KJ Biosciences LLC, College Station, TX, United States.
Department of Veterinary Pathobiology, Texas A&M University, College Station, TX, United States.
Front Immunol. 2018 Aug 9;9:1815. doi: 10.3389/fimmu.2018.01815. eCollection 2018.
Current inactivated influenza vaccines are strain-specific and poorly effective against variant or mismatched viruses. They are standardized based on their hemagglutinin (HA) or ability to induce strain-specific hemagglutination inhibition (HAI) antibodies. The HA is known to undergo major conformational changes when exposed to the low pH environment of endosomes (pH 5.0 and 37°C), which are required for membrane fusion during virus cell entry. In an effort to improve these vaccines, influenza antigens treated under various low pH conditions were evaluated for increased cross-reactive antibody response and cross protection. It was found that a full range of structural and antigenic changes in HA could be induced by varying low pH treatment conditions from the mild (low pH at ≤25°C) to the strong (low pH at ≥37°C) as determined by analysis of potency, HA morphology, protease sensitivity, and reactivity with an anti-HA2 domain (CD) antibody. Inactivated antigens of both H1N1 and H3N2 strains treated at mild low pH conditions (0-25°C) exhibited only moderate HA structural and antigenic changes and markedly increased antibody response against HA2, the highly conserved part of HA, and cross protection against heterologous challenge in mice by up to 30% in survival. By contrast, antigen treated with low pH at 37°C showed more extensive structural and antigenic changes, and induced much less of an increase in antibody response against HA2, but a greater increase with response against HA1, and did not provide any increased cross protection. These results suggest that the increased response against HA2 obtained with the mild low pH treatment is associated with the increased cross protection. These antigens treated at the mild low pH conditions remained capable of inducing a high level of strain-specific HAI antibodies. Thus, they could readily be formulated as an inactivated influenza vaccine which not only provides the same strain-specific protection but also an increased cross protection against heterologous viruses. Such a vaccine could be particularly beneficial in cases of vaccine mismatch.
目前的流感灭活疫苗是针对特定毒株的，对变异或不匹配的病毒效果不佳。它们是基于其血凝素（HA）或诱导针对特定毒株的血凝抑制（HAI）抗体的能力来标准化的。已知 HA 在暴露于内体的低 pH 环境（pH5.0 和 37°C）时会发生重大构象变化，这是病毒进入细胞时膜融合所必需的。为了改进这些疫苗，评估了在各种低 pH 条件下处理的流感抗原，以提高交叉反应性抗体反应和交叉保护。研究发现，通过改变从温和（≤25°C 的低 pH）到强烈（≥37°C 的低 pH）的低 pH 处理条件，可以诱导 HA 的全范围结构和抗原变化，这是通过分析效力、HA 形态、蛋白酶敏感性以及与抗 HA2 结构域（CD）抗体的反应性来确定的。在温和低 pH 条件（0-25°C）下处理的 H1N1 和 H3N2 株的灭活抗原仅表现出中度的 HA 结构和抗原变化，并显著增加了对 HA2 的抗体反应，HA2 是 HA 的高度保守部分，对异源挑战的交叉保护提高了 30%，在小鼠中的存活率。相比之下，用低 pH（37°C）处理的抗原表现出更广泛的结构和抗原变化，对 HA2 的抗体反应增加幅度较小，但对 HA1 的抗体反应增加幅度较大，并且没有提供任何增加的交叉保护。这些结果表明，温和低 pH 处理获得的对 HA2 的增加反应与增加的交叉保护有关。这些在温和低 pH 条件下处理的抗原仍然能够诱导高水平的针对特定毒株的 HAI 抗体。因此，它们可以很容易地被制成灭活流感疫苗，不仅提供针对特定毒株的保护，还提供针对异源病毒的增加交叉保护。在疫苗不匹配的情况下，这种疫苗尤其有益。
