Abstract
<title>Abstract</title> <p>Defining immune correlates associated with protection from detectable infection with SARS-CoV-2 remains a key question in the design of next-generation vaccines, yet the immune responses that prevent early viral replication after exposure remain incompletely defined. Here, we describe detailed immunological findings from a SARS-CoV-2 controlled human infection model in 48 healthy participants, aged 18-30, with pre-existing immunity against SARS-CoV-2 and analyse immune markers as potential correlates of protection from viral shedding. Participants underwent extensive pre-inoculation nasal and systemic immune profiling up to 48 hours before undergoing intranasal inoculation with one of five dose levels of pre-alpha wild-type SARS-CoV-2. Sustained infection was uncommon, but 22 out of 48 participants developed quantifiable viral shedding, consistent with early virological breakthrough in an immunologically experienced cohort. We analysed associations between pre-inoculation immune markers and quantifiable viral shedding after inoculation, whilst accounting for inoculum dose and observed correlations between biologically related immune measures. Across multiple statistical approaches, coupled with additional sensitivity analyses, we show that higher pre-inoculation nasal IgG anti-spike and particularly receptor-binding domain antibodies are strongly associated with protection from quantifiable shedding of SARS-CoV-2 after controlled inoculation. Our results identify key immune correlates of protection that should inform the design of next-generation vaccines.</p>