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1.
Polymer Chemistry ; 2022.
Article in English | Scopus | ID: covidwho-1972677

ABSTRACT

Designing a surface that can disinfect itself can reduce labor-intensive cleanings and harmful waste, and mitigate spread of surface borne diseases. Additionally, since COVID-19 is an airborne pathogen, surface modification of masks and filters could assist with infection control. Styrene-maleic acid (SMA) copolymers and their derivatives were shown to have lipid-bilayer disrupting properties, making them candidates as anti-viral materials. A series of network polymers with styrene-maleic acid-based polymers and control over polymer chain-length and composition were synthesized. All the polymers formed mechanically robust structures, with tunable Young's moduli on the order of MPa, and tunable swelling capability in water. The SMA-based bulk materials, containing a zwitterionic polar unit, showed excellent lipid disrupting properties, being up to 2 times more efficient than a 10% Triton solution. The highest performance was observed for materials with lower crosslink densities or shorter chain-lengths, with lipid disruption capability correlating with swelling ratio. Additionally, the material can capture the spike protein of SARS-CoV-2, with up to 90% efficiency. Both the lipid disrupting and spike protein capture ability could be repeated for multiple cycles. Finally, the materials are shown to modify various porous and non-porous substrates including surgical and KN95 masks. Functional network modified masks had up to 6 times higher bilayer disruption ability than the unmodified masks without inhibiting airflow. © 2022 The Royal Society of Chemistry.

2.
mBio ; : e0137622, 2022 Aug 01.
Article in English | MEDLINE | ID: covidwho-1973797

ABSTRACT

The continuous emergence of new variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) urges better understanding of the functional motifs in the spike (S) protein and their tolerance to mutations. Here, we focused on the S2' motif, which, during virus entry, requires cleavage by a host cell protease to release the fusion peptide. Though belonging to an immunogenic region, the SARS-CoV-2 S2' motif (811-KPSKR-815) has shown hardly any variation, with its three basic (K/R) residues being >99.99% conserved thus far. By creating a series of mutant pseudoviruses bearing the spikes of Wuhan-Hu-1, its G614 mutant or the Delta and Omicron variants, we show that residue K814 (preceding the scissile R815) is dispensable for TMPRSS2 yet favored by the alternative TMPRSS13 protease. Activation by TMPRSS13 was drastically reduced when the SARS-CoV-2 S2' motif was swapped with that of the low pathogenic 229E coronavirus (685-RVAGR-689), and also, the reverse effect was seen. This swap had no impact on recognition by TMPRSS2. In the Middle East respiratory syndrome coronavirus (MERS-CoV) spike, introducing a dibasic scissile motif was easily accepted by TMPRSS13 but less so by TMPRSS2, confirming that TMPRSS13 favors a sequence rich in K/R residues. Pseudovirus entry experiments in Calu-3 cells confirmed that the S2' mutations have minor impact on TMPRSS2. Our findings are the first to demonstrate which S2' residues are important for SARS-CoV-2 spike activation by these two airway proteases, with TMPRSS2 being more tolerant to variation than TMPRSS13. This preemptive insight will help to estimate the impact of S2' motif changes as they appear in new SARS-CoV-2 variants. IMPORTANCE Since its introduction in humans, SARS-CoV-2 is evolving with frequent appearance of new variants. The surveillance would benefit from proactive characterization of the functional motifs in the spike (S) protein, the most variable viral factor. This is linked to immune evasion but also influences spike functioning. Remarkably, though located in a strongly immunogenic region, the S2' cleavage motif has, thus far, remained highly conserved. This suggests that its sequence is critical for spike activation by airway proteases. To investigate this, we assessed how pseudovirus entry is affected by changes in the S2' motif. We demonstrate that TMPRSS2 readily accepts variations in this motif, whereas the alternative TMPRSS13 protease is more fastidious. The Wuhan-Hu-1, G614, Delta and Omicron spikes showed no difference in this regard. Being the first in its kind, our study will help to assess the impact of S2' variations as soon as they are detected during variant surveillance.

3.
CLINICAL AND EXPERIMENTAL HEALTH SCIENCES ; 12(2):472-478, 2022.
Article in English | Web of Science | ID: covidwho-1970033

ABSTRACT

Objective: In this study, it was aimed to determine the mutation frequency in spike (S) genes of SARS CoV2 from six different regions of the world, their distribution on the gene and reflections of these mutations to the S protein. Methods: SARS CoV2 S gene sequences originating from Asia, Africa, Europe, South America, Oceania and North America were obtained from NCBI virus database. The sequences were analyzed with Geneious and BioEdit multiple sequence alignment programs. Results:865 distinct mutations on the S genes were detected in the virus samples. Among these, 59 variants with numbers of 10 and above in the virus population were detected. The D614G(A1841G) substitution was found to be the most common with an average of 88.6%. Furthermore, it was determined that 5477N(G1430A) substitution in the viruses of Oceania differed from other regions with a rate of 86.7%. The average mutation frequency of the S genes from different regions was calculated as 3,93x10(5). Conclusion: The significant differences among the mutation frequencies in SARS CoV2 S genes isolated from different regions was identified. At least five distinct amino acid substitutions with high ratios in the population were detected in the RBD domain, which is involved in the binding of the viruses to the ACE2 receptor. These substitutions are T1355G (L452R), G1430A (5477N), C1433A (T478K), G1450A (E484K) and A1501T (N501Y). Among these, the S477N is the most predominant in the population. However, the importance of these mutations needs to be demonstrated both in silico and experimental studies.

4.
NeuroQuantology ; 20(6):5859-5866, 2022.
Article in English | EMBASE | ID: covidwho-1969817

ABSTRACT

Globally, over 100 million confirmed cases of COVID-19 have been reported. The virus that causes COVID-19 is designated SARS-CoV-2;previously, it was referred to as 2019-nCoV. At the end of 2019, cases have been reported in all continents. The main aim of the COVID-19 vaccine is to establish immunity to the spike protein of SARS-CoV-2. Immune system dysfunction is one of the serious complications of chronic kidney disease (CKD). On the other hand, the immune system has a central role in the initiation and progression of this disease by promoting and persistence of systemic inflammation. Patients with end stage renal disease (ESRD) are particularly vulnerable to severe COVID-19 due to the older age and high frequency of comorbidity, such as diabetes and hypertension, in this population. This study aimed to review the immune response following vaccination with the COVID-19 vaccines in patients on maintenance HD and the factors associated with it.

5.
Journal of Clinical and Diagnostic Research ; 16(7):DC18-DC21, 2022.
Article in English | EMBASE | ID: covidwho-1969754

ABSTRACT

Introduction: Assay kits for detection of Immunoglobulin G (IgG) against the nucleocapsid protein (anti-nucleocapsid IgG) and spike proteins (anti-spike IgG) of Severe Acute Respiratory Syndrome Corona Virus 2 (SARS-CoV-2) were commercially provided by several manufacturers. These assay kits should be verified by measuring the same sample. Aim: To compare the diagnostic value of three Coronavirus Disease-2019 (COVID-19) kits in evaluating six immunoassays developed by three manufacturers (Abbott, Euglena, and Roche) to detect anti-nucleocapsid IgG and anti-spike IgG. Materials and Methods: Present study was an observational cross-sectional study conducted from June 2020 to December 2020. Antibody titers for anti-nucleocapsid IgG and anti-spike IgG among 429 Healthcare Workers (HCWs) in a Tone Central Hospital, Japan where a nosocomial infection of the COVID-19 occurred were measured by six immunoassays with kits developed by three different manufacturers. The sensitivity and specificity of each kit was compared to real-time Reverse Transcription-Polymerase Chain Reaction (RT-qPCR). Results: Six of the HCWs tested positive for SARS-CoV-2 via RT-qPCR, and the rest tested negative. The severity of COVID-19 among these six HCWs ranged from mild to moderate. The sensitivity and specificity values against RT-qPCR were, 100% and 99.5% for Abbott, 83.3% and 100% for Euglena, and 100% and 100% for Roche when using the nucleocapsid protein assay and 100% and 99.8% for Abbott, 100% and 100% for Euglena, and 100% and 100% for Roche when using the spike protein assay kit. Conclusion: The commercial kits provided by three manufacturers reflected the immune status of individuals. There were no major differences in the performance of these test kits. Discordant results with the antibody titer for anti-nucleocapsid IgG and anti-spike IgG were detected by using assay kits provided by Abbott and Euglena. To evaluate the past history of COVID-19, it should be noted that the single measurement of anit-nucleocapsid IgG or anti-spike IgG could not exclude false negative or positives

6.
JOURNAL OF CLINICAL AND DIAGNOSTIC RESEARCH ; 16(7):EC13-EC16, 2022.
Article in English | Web of Science | ID: covidwho-1969753

ABSTRACT

Introduction: There is inadequate information on infections with the Severe Acute Respiratory Syndrome Virus 2 (SARS-CoV-2) in children. Their clinical, as well as pathological correlation, is poorly understood. In India, children and adolescents account for 12% of all Coronavirus Disease 2019 (COVID-19) cases reported. Children accounted for roughly 11% of those impacted globally last year. However, this year, we are seeing around 20-40% of youngsters in positive instances over the world. Even babies and infants are testing positive for COVID-19, although their illness is under control and seldom becomes fatal. Children aged 5 to 12 years, on the other hand, are at a higher risk. Aim: To study the clinical, pathological and genomic characteristics among children with SARS-CoV-2 infection. Materials and Methods: This cross-sectional study was conducted among 48 paediatric positive patients for SARS-CoV-2 at Government Institute of Medical Sciences, Noida, Uttar Pradesh, and CSIR-Institute of Genomics and Integrative Biology, New Delhi, India, from 2021 and May 2021. The laboratory testing was done by the real-time Reverse Transcription-Polymerase Chain Reaction (RT-PCR) method. The patients were classified as mild, moderate, severe, or asymptomatic. Their clinical and pathological findings were recorded in the case sheet. Genomic analyses were done for identifying the genetic variant in the nine selected samples. Data entry and analysis were performed using Statistical Package for Social Sciences (SPSS) version 26.0. Chi-square test was used for categorical variables and the t-test was used for continuous variables. Results: The study group has median age of 12 years. Male:Female ratio was 2:3. Most children had acquired infection from the community and 30% had the moderate illness and were admitted. Serum Glutamic-Oxalacetic Transaminase (SGOT) and Glutamic-Pyruvic Transaminase (SGPT) were raised in six patients. Alkaline Phosphatase (ALP) was raised in 21 patients and bilirubin was raised in two patients. The average duration of hospitalization was 6 days (range 2-13 days). No mortality among the 48 paediatric patients studied was identified in the hospital. Delta variant (B.1.617.2) was identified in seven patients with D614, P681R, L452R mutations and B.1.617.2 was identified in two patients. Delta variant was present in the paediatric patients but it did not prolong the hospital stay or cause mortality. Conclusion: The findings of the study suggest that children may be a potential source of infection in the SARS CoV2 pandemic while having an asymptomatic to mild illness.

7.
INTERNATIONAL JOURNAL OF PHARMACEUTICAL INVESTIGATION ; 12(2):129-135, 2022.
Article in English | Web of Science | ID: covidwho-1969706

ABSTRACT

A spike protein is a protein that builds a huge spike that ejects from an enveloped virus's membrane. The spike protein is the only virus membrane protein that enables the virus to penetrate through the cell. Spike Protein has three potential methods of action. Most common viral illnesses have relatively similar virus structures, which are predominantly made up of dimers or trimers of the spike glycoprotein, as well as analogous mechanisms of host cell invasion. The purpose of this paper is to explore the structure of the spike protein and its cell invasion method. The prevalence of spike protein in distinct viruses, as well as their similar invasion mechanisms, are also highlighted in the paper. We observed that many infectious viruses have very identical structures, predominantly constituted of spike glycoprotein, as well as similar processes of invasion into host cells. There are diverse sorts of pathogenesis that have been identified, especially those relating to host cell contamination and the means wherein the infection spreads and produces disease. The Spike protein must be operational for the virus to penetrate the host organism, and variations in the protein's activation techniques are thought to have an influence in viral pathogenesis. Vaccines struggle to prevent the transmission of all virus variants due to variances in the spike protein in different viral versions, as well as modifications in them. More research into the structure of spike glycoproteins, as well as the creation of more effective vaccines to inhibit spike protein invasion and infection, are required.

8.
Scandinavian Journal of Immunology ; 95(6), 2022.
Article in English | EMBASE | ID: covidwho-1968194

ABSTRACT

Vaccination is a successful tool against influenza. However, antigenic drift of the virus requires an annual update of the vaccine. A universal vaccine approach which can elicit immune responses reactive to ideally all seasonal as well as zoonotic influenza strains is urgently needed. To explore this we used a flexible DNA vaccine platform, increasing immunogenicity by targeting dimeric vaccine molecules to antigen-presenting cells (APCs). We hypothesize that when including multiple antigen variants from different influenza strains in one heterodimeric APC-targeted mix DNA vaccine, antibody responses can be focused on conserved epitopes which are shared between the different variants. Neuraminidase (NA) is the second most abundant surface protein on the influenza virus after hemagglutinin and has been established as an independent correlate of protection. We have previously shown that an APC-targeted DNA vaccine with NA induced highly protective antibody responses. NA is divided into 9 different subtypes (N1-N9), and two NA-like antigens in bats (N10 and N11). Here, we created a NA mix vaccine which successfully expressed heterodimeric vaccine molecules with 8 different NA variants (N2-N9) that were targeted to MHC class II on APCs. Upon intramuscular DNA immunization and electroporation in mice, the NA mix vaccine induced cross-reactive antibody responses towards N1, which was not included in the vaccine. The NA mix approach has the potential to fill knowledge gaps about NA immunity and would be a great advancement in universal vaccine design for influenza as well as for other emerging and rapidly changing viruses. WS5.4 ;SARS-CoV- 2- specific T cell responses to COVID-19 BNT162b2 vaccination in chronic lymphocytic leukaemia patients Lisa Blixt1,2;David Wullimann2;Soo Aleman1,2;Jeanette Lundin1,2;Puran Chen2;Yu Gao2;Angelica Cuapio2;Mira Akber2;Joshua Lange2;Olga Rivera-Ballesteros2;Marcus Buggert2;Hans-Gustaf Ljunggren2;Anders Hansson;Lotta1,2;Österborg1,2 1Karolinska University Hospital;Stockholm, Sweden;2Karolinska Institutet, Stockholm, Sweden Immunocompromised patients have an increased risk for severe disease and mortality from viral infection. Importantly, disease and treatment reduce humoral and cellular immune responses to vaccination, which offer the best protection from severe COVID-19 disease during the ongoing pandemic. We recently reported from a prospective clinical trial that BNT162b2 vaccination in different immunodeficient groups had significantly lower SARS-CoV- 2- specific antibody titers compared to healthy controls. The seroconversion rate observed was 63% in chronic lymphocytic leukaemia (CLL) patients, with a negative impact of ibrutinib treatment. Whether T cells in the absence of sufficient levels of SARS-CoV- 2- specific antibody titers can confer immunity after BNT162b2 vaccination remains unclear. We measured reactive SARS-CoV- 2- specific T cell responses in uninfected (naive) and previously infected CLL patients following BNT162b2 vaccination. Out of 52 naive CLL patients, 12 (29%) had a specific IFN-γ T cell response compared to 24/41 (59%) in controls after two doses. In previously infected CLL patients, mainly spike-specific CD8 T cells expanded after the third dose, at which 11/12 (92%) had detectable responses, and all 12 (100%) had spike-specific CD4 T cell responses. Relative to the Wuhan reference strain (wild-type) variant, the median reduction of antigen-specific CD8 and CD4 T cells to the B.1.1.529 (Omicron) variant were 51% and 13%, respectively. Collectively, these data indicate that CLL patients respond with T-cells specific to SARS-CoV- 2 spike protein after BNT162b2 vaccination or infection. The increased T-cell response rate after the third dose and ability to recognize the Omicron variant of concern demonstrates the importance of a booster dose in this patient group.

9.
Scandinavian Journal of Immunology ; 95(6), 2022.
Article in English | EMBASE | ID: covidwho-1968190

ABSTRACT

The ongoing COVID-19 pandemic has hit long-term care facilities (LTCF), with outbreaks affecting both residents and health care workers (HCWs). Elderly persons have been prioritized in the implementation of vaccination programs. Here we investigated a COVID-19 outbreak, caused by the Beta variant (B.1.351) in a LTCF where residents and HCWs had received 2 doses of Comirnaty vaccine (Pfizer/BioNTech) until one month before the outbreak. Samples from 14 residents (SARS-CoV-2 PCR-negative: n = 8, PCR-positive: n = 6) and 10 HCWs (PCR-negative: n = 10) were collected at a median of 54 days following the second vaccine dose. IgG antibodies to SARS-CoV-2 spike glycoprotein and neutralizing antibody (NAb) titers were measured. Additionally, functional responses of PBMCs to SARS-CoV-2 spike and nucleocapsid proteins were investigated. We observed that Comirnaty induced higher IgG concentrations and NAb titers in HCWs compared to residents. PBMCs of HCWs responded vigorously to stimulation with SARS-CoV-2 spike glycoprotein, with the secretion of interferon gamma, granzyme B and perforin-1 into supernatants. In comparison, only 3 of 9 samples from residents showed positive cellular responses to spike glycoprotein. Group-level cellular responses directed at SARS-CoV-2 nucleoprotein remained low both in HCWs and in residents. Only 2 of 2 PCR-positive residents showed a positive response consistent with exposure to SARS-CoV-2 breakthrough infection. Our results show that elderly persons are at increased risk for breakthrough infection after vaccination. Weak vaccine-directed responses in the elderly need to be addressed in vaccination protocols.

10.
Zeitschrift fur Phytotherapie ; 43:S46, 2022.
Article in English | EMBASE | ID: covidwho-1967698

ABSTRACT

Introduction SARS-CoV-2 variants of concern (VOCs) represent an alarming threat as they may escape vaccination effectiveness. Broad-spectrum antivirals could complement and further enhance preventive benefits achieved through SARS-CoV-2 vaccination campaigns. Aim Testing the antiviral activity of Echinacea purpurea against VOCs and exploring underlying modes-of-action. Method A hydroethanolic extract of freshly harvested E. purpurea herb and roots (Echinaforce®, EF extract) was tested to inhibit infection of VOCs B1.1.7 (alpha), B.1.351.1 (beta), P.1 (gamma), B1.617.2 (delta), AV.1 (Scottish) and B1.525 (eta). Molecular dynamics (MD) were used to study interaction of EF phytochemical markers with known pharmacological viral and host cell targets. Results EF broadly inhibited propagation of all tested SARS-CoV-2 VOCs at EC50 < 12.0 ;jg/ml. Treatment of epithelial cells with 20 jg/ml EF prevented sequential infection with SARS-CoV-2 (Hu-1). MD analyses showed for alkylamides, caftaric acid and feruoyl-tartaric constant binding affinity to spike proteins of all VOCs and to TMPRSS-2, a serine protease required for virus endocytosis. Conclusion EF extract exhibits virucidal activity against all tested SARS-CoV-2 VOCs and protects epithelial cells from infection.

11.
Emerg Microbes Infect ; : 1-38, 2022 Aug 02.
Article in English | MEDLINE | ID: covidwho-1967813

ABSTRACT

Spike (S) glycoproteins is the most significant structural protein of SARS-CoV-2 and a key target for neutralizing antibodies. In light of the ongoing SARS-CoV-2 pandemic, identification and screening of epitopes of spike glycoproteins will provide vital progress in the development of sensitive and specific diagnostic tools. In the present study, NTD, RBD and S2 gene were inserted to the pcDNA3.1(+) vector and designed with N-terminal 6×His-tag for fusion expression in HEK293F cells by transient transfection. Six monoclonal antibodies (4G, 9E, 4B, 7D, 8F, 3D) were prepared using the expressed proteins by cell fusion technique. The characterization of mAbs were performed by indirect -ELISA, western blot and IFA. We designed 49 overlapping synthetized peptides cover the extracellular region of S protein which 6 amino acid residues were offset between adjacent (S1-S49). Peptides S12, S19 and S49 were identified as the immunodominant epitopes regions by the mAbs. These regions were further truncated and the peptides S12.2 286TDAVDCALDPLS297, S19.2 464FERDISTEIYQA475 and S49.4 1202ELGKYEQYIKWP1213 were identified as B- cell linear epitopes for the first time. Alanine scans showed that, the D467, I468, E471, Q474, A475 of the epitope S19.2 and K1205, Q1208, Y1209 of the epitope S49.4 were the core sites involved in the mAbs binding. Multiple sequence alignment analysis showed that these three epitopes were highly conserved among the variants of concern (VOCs) and variants of interest (VOIs). Taken together, the findings provide a potential material for rapid diagnosis methods of COVID-19.

12.
Gastroenterology ; 162(7):S-1004-S-1005, 2022.
Article in English | EMBASE | ID: covidwho-1967389

ABSTRACT

Background: IBD patients on immune-modulatory therapies are considered high-risk for SARS-CoV-2 infection. Direct comparisons of serological responses to SARS-CoV-2 infection in IBD patients across different continents and medications are lacking. We performed SARSCoV- 2 sero-surveillance of IBD patients prior to vaccination at seven large tertiary centres in Asia, Europe, and North America. Methods: Clinical data and sera were collected from 2,241 IBD patients receiving routine care at institutions in Belgium, Canada, Hong Kong, India, Japan, United Kingdom, and the United States between May 2020 and September 2021 (Table 1). Sera were taken prior to vaccination. Clinical data were collected from patient questionnaires and medical records. Antibody reactivity to the SARS-CoV-2 spike protein was assessed using the Roche SARS-CoV-2 anti-spike total antibody and/or Siemens Healthineers COV2T anti-spike total antibody assays, which showed 99.4% concordance. We performed univariate analysis to evaluate association between variables and sero-status. Results: The pre-vaccination seroprevalence of antibodies to SARS-CoV-2 in IBD patient varied widely according to location from 0% in Hong Kong, China, to 57.9% in New Delhi, India. Rates in Europe and North America were similar (range 3.6%-8.9%). Overall, SARSCoV- 2 seroprevalence appears to be equal to or less than local populations (Table 1). Seroprevalence rates were associated with IBD type (Crohn's disease 7.8%, ulcerative colitis 12.4%, IBD-unclassified 15.0%, p<0.001), smoking status (p<0.001), and history of COVID diagnosis (p<0.001) or COVID hospitalization (p=0.001), and any immunomodulator (IMM) (p<0.001) (Table 1). Infection as indicated by seropositivity in the absence of known COVID infection occurred in 7.3% of patients. Whilst there were no significant differences in seroprevalence between patients receiving anti-tumor necrosis factor (anti-TNF) medications, vedolizumab (VDZ), and ustekinumab (UST), antibody levels were attenuated in patients on anti-TNF monotherapy (p=0.002), anti-TNF + IMM combination therapy (p=0.002), and VDZ (p=0.02), compared with no medications (Figure 1). Conclusion: We confirm in diverse populations that exposure to anti-TNFs, vedolizumab and immunomodulators, type of disease, and smoking status are associated with seroprevalence and antibody levels. We show for the first time the dominant influence of geographical location on sero-status in these patients. These observations should be considered as we look towards post-vaccination data to help stratify patients for clinical guidelines on SARS-CoV-2 vaccination. (Table Presented) Table 1. Seroprevalence of total anti-SARS-CoV-2 spike antibodies in IBD patients by ICARUS centre with non-IBD controls noted for New Delhi, India, and publicly reported local seroprevalence and by selected patient characteristics.(Figure Presented) Figure 1. Antibody levels by medication group.

13.
Gastroenterology ; 162(7):S-886-S-887, 2022.
Article in English | EMBASE | ID: covidwho-1967382

ABSTRACT

Introduction: Coronavirus Disease 2019 (COVID-19) is an ongoing public health crisis that has sickened or precipitated death in millions. The etiologic agent of COVID-19, Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), infects the intestinal epithelium and can persist long after the respiratory infection has cleared. We previously observed that intestinal SARS-CoV-2 infection levels varied by individual donors and did not correlate positively with ACE2, the cognate SARS-CoV-2 receptor. Therefore we aimed to delineate host factors that influence viral infection in the intestine. Methods: Published dataset GSE75214 was downloaded and expression levels of select genes were querried. Primary human ileal spheroids (enteroids), derived from healthy donors and patients with Crohn's disease (CD), were grown on 2D transwells until confluent. Cells were differentiated for 3d before infection with a modified vesicular stomatitis virus expressing the SARS-CoV-2 spike protein (VSV-SARS-CoV-2) and GFP for 1h at a multiplicity of infection of ~0.5. Cells were harvested pre-infection and 24h after infection and expression of select genes was performed by qRT-PCR. Expression data were fit to a linear regression model to predict viral RNA levels. Results: Small intestine biopsy samples from CD patients demonstrated a reduction in ACE and an increase in CTSB and CTSL expression during active inflammation compared to healthy controls. Viral RNA expression did not correlate with ACE2 expression in CD enteroids. A subset of CD enteroids exhibited enhanced protease expression (TMPRSS2, TMPRSS4, CTSL), each of which correlated with higher viral RNA levels (P=0.04, P=0.002, P=0.006, respectively). Expression of these proteases was higher in the pre-infection for the sample subset. Principle component analysis of uninfected expression data demonstrated these samples clustered separately from the others, with the difference driven by TMPRSS2, TMPRSS4, and CTSL. Modeling viral RNA levels based on gene expression revealed expression levels of these proteases are a predictive expression signature. Conclusions: Host protease expression can predict SARS-CoV-2 infection and represent potential therapeutic targets for COVID-19. This is consistent with the recent report showing that cathepsin inhibition reduces SARS-CoV-2 spike-mediated syncytia formation. High expression of these proteases in the intestine may also be a novel biomarker for the risk of intestinal complications associated with COVID-19.(Figure Presented)RNA data from dataset GSE75214 demonstrating reduced ACE2 and increased CTSB and CTSL in patients with Crohn's disease during active inflammation compared to healthy controls. (Figure Presented) Enteroids from healthy control donors and patients with Crohn's disease were grown in 2D transwells and expression of indicated genes was assessed in pre-infection (A) and after infection with VSV-SARS-CoV-2 (B)

14.
Gastroenterology ; 162(7):S-599-S-600, 2022.
Article in English | EMBASE | ID: covidwho-1967346

ABSTRACT

Objective: Patients with inflammatory bowel disease (IBD) have attenuated responses to current vaccinations. There is a limited body of evidence suggesting patients with IBD receiving TNF antagonists have an attenuated response to vaccination against COVID-19. We sought to determine the impact of IBD and various medications for the treatment of IBD on antibody responses to vaccination against COVID-19. Design: Patients with IBD (n=270) and healthy controls (HC, n=116) were recruited prospectively and quantitative antibody responses assessed following COVID-19 vaccination. The impact of IBD and medications for treatment of IBD on vaccine response rates was investigated. Results: All HC seroconvert post complete vaccination with two vaccine doses [100%]. A small proportion of patients with IBD failed to seroconvert [2%]. Median anti-spike protein (SP) immunoglobulin (Ig)G levels post one vaccination and complete vaccination in our IBD cohort was significantly lower than HC [2,613 AU/mL versus 6,871 AU/mL, p=<0.001] [Figure 1]. A diagnosis of IBD was independently associated with lower anti-SP IgG levels [β coefficient -0.2, p = 0.001] whereas use of mRNA vaccines was independently associated with higher anti-SP IgG levels [β coefficient 0.25, p = < 0.001]. Patients with IBD receiving anti-TNF therapy had significantly lower anti-SP IgG levels [2444.6 AU/mL] than IBD patients not receiving these agents [3867.6 AU/mL] [p = < 0.001]. Patients with IBD not receiving TNF inhibitors still showed attenuated responses compared to HC receiving a similar vaccine [p = 0.001] [Figure 2]. 58 patients had an additional follow-up serology sample at a median of 12 weeks to complete vaccination to allow assessment of the durability of the response after their initial post-vaccination IgG level. There was a significant drop in IgG levels from 3952.85 AU/mL at the first timepoint checked post-complete vaccination to 921.1 AU/mL (343.1 – 2102.7) on follow-up sampling (p = <0.001). Median anti-SP IgG levels were numerically lower in our cohort receiving anti-TNF therapy (794.8 AU/mL) compared to those not receiving anti-TNF therapy (3136.9 AU/mL) on final follow-up samples (p =0.28). HC participants with previous COVID-19 infection (n= 5) had significantly higher anti-SP IgG levels post complete vaccination (20,719.6 AU/mL) compared to IBD patients (n=4) with prior infection (3,938.2 AU/mL) (p = < 0.001). Conclusions: Patients with IBD have attenuated serological responses to SARS-CoV-2 vaccination. Patients with IBD who do not seroconvert post-vaccination against COVID-19 are a particularly vulnerable cohort. Use of anti-TNF therapy negatively impacts anti-SP IgG levels. Impaired responses to vaccination in our study highlights the importance of booster vaccination programmes for patients with IBD. (Figure Presented) Differences in median IgG levels across three time points (Figure Presented) Differences in median anti-SP Levels dependent on medication for treatment of IBD.

15.
Gastroenterology ; 162(7):S-593-S-594, 2022.
Article in English | EMBASE | ID: covidwho-1967336

ABSTRACT

Background: The immune response of SARS-CoV-2 vaccines is uncertain in those with Inflammatory Bowel Disease (IBD) due to a diverse array of immune-modifying therapies that vary in the mechanism of immunosuppression. Aim: We aimed to quantify the serological response to SARS-CoV-2 vaccines in those with IBD and determine antibody levels across varying therapeutic options. Methods: Individuals with IBD who received a first and/or second dose of a COVID-19 vaccine (Pfizer-BioNTech, Moderna, and/or AstraZeneca) were assessed for serological response (1–8 weeks after first dose;1–8 weeks after second dose, 8–18 weeks after second dose, 18+ weeks after second dose) using the SARS-CoV-2 IgG II Quant assay to the receptor-binding domain of the SARS-CoV-2 spike protein. The cohort was stratified based on age, sex, vaccine received, IBD type, IBD therapeutic, and prior confirmed diagnosis of COVID-19. The primary outcome was seroconversion defined as IgG levels of ³50 AU/mL. Secondarily, we evaluated the geometric mean titer (GMT) with 95% confidence intervals (CI). Results: Table 1 describes the characteristics of individuals with IBD (n=466) with serological data following the first dose (n=247) and/or second dose (n=413) of a COVID-19 vaccine. After 1–8 weeks following first dose of the vaccine, 81.4% seroconverted, with the lowest first-dose conversion rates in patients taking anti- TNF monotherapy (80.3%), anti-TNF combination therapy (51.5%), and corticosteroids (50.0%) (Table 1). Overall, 98.4% of the cohort seroconverted within 1–8 weeks of the second dose. Over time, seropositive rates decreased with 95.8% seroconversion within 8– 18 weeks of the second dose and 90.5% after 18 weeks. Seroconversion after second dose was consistently high across all medication classes (range: 94.6%–100.0%), except for oral corticosteroids (62.5%). GMT levels significantly increased (p<0.0001) from first dose (1825 AU/mL [95% CI: 981, 2668 AU/mL]) to second dose at 1–8 week (9059 AU/mL [7698, 10420 AU/mL]) but fell significantly (p<0.0001) to 3649 AU/mL (95% CI: 2562, 4736 AU/ mL) 8–18 weeks from second dose and 2527 AU/mL (95% CI: 883, 4172 AU/mL) 18+ weeks after second dose (Table 1, Figure 1). GMT levels 1–8 weeks after second dose were higher in those with prior COVID-19 (16,770 AU/mL), but lower in those receiving anti- TNF combination therapy (4231 AU/mL) and oral corticosteroids (5996 AU/mL) (Table 1). Conclusion: Seroconversion rates following full-regimen vaccination are high in patients with inflammatory bowel disease across all medication classes except for anti-TNF combination therapy and oral corticosteroids. Antibody titres and seroconversion rates tend to decrease after eight weeks post-full vaccination, which is consistent across medication classes. (Table Presented) Table 1. Patient and vaccine characteristics, seroconversion rates, and geometric mean titres by prior PCR-confirmed COVID-19 status for each medication class. (Figure Presented) Figure 1. Log-transformed anti-SARS-CoV-2 spike antibody concentration per vaccine category. Black points represent GMTs while narrow black bars represent bounds of 95% CI associated with each GMT. Solid blue line represents threshold for positive seroconversion [ln (50 AU/mL)].

16.
Gastroenterology ; 162(7):S-287, 2022.
Article in English | EMBASE | ID: covidwho-1967277

ABSTRACT

Introduction: The immunogenicity and safety following standard two-dose SARS-CoV-2 vaccination in patients with immune-mediated inflammatory diseases (IMIDs) are not well characterised, and data on third dose vaccination in this patient group are currently lacking. Methods & Aims: This prospective, observational cohort study included adult patients on immunosuppressive therapy for Crohn's disease (CD), ulcerative colitis (UC), rheumatoid arthritis (RA), spondyloarthritis (SpA), psoriatic arthritis (PsA), and healthy controls receiving standard two-dose SARS CoV-2 vaccination. Patients with a weak serologic response (<100 AU/ml) were allotted a third vaccine dose. Serum samples were collected prior to, and after vaccination for analyses of antibodies to the receptor-binding domain (RBD) of the SARSCoV- 2 spike protein. The aim of the study was to evaluate the immunogenicity and safety following standard and three dose SARS-CoV-2 vaccination in IMID patients on immunosuppressive therapies. Results: a total of 1641 patients (280 CD, 195 UC, 566 RA, 305 SpA, 295 PsA, median age 52 [IQR 40-63], 899 [55%] women), and 1114 healthy controls (median age 43 [IQR 32-55], 854 [77%] women), were included in the study. After standard SARS-CoV-2 two dose vaccination, 1504 (91%) patients compared to 1096 (98%) healthy controls were responders, p<0,001. Anti-RBD levels were lower in patients (median 619 AU/ml [IQR 192-4191]) than controls (median 3355 AU/ml [IQR 896–7849]), p<0,001. Response was shown in ≤90% of patients receiving methotrexate, tumor necrosis factor inhibitor (TNFi) monotherapy, ustekinumab, tozilizumab and vedolizumab, in 80–90% of patients receiving TNFi combination therapy and secukinumab and in £ 80% for JAK inhibitors (78%), and abatacept (53%) (fig.1). Lower age (OR 0.96 [95% CI 0.95–0.98]) and receiving the mRNA-1273 vaccine (OR 5.4 [95% CI 2.4–11.9]) were predictors of response. Of 153 patients with a weak response receiving a third vaccine dose, 129 (84%) became responders. After standard two dose vaccination, adverse events (AE) were reported in 50% of patients and in 78% of controls, with a comparable safety profile. Following the third dose, 44% of patients reported AEs, without new safety issues emerging. No serious AEs were reported. Conclusion: Response rate as well as anti-RBD levels were lower in IMID patients than healthy controls following standard vaccination. Third dose vaccination in serologically weak responders was safe and resulted in a response in most patients. Our data facilitate identification of patient groups at risk of an attenuated vaccine response eligible for post-vaccination serological monitoring. The data also support a third vaccine dose following standard SARS-CoV-2 vaccination to weak-responding IMID-patients. (Figure Presented) Fig.1 Anti-SARS-CoV-2 IgG antibodies following standard two dose SARS-CoV-2 vaccination according to medication group, compared to healthy controls. Violin plot showing the probability density of the data at different values, smoothed by a kernel density estimator. Each data point is a participant, and the solid orange line show the group median. The last row (CTRL vs) shows p-values for a comparison (Mann-Whitney U test) of anti-SARS-COV 2 antibodies between medication groups and healthy controls. ACE=Angiotensin converting enzyme, FL=full length, CTRL=Controls, TNF=Tumor necrosis factor inhibitor, TNF+= Tumor necrosis factor inhibitor combination therapy, MTX=methotrexate, VDZ=vedolizumab, JAK=Janus kinase inhibitor, TCZ=tocilizumab, UST=ustekinumab, ABA=abatacept, SCK=secukinumab.

17.
Gastroenterology ; 162(7):S-160-S-161, 2022.
Article in English | EMBASE | ID: covidwho-1967251

ABSTRACT

Background: The immune response to a two-dose regimen of SARS-CoV-2 vaccination in those with Inflammatory Bowel Disease (IBD) has been consistently high in emerging research. Serological responses following a third dose have yet to be established. Aim: We aimed to quantify the serological response to a third dose of SARS-CoV-2 vaccines in those with IBD and compare to responses after a two-dose regimen. Methods: Individuals with IBD who have received at least two doses of a COVID-19 vaccine were assessed for serological response using the SARS-CoV-2 IgG II Quant assay to the receptor-binding domain of the SARSCoV- 2 spike protein at least eight weeks after second dose and then after third dose. The primary outcome was seroconversion defined as IgG levels of ≥50 AU/mL. Secondarily, we evaluated the geometric mean titer (GMT) with 95% confidence intervals (CI). Outcomes were stratified by prior COVID-19 history. A Wilcoxon rank sum test was used to compare antibody titres following 3rd dose vaccination and titres following 2nd dose vaccination. For patients with both post-2nd and post-3rd vaccination serology, the difference in antibody titres between doses was determined and the mean difference was tested using one-sample Student's t-tests. Results: Table 1 describes the characteristics of individuals with IBD (n = 271) with serological data following the corresponding dose for those with 2nd dose vaccination (n = 175) compared to those with a 3rd dose of vaccine (n = 96). Seroconversion following 3rd dose vaccination occurred for all individuals (100.0%), compared to a 94.4% seroconversion rate at least eight weeks following 2nd dose vaccination (range: 8 to 35 weeks post-2nd dose). GMT for the post-3rd dose cohort (16424 AU/mL [13437, 19411 AU/mL]) was significantly higher (p<0.0001) than the post-2nd dose cohort (3261 AU/mL [2356, 4165 AU/mL] (Table 1, Figure 1b). Individual titres as a function of time following 2nd dose vaccination are seen in Figure 1a for both 3rd dose and 2nd dose cohorts. For individuals with serology following both 2nd dose and 3rd dose vaccination (n = 82), seroconversion rates increased from 97.6% to 100.0% after the 3rd dose. GMT following post-3rd dose vaccination also increased with a mean difference in antibody titres between post-3rd dose and post-2nd dose vaccination of 11384 AU/mL (8541, 14228 AU/mL, p < 0.0001). This difference was significant for both individuals with prior COVID-19 history (11682 AU/mL [95% CI: 8618, 14746 AU/mL, p<0.0001]) and individuals without (8194 AU/mL [95% CI: 988, 15400 AU/mL]). Conclusion: Seroconversion rates and antibody response following third dose vaccination are substantially increased as compared to second dose in patients with IBD. Third dose vaccination can counter the decrease in antibody concentration over time following a two-dose regimen. (Table Presented) Table 1. Patient characteristics, vaccine type, seroconversion rates, and geometric mean titres by prior COVID-19 status for post-3rd dose and post-2nd dose cohorts

18.
Gastroenterology ; 162(7):S-160, 2022.
Article in English | EMBASE | ID: covidwho-1967250

ABSTRACT

Background: Vaccine-induced protection against SARS-CoV-2 infection is predominantly mediated by humoral immunity;protection against disease progression is primarily determined by cellular immunity. Patients with inflammatory bowel disease (IBD) have high rates of post-vaccination anti-Spike IgG [IgG(S)] seroconversion, but postvaccination immune responses relative to non-IBD controls have not been well described. We aimed to assess post-vaccination humoral (antibody) and cellular (T-cell) responses in IBD relative to healthcare worker (HCW) controls. Methods: We evaluated IBD patients enrolled in a US registry referred from 26 centers at 2, 8, and 16 weeks after completing 2 doses of SARSCoV- 2 mRNA vaccination and compared results to non-IBD non-immunosuppressed HCW participating in a parallel study. We analyzed plasma antibodies to the receptor binding domain of the viral spike protein using the SARS-CoV-2 IgG-II assay (Abbott Labs, Abbott Park, IL);IgG(S) > 50 AU/mL was defined as positive. Those with prior COVID were excluded. We also performed T-cell clonal analysis by T-cell receptor (TCR) immunosequencing at 8 weeks (Adaptive Biotechnologies, Seattle, WA). The breadth (number of unique sequences to a given protein) and depth (relative abundance of all the unique sequences to a given protein) of the T-cell clonal response were quantified using reference datasets. Analyses were adjusted for age, sex and vaccine type. Results: Overall, 1805 subjects were included (IBD n=1074 (65% Crohn's disease, 35% ulcerative colitis);HCW n=731). Age and sex were similar between both cohorts;Hispanic ethnicity and Asian race were less common among IBD than HCW (Table). Vaccine type included BNT162b2 (Pfizer) (75% of IBD, 98% of HCW) and the remainder mRNA-1274 (Moderna). IBD treatments included anti- TNF (46%), other biologics (33%), other immune suppressing therapy (9%), and no immune suppression (12%). Postvaccination antibody levels were lower among IBD than HCW both before and after adjusting for vaccine type (p<0.0001 each timepoint;Figure). After further restricting the IBD cohort to those on no immune-suppressive therapies, antibodies remained lower in IBD vs HCW at 2w (p=0.008) and 8w (p<0.0001), but not 16w (p=0.07). Among 321 subjects with available whole cell samples at 8 weeks (IBD n=163, HCW =158), Spikespecific TCR responses were similar between IBD and HCW for both clonal breadth and depth in both unadjusted and adjusted analyses;sub-analyses of those on biologics yielded similar results. Conclusion: Patients with IBD have dampened humoral responses, but similar cellular responses, after SARS-CoV-2 mRNA vaccination relative to HCW. These findings suggest a potentially greater risk of infection, but not of disease progression, among those with IBD, and should be considered to help guide booster dosing strategies for the IBD population. (Figure Presented) (Figure Presented) Figure: Post-vaccination immune responses: (A) Antibody responses are lower in IBD relative to non-IBD healthcare workers at 2, 8, and 16 weeks (p<0.0001 at each timepoint). In contrast, post-vaccination Spike-specific T-cell receptor clonal breadth (B1) and clonal depth (B2) at 8 weeks are similar in IBD compared to healthcare workers.

19.
Gastroenterology ; 162(7):S-14-S-15, 2022.
Article in English | EMBASE | ID: covidwho-1967236

ABSTRACT

Background & Aimss: Poor antibody (Ab) response after SARS-CoV-2 vaccination has been reported in liver transplant (LT) recipients and those with chronic liver diseases (CLD). The role of a booster dose in those with poor response to initial vaccination is not well defined in this patient population. Methods: In this prospective study, we studied LT recipients and those with CLD (with or without cirrhosis) who had poor antibody response to SARSCoV- 2 spike protein after 2 doses of mRNA vaccines or a single dose of JnJ vaccine. Antibodies (predominantly IgG) against receptor binding domain to SAR-CoV-2 spike protein was assessed using the Roche electrochemiluminescence, semi-quantitative immunoassay (Elecsys ® Ant-SARS-CoV2 semi-quantitative) via LabCorp. We defined poor Ab response as `undetectable' if Ab levels are ≤0.80 U/mL and `low' if levels are between 0.80 U/mL and 249.9 U/mL. Results: Of the 80 patients enrolled, 45 had LT, and 35 had CLD (18 with cirrhosis). The median days between standard vaccination and measurement of Ab titers (prebooster) was 41 days and post-booster dose was 28 days. A booster dose was given at a median of 138.5 days after the completion of the standard regimen Among these, 47 of 80 (59%) patients received booster doses with Pfizer, 27 (34%) Moderna, and 6 (7%) JnJ vaccine;the corresponding numbers for initial vaccination was 41 (51%), 24 (30%) and 15 (19%) respectively. After the booster dose, 58 (73%, 31 LT, 27 CLD) had good response (≥250 U/mL), and 22 (28%, 14 LT, and 8 CLD) had poor response (7 undetectable and 15 with low Ab levels). No patient had any serious adverse events. The favorable Ab responses were lower in those who had initial undetectable Ab levels Ab (<0.80 U/mL) than those who had low Ab levels (0.80-249 U/mL) after the standard vaccination regimen (42% vs. 87%, p=0.0001). There were no significant differences between the immunosuppressed (defined as liver transplant or at least one immunosuppressant medicine) and the immunocompetent patients in the antibody titer levels after booster vaccines. The antibody response after homologous and heterologous booster doses were similar. Conclusions: Booster dose can enhance Ab response in LT recipients and CLD patients who have a poor response to initial standard vaccine regimen. (Table Presented)

20.
Arzneimitteltherapie ; 40(5):151-152, 2022.
Article in German | EMBASE | ID: covidwho-1965507
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