Cobbin Joanna C A, Zeng Weiguang, Jackson David C, Brown Lorena E
Department of Microbiology and Immunology, The University of Melbourne at the Peter Doherty Institute of Infection and Immunity, Parkville, Victoria, Australia.
PLoS One. 2014 Dec 18;9(12):e115356. doi: 10.1371/journal.pone.0115356. eCollection 2014.
Current split influenza virus vaccines that induce strain-specific neutralising antibodies provide some degree of protection against influenza infection but there is a clear need to improve their effectiveness. The constant antigenic drift of influenza viruses means that vaccines are often not an exact match to the circulating strain and so levels of relevant antibodies may not be sufficiently high to afford protection. In the situation where the emergent influenza virus is completely novel, as is the case with pandemic strains, existing vaccines may provide no benefit. In this study we tested the concept of a combination vaccine consisting of sub-optimal doses of split influenza virus vaccine mixed with a cross-protective T-cell inducing lipopeptide containing the TLR2 ligand Pam2Cys. Mice immunised with combination vaccines showed superior levels of lung viral clearance after challenge compared to either split virus or lipopeptide alone, mediated through activation of enhanced humoral and/or additional cellular responses. The mechanism of action of these vaccines was dependent on the route of administration, with intranasal administration being superior to subcutaneous and intramuscular routes, potentially through the induction of memory CD8+ T cells in the lungs. This immunisation strategy not only provides a mechanism for minimising the dose of split virus antigen but also, through the induction of cross-protective CD8+ T cells, proves a breadth of immunity to provide potential benefit upon encounter with serologically diverse influenza isolates.
目前的裂解流感病毒疫苗可诱导产生毒株特异性中和抗体，能提供一定程度的流感感染防护，但显然有必要提高其有效性。流感病毒不断的抗原漂移意味着疫苗往往与流行毒株不完全匹配，因此相关抗体水平可能不够高，无法提供保护。在出现全新的流感病毒（如大流行毒株）的情况下，现有疫苗可能毫无益处。在本研究中，我们测试了一种联合疫苗的概念，该联合疫苗由次优剂量的裂解流感病毒疫苗与一种含有TLR2配体Pam2Cys的交叉保护性T细胞诱导脂肽混合而成。与单独使用裂解病毒或脂肽相比，用联合疫苗免疫的小鼠在攻毒后肺内病毒清除水平更高，这是通过增强体液免疫和/或额外的细胞免疫反应的激活介导的。这些疫苗的作用机制取决于给药途径，鼻内给药优于皮下和肌肉注射途径，这可能是通过在肺内诱导记忆性CD8+T细胞实现的。这种免疫策略不仅提供了一种减少裂解病毒抗原剂量的机制，而且通过诱导交叉保护性CD8+T细胞，证明了一种免疫广度，在遇到血清学上不同的流感分离株时可能会带来益处。
