Symptomatic SARS-CoV-2 breakthrough infections broaden the repertoire of Spike-reactive CD4 T cells

SARS-CoV-2 mRNA vaccines have been shown to induce robust T-cell responses, crucial for long-term protection against severe SARS-CoV-2 infection. Hybrid immunity, created by a combination of vaccination and infection, has been associated with improved protection against severe SARS-CoV-2 infection. Here, we have investigated the impact of asymptomatic and symptomatic breakthrough infections (BTIs) on T-cell responses toward Spike, compared to donors that have only received mRNA SARS-CoV-2 vaccines. Symptomatic, and to a lesser extent asymptomatic, BTIs broadened the repertoire of Spike-reactive CD4 T cells and induced a more pro-inflammatory Spike-reactive T-cell response capable of enhancing activation of TH17-like cells. These findings represent the first characterization of T-cell responses in ABTI in comparison to SBTI, and in comparison to vaccinated individuals (VAX) who did not experience BTIs.