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首页> 外文会议>Conference on vaccine technology VI >A PRE-FUSION, TRIMERIC SUBUNIT INFLUENZA HA-BASED VACCINE ELICITS CROSS-PROTECTION BETWEEN HIGHLY DIVERGENT INFLUENZA A VIRUSES
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A PRE-FUSION, TRIMERIC SUBUNIT INFLUENZA HA-BASED VACCINE ELICITS CROSS-PROTECTION BETWEEN HIGHLY DIVERGENT INFLUENZA A VIRUSES

机译：基于高融合性流感病毒的融合前三聚体亚型流感疫苗可交叉保护

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Despite our best efforts to vaccinate against influenza viruses they remain a major cause of morbidity and mortality worldwide, resulting in 3-5 million severe infections and more than 250,000 deaths annually. Constant antigenic changes in circulating viruses means current vaccines must be updated and re-administered annually. This approach is time-consuming and expensive, and is often hindered by mismatches between circulating and vaccine strains. Strain mismatch can contribute to insufficient vaccine efficacy, which has ranged from just 10-60% over the last decade. Furthermore, recent sporadic zoonotic outbreaks of novel highly pathogenic viruses from avian species, to which current vaccines provide no immunity, have been observed, with fatality rates around 40%. This raises serious concerns of a global pandemic with the potential to spread rapidly before a vaccine can be manufactured. Novel approaches to influenza vaccination are clearly needed in order to overcome these limitations with 'universal' flu vaccines being the holy grail. We have stabilized recombinant influenza haemagglutinin (rHA) in its native, pre-fusion conformation by the addition of a novel 'clamp' stabilization motif to enhance subunit vaccine potency and breadth of protection. Immunisation of mice with clamp-stabilized prefusion rHA elicited a potent neutralizing antibody response (~4-fold improvement over current vaccines). Most importantly, antibodies elicited upon immunisation with clamp-stabilised prefusion rHA showed an 80-fold increase in cross-reactivity to rHA derived from a divergent, highly pathogenic avian virus (H5N1) when compared to the current influenza vaccines. We have also shown that vaccination with clamp-stabilisted rHA based on the H3 subtype (group 2) is capable of providing cross-protection to a challenge with a highly-divergent group 1 virus (H1N1). Ultimately, this approach could represent a potential universal influenza vaccine, providing enhanced cross-protection against both group 1 and 2 seasonal influenza virus strains while simultaneously providing an increased cross-reactive humoral immune response to potential zoonotic pandemic strains.
机译：尽管我们已尽最大努力为流感病毒接种疫苗，但它们仍然是全世界发病率和死亡率的主要原因，每年导致3-5百万例严重感染和25万多例死亡。循环病毒中抗原的不断变化意味着当前的疫苗必须每年更新并重新施用。这种方法既费时又昂贵，并且经常被循环和疫苗株之间的不匹配所阻碍。菌株不匹配会导致疫苗效力不足，在过去十年中，疫苗效力仅占10-60％。此外，已经观察到最近来自禽类的新型高致病性病毒的零星人畜共患病暴发，目前的疫苗无法提供免疫力，致死率约为40％。这引起了对全球大流行病的严重关注，这种大流行病可能在生产疫苗之前迅速传播。为了克服这些局限性，以“通用”流感疫苗为圣杯，显然需要新颖的流感疫苗接种方法。我们通过添加新颖的“钳位”稳定基序来增强亚单位疫苗的效力和保护广度，以其天然的融合前构象稳定了重组流感血凝素（rHA）。用钳夹稳定的预融合rHA免疫小鼠会引起有效的中和抗体反应（比当前疫苗提高约4倍）。最重要的是，与目前的流感疫苗相比，用钳夹稳定的预融合rHA免疫后引发的抗体与衍生自多种高致病性禽病毒（H5N1）的rHA的交叉反应性提高了80倍。我们还显示，使用基于H3亚型（组2）的钳夹稳定型rHA进行疫苗接种能够为高分化1组病毒（H1N1）的攻击提供交叉保护。最终，这种方法可能代表了一种潜在的通用流感疫苗，可增强针对第1组和第2组季节性流感病毒株的交叉保护，同时提供对潜在人畜共患大流行株的交叉反应性体液免疫应答。

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