Successful vaccine design requires an assessment of antibody responses and their protectivity over time. In this preprint, Sterlin et al. characterize the early humoral immune response to SARS-CoV-2 in 38 patients. Longitudinal serum analysis revealed that IgA and IgG differ in potency and prevalence over time. At onset of disease, mucosal-homing IgA-secreting plasmablasts predominate; these appear to arise in a germinal centre-independent fashion. Most SARS-CoV-2-targeted antibodies bound to the receptor-binding domain region and IgA provided more efficient neutralization than IgG. However, as infection progressed, IgA serum levels declined whereas IgG levels increased. Therefore, testing for virus-specific IgA should be suitable for early diagnosis, whereas testing for IgG is more relevant post-infection. However, bronchoalveolar lavage of patients with severe infection revealed a predominance of IgG, highlighting differences in mucosal and systemic responses to SARS-CoV-2.