The gift of preexisting immunity for developing an alternative vaccine strategy.

Despite the worldwide application of vaccination and other antiviral interventions, pulmonary viral infections remain a persistent threat to human health. The 1918 influenza pandemic killed more than 40 million people in just one year, and the SARS-CoV-2 pandemic has killed more than 6.9 million people since 2019. While the current approved COVID-19 vaccines are administered parenterally and induce systemic immunity, they only prevent the progression to severe disease. Thus, other vaccine platforms are still needed for completely preventing the disease and subsequent transmission. In this issue of the JCI, Kawai et al. present an adjuvant-free subunit (RBD-HA) fusion vaccine, which produces robust IgG and IgA antibody responses against SARS-CoV-2, enriched within the nasal cavity, by using the host's preexisting immunity to influenza infection. This preclinical study has tremendous implications for future mucosal vaccine design and provides a roadmap for generating a safer and effective intranasal vaccine against pulmonary infections.