When a novel strain of influenza emerges, the preexisting antibody response directed largely at the surface glycoproteins is rendered ineffective. In these cases, the mechanisms underlying heterosubtypic cross-protection assume a dominant role and it is, therefore, not surprising that immune dysfunction caused by underlying genetic polymorphisms may lead to impaired responses and would therefore be associated with adverse outcomes. During the 2009 H1N1 pandemic, several immunogenetic determinants of severe disease were identified.