Summary paragraph Influenza vaccines that confer broad and durable protection against diverse virus strains would have a major impact on global health 1 . Here we show that computationally designed, two-component nanoparticle immunogens 2 induce potently neutralizing and broadly protective antibody responses against a wide variety of influenza viruses. The nanoparticle immunogens display 20 hemagglutinin (HA) trimers in an ordered array, and their assembly in vitro enables precisely controlled co-display of multiple distinct HAs in defined ratios. Nanoparticle immunogens co-displaying the four HAs of licensed quadrivalent influenza vaccines (QIV) elicited antibody responses against vaccine-matched strains that were equivalent or superior to commercial QIV, and simultaneously induced broadly protective antibody responses to heterologous viruses by targeting the subdominant yet conserved HA stem. The combination of potent receptor-blocking and cross-reactive stem-directed antibodies induced by the nanoparticle immunogens make them attractive candidates for a supraseasonal influenza vaccine candidates with potential to replace conventional seasonal vaccines 3 .

Vaccination represents an efficient and cost-effective way to contain influenza epidemics and preserve public health. Since their introduction in the 1940s, seasonal influenza vaccines have saved countless lives and limited pandemic spread. Influenza viruses nonetheless continue to evolve through genetic mutation and escape from natural immunity, and vaccines must be updated yearly. The protective efficacy of the current licensed vaccines varies each year (Fig. 1a), depending on the antigenic match between circulating viruses and vaccine strains. The immune status of the host can also affect vaccine efficacy. For example, young and elderly individuals are more susceptible to the complications of influenza infection [1][2][3] .New influenza viruses have precipitated pandemics several times over the past 100 years, specifically in 1918, 1957, 1968 and 2009 (reF. 4 ). The threat of the reemergence of old pandemic viruses and the emergence of novel viruses with pandemic potential underscore the need for durable and broadly protective influenza vaccines. Advances in immunology and virology, together with information from structural biology and bioinformatics, are facilitating the development of novel vaccine approaches [5][6][7][8] . Of particular interest are human broadly neutralizing antibodies directed to conserved viral structures. These antibodies arise naturally and can also be elicited through immunization .Current licensed influenza vaccines contain either in activated or live attenuated influenza viruses. Most in activated vaccines consist of split viruses or subunit influenza antigens (Table 1). Split vaccines are produced by disrupting viral particles with chemicals or detergents Haemagglutinin (Ha). a homotrimeric glycoprotein found on the surface of influenza virus particles responsible for the recognition of the host target cell through the binding of sialic acid-containing receptors.

Here, we show that interleukin-1 (IL-1) enhances antigen-driven CD8 T cell responses. When administered to recipients of OT-I T cell receptor transgenic CD8 T cells specific for an ovalbumin (OVA) peptide, IL-1 results in an increase in the numbers of wild-type but not IL1R1−/− OT-I cells, particularly in spleen, liver, and lung, upon immunization with OVA and lipopolysaccharide. IL-1 administration also results in an enhancement in the frequency of antigen-specific cells that are granzyme B+, have cytotoxic activity, and/ or produce interferon γ (IFN-γ). Cells primed in the presence of IL-1 display enhanced expression of granzyme B and increased capacity to produce IFN-γ when rechallenged 2 mo after priming. In three in vivo models, IL-1 enhances the protective value of weak immunogens. Thus, IL-1 has a marked enhancing effect on antigen-specific CD8 T cell expansion, differentiation, migration to the periphery, and memory.