Based upon body weight of BALB/c mice after H5N1 challenge, non-HA antigen vaccines can build upon immunity conferred previously by natural heterologous infection (empty squares), reaching the level of weight loss protection provided by H5 HA (solid red diamonds) delivered two times. Mice in groups of eight were immunized two times using MVA vaccines (solid symbols) or after natural INFV exposure (“Prime”, empty symbols) using low dose non-lethal PR8 INFV A. After H5N1 lethal challenge, mice were monitored for daily body weight and survival for 14 days. The period of 4 to 7–8 days post challenge is framed in each panel to illustrate absence of weight loss due to natural INFV exposure. Heterologous exposure to native PR8 H1N1 INFV A, followed by administration of NP + METRC + M1 expressed as a single insert in MVA ((A), empty squares, “Prime, single insert”) or as a blended vaccine of individually expressed antigens in MVA ((B), empty squares, “prime, blend”) conferred minor weight loss similar to homologous HA vaccine.