的存在相关。此外，给予 VesiVax® Af3/9 和后续疗程的脂质体两性霉素 B (AmBisome®) 的小鼠比单独给予任一治疗的小鼠存活率有所提高，这表明即使在需要遵循的感染的情况下，接种 VesiVax® Af3/9 也有益处向上抗真菌治疗。这些数据表明，使用 VesiVax® Af3/9 进行预防性疫苗接种是一种很有前途的预防侵袭性肺曲霉病的方法，即使该疾病的面貌不断变化使目前的治疗无效。