Evolution of antibody profiles against SARS-CoV-2 in experienced and naïve vaccinated elderly people

Introduction The third dose of the COVID-19 vaccine is especially necessary in people over 65 years of age due to their lower immune response. Methods We designed a multicentre, prospective observational study including 98 people ≤65 years old who lived in two nursing homes in Valladolid, Spain. One of the groups had previous experience with SARS-CoV-2 (n=68;69.4%) and the other was naïve (n=30;30.6%). We evaluated the response to the three doses of the Comirnaty vaccine and the dynamics of antibodies during 5 consecutive serum samplings: 2 after the first two doses of vaccination, one three months after the first dose, another at 6 months and the last one month after the third dose. IgG antibodies against SARS-CoV-2 S1, RBD and N antigens were analysed. Results Both groups increased the level of Abs against S1 and RBD, but the experienced group showed a 130-fold higher humoral response due to hybrid immunisation (infection+vaccination). The response to vaccination with Comirnaty against COVID-19 was higher in those ≤65 years with previous experience than those who were naïve. However, the amount of antibodies against S1 and RBD equalised at 6 months. After the third dose, both groups raised the amount of antibodies to a similar level. The reinfections suggested by the analysis of antibodies against N were frequent in both groups. Discussion The third dose showed a clear benefit for elderly people, with the reinforcement of the antibody levels after the decline suffered after six months of the first two doses.

Evolution of antibody profiles against SARS-CoV-2 in experienced and naïve vaccinated elderly people.

Introduction: The third dose of the COVID-19 vaccine is especially necessary in people over 65 years of age due to their lower immune response. Methods: We designed a multicentre, prospective observational study including 98 people ≤65 years old who lived in two nursing homes in Valladolid, Spain. One of the groups had previous experience with SARS-CoV-2 (n=68;69.4%) and the other was naïve (n=30;30.6%). We evaluated the response to the three doses of the Comirnaty vaccine and the dynamics of antibodies during 5 consecutive serum samplings: 2 after the first two doses of vaccination, one three months after the first dose, another at 6 months and the last one month after the third dose. IgG antibodies against SARS-CoV-2 S1, RBD and N antigens were analysed. Results: Both groups increased the level of Abs against S1 and RBD, but the experienced group showed a 130-fold higher humoral response due to hybrid immunisation (infection+vaccination). The response to vaccination with Comirnaty against COVID-19 was higher in those ≤65 years with previous experience than those who were naïve. However, the amount of antibodies against S1 and RBD equalised at 6 months. After the third dose, both groups raised the amount of antibodies to a similar level. The reinfections suggested by the analysis of antibodies against N were frequent in both groups. Discussion: The third dose showed a clear benefit for elderly people, with the reinforcement of the antibody levels after the decline suffered after six months of the first two doses.

Altered Surface Expression of Insulin-Degrading Enzyme on Monocytes and Lymphocytes from COVID-19 Patients Both at Diagnosis and after Hospital Discharge.

Although the COVID-19 disease has developed into a worldwide pandemic, its pathophysiology remains to be fully understood. Insulin-degrading enzyme (IDE), a zinc-metalloprotease with a high affinity for insulin, has been found in the interactomes of multiple SARS-CoV-2 proteins. However, the relevance of IDE in the innate and adaptative immune responses elicited by circulating peripheral blood mononuclear cells is unknown. Here, we show that IDE is highly expressed on the surface of circulating monocytes, T-cells (both CD4+ and CD4-), and, to a lower extent, in B-cells from healthy controls. Notably, IDE's surface expression was upregulated on monocytes from COVID-19 patients at diagnosis, and it was increased in more severe patients. However, IDE's surface expression was downregulated (relative to healthy controls) 3 months after hospital discharge in all the studied immune subsets, with this effect being more pronounced in males than in females, and thus it was sex-dependent. Additionally, IDE levels in monocytes, CD4+ T-cells, and CD4- T-cells were inversely correlated with circulating insulin levels in COVID-19 patients (both at diagnosis and after hospital discharge). Of note, high glucose and insulin levels downregulated IDE surface expression by ~30% in the monocytes isolated from healthy donors, without affecting its expression in CD4+ T-cells and CD4- T-cells. In conclusion, our studies reveal the sex- and metabolism-dependent regulation of IDE in monocytes, suggesting that its regulation might be important for the recruitment of immune cells to the site of infection, as well as for glucometabolic control, in COVID-19 patients.

Whole blood DNA methylation analysis reveals respiratory environmental traits involved in COVID-19 severity following SARS-CoV-2 infection.

SARS-CoV-2 infection can cause an inflammatory syndrome (COVID-19) leading, in many cases, to bilateral pneumonia, severe dyspnea, and in ~5% of these, death. DNA methylation is known to play an important role in the regulation of the immune processes behind COVID-19 progression, however it has not been studied in depth. In this study, we aim to evaluate the implication of DNA methylation in COVID-19 progression by means of a genome-wide DNA methylation analysis combined with DNA genotyping. The results reveal the existence of epigenomic regulation of functional pathways associated with COVID-19 progression and mediated by genetic loci. We find an environmental trait-related signature that discriminates mild from severe cases and regulates, among other cytokines, IL-6 expression via the transcription factor CEBP. The analyses suggest that an interaction between environmental contribution, genetics, and epigenetics might be playing a role in triggering the cytokine storm described in the most severe cases.

PCR-based diagnosis of respiratory virus in postsurgical septic patients: A preliminary study before SARS-CoV-2 pandemic.

Respiratory viruses are part of the normal microbiota of the respiratory tract, which sometimes cause infection with/without respiratory insufficiency and the need for hospital or ICU admission. The aim of this study is to determine the prevalence of respiratory viruses in nontransplanted postoperative septic patients as well as lymphocyte count influence in their presence and its relationship to mortality. 223 nontransplanted postsurgical septic patients were recruited on the Intensive Care Unit (ICU) at Hospital Clínico Universitario de Valladolid prior to the SARS-COV-2 pandemic. Patients were split into 2 groups according to the presence/absence of respiratory viruses. Multivariate logistic regression analysis was used to identify independent factors related to positive respiratory virus PCR test. Respiratory viruses were isolated in 28.7% of patients. 28-day mortality was not significantly different between virus-positive and virus-negative groups. Logistic regression analysis revealed that lymphocyte count ≤ 928/µl is independently associated with a positive PCR result [OR 3.76, 95% CI (1.71-8.26), P = .001] adjusted by platelet count over 128,500/µL [OR 4.27, 95% CI (1.92-9.50) P < .001] and the presence of hypertension [OR 2.69, 95% CI (1.13-6.36) P = .025] as confounding variables. Respiratory viruses' detection by using PCR in respiratory samples of nontransplanted postoperative septic patients is frequent. These preliminary results revealed that the presence of lymphopenia on sepsis diagnosis is independently associated to a positive virus result, which is not related to a higher 28-day mortality.

Growth Arrest-Specific Factor 6 (GAS6) Is Increased in COVID-19 Patients and Predicts Clinical Outcome.

BACKGROUND: Growth arrest-specific factor 6 (GAS6) and the Tyro3, AXL, and MERTK (TAM) receptors counterbalance pro-inflammatory responses. AXL is a candidate receptor for SARS-CoV-2, particularly in the respiratory system, and the GAS6/AXL axis is targeted in current clinical trials against COVID-19. However, GAS6 and TAMs have not been evaluated in COVID-19 patients at emergency admission. METHODS: Plasma GAS6, AXL, and MERTK were analyzed in 132 patients consecutively admitted to the emergency ward during the first peak of COVID-19. RESULTS: GAS6 levels were higher in the SARS-CoV-2-positive patients, increasing progressively with the severity of the disease. Patients with initial GAS6 at the highest quartile had the worst outcome, with a 3-month survival of 65%, compared to a 90% survival for the rest. Soluble AXL exhibited higher plasma concentration in deceased patients, without significant differences in MERTK among SARS-CoV-2-positive groups. GAS6 mRNA was mainly expressed in alveolar cells and AXL in airway macrophages. Remarkably, THP-1 human macrophage differentiation neatly induces AXL, and its inhibition (bemcentinib) reduced cytokine production in human macrophages after LPS challenge. CONCLUSIONS: Plasma GAS6 and AXL levels reflect COVID-19 severity and could be early markers of disease prognosis, supporting a relevant role of the GAS6/AXL system in the immune response in COVID-19.