SARS-CoV-2 mucosal neutralising immunity after vaccination

In response, we describe an adapted version of our high-throughput live virus microneutralisation assay for mucosal samples to establish the effect of fourth dose intramuscular mRNA vaccination on neutralising antibodies against six SARS-CoV-2 variants (Omicron BA.1, BA.2, BA.5, BQ.1.1, XBB.1.5, and XBB.1.16) in paired serum and mucosal samples from 149 participants (appendix p 4)2 enrolled in the University College London Hospital and Francis Crick Institute Legacy study (NCT04750356).2–6 Mucosal samples were self-collected via nasopharyngeal swabs into viral transport media. Importantly, parenteral vaccination boosts total mucosal neutralising capacity. Since this boost occurs in individuals both with and without previous mucosal challenge from infection, our data argue against a closed system of mucosal immunity only triggered by a mucosal challenge, such as infection.7 Similarly, we identified a positive correlation between serum and mucosal neutralisation that was most apparent in individuals with previous infections, thus showing that infection propagates antibodies in both serum and mucosal compartments, and arguing against large mucosal-only locally produced antibody after infection.8 Furthermore, similar quantities of mucosal neutralisation after equivalent numbers of exposures to SARS-CoV-2 spike proteins—via infection or vaccination—suggest that further boosts with intramuscular vaccines can enhance and potentially broaden mucosal neutralising capacity, as we have seen in the serum compartment. The viral transport medium sampling approach described here enables large-scale sample collection and testing for mucosal neutralisation required for vaccine evaluation,9 and will allow further exploration of cross-compartment neutralisation—for both present and future generation vaccines—including those directly generating a mucosal response.