Vaccination Ameliorates Cellular Inflammatory Responses in SARS-CoV-2 Breakthrough Infections

Background Data on cellular immune responses in persons with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection following vaccination are limited. The evaluation of these patients with SARS-CoV-2 breakthrough infections may provide insight into how vaccinations limit the escalation of deleterious host inflammatory responses. Methods We conducted a prospective study of peripheral blood cellular immune responses to SARS-CoV-2 infection in 21 vaccinated patients, all with mild disease, and 97 unvaccinated patients stratified based on disease severity. Results We enrolled 118 persons (aged 50 years [SD 14.5 years], 52 women) with SARS-CoV-2 infection. Compared to unvaccinated patients, vaccinated patients with breakthrough infections had a higher percentage of antigen-presenting monocytes (HLA-DR+), mature monocytes (CD83(+)), functionally competent T cells (CD127(+)), and mature neutrophils (CD10(+)); and lower percentages of activated T cells (CD38(+)), activated neutrophils (CD64(+)), and immature B cells (CD127(+)CD19(+)). These differences widened with increased disease severity in unvaccinated patients. Longitudinal analysis showed that cellular activation decreased over time but persisted in unvaccinated patients with mild disease at 8-month follow-up. Conclusions Patients with SARS-CoV-2 breakthrough infections exhibit cellular immune responses that limit the progression of inflammatory responses and suggest mechanisms by which vaccination limits disease severity. These data may have implications for developing more effective vaccines and therapies. Clinical Trials Registration . NCT04401449. The cellular immune signature found in vaccinated patients with breakthrough infections shows more favorable myeloid and lymphoid compartments that limit inflammatory responses associated with disease severity and may lead to a better control of viral replication and less immune activation.