Pandemic preparedness: toward a universal influenza vaccine.

The possible emergence of a new influenza pandemic is considered a major threat for human health worldwide. Pandemics start by the introduction or reintroduction and spread in the human population of an influenza virus subtype against which almost nobody has protective immunity. Currently used influenza vaccines provide good protection only against antigenically matching influenza strains. However, neither the timing nor the subtype of the next pandemic virus is known. Therefore, different approaches are being pursued in anticipation of this pandemic threat. In the present article, we review approaches that aim to induce heterosubtypic immunity, that is, protection against challenge with influenza A viruses belonging to two or more subtypes. Experimental and epidemiological studies indicate that natural infection can provide some heterosubtypic immunity, possibly involving cellular immune responses directed against matrix and/or nucleoprotein as well as humoral responses against neuraminidase. Other approaches have focused on the use of conserved epitopes of the viral proteins, including matrix protein 2 ectodomain (M2e) and nucleoprotein (NP). Proof-of-concept of protection by these novel vaccines has been obtained in animal models, and promising results from several clinical trials have recently been reported. Demonstrating the efficacy of these new vaccines against a potential pandemic influenza endowed with human transmissibility remains a major challenge.