The host response to infl uenza (H5N1) infection has not been defi ned, which has proven a considerable challenge in epidemiology and public health research. To develop effi cient vaccines, understanding how the virus interacts with the host in natural infection is necessary. Having insights into the hosts' responses to infl uenza (H5N1) would help defi ne targets for therapeutic intervention. Whether humans can develop immunity during a primary infection that would control replication and spread of subtype H5N1 viruses has been questioned (1). However, marked infl ammatory responses develop after infection with infl uenza (H5N1) in humans and other animals (2) (3) (4) . This condition is associated with statistically signifi cant synthesis of various proinfl ammatory cytokines, such as tumor necrosis factor-α, interleukin (IL)-6, interferon (IFN)-γ, IL-1α, and chemokines, including IP-10, MIG, monocyte chemoattractant protein-1 (MCP-1, IL-8, and RANTES. i.e., regulated on activation, normal T-cell expressed and secreted). If this is the case, these observations are consistent with the possible induction of innate immune responsiveness in the persons infected with infl uenza (H5N1 (5) . The death rate of ≈25% was half that of previously known outbreaks, and 5 mild or completely asymptomatic cases have been reported. One theory holds that milder cases have been occurring elsewhere but are not being recorded. Recently, 3 persons among 120 apparently healthy volunteers from the People's Republic of China, showed detectable virus-neutralizing antibody response to subtype H5N1 before vaccination (6) . Moreover, pigs infected with subtype H5N1 have become asymptomatic in Indonesia. Are these signs of development of some degree of immunity to virus, containing its replication and thus causing milder infection in naturally infected mammals? Recently, clusters of bird fl u cases were reported in Western Java, Indonesia (7); fatal disease developed in 6 persons there from the same family. Two other family members became ill but survived. All the family members likely had similar levels of exposure because they all lived in the same household. Other cases of nonfatal infections have been seen in Thailand and Vietnam. Unfortunately, there is little information about the immune response to the virus in those who survived, which would be valuable for understanding the mechanisms of protection. Indeed, following up the persons (cohort) living in the same affected villages, presumably mostly not exposed to virus, should clarify whether the maintained response refl ects boosting through natural exposure. Persons with prior exposure, as measured by antibody or viral RNA at recruitment, would likely have substantially higher responses to the vaccine than those naïve at recruitment if the vaccinating antigen contains homologous or cross-reacting determinants. Conceivably, boosting the "natural" immunity is a desirable outcome to improve protective effi cacy of any vaccine approach. Additional studies are required to evaluate the merits of priming populations in advance of an infl uenza (H5N1) pandemic.