Immune signature in vaccinated versus nonvaccinated aged people with COVID-19 pneumonia

Background: A definition of the immunological features of COVID-19 pneumonia is needed to support clinicalmanagement of aged patients. In this study, we characterized the humoral and cellular immune responses inpresence or absence of SARS-CoV-2 vaccination, in aged patients admitted to the IRCCS San Raffaele Hospital (Italy)for COVID-19 pneumonia between November 2021 and March 2022.Methods: The study was approved by local authorities. Disease severity was evaluated according to WHO guidelines.We tested: (A) anti-SARS-CoV-2 humoral response (anti-RBD-S IgG, anti-S IgM, anti-N IgG, neutralizing activity againstDelta, BA1, BA4/5 variants); (B) Lymphocyte B, CD4 and CD8 T-cell phenotype; (C) plasma cytokines. The impact ofvaccine administration and different variants on the immunological responses was evaluated using standard linearregression models and Tobit models for censored outcomes adjusted for age, vaccine doses and gender.Results: We studied 47 aged patients (median age 78.41), 22 (47%) female, 33 (70%) older than 70 years (elderly). Athospital admission, 36% were unvaccinated (VACno), whilst 63% had received 2 (VAC2) or 3 doses (VAC3) of vaccine.During hospitalization, WHO score > 5 was higher in unvaccinated (14% in VAC3 vs. 43% in VAC2 and 44% VACno).Independently from vaccination doses and gender, elderly had overall reduced anti-SARS-CoV-2 humoral response(IgG-RBD-S, p = 0.0075). By linear regression, the anti-RBD-S (p = 0.0060), B (p = 0.0079), CD8 (p = 0.0043) and Th2 cellcounts (p = 0.0131) were higher in VAC2 + 3 compared to VACno. Delta variant was the most representative in VAC2(n = 13/18, 72%), detected in 41% of VACno, whereas undetected in VAC3, and anti-RBD-S production was higher inVAC2 vs. VACno (p = 0.0001), alongside neutralization against Delta (p = 0141), BA1 (p = 0.0255), BA4/5 (p = 0.0162).Infections with Delta also drove an increase of pro-inflammatory cytokines (IFN-α, p = 0.0463; IL-6, p = 0.0010).Conclusions: Administration of 3 vaccination doses reduces the severe symptomatology in aged and elderly.Vaccination showed a strong association with anti-SARS-CoV-2 humoral response and an expansion of Th2 T-cells.