Summary Project 1, Moody The overall goal of the research program is to design immunogens that elicit a broadly neutralizing response Influenza remains a persistent global health threat requiring surveillance of circulating strains. The primary method of preventing influenza infection is vaccination, and in the last two decades, the recommendations for influenza vaccination have been expanded to include almost all people in the US. In a study of recipients of the 2008 trivalent influenza vaccine, we found that the response to influenza vaccination had subtype dominance: most of the responses in any particular individual were directed to a single component of the multivalent vaccine, and included responses to the hemagglutinin (HA) receptor binding site (RBS). We have now found that this dominant response derived from B cells descended from those elicited by the influenza strain circulating when these adults were infants, suggesting that an early influenza exposure may affect the outcome of later responses ("imprinting"). Investigating these observations has public health implications for the use of various influenza vaccines in infants and adults. Project 1 will test the hypotheses that (i) imprinting of the immune system by early infection with influenza results in subtype dominance in subsequent responses, but that (ii) early vaccination with multivalent vaccine in infants can prime the immune system to produce responses to multiple strains that persist across vaccine seasons and that can remain balanced even after an infection later in life, and (iii) that immunization with HAs designed to stimulate clonal lineages of RBS antibodies can modify an imprinted response. We will investigate these hypotheses in humans and rhesus macaques (RMs).