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

Abstract

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.

Keywords: SARS-CoV-2; breakthrough infections; flow cytometry; immune response; vaccines.

Graphical Abstract

Figure 1.

Percentages of immune cells according to vaccination status and disease severity. The values of the markers summarized in this figure are derived from nontransformed data with adjusted statistical analysis as described. Vaccinated patients had significantly (A) higher HLA-DR⁺ monocytes than unvaccinated patients with moderate and severe disease; (B) higher CD83⁺ monocytes than unvaccinated patients with mild, moderate, and severe disease; (C) higher CD127⁺CD8⁺CM⁺ T cells than unvaccinated patients with mild and moderate disease; (D) lower CD127⁺CD19⁺ B cells than unvaccinated patients with moderate and severe disease; (E) lower CD64⁺ neutrophils than unvaccinated patients with moderate and severe disease; (F) higher CD10⁺ neutrophils than unvaccinated patients with mild, moderate, and severe disease; (G) lower CD38⁺CD8⁺CM⁺ T cells than unvaccinated patients with mild and moderate disease; (H) lower CD38⁺CD8⁺EM⁺ T cells than unvaccinated patients with mild, moderate, and severe disease; and (I) lower CD38⁺CD8⁺TEMRA⁺ T cells than unvaccinated patients with mild, moderate, and severe disease. Data of the reference population are also shown. Abbreviations: CM, central memory; Mod, moderate; Ref-Pop, reference population; Sev, severe; TEMRA, terminally differentiated effector memory; Unv, unvaccinated. Tukey method: Line, median; box, interquartile range (IQR); whiskers, 1.5 times IQR; grey points, outliers; asterisks, FDR<0.05; hash, FDR<0.10.

Figure 2.

MFI of selected markers in lymphocytes cells according to vaccination status and disease severity. The values of the markers summarized in this figure are derived from nontransformed data with adjusted statistical analysis as described. Vaccinated patients had significantly (A) lower CD38 on N CD4⁺ T cells than unvaccinated patients with mild disease; (B) lower CD38 on N CD8⁺ T cells than unvaccinated patients with mild, moderate, and severe disease; (C) lower CD38 on CM CD4⁺ T cells than unvaccinated patients with mild, moderate, and severe disease; (D) lower CD38 on CM CD8⁺ T cells than unvaccinated patients with mild, moderate, and severe disease; (E) lower CD38 on EM CD4⁺ T cells than unvaccinated patients with mild, moderate, and severe disease; (F) lower CD38 on EM CD8⁺ T cells than unvaccinated patients with mild, moderate, and severe disease; (G) lower CD38 on TEMRA CD4⁺ T cells than unvaccinated patients with mild, moderate, and severe disease; and (H) lower CD38 on TEMRA CD8⁺ T cells than unvaccinated patients with mild, moderate, and severe disease. Data of the reference population are also shown. Abbreviations: CM, central memory; EM, effector memory; MFI, mean fluorescence intensity; Mod, moderate; N, naive; Ref-Pop, reference population; Sev, severe; TEMRA, terminally differentiated effector memory; Unv, unvaccinated. Tukey method: Line, median; box, interquartile range (IQR); whiskers, 1.5 times IQR; grey points, outliers; asterisks, FDR<0.05; hash, FDR<0.10.

Figure 3.

MFIs of markers in monocytes, neutrophils, and B lymphocytes cells according to vaccination status and disease severity. The values of the markers summarized in this figure are derived from nontransformed data with adjusted statistical analysis as described. Vaccinated patients had significantly (A) higher HLA-DR on monocytes than unvaccinated patients with moderate and severe disease; (B) lower CD16 on monocytes than unvaccinated patients with moderate disease; (C) lower HLA-DR on neutrophils than unvaccinated patients with severe disease; (D) lower CD64 on neutrophils than unvaccinated patients with mild, moderate, and severe disease; (E) higher HLA-DR on CD19⁺ B cells than unvaccinated patients with moderate and severe disease; and (F) lower CD127 on CD19⁺ B cells than unvaccinated patients with moderate and severe disease. Data of the reference population are also shown. Abbreviations: MFI, mean fluorescence intensity; Mod, moderate; Ref-Pop, reference population; Sev, severe; Unv, unvaccinated. Tukey method: Line, median; box, interquartile range (IQR); whiskers, 1.5 times IQR; grey points, outliers; asterisks, FDR<0.05; hash, FDR<0.10.