Most people who get the seasonal influenza vaccine - which contains strains of viruses from distinct virus subtypes - mount a strong immune response to one strain, leaving them vulnerable to infection by the others, and researchers have long wondered what impacts such variable responses more - host genetics or prior exposure to virus strains. Now, researchers report that host genetics is a stronger driver of these individual differences in influenza vaccine response. Their study also presents a novel vaccine platform that improved protection against diverse influenza subtypes when tested in animal models and human organoids. Influenza annually claims hundreds of thousands of lives and causes millions of hospitalizations worldwide, underscoring its significant global health burden. Human infections are largely caused by specific subtypes of influenza A (H1N1 and H3N2) and B (Victoria and Yamagata lineages) viruses, each comprising multiple strains. However, many vaccinated individuals elicit a greater response to one strain in the mix and are thus more vulnerable to infection by others. A phenomenon known as "original antigenic sin" (OAS) highlights how the immune system's memory of its first influenza exposure can skew responses to future vaccines, potentially limiting their effectiveness. Additionally, genetic variations in the human leukocyte antigen (HLA) system shape how individuals process and present vaccine antigens, influencing immune outcomes. The relative contributions of previous exposures and host genetics in influenza vaccine efficacy are poorly understood. To address this question, Vamsee Mallajosyula and colleagues analyzed antibody responses in monozygotic twins, vaccinated infants, and mouse models, finding that influenza subtype-bias is primarily driven by host genetics, particularly major histocompatibility complex (MHC) class-II polymorphisms, with prior exposure playing a secondary role. Mallajosyula et al. then developed a method to couple heterologous antigens from different viral strains via a scaffold, which enhanced CD4T cell activation, broadening antibody response. Testing in mice and human tonsil organoids showed increased antibody production across strains, demonstrating the platform's potential to improve vaccine effectiveness, including responses to avian influenza strains.