The Center for Influenza Vaccine Research for High-Risk Populations (CIVR-HRP) provides comprehensive assessment of broadly protective influenza vaccine candidates integrated with fundamental research on protective host responses to provide insight into the mechanisms that drive influenza vaccine effectiveness in the most vulnerable, high-risk populations. Using computational methodologies, broadly reactive hemagglutinin- and neuraminidase-based vaccines are being assessed using cutting-edge scientific and statistical modeling technologies. Additionally, the CIVR-HRP network is investigating novel platforms to deliver universal influenza vaccines, including recombinant proteins, microparticles, live attenuated viruses, and microneedle skin patches. Combining traditional and cutting-edge immunology, epigenetics, structural biology, virology, systems biology, and statistical modeling with various OMICs assessments of host responses to influenza vaccination and infection in high-risk models, the CIVR-HRP is developing the next generation flu vaccines for people and the models needed to predict their effectiveness.