Prior Vaccination Prevents Overactivation of Innate Immune Responses During COVID-19 Breakthrough Infection

The study aimed to investigate how prior SARS-CoV-2 vaccination influences innate and adaptive immune responses during breakthrough COVID-19 infections. The study sought to understand the immunological mechanisms differentiating breakthrough infections in vaccinated individuals (VI) from primary infections in unvaccinated individuals (UVI), with a focus on transcriptional, proteomic, and functional immune profiling.The study included healthy controls (HC) (n = 6), UVI with primary SARS-CoV-2 infection (n = 19), and VI with breakthrough infection (n = 17), all recruited during the Delta variant wave from April to December 2021. Participants included had mild to moderate disease, and those with immunosuppressive treatments were excluded. The vaccinated group received a full course of 2 doses of the mRNA vaccines (Pfizer or Moderna) or a full course of 1 dose of the Janssen COVID-19 vaccine.Peripheral blood mononuclear cells and plasma samples were collected and analyzed using single-cell RNA sequencing, mass cytometry, and Olink plasma proteomics. The study assessed transcriptional profiles, protein expression, and cell-cell communication pathways among immune cell subsets. Comparative analyses were conducted between UVI and VI groups, with additional stratification by sex and validation using an external study cohort vaccinated with the ChAdOx1 nCoV-19 vaccine.Breakthrough infections in VI participants exhibited attenuated activation of monocytes and natural killer (NK) cells responses compared with primary infections in UVI participants. Additionally, VI demonstrated monocytes with lower migratory potential and altered metabolic profiles and their NK cells had reduced proliferation (downregulation of genes associated chemotaxis and recruitment) and activation markers. Transcriptomic and proteomic analyses revealed reduced expression of inflammatory and interferon-stimulated genes while adaptive immune responses were attenuated in VI participants, with sex-specific differences indicating heightened innate immune activation in female individuals.Prior vaccination modulates the immune response during SARS-CoV-2 breakthrough infections by preventing overactivation of innate immune cells, particularly monocytes and NK cells. The findings suggest that signals sent by monocytes and NK cells likely prevent overactive adaptive immune responses in VI participants. The immunomodulation responses differed between sexes, with female individuals exhibiting greater innate immune activity than male individuals with breakthrough infection, and was consistent across different vaccine platforms. The study highlights the role of COVID-19 vaccination in shaping protective immune responses and mitigating excessive inflammation during infection.This comprehensive study provides valuable insights into the protective vs pathogenic immune responses to SARS-CoV-2 infections in vaccinated and unvaccinated individuals. The authors conclude that COVID-19 vaccination refines the innate immune responses, thereby attenuating excessive inflammation often associated with severe COVID-19 infection, while still supporting effective viral control. Limitations include that the patients’ strain of COVID (while thought to be the Delta variant due to timing of the study) was not confirmed through sequencing. Additionally, the study could not rule out that patients involved in the study may have had previous asymptomatic COVID infections. Cell-cell communication analysis provided potential mechanisms behind the observed immune response differences between VI and UVI patients, which provides an opportunity for future studies to further evaluate and validate these findings. The identification of sex-specific immune responses and the modulation of innate immunity by prior vaccination offer important considerations for future vaccine strategies and personalized medicine.