VaxInnate Corporation, Cranbury, New Jersey, United States of America.
PLoS One. 2011;6(6):e20928. doi: 10.1371/journal.pone.0020928. Epub 2011 Jun 7.
We have previously demonstrated that the globular head of the hemagglutinin (HA) antigen fused to flagellin of Salmonella typhimurium fljB (STF2, a TLR5 ligand) elicits protective immunity to H1N1 and H5N1 lethal influenza infections in mice (Song et al., 2008, PLoS ONE 3, e2257; Song et al., 2009, Vaccine 27, 5875-5888). These fusion proteins can be efficiently and economically manufactured in E. coli fermentation systems as next generation pandemic and seasonal influenza vaccines. Here we report immunogenicity and efficacy results of three vaccine candidates in which the HA globular head of A/California/07/2009 (H1N1) was fused to STF2 at the C-terminus (STF2.HA1), in replace of domain 3 (STF2R3.HA1), or in both positions (STF2R3.2xHA1). For all three vaccines, two subcutaneous immunizations of BALB/c mice with doses of either 0.3 or 3 µg elicit robust neutralizing (HAI) antibodies, that lead to > = 2 Log(10) unit reduction in day 4 lung virus titer and full protection against a lethal A/California/04/2009 challenge. Vaccination with doses as low as 0.03 µg results in partial to full protection. Each candidate, particularly the STF2R3.HA1 and STF2R3.2xHA1 candidates, elicits robust neutralizing antibody responses that last for at least 8 months. The STF2R3.HA1 candidate, which was intermediately protective in the challenge models, is more immunogenic than the H1N1 components of two commercially available trivalent inactivated influenza vaccines (TIVs) in mice. Taken together, the results demonstrate that all three vaccine candidates are highly immunogenic and efficacious in mice, and that the STF2R3.2xHA1 format is the most effective candidate vaccine format.
我们之前已经证明，将血凝素（HA）抗原的球形头部融合到沙门氏菌 typhimurium fljB 的鞭毛蛋白（STF2，TLR5 配体）中，可以激发对 H1N1 和 H5N1 致死性流感感染的保护性免疫（Song 等人，2008 年，PLoS ONE 3，e2257；Song 等人，2009 年，疫苗 27，5875-5888）。这些融合蛋白可以在大肠杆菌发酵系统中高效且经济地生产，作为下一代大流行性流感和季节性流感疫苗。在这里，我们报告了三种候选疫苗的免疫原性和疗效结果，其中 A/California/07/2009（H1N1）的 HA 球形头部融合到 STF2 的 C 末端（STF2.HA1），取代了结构域 3（STF2R3.HA1），或在两个位置（STF2R3.2xHA1）。对于所有三种疫苗，用 0.3 或 3μg 的两种皮下免疫剂量，可引发 BALB/c 小鼠产生强烈的中和（HAI）抗体，导致第 4 天肺部病毒滴度降低> = 2Log(10)单位，并完全保护免受致命的 A/California/04/2009 挑战。用低至 0.03μg 的剂量接种可导致部分至完全保护。每个候选疫苗，特别是 STF2R3.HA1 和 STF2R3.2xHA1 候选疫苗，都能引发强烈的中和抗体反应，持续至少 8 个月。在挑战模型中具有中等保护作用的 STF2R3.HA1 候选疫苗，在小鼠中比两种市售的三价灭活流感疫苗（TIV）的 H1N1 成分更具免疫原性。综上所述，结果表明，所有三种候选疫苗在小鼠中均具有高度的免疫原性和疗效，并且 STF2R3.2xHA1 格式是最有效的候选疫苗格式。
