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1.
Vaccines ; 10(3), 2022.
Article in English | EMBASE | ID: covidwho-1818229

ABSTRACT

Introduction: Onset of oral lichenoid lesions (OLL) or oral lichen planus (OLP) can be rare adverse reactions to vaccines. Recently, the first solitary cases were reported after COVID-19 vaccination. The aim of the present study was to assess if an increased frequency of OLL/OLP can be found after COVID-19 vaccination within a large real-world cohort. It was assumed that the incidence of OLL/OLP was significantly higher in subjects who received COVID-19 vaccine (cohort I) compared to individuals who were not vaccinated (cohort II). Patients and Methods: Initial cohorts of 274,481 vaccinated and 9,429,892 not vaccinated patients were retrieved from the TriNetX database (TriNetX, Cambridge, Massachusetts, USA), and matched for age, gender and the frequency of use of non-steroidal anti-inflammatory drugs, beta blockers, and angiotensin-converting enzyme inhibitors. Results: After matching each cohort, we accounted for 217,863 patients. Among cohort I, 146 individuals had developed OLL/OLP within 6 days after COVID-19 vaccination (88 and 58 subjects had received mRNA-and adenovirus vector-based vaccines), whereas in cohort II, 59 patients were newly diagnosed with OLL/OLP within 6 days after having visited the clinic for any other reason. The risk of developing OLL/OLP was calculated as 0.067% vs. 0.027%, for cohorts I and II, whereby the risk difference was highly significant (p < 0.001;log-rank test). RR and OR were 2.475 (95% CI = 1.829;3.348) and 2.476 (95% CI = 1.830;3.350), respectively. Discussion: The hypothesis was confirmed. Accordingly, the obtained results suggest that the onset of OLL/OLP is a rare adverse drug reaction to COVID-19 vaccines, especially to mRNA vaccines. Thus far, it remains unknown if specific components of the formulations cause a type IV hypersensitive reaction corresponding to OLL, or if the immune response post vaccination triggers a T cell-driven autoimmune reaction directed against the basal layer of keratinocytes of the oral mucosa in terms of OLP. Although OLL and OLP are both classified as premalignant lesions, spontaneous remission may be expected over time, at least in the case of OLL. Therefore, the presented findings should not place any limitation toward the use of COVID-19-vaccines in broad levels of the population.

2.
Allergy, Asthma and Clinical Immunology ; 18(SUPPL 1), 2022.
Article in English | EMBASE | ID: covidwho-1817257

ABSTRACT

Background: Multiple factors (age, male sex, lymphopenia, co-morbidities) are associated with the severity of Coronavirus disease-2019 (COVID-19). Evidence of circulating autoantibodies [1] and neutrophil extracellular trap (NETs) [2] during acute phase of the infection indicate a possible autoimmune pathomechanism. We investigated if autoimmune markers in critically ill COVID-19 patients predict fatality Methods: In a single-center, prospective, multiple time-point observational study with mechanically ventilated COVID-19 patients, blood and endotracheal aspirates (ETA) were collected at the time of intubation, at worsening (and/or 7 days), and at extubation. Seventeen common autoantibodies associated with clinical pathologies, and anti- DFS70 (dense fine speckled 70, an exclusion marker for rheumatologic disease), were detected using anti-nuclear/extra-nuclear antibody line immunoassay (IMTEC-ANA-LIA XL, Human Diagnostics, Germany). Results: Of our interim analysis with 22 patients who completed the study, 10 had a fatal outcome (45%). Demographics/clinical parameters were unremarkable between survivor and fatal sub-groups. At 1:100 titer, 68% (15) patients had > 2 circulating autoreactivities on the ANA panel. Mortality was associated with increased dsDNA and NETs in serum and endotracheal aspirates, and low levels of circulating T-regulatory cells (P<0.05). However, presence of anti-DFS70 predicted good outcome (Odd ratio:41.3, P = 0.04) irrespective of other autoreactivities (Kaplan Meier, Log-rank test, P = 0.003). Conclusions: To our knowledge, this is the first study to analyze markers of autoimmunity in ventilated patients to predict mortality. The data provides a strong rationale to develop anti-DFS70 as a biomarker as well as investigate their protective mechanism against an autoimmune pathology.

3.
Clinical Cancer Research ; 27(6 SUPPL 1), 2021.
Article in English | EMBASE | ID: covidwho-1816927

ABSTRACT

Introduction Treatment of B-lineage lymphoma with B-cell depleting immunotherapy causes B-cell aplasia and impairs immune response. Case studies have reported patients treated with anti-CD20 therapy who suffered from persistent Covid-19. We aimed to assess the incidence, risk factors and long-term outcomes of persistent Covid-19 in patients with lymphoma. Patients and methods This retrospective multicentric study was conducted in 16 French hospitals. All adult patients with lymphoma who were admitted for Covid-19 in March and April 2020 were included. Persistent Covid-19 was defined as persisting severe Covid-19 symptoms requiring in-hospital stay for >30 days. Patients who re-experienced severe Covid-19 symptoms after initial improvement, requiring repeated hospitalizations for a total in-hospital length of stay >30 days were added to the persistent Covid-19 cases. Results One hundred eleven patients were included. Thirty days after admission for Covid-19, 24 patients had died, 55 had been definitively discharged from hospital, 31 were still hospitalized and 1 was later rehospitalized for Covid-19 recurrence. The incidence of persistent Covid-19 was 32/111 (29%). Patients with persistent Covid-19 had a median age of 64 years (range, 43-87) and 63% were male. Twenty-two patients (69%) had at least one significant comorbidity. None of the patients with T-cell (n=8) lymphoma or classical Hodgkin's disease (n=8) experienced persistent Covid-19. In the 32 patients with persistent Covid-19, the median time between first admission and final discharge was 58 days (range, 31-235) and the median duration of Covid-19 symptoms was 83 days (range, 32-237). Eight patients received corticosteroids and 9 convalescent plasma: all patients recovered from their symptoms, except one. Overall, 9 patients with persistent Covid-19 died (27%). After a median follow-up of 191 days (range, 3-260), the 6-month overall survival was 69% (95% CI 60-78%) for the whole cohort. In multivariate analysis, administration of anti-CD20 monoclonal antibody within 12 months before admission to hospital for Covid-19 was both associated with decreased overall survival (HR 2.13, 95% CI 1.03-4.44, p = 0.043) and prolonged in-hospital stay (HR 1.97, 95% CI 1.24-3.13, p = 0.004). The two other significant factors associated with decreased overall survival and prolonged in-hospital stay: age ≥ 70 years and refractory or relapsed lymphoma. Conclusion Patients with B-cell non-Hodgkin lymphoma hospitalized for Covid-19 have a high incidence of prolonged evolution of SARS-CoV-2 infection. Administration of anti-CD20 therapy within the last 12 months is one of the main risk factors for longer in-hospital stay and death of Covid-19. The risk of persistent Covid-19 was also higher in patients older than 70 years or with refractory or relapsed disease. These findings may contribute to guide the management of lymphoma patients during the Covid-19 pandemic.

4.
Clinical Cancer Research ; 27(6 SUPPL 1), 2021.
Article in English | EMBASE | ID: covidwho-1816919

ABSTRACT

Cancer patients display immunomodulation related to malignancy and anti-cancer therapies, but how these factors impact COVID-19 remains unknown. To investigate immune responses in cancer patients with COVID-19, we undertook a prospective case-control study, enrolling hospitalized solid tumor patients with acute COVID-19, as well as age-, gender-, and comorbidity-matched COVID-19 patients without cancer as controls. Using biospecimens collected during hospitalization, we performed virologic measurements as well as in-depth immunophenotyping of cellular, antibody and cytokine responses. We enrolled 17 cancer patients (cases) admitted to Yale-New Haven Hospital between March 15 and June 30, 2020 with COVID-19, as well as 17 matched non-cancer patients (controls) admitted with COVID-19. No significant differences were observed between cases and controls based on patient characteristics (age, gender, race, co-morbidities, smoking history, days from symptom onset to COVID-19 diagnosis) or outcomes (COVID-19 severity, length of hospital stay, rate of intubation or mortality). The most common primary tumor sites were lung (4/17) and gastrointestinal (4/17);all cases had received cancer-directed therapy within 6 months of COVID-19 diagnosis, with 13/17 receiving treatment less than 1 month prior to hospitalization. Three of 17 cases had received immune checkpoint inhibitor therapies. Despite having similar SARS-CoV-2 viral RNA loads at the time of COVID-19 diagnosis when compared with controls, cancer cases had increased viral RNA abundance during hospitalization, suggesting slower clearance. Antibody responses against SARS-CoV-2 were preserved in cancer cases, with cases displaying similar levels of IgM and IgG antibodies directed against SARS-CoV-2 epitopes compared to controls. Cytokine profiling revealed higher plasma levels of CCL3, IL1A and CXCL12 in cancer cases compared to controls. Using flow cytometric immunophenotyping, we found that innate immune and non-T cell adaptive immune parameters were similar between cases and controls hospitalized with COVID-19. However, among cancer cases on conventional therapies, T cell lymphopenia was more profound, and these cases demonstrated higher levels of CD8+ exhausted (CD8+CD45RA-PD1+TIM3+ ), CD8+GranzymeB+ and CD4+CD38+HLA-DR+ and CD8+CD38+HLA-DR+ activated T cells when compared with controls;interestingly, these differences were not observed in patients who had received immune checkpoint inhibition. Thus, we found reduced viral RNA clearance and specific alterations in T cell and cytokine responses in cancer patients hospitalized with COVID-19 compared with matched controls with COVID-19. This dysregulated T cell response in cancer patients, which may reflect immune modulation due to chronic antigen stimulation as well as cancer therapies, may lead to altered virologic and clinical outcomes in this population.

5.
Clinical Cancer Research ; 27(6 SUPPL 1), 2021.
Article in English | EMBASE | ID: covidwho-1816918

ABSTRACT

There is a pressing need to characterise the nature, extent and duration of immune response to SARS-CoV-2 in cancer patients, to inform risk-reduction strategies and preserve cancer outcomes. CAPTURE is a prospective, longitudinal cohort study of cancer patients and healthcare workers (HCWs) integrating immune profiles and clinical annotation. We evaluated 529 blood samples and 1051 oronasopharyngeal swabs from 144 cancer patients and 73 HCWs and correlated with >200 clinical variables. In patients with solid cancers and HCWs, S1-reactive and neutralising antibodies to SARS-CoV-2 were detectable five months post-infection. In these participants, SARS-CoV-2-specific T-cell responses were detected. CD4+ T-cell response correlated with S1 antibody levels. Patients with haematological malignancies had impaired but partially compensated immune responses, depending on malignancy and therapy. Overall, cancer stage, disease status, and therapies did not correlate with immune responses. These findings have implications for understanding individual risks and potential effectiveness of SARS-CoV-2 vaccination in this population.

6.
Clinical Cancer Research ; 27(6 SUPPL 1), 2021.
Article in English | EMBASE | ID: covidwho-1816903

ABSTRACT

Vimentin intermediate filament is involved in multiple steps of viral infection such as viral entry, trafficking and egress, as well as in various mechanisms of hyperinflammation such as the restraint of Treg cell functions and the activation of NLRP3 inflammasome. We evaluated a vimentin-binding small molecule compound ALD-R491 for its effects on cellular processes related to viral infection and for its efficacy in treating SARS-CoV2 infection in vitro and in vivo. In cultured cells, the compound could reduce endocytosis by 10%, endosomal trafficking by 40% and exosomal release by over 30%. In an infection system consisting of a lentiviral pseudotype bearing the SARS-CoV-2 spike protein and HEK293 cells over-expressing the human ACE2 receptor with multiplicity of infection (MOI) of 1, 10 and 100, the compound inhibited the infection up to a maximum of over 90%, with IC 50 < 50 nM, CC50 > 10 μM, and SI > 200. After oral administration of ALD-R491 in rats, the plasma concentration of the compound reached the peak (Tmax) at around 5 h with a half-life (T1/2) of about 5 h. The compound was widely distributed and enriched in tissues in vivo in rats with a volume of distribution (Vd) of over 2,000 ml/kg. The lung and the lymph nodes were among the tissues with high drug exposures. In rats receiving oral gavage of the compound at 30 mg/kg, the drug exposure in the lung and the lymph nodes maintained at levels over 1 μM from 1 h to 6 h after the oral dosing. In the syngeneic mouse tumor CT26 model, ALD-R491 was found to activate regulatory T cells (Tregs) in vivo and enhance de novo generation of Tregs in lymph nodes of the mice. In the Mouse-Adapted SARS-CoV2 model, aged mice (11-12 months) were used to provide a harder test of recovery from infection that reflects the severeness of COVID-19 in old patients. For therapeutic treatment, the mice were orally administered with the compound 24 h after the SARS-CoV2 infection once per day on Day 1, Day 2 and Day 4. At 10 mg/kg, ALD-R491 significantly reduced the body weight loss of the mice (p<0.01 on Day 5 post-infection). At both 3 mg/kg and 10 mg/kg, the compound significantly reduced the hemorrhagic score for the lungs (p<0.01 and p<0.05, respectively, on Day 5). These results indicate that vimentin intermediate filament is an effective host-directed antiviral target. Importantly, the vimentin-binding small molecule ALD-R491 impacts multiple aspects of SARS-CoV2 infection, has a favorable oral pharmacokinetics and a wide therapeutic window, and therefore may be a promising therapeutic candidate for treating COVID-19. Statement: Aluda Pharmaceuticals, Inc. has utilized the non-clinical and pre-clinical services program offered by the National Institute of Allergy and Infectious Diseases.

7.
Clinical Cancer Research ; 27(6 SUPPL 1), 2021.
Article in English | EMBASE | ID: covidwho-1816892

ABSTRACT

Introduction: The emergence of SARS-CoV-2 virus, which causes COVID-19, is a major global health hazard. Therefore, a comprehensive characterization of the humoral and cellular immune responses to this virus is essential to combat the COVID-19 pandemic. Our goal was to develop reliable methods and tools for the analysis of humoral and cellular B- and T- cell responses, which will facilitate scientific research for prediction of disease progression, long-term immunity and will support vaccine development. Methods: Plasma samples and PBMCs of COVID-19 convalescent and healthy donors were obtained. For the detection of SARS-CoV-2 specific antibodies and identification of antigen-specific B cells, we manufactured recombinant mono-biotinylated protein variants of the Spike (S), Receptor Binding Domain (RBD) and Nucleoprotein (N). To identify antigen-reactive T cells, SARS-CoV-2 peptide pools were synthetized for the S, N and Membrane (M) antigens and used for stimulation. The peptide pools consist of mainly 15-mer peptides having an 11-mer amino acid overlap and thereby overspan a whole protein sequence. Results: To determine the presence of SARS-CoV-2 reactive antibodies a flow-based bead assay using recombinant, mono-biotinylated SARS-CoV-2 antigens loaded onto Streptavidin (SAV)-coated-PMMA beads was set up. The beads were incubated with plasma samples and fluorochrome conjugated anti-human isotype specific antibodies for flow cytometric analysis. All the antigens tested were shown to be suitable for the detection of antibodies to SARS-CoV-2 in COVID-19 convalescent plasma. To assess the feasibility of recombinant antigens for the detection and isolation of antigen-specific B cells, the mono-biotinylated Spike and RBD antigens were tetramerized on fluorochrome-conjugated SAV. These tetramers were used for staining, magnetic enrichment and flow cytometric sorting of B cells specific to SARS-CoV-2 antigens. We were able to demonstrate that our recombinant antigens can be used to assess the presence and enable the phenotyping and isolation of rare antigen-specific B cells. For further characterization of the SARS-CoV-2 reactive T cell immunity PBMCs were short term stimulated with the S, M and N peptide pools. After intracellular staining of IFNg, TNFa, IL-2 and CD154, reactive T cells were detected using flow cytometry. We could demonstrate T cell reactivity towards each peptide pool. However, strengths of T cell responses towards the S, M and N peptide pools were heterogeneous between different COVID-19 convalescent individuals. Conclusion: To support and improve current research activities for the identification and characterization of SARS-CoV-2 reactive humoral and cellular B- and T- cell responses, potent tools and assays were developed. Described here research solutions offer the opportunity to successfully address and contribute to the investigation on healthy and dysfunctional immune reactions towards SARS-CoV-2.

8.
Clinical Cancer Research ; 27(6 SUPPL 1), 2021.
Article in English | EMBASE | ID: covidwho-1816884

ABSTRACT

The COVID-19 pandemic brought with it TX changes for many patients (pts) with AMEL, as it did for other pts with cancer. The long-term impacts of mandated area lockdowns, social distancing, medical society guidelines, and patient preference will not be fully understood for some time. The first step to learning from the pandemic is to assess how AMEL care was rendered in 2020. We performed a retrospective analysis of systemic TX for AMEL in KPNC, an integrated community healthcare system with approximately 4 million pts and about 150 de novo diagnoses of AMEL annually. We performed a chart review of pts with AMEL who were treated with standard of care systemic therapy, either immune-checkpoint inhibitors (ICI) or BRAF/MEK inhibitors (BRAF/MEKi), from January 1 to March 15, 2020, as a control group, and between March 15 and May 20, during the first wave of the COVID-19 pandemic in California with follow-up through November 4, 2020. Between January 1 and March 15, 26 pts started palliative ICI of whom 11 started combination PD1 (PD1i) and CTLA4 inhibitors. Among 15 pts who started on single-agent PD1i, 14 pts received short-interval TX (SIT), while 1 started long-interval TX (LIT). All 21 pts who started perioperative PD1i pre-pandemic, started on SIT. Between March 15 and May 20, 21 pts started palliative ICI, of whom only 3 started combination TX. Among pts who started palliative single-agent PD1i 40% started on LIT in this initial phase of the pandemic. 27 pts started perioperative ICI during this time. We found 3 started with neoadjuvant therapy and 78% started on LIT. Among 78 pts who were already on palliative single-agent ICI at the start of the COVID-19 pandemic, 15% remained on SIT and 24% changed to LIT. Sixteen pts (21%) also interrupted palliative ICI between March 15 and April 15 after a median time on TX of 45 weeks and for 63% the cited reason for interruption on chart review was the COVID 19 pandemic. Three of these pts who stopped ICI changed to BRAF/MEKi, the remainder continue in active follow-up as of November 2020. Among 72 pts already receiving perioperative ICI in March 2020, 19% remained on SIT, 35% changed to LIT, and 11% were already on LIT. 39% of pts interrupted perioperative ICI after a median time of 20 weeks on TX and 46% of these cited COVID 19 as the reason for interruption. Three pts have since resumed peri-operative TX, but the others remain in active follow-up off therapy. Between 3/15 and 5/30/2020, we noted a 325% increase in pts started on BRAF/MEKi;69% of pts received therapy for palliative intent. The start of the COVID-19 pandemic saw many different changes in AMEL TX in KPNC, with increased use of single-agent ICI, LIT, and oral therapy, in line with public health guidance, oncology societal guidelines and patient preference. It will be important to assess the long-term outcomes relating to these changes, including the impact of early discontinuation of ICI, to help guide future Melanoma care during and after the pandemic.

9.
Clinical Cancer Research ; 27(6 SUPPL 1), 2021.
Article in English | EMBASE | ID: covidwho-1816880

ABSTRACT

Cancer immunotherapy has shaped the way in which we design cancer treatments, introducing the paradigm of taking advantage of our immune system to fight cancer. We propose that the same concept could be applied to infectious diseases and, especially, to those that hamper the immune system like COVID-19. It is well known that an adaptive immune response is able to eradicate viral infections and CD8+ T-cells are key in such anti-viral response. Furthermore, several studies reported that the number of CD8+ T-cells is reduced in COVID-19 patients since the beginning of SARS-CoV-2 infection and further decreased in severe cases. CD8+ T-cells often show signs of exhaustion, loss of T-cell functions and suppression in COVID-19 patients, suggesting that hampering CD8+ T-cells could be a way by which SARS-CoV-2 infection progresses. Importantly, the number of CD8+ T cells appears to re-increase in patients that are recovering from COVID-19, suggesting that CD8+ T-cells could be a key factor that determines whether our body can recover from the disease. We propose that therapies that boost CD8+ T cells could be effective in clearing SARS-CoV-2 infection in COVID-19. To test this, we will take advantage of the adenosine-mediated immunomodulation. Adenosine, an ATP metabolite that is produced during inflammation, hypoxia and in the tumor microenvironment, was found to suppress the immune response through activation of adenosine receptors present on immune cells. Small molecules antagonists that block one of these receptors, adenosine A2A receptor (A2AR) antagonists, are currently being studied to boost anti-cancer T-cell mediated immune responses. Our data show that treatment with an A2AR antagonist restores and stabilizes Notch1, a key pathway for T-cell functions, along with production of INF-gamma and Granzyme B and proliferation in CD8+ T-cells. As a proof of concept, our data indicates that treatment with an A2AR antagonist increases CD8+ T-cells anti-cancer response in tumor-derived organoids, suggesting that the treatment boosts CD8+ T-cells-mediated immune response. Ongoing work aims to test whether the A2AR antagonist treatment restores several parameters of T-cell function that are specifically modified in COVID-19. This analysis will help to predict the action of the A2AR antagonist on T-cells in vivo and we ultimately aim to test this treatment in a mouse model for COVID-19. Overall, our work could introduce a new paradigm and new therapies for COVID-19 and other infectious diseases.

10.
Respirology ; 27(SUPPL 1):73, 2022.
Article in English | EMBASE | ID: covidwho-1816629

ABSTRACT

Introduction: The induction of regulatory T cells (Tregs) is indicated as a potential therapeutic strategy in inflammatory lung diseases including, asthma, viral-induced pneumonia, viral-induced acute lung injury (ALI), severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) and SARSCoV- 2-induced ALI. We previously identified that components of the bacteria Streptococcus pneumoniae (T + P) are able to increase Tregs to suppress experimental allergic airways disease, however, this mechanism of suppression and therapy has not been examined in ALI. Methods: We established a murine model of ALI using aerosolized LPS (100 μg/ml) in BALB/c mice. ALI was measured by the presence of neutrophils in the airways up to 96 hours post-exposure, and Tregs and dendritic cells were assessed by flow cytometry. To assess the therapeutic of T + P in ALI and the mechanisms involved, the combination was administered prior to LPS exposure in the absence or presence of anti-CD25. Results: Treatment with T + P significantly reduced total airway inflammation and suppressed the neutrophil chemokine C-X-C motif chemokine ligand 1 (Cxcl1) compared to Saline+LPS alone in experimental ALI. The numbers of Tregs were reduced in experimental ALI model and were restored by T + P treatment. Depletion of Tregs with anti- CD25 confirmed that the suppressive effects of T + P on ALI was through the induction of Tregs. Conclusion: Treatment with S. pneumoniae components T + P suppresses neutrophilic inflammation in ALI through immunoregulatory mechanisms that involve Tregs and may be a novel treatment for ALI including in COVID-19.

11.
Journal of the European Academy of Dermatology and Venereology ; 36(5):632, 2022.
Article in English | EMBASE | ID: covidwho-1816588
12.
Regenerative Therapy ; 20:61-71, 2022.
Article in English | EMBASE | ID: covidwho-1815134

ABSTRACT

COVID-19 disease caused by the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), started in December 2019 in Wuhan, China, and quickly became the global pandemic. The high spread rate, relatively high mortality rate, and the lack of specific medicine have led researchers and clinicians worldwide to find new treatment strategies. Unfortunately, evidence shows that the virus-specific receptor Angiotensin-Converting Enzyme 2 (ACE-2) is present on the surface of most cells in the body, leading to immune system dysfunction and multi-organ failure in critically ill patients. In this context, the use of Mesenchymal Stem Cells (MSCs) and their secret has opened new therapeutic horizons for patients due to the lack of ACE2 receptor expression. MSCs exert their beneficial therapeutic actions, particularly anti-inflammatory and immunomodulatory properties, mainly through paracrine effects which are mediated by exosomes. Exosomes are bilayer nanovesicles that carry a unique cargo of proteins, lipids and functional nucleic acids based on their cell origin. This review article aims to investigate the possible role of exosomes and the underlying mechanism involved in treating COVID-19 disease based on recent findings.

13.
Cytometry Part B - Clinical Cytometry ; 102(2):85-87, 2022.
Article in English | EMBASE | ID: covidwho-1813493
14.
Biochemical and Cellular Archives ; 21(2):1-2, 2021.
Article in English | EMBASE | ID: covidwho-1812557
15.
Front Immunol ; 13:832106, 2022.
Article in English | PubMed | ID: covidwho-1809389

ABSTRACT

Coronavirus disease 2019 (COVID-19) is the most devastating pandemic of the century, which is still far from over. The remarkable success of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines is the working hope, but the evolving variants are the huge concern that can turn the tide. Potential immune escape mutations (PIEMs) in the past and circulating variants were not studied at large scale (all available data). Hence, the conservation of antigenic determinants (epitopes) was analyzed in all available sequences of SARS-CoV-2 according to time (months), proteins, hosts, and variants. Numerous highly conserved B- and T-cell epitopes were identified in 24 proteins of SARS-CoV-2. A decrease in the conservation of epitopes with time was observed in almost all proteins, which was more rapid in neutralizing epitopes. Delta variant still has the highest PIEM in the circulating strains, which pose threat to the effectiveness of current vaccines. The inclusion of identified, highly conserved, and important epitopes in subunit vaccines can increase vaccine effectiveness against evolving variants. Trends in the conservation of epitopes in different proteins, hosts, and variants with time may also help to inspire the counter measure against the current pandemic.

16.
Embase; 2022.
Preprint in English | EMBASE | ID: ppcovidwho-333915

ABSTRACT

Background Limited information is available on the impact of immunosuppressants on COVID-19 vaccination in patients with immune-mediated inflammatory diseases (IMID). Methods This observational cohort study examined the immunogenicity of SARS-CoV-2 mRNA vaccines in adult patients with inflammatory bowel disease, rheumatoid arthritis, ankylosing spondylitis, or psoriatic disease, with or without maintenance immunosuppressive therapies. Antibody and T cell responses to SARS-COV-2, including neutralization against SARS-CoV-2 variants were determined before and after 1 and 2 vaccine doses. Results We prospectively followed 150 subjects, 26 healthy controls, 9 IMID patients on no treatment, 44 on anti-TNF, 16 on anti-TNF with methotrexate/azathioprine (MTX/AZA), 10 on anti-IL-23, 28 on anti-IL-12/23, 9 on anti-IL-17, and 8 on MTX/AZA. Antibody and T cell responses to SARS-CoV-2 were detected in all participants, increasing from dose 1 to dose 2 and declining 3 months later, with greater attrition in IMID patients compared to healthy controls. Antibody levels and neutralization efficacy against variants of concern were substantially lower in anti-TNF treated patients than in healthy controls and were undetectable against Omicron by 3 months after dose 2. Conclusions Our findings support the need for a third dose of mRNA vaccine and for continued monitoring of immunity in these patient groups.

17.
Pharmacy Education ; 22(2):259-262, 2022.
Article in English | EMBASE | ID: covidwho-1798550

ABSTRACT

A severe pneumonia-associated respiratory syndrome caused by the new coronavirus 2 (SARS-CoV-2) was identified in December 2019 as Coronavirus Disease 2019 (COVID-19). It has spread rapidly and has become a worldwide health challenge. Some patients experienced severe complications, including acute respiratory distress syndrome (ARDS), and have even progressed to an intensive care unit (ICU) admission and death. Research has reported that pathogenic T cells and inflammatory monocytes prompt an inflammatory storm with large amounts of interleukin 6. Consequently, IL-6 receptor inhibitors have been repurposed to treat COVID-19, but their exact role in treatment remains unclear. Tocilizumab (TCZ), a monoclonal antibody against IL-6, emerged as an alternative treatment in COVID-19 patients with ARDS syndrome. Therefore, the authors hypothesise that tocilizumab might be effective in decreasing the inflammatory storm and reducing mortality in COVID-19 severe cases. This observational retrospective study explored the use of a single dose of tocilizumab 400 mg intravenous infusion for an hour in COVID-19 patients. The results showed that tocilizumab could not improve the parameters related to mortality rates, such as IL-6 levels, leukocytes, C-reactive protein (CRP), Neutrophil-to-lymphocyte ratio (NLR), and ferritin. IL-6 levels increased after tocilizumab administration.

18.
American Journal of Blood Research ; 12(1):43-53, 2022.
Article in English | EMBASE | ID: covidwho-1798258

ABSTRACT

Coronavirus disease 2019 (COVID-19) is caused by pathogenic and highly transmissible Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) which is a single stranded RNA virus. It rapidly emerged from an epidemic to a global pandemic form spreading in alarming levels. The pathogenesis involving spike protein which is present on the viral surface, plays a key role in host attachment and penetration. SARS-CoV-2 infection significantly affects respiratory system, but may involve other systems including haematopoietic system and homeostasis. Aim of the review article is to discuss spectrum of haematological changes in the blood counts, coagulation, peripheral blood and bone marrow in COVID-19 for complete understanding the disease process, the knowledge of which is helpful in early diagnosis and management of these patients. An extensive immune profiling of B and T cell population with analysis of spectrum of immune changes during the period of infection were also discussed. In COVID-19, changes in laboratory parameters and hematologic abnormalities have been reported and its association with early diagnosis, disease prognosis and severity has been repeatedly discussed in the literature. Changes in laboratory investigations help in risk stratification and early intervention. The most common laboratory finding in COVID-19 is lymphopenia. COVID-19 patients presented with coagulopathy is at high risk of morbidity and mortality. In severe COVID-19 patients, bone marrow aspirate shows histiocytic proliferation with hemophagocytosis. To understand the correlations between immune responses and severity of COVID-19, immune profiling of B and T cell population was compared with extensive clinical data. A deep understanding of the laboratory findings and haematological abnormalities associated with SARS-CoV-2 infection would help to raise disease suspicion in absence of Real time polymerase chain reaction or antibody results. Also the blood counts along with the morphological changes in peripheral blood would be helpful in prompt screening, diagnosis, prognosis and management of COVID-19 patients.

19.
Critical Care ; 26(SUPPL 1), 2022.
Article in English | EMBASE | ID: covidwho-1793896

ABSTRACT

Introduction: After viral or bacterial sepsis, most intensive care unit (ICU) patients enter a state of profound immunosuppression contributing to patients' worsening. Transgene has developed an immunotherapy based on a viral vector encoding human interleukin-7 (hIL-7) to restore both innate and adaptive immune responses. Here, we assessed the capacity of hIL-7 to improve ex vivo T lymphocyte function from septic shock and COVID-19 patients. Methods: Primary human hepatocytes were transduced with MVAhIL- 7-Fc, a recombinant Modified Vaccinia virus Ankara (MVA) encoding the hIL-7 fused to the human IgG2 Fc fragment, or with empty MVA as control. Cell culture supernatants were harvested for further assays. T cells were collected from ICU patients (septic shock = 11, COVID- 19 = 29) and healthy donors (n = 21). STAT5 phosphorylation, cytokine production (ELISpot and intracellular staining) and cell proliferation were assessed upon TCR stimulation with supernatants containing or not hIL-7 produced after MVA transduction or with the counterpart recombinant hIL-7 (rhIL-7). Results: Patients with viral and bacterial sepsis display T lymphocyte alterations compared to healthy donors with a decreased production of cytokines and a decreased proliferation capacity. Supernatant containing hIL-7 induces STAT5 phosphorylation in CD3 lymphocytes of all patients. With 90% of responders, hIL-7 boosts cytokines production (single and double IFN-TNF) and T lymphocytes proliferation capacity at the same level as rhIL-7 in both cohorts whereas empty MVA has no effect. Conclusions: This study indicates that hIL-7-Fc produced after MVA transduction initiates IL-7 signaling through the phosphorylation of STAT5 and restores ex vivo human lymphocyte functions in cells from septic patients with acquired immunosuppression. This proof-of-concept study, along with experimental results in animal models, supports the clinical development of the MVA-hIL-7-Fc in sepsis immunosuppressed patients.

20.
Critical Care ; 26(SUPPL 1), 2022.
Article in English | EMBASE | ID: covidwho-1793887

ABSTRACT

Introduction: Hyperinflammation plays an important role in severe COVID-19. Using inconsistent criteria, researchers define hyperinflammation as a form of very severe inflammation with cytokine storm. Our paper gives a novel definition. Subsequently, we describe the treatment of ICU-patients with COVID-19 requiring ECMO and/or mechanical ventilation. Methods: We searched scientific articles on P2X7 purinergic receptors (P2X7Rs) to underpin our definition of hyperinflammation. We found that lidocaine can block P2X7Rs. The issue is that the halfmaximal effective concentration of lidocaine for P2X7R inhibition is much higher than the maximal tolerable plasma concentration. To overcome this, we selectively inhibit the P2X7Rs of the cells of the lymph nodes. We do this by subdermal infusion of lidocaine HCL inducing clonal expansion of Tregs in local lymph nodes. Secondarily, these Tregs migrate throughout the body suppressing systemic hyperinflammation (Fig. 1). We treated six COVID-19 ICU-patients with subdermal lidocaine infusion (1 mg/kg/h). Results: We found 437 articles to underpin our definition of hyperinflammation. The essence is that hyperinflammation is initiated when SARS-CoV-2 infection causes prolonged and vigorous activation of the P2X7Rs of the immune cells. This leads to cytokine storm and desensitisation of purinergic receptors of immune cells other than the P2X7Rs, resulting in immune paralysis with secondary infections. The six ICU-patients with COVID-19 we treated with lidocaine all recovered completely. Conclusions: Applying consistent criteria, we defined hyperinflammation as prolonged and vigorous activation of P2X7Rs of the immune cells and established that selective inhibition of these receptors can calm down cytokine storm in COVID-19. Our experience with subdermal administration of lidocaine in the ICU made clear that this method may not be suitable outside hospitals. Therefore, we developed a novel oral transmucosal administration route using xylocaine 10% spray, as shown in the Figure. (Figure Presented).

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