RESUMO
BACKGROUND: Comparative analyses of SARS-CoV-2-specific immune responses elicited by diverse prime-boost regimens are required to establish efficient regimens for the control of COVID-19. METHOD: In this prospective observational cohort study, spike-specific immunoglobulin G (IgG) and neutralizing antibodies (nAbs) alongside spike-specific T-cell responses in age-matched groups of homologous BNT162b2/BNT162b2 or AZD1222/AZD1222 vaccination, heterologous AZD1222/BNT162b2 vaccination, and prior wild-type SARS-CoV-2 infection/vaccination were evaluated. RESULTS: Peak immune responses were achieved after the second vaccine dose in the naïve vaccinated groups and after the first dose in the prior infection/vaccination group. Peak titers of anti-spike IgG and nAb were significantly higher in the AZD1222/BNT162b2 vaccination and prior infection/vaccination groups than in the BNT162b2/BNT162b2 or AZD1222/AZD1222 groups. However, the frequency of interferon-γ-producing CD4+ T cells was highest in the BNT162b2/BNT162b2 vaccination group. Similar results were observed in the analysis of polyfunctional T cells. When nAb and CD4+T-cell responses against the Delta variant were analyzed, the prior infection/vaccination group exhibited higher responses than the groups of other homologous or heterologous vaccination regimens. CONCLUSION: nAbs are efficiently elicited by heterologous AZD1222/BNT162b2 vaccination, as well as prior infection/vaccination, whereas spike-specific CD4+T-cell responses are efficiently elicited by homologous BNT162b2 vaccination. Variant-recognizing immunity is more efficiently generated by prior infection/vaccination than the other homologous or heterologous vaccination regimens.
Assuntos
Anticorpos Neutralizantes , COVID-19 , Humanos , Anticorpos Antivirais , Vacina BNT162 , ChAdOx1 nCoV-19 , Imunoglobulina G , Estudos Prospectivos , SARS-CoV-2 , Vacinação , Linfócitos T/imunologia , Memória ImunológicaRESUMO
Nuclear factor-kappaB (NF-kappaB) is a transcription factor that plays crucial roles in inflammation and immunity. Understanding the positive and negative regulation of NF-kappaB activity is therefore of fundamental importance. A few previous studies reported that inhibition of the phosphatidylinositol 3-kinase (PI3K)-Akt pathway enhances lipopolysaccharide (LPS)-induced activation of NF-kappaB. However, many aspects of the PI3K negative regulation of NF-kappaB activation remain to be clarified. The present study was conducted to shed light on cell-type specificity, stimulus specificity, and upstream mechanisms of the enhanced NF-kappaB activation by PI3K inhibitors. Gel shift assays showed that LY294002 (LY29) potently increased interleukin (IL)-1-induced NF-kappaB DNA binding in human monocytic THP-1 cells. Moreover, another PI3K inhibitor 3-methyladenine also strongly enhanced IL-1-induced NF-kappaB DNA binding, while LY303511, an inactive analogue of LY29, did not increase the NF-kappaB DNA binding. Compared with LY29, wortmannin (WM) effected only a marginal enhancement of NF-kappaB DNA binding. LY29 treatment also augmented tumor necrosis factor (TNF)-mediated NF-kappaB DNA binding. Furthermore, LY29, but not WM, increased cyclooxygenase (COX)-2 mRNA expression by IL-1 or TNF in THP-1 cells. Likewise, prostaglandin E2 production by IL-1 was increased by LY29, but not by WM. Western blot analysis demonstrated that IkappaB kinase (IKK) activation as well as IkappaB-alpha degradation and NF-kappaB nuclear translocation was elevated by LY29 and WM. Among the tested cell lines (HL-60, ECV304, Hep-2, and Molt-4), only HL-60, a promyelocytic cell line, showed enhanced NF-kappaB DNA binding by LY29. These results suggest that pharmacological inhibition of PI3K enhances the NF-kappaB-activating pathways by IL-1 through augmentation of IKK activation in myeloid/monocytic cells and the NF-kappaB enhancement is more robustly achieved by LY29 than by WM.