Impacts of delta and omicron variants on inactivated SARS-CoV-2 vaccine-induced T cell responses in patients with autoimmune diseases and healthy controls.

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection causes coronavirus disease 2019 (COVID-19), which is still devastating economies and communities globally. The increasing infections of variants of concern (VOCs) in vaccinated population have raised concerns about the effectiveness of current vaccines. Patients with autoimmune diseases (PAD) under immunosuppressant treatments are facing higher risk of infection and potentially lower immune responses to SARS-CoV-2 vaccination. METHODS: Blood samples were collected from PAD or healthy controls (HC) who finished two or three doses of inactivated vaccines. Spike peptides derived from wild-type strain, delta, omicron BA.1 were utilised to evaluate T cell responses and their cross-recognition of delta and omicron in HC and PAD by flow cytometry and ex vivo IFNγ-ELISpot. RESULTS: We found that inactivated vaccine-induced spike-specific memory T cells were long-lasting in both PAD and HC. These spike-specific T cells were highly conserved and cross-recognized delta and omicron. Moreover, a third inactivated vaccine expanded spike-specific T cells that responded to delta and omicron spike peptides substantially in both PAD and HC. Importantly, the polyfunctionality of spike-specific memory T cells was preserved in terms of cytokine and cytotoxic responses. Although the extent of T cell responses was lower in PAD after two-dose, T cell responses were boosted to a greater magnitude in PAD by the third dose, bringing comparable spike-specific T cell immunity after the third dose. CONCLUSION: Inactivated vaccine-induced spike-specific T cells remain largely intact against delta and omicron variants. This study expands our understanding of inactivated vaccine-induced T cell responses in PAD and HC, which could have important indications for vaccination strategy.

A fourth dose of the inactivated SARS-CoV-2 vaccine redistributes humoral immunity to the N-terminal domain.

The effectiveness of a 3rd dose of SARS-CoV-2 vaccines waned quickly in the Omicron-predominant period. In response to fast-waning immunity and the threat of Omicron variant of concern (VOC) to healthcare workers (HCWs), we conduct a non-randomized trial (ChiCTR2200055564) in which 38 HCWs volunteer to receive a homologous booster of inactivated vaccines (BBIBP-CorV) 6 months after the 3rd dose. The primary and secondary outcomes are neutralizing antibodies (NAbs) and the receptor-binding domain (RBD)-directed antibodies, respectively. The 4th dose recalls waned immunity while having distinct effects on humoral responses to different antigens. The peak antibody response to the RBD induced by the 4th dose is inferior to that after the 3rd dose, whereas responses to the N-terminal domain (NTD) of spike protein are further strengthened significantly. Accordingly, the 4th dose further elevates the peak level of NAbs against ancestral SARS-CoV-2 and Omicron BA.2, but not BA.1 which has more NTD mutations. No severe adverse events related to vaccination are recorded during the trial. Here, we show that redistribution of immune focus after repeated vaccinations may modulate cross-protective immune responses against different VOCs.

Effect of Inactivated SARS-CoV-2 Vaccine on Thyroid Function and Autoimmunity Within 28 Days After the Second Dose.

Background: The safety of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines is widely appreciated. However, there is limited knowledge regarding the potential impact of SARS-CoV-2 vaccines on the thyroid. Methods: We performed two prospective clinical trials between April and June, 2021, enrolling recipients of the inactivated SARS-CoV-2 vaccine (BBIBP-CorV and CoronaVac). Thyroid function, antithyroid antibody levels, and SARS-CoV-2 neutralizing antibody levels were detected for each participant before receiving the first vaccine dose and 28 days after receiving the second vaccine dose. Results: A total of 657 recipients participated in the study. The overall median thyroid function and levels of antithyroid antibodies before and after SARS-CoV-2 vaccination were within the normal range. Among the 564 participants with normal thyroid function at baseline, 36 (6.38% [confidence interval; CI 4.51-8.73]) developed thyroid dysfunction. Of the 545 recipients with negative antithyroid antibodies at baseline, none developed abnormal antibodies after vaccination. Notably, 75.27% (70/93 [CI 65.24-83.63]) of the 93 recipients with thyroid dysfunction returned to normal function after vaccination. The levels of antithyroid peroxidase antibody (96.20% [CI 89.30-99.21]) and antithyroglobulin antibody (TgAb; 88.31% [CI 78.97-94.51]) remained positive after vaccination in most patients with abnormal values at baseline. However, the TgAb levels in more than half of the patients (48/77) decreased. All of 11 abnormal thyrotropin receptor antibody levels at baseline decreased postvaccination. Conclusions: Vaccination with an inactivated SARS-CoV-2 vaccine had no significant adverse impact on thyroid function or antithyroid antibodies within the first 28 days after the second dose. Clinical Trial Registration: ChiCTR2100045109 and ChiCTR2100042222.

Robust induction of B cell and T cell responses by a third dose of inactivated SARS-CoV-2 vaccine.

SARS-CoV-2 inactivated vaccines have shown remarkable efficacy in clinical trials, especially in reducing severe illness and casualty. However, the waning of humoral immunity over time has raised concern over the durability of immune memory following vaccination. Thus, we conducted a nonrandomized trial among the healthcare workers (HCWs) to investigate the long-term sustainability of SARS-CoV-2-specific B cells and T cells stimulated by inactivated vaccines and the potential need for a third booster dose. Although neutralizing antibodies elicited by the standard two-dose vaccination schedule dropped from a peak of 29.3 arbitrary units (AU)/mL to 8.8 AU/mL 5 months after the second vaccination, spike-specific memory B and T cells were still detectable, forming the basis for a quick recall response. As expected, the faded humoral immune response was vigorously elevated to 63.6 AU/mL by 7.2 folds 1 week after the third dose along with abundant spike-specific circulating follicular helper T cells in parallel. Meanwhile, spike-specific CD4+ and CD8+ T cells were also robustly elevated by 5.9 and 2.7 folds respectively. Robust expansion of memory pools by the third dose potentiated greater durability of protective immune responses. Another key finding in this trial was that HCWs with low serological response to two doses were not truly "non-responders" but fully equipped with immune memory that could be quickly recalled by a third dose even 5 months after the second vaccination. Collectively, these data provide insights into the generation of long-term immunological memory by the inactivated vaccine, which could be rapidly recalled and further boosted by a third dose.

Syndecan-1, an indicator of endothelial glycocalyx degradation, predicts outcome of patients admitted to an ICU with COVID-19.

BACKGROUND: We investigated the feasibility of two biomarkers of endothelial damage (Syndecan-1 and thrombomodulin) in coronavirus disease 2019 (COVID-19), and their association with inflammation, coagulopathy, and mortality. METHODS: The records of 49 COVID-19 patients who were admitted to an intensive care unit (ICU) in Wuhan, China between February and April 2020 were examined. Demographic, clinical, and laboratory data, and outcomes were compared between survivors and non-survivors COVID-19 patients, and between patients with high and low serum Syndecan-1 levels. The dynamics of serum Syndecan-1 levels were also analyzed. RESULTS: The levels of Syndecan-1 were significantly higher in non-survivor group compared with survivor group (median 1031.4 versus 504.0 ng/mL, P = 0.002), and the levels of thrombomodulin were not significantly different between these two groups (median 4534.0 versus 3780.0 ng/mL, P = 0.070). Kaplan-Meier survival analysis showed that the group with high Syndecan-1 levels had worse overall survival (log-rank test: P = 0.023). Patients with high Syndecan-1 levels also had significantly higher levels of thrombomodulin, interleukin-6, and tumor necrosis factor-α. Data on the dynamics of Syndecan-1 levels indicated much greater variations in non-survivors than survivors. CONCLUSIONS: COVID-19 patients with high levels of Syndecan-1 develop more serious endothelial damage and inflammatory reactions, and have increased mortality. Syndecan-1 has potential for use as a marker for progression or severity of COVID-19. Protecting the glycocalyx from destruction is a potential treatment for COVID-19.

Construction of an autophagy interaction network based on competitive endogenous RNA reveals the key pathways and central genes of SARS-CoV-2 infection in vivo.

As of April 1, 2021, more than 2.8 million people have died of SARS-CoV-2 infection. In addition, the mutation of virus strains that have accompanied the pandemic has brought more severe challenges to pandemic control. Host microRNAs (miRNAs) are widely involved in a variety of biological processes of coronavirus infection, including autophagy in SARS-CoV-2 infection. However, the mechanisms underlying miRNAs involved in autophagy in SARS-CoV-2 infection have not been fully elucidated. In this study, the miRNA and messenger RNA (mRNA) expression profiles of patients with SARS-CoV-2 infection were investigated based on raw data from Gene Expression Omnibus (GEO) datasets, and potential novel biomarkers of autophagy were revealed by bioinformatics analyses. We identified 32 differentially expressed miRNAs and 332 differentially expressed mRNAs in patients with SARS-CoV-2 infection. Cytokine receptor related pathways were the most enriched pathways for differentially expressed miRNAs identified by pathway analysis. Most importantly, an autophagy interaction network, which was associated with the pathological processes of SARS-CoV-2 infection, especially with the cytokine storm, was constructed. In this network, hsa-miR-340-3p, hsa-miR-652-3p, hsa-miR-4772-5p, hsa-miR-192-5p, TP53INP2, and CCR2 may be biomarkers that predict changes in mild SARS-CoV-2 infection. Some molecules, including hsa-miR-1291 and CXCR4, were considered potential targets to predict the emergence of severe symptoms in SARS-CoV-2 infection. To our knowledge, this study provided the first profile analysis of an autophagy interaction network in SARS-CoV-2 infection and revealed several novel autophagy-related biomarkers for understanding the pathogenesis of SARS-CoV-2 infection in vivo.

Ferritin in the coronavirus disease 2019 (COVID-19): A systematic review and meta-analysis.

OBJECTIVE: The coronavirus disease 2019 (COVID-19) has rapidly developed into a pandemic. Increased levels of ferritin due to cytokine storm and secondary hemophagocytic lymphohistiocytosis were found in severe COVID-19 patients. Therefore, the aim of this study was to determine the role of ferritin in COVID-19. METHODS: Studies investigating ferritin in COVID-19 were collected from PubMed, EMBASE, CNKI, SinoMed, and WANFANG. A meta-analysis was performed to compare the ferritin level between different patient groups: non-survivors versus survivors; more severe versus less severe; with comorbidity versus without comorbidity; ICU versus non-ICU; with mechanical ventilation versus without mechanical ventilation. RESULTS: A total of 52 records involving 10 614 COVID-19-confirmed patients between December 25, 2019, and June 1, 2020, were included in this meta-analysis, and 18 studies were included in the qualitative synthesis. The ferritin level was significantly increased in severe patients compared with the level in non-severe patients [WMD 397.77 (95% CI 306.51-489.02), P < .001]. Non-survivors had a significantly higher ferritin level compared with the one in survivors [WMD 677.17 (95% CI 391.01-963.33), P < .001]. Patients with one or more comorbidities including diabetes, thrombotic complication, and cancer had significantly higher levels of ferritin than those without (P < .01). Severe acute liver injury was significantly associated with high levels of ferritin, and its level was associated with intensive supportive care, including ICU transfer and mechanical ventilation. CONCLUSIONS: Ferritin was associated with poor prognosis and could predict the worsening of COVID-19 patients.