Scientists have detected preexisting antibody-driven immunity against SARS-CoV-2 in a small proportion of individuals who were uninfected at the time of sampling. Sixteen out of 302 adults (5.3%) harbored IgG antibodies that were likely generated during previous seasonal "common cold" coronavirus infections, and which cross-reacted with subunit S2 of the SARS-CoV-2 spike protein complex. Notably, the presence of these cross-reactive IgG antibodies was much more prevalent in an additional cohort of SARS-CoV-2-uninfected children and adolescents (aged 1 to 16 years): at least 21 of these 48 subjects (43.8%) had detectable levels of SARS-CoV-2 S-reactive IgG antibodies. Together, these findings may help explain higher COVID-19 susceptibility in older people and provide insight into whether pre-established immunity to seasonal coronaviruses offers protection against SARS-CoV-2. Though previous studies suggest cross-reactive immunity is neither sterilizing nor long-lasting, the presence of cross-reactivity can reduce viral transmission and ameliorate symptoms and is, therefore, an important area of study. Using a technique based on flow cytometry, Kevin Ng and colleagues found that the SARS-CoV-2-reactive antibodies from uninfected individuals were predominantly of the IgG class--rather than IgM or IgA antibodies--that targeted the viral S2 protein, responsible for cell entry and thought to more similarly structured across different coronaviruses than subunit S1. (By comparison, individuals previously infected with SARS-CoV-2 retained higher numbers of IgA, IgG, and IgM antibodies, which could target both S1 and S2 subunits.) In cell culture experiments, sera from both older and younger uninfected individuals with cross-reactive antibodies showed the ability to neutralize SARS-CoV-2 and SARS-CoV-2 S pseudotypes, whereas sera from uninfected patients lacking cross-reactive antibodies exhibited no such neutralizing activity. Further exploring potential targets on S2 that are conserved across multiple coronaviruses may hold the promise of a universal coronavirus vaccine, the authors say.