Protective immunity against influenza virus infection and disease is primarily conferred through HA via the induction of anti-HA antibodies. As protection from influenza virus infection correlates with anti-HA titers, nearly all vaccine approaches aim to induce high levels thereof. Therefore, the HA protein is the antigen of choice for the development of recombinant subunit vaccines to protect against HPAI H5N1. An influenza vaccine based on recombinant purified HA could offer the following advantages: I) The HA antigen can be produced using safe, quality-controlled and scalable conditions. II) There will be no need for virus cultivation, thus avoiding the necessity a) to obtain viruses that replicate efficiently in eggs or cell culture, b) to use biocontainment facilities and c) to inactivate the virus using procedures that may affect antigenicity and raise safety concerns. III) The recombinant HA protein can be highly purified thereby limiting adverse reactions caused e.g. by the presence of egg contaminants. IV) Immunization with recombinant HA will allow the serological differentiation of naturally infected from vaccinated animals/flocks (the so-called DIVA principle; [14] ). IV) Recombinant HA vaccines are manufactured with a relatively short lead time, allowing an accelerated response to emerging influenza strains.