scholarly journals Egg-derived anti-SARS-CoV-2 immunoglobulin Y (IgY) with broad variant activity as intranasal prophylaxis against COVID-19: preclinical studies and randomized controlled phase 1 clinical trial

2022 ◽  
Author(s):  
Lyn Frumkin ◽  
Michaela Lucas ◽  
Curt Scribner ◽  
Nastassja Ortega-Heinly ◽  
Jayden Rogers ◽  
...  
Keyword(s):  
Low Cost ◽  
Phase 1 ◽  
Cross Reactivity ◽  
Vaccine Hesitancy ◽  
Systemic Absorption ◽  
Enzyme Linked Immunosorbent Assay ◽  
Tolerability Profile ◽  
Immunoglobulin Y ◽  
Double Blind ◽  
Novel Coronavirus

COVID-19 emergency use authorizations and approvals for vaccines were achieved in record time. However, there remains a need to develop additional safe, effective, easy-to-produce, and inexpensive prevention to reduce the risk of acquiring SARS-CoV-2 infection. This need is due to difficulties in vaccine manufacturing and distribution, vaccine hesitancy, and, critically, the increased prevalence of SARS-CoV-2 variants with greater contagiousness or reduced sensitivity to immunity. Antibodies from eggs of hens (immunoglobulin Y; IgY) that were administered receptor-binding domain (RBD) of the SARS-CoV-2 spike protein were developed as nasal drops to capture the virus on the nasal mucosa. Although initially raised against the 2019 novel coronavirus index strain (2019-nCoV), these anti-SARS-CoV-2 RBD IgY surprisingly had indistinguishable enzyme-linked immunosorbent assay binding against variants of concern that have emerged, including Alpha (B.1.1.7), Beta (B.1.351), Delta (B.1.617.2), and Omicron (B.1.1.529). This is distinct for sera from immunized or convalescent patients. Culture neutralization titers against available Alpha, Beta, and Delta were also indistinguishable from the index SARS-CoV-2 strain. Efforts to develop these IgY for clinical use demonstrated that the intranasal anti-SARS-CoV-2 RBD IgY preparation showed no binding (cross-reactivity) to a variety of human tissues and had an excellent safety profile in rats following 28-day intranasal delivery of the formulated IgY. A double-blind, randomized, placebo-controlled phase 1 study evaluating single-ascending and multiple doses of anti-SARS-CoV-2 RBD IgY administered intranasally for 14 days in 48 healthy participants also demonstrated an excellent safety and tolerability profile, and no evidence of systemic absorption. As these antiviral IgY have broad selectivity against many variants of concern, are fast to produce, and are a low-cost product, their use as prophylaxis to reduce SARS-CoV-2 viral transmission warrants further evaluation.

scholarly journals Characterization of the Diagnostic Performance of a Novel COVID-19 PETIA in Comparison to Four Routine N-, S- and RBD-Antigen Based Immunoassays

Diagnostics ◽  
2021 ◽  
Vol 11 (8) ◽  
pp. 1332
Author(s):  
Alexander Spaeth ◽  
Thomas Masetto ◽  
Jessica Brehm ◽  
Leoni Wey ◽  
Christian Kochem ◽  
...  
Keyword(s):  
Immune Response ◽  
Cross Reactivity ◽  
Enzyme Linked Immunosorbent Assay ◽  
Chemiluminescence Immunoassay ◽  
Face To Face ◽  
Comprehensive Comparison ◽  
Broad Variety ◽  
Viral Responses ◽  
Novel Coronavirus ◽  
High Consistency

In 2019, a novel coronavirus emerged in Wuhan in the province of Hubei, China. The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) quickly spread across the globe, causing the neoteric COVID-19 pandemic. SARS-CoV-2 is commonly transmitted by droplet infection and aerosols when coughing or sneezing, as well as high-risk exposures to infected individuals by face-to-face contact without protective gear. To date, a broad variety of techniques have emerged to assess and quantify the specific antibody response of a patient towards a SARS-CoV-2 infection. Here, we report the first comprehensive comparison of five different assay systems: Enzyme-Linked Immunosorbent Assay (ELISA), Chemiluminescence Immunoassay (CLIA), Electro-Chemiluminescence Immunoassay (ECLIA), and a new Particle-Enhanced Turbidimetric Immunoassay (PETIA) for SARS-CoV-2. Furthermore, we also evaluated the suitability of N-, S1- and RBD-antigens for quantifying the SARS-CoV-2 specific immune response. Linearity and precision, overall sensitivity and specificity of the assays, stability of samples, and cross-reactivity of general viral responses, as well as common coronaviruses, were assessed. Moreover, the reactivity of all tests to seroconversion and different sample matrices was quantified. All five assays showed good overall agreement, with 76% and 87% similarity for negative and positive samples, respectively. In conclusion, all evaluated methods showed a high consistency of results and suitability for the robust quantification of the SARS-CoV-2-derived immune response.

scholarly journals Development of a Smartphone-Based Nanozyme-Linked Immunosorbent Assay for Quantitative Detection of SARS-CoV-2 Nucleocapsid Phosphoprotein in Blood

2021 ◽  
Vol 12 ◽  
Author(s):  
Bochao Liu ◽  
Ze Wu ◽  
Chaolan Liang ◽  
Jinhui Lu ◽  
Jinfeng Li ◽  
...  
Keyword(s):  
Immunosorbent Assay ◽  
Cross Reactivity ◽  
Quantitative Detection ◽  
Enzyme Linked Immunosorbent Assay ◽  
Serum Samples ◽  
Primary Screening ◽  
Global Pandemic ◽  
Novel Coronavirus ◽  
Acid Test ◽  
Control Samples

Since December 2019, a novel coronavirus (SARS-CoV-2) has resulted in a global pandemic of coronavirus disease (COVID-19). Although viral nucleic acid test (NAT) has been applied predominantly to detect SARS-CoV-2 RNA for confirmation diagnosis of COVID-19, an urgent need for alternative, rapid, and sensitive immunoassays is required for primary screening of virus. In this study, we developed a smartphone-based nanozyme-linked immunosorbent assay (SP-NLISA) for detecting the specific nucleocapsid phosphoprotein (NP) of SARS-CoV-2 in 37 serum samples from 20 COVID-19 patients who were diagnosed by NAT previously. By using SP-NLISA, 28/37 (75.7%) serum samples were detected for NP antigens and no cross-reactivity with blood donors’ control samples collected from different areas of China. In a control assay using the conventional enzyme-linked immunosorbent assay (ELISA), only 7/37 (18.91%) serum samples were detected for NP antigens and no cross-reactivity with control samples. SP-NLISA could be used for rapid detection of SARS-CoV-2 NP antigen in primary screening of SARS-CoV-2 infected individuals.

scholarly journals A multi centre randomized open label trial of chloroquine for the treatment of adults with SARS-CoV-2 infection in Vietnam

2020 ◽  
Vol 5 ◽  
pp. 141
Author(s):  
Evelyne Kestelyn ◽  
Nguyen Thi Phuong Dung ◽  
Yen Lam Minh ◽  
Le Manh Hung ◽  
Nguyen Minh Quan ◽  
...  
Keyword(s):  
Low Cost ◽  
Controlled Trial ◽  
Standard Of Care ◽  
Rapid Decline ◽  
Tolerability Profile ◽  
Open Label ◽  
Field Hospital ◽  
Novel Coronavirus ◽  
Randomised Controlled ◽  
Evidence Based Guidelines

Background: COVID-19 is a respiratory disease caused by a novel coronavirus (SARS-CoV-2) and causes substantial morbidity and mortality. There is currently no vaccine to prevent COVID-19 or therapeutic agent to treat COVID-19. This clinical trial is designed to evaluate chloroquine as a potential therapeutic for the treatment of hospitalised people with COVID-19. We hypothesise that chloroquine slows viral replication in patients with COVID-19, attenuating the infection, and resulting in more rapid decline of viral load in throat/nose swabs. This viral attenuation should be associated with improved patient outcomes. Method: The study will start with a 10-patient prospective observational pilot study following the same entry and exclusion criteria as for the randomized trial and undergoing the same procedures. The main study is an open label, randomised, controlled trial with two parallel arms of standard of care (control arm) versus standard of care with 10 days of chloroquine (intervention arm) with a loading dose over the first 24 hours, followed by 300mg base orally once daily for nine days. The study will recruit patients in three sites in Ho Chi Minh City, Vietnam: the Hospital for Tropical Diseases, the Cu Chi Field Hospital, and the Can Gio COVID hospital. The primary endpoint is the time to viral clearance from throat/nose swab, defined as the time following randomization until the midpoint between the last positive and the first of the negative throat/nose swabs. Viral presence will be determined using RT-PCR to detect SARS-CoV-2 RNA. Discussion: The results of the study will add to the evidence-based guidelines for management of COVID-19. Given the enormous experience of its use in malaria chemoprophylaxis, excellent safety and tolerability profile, and its very low cost, if proved effective then chloroquine would be a readily deployable and affordable treatment for patients with COVID-19. Trial registration: Clinicaltrials.gov NCT04328493 31/03/2020

scholarly journals Safety and immunogenicity trial of an inactivated SARS-CoV-2 vaccine-BBV152: a phase 1, double-blind, randomised control trial

2020 ◽  
Author(s):  
Raches Ella ◽  
Krishna Mohan ◽  
Harsh Jogdand ◽  
Sai Prasad ◽  
Siddharth Reddy ◽  
...  
Keyword(s):  
Phase 1 ◽  
Neutralizing Antibody ◽  
Cold Chain ◽  
Wild Type Virus ◽  
Randomised Control Trial ◽  
Enzyme Linked Immunosorbent Assay ◽  
Double Blind ◽  
Efficacy Trials ◽  
National Immunization ◽  
Antibody Titers

Background: BBV152 is a whole-virion inactivated SARS-CoV-2 vaccine formulated with a TLR 7/8 agonist molecule adsorbed to alum (Algel-IMDG). Methods We conducted a double-blind randomized controlled phase 1 clinical trial to evaluate the safety and immunogenicity of BBV152. A total of 375 participants were randomized equally to receive three vaccine formulations (n=100 each) prepared with 3 μg with Algel-IMDG, 6 μg with Algel-IMDG, and 6 μg with Algel, and an Algel only control arm (n=75). Vaccines were administered on a two-dose intramuscular accelerated schedule on day 0 (baseline) and day 14. The primary outcomes were reactogenicity and safety. The secondary outcomes were immunogenicity based on the anti-IgG S1 response (detected with an enzyme-linked immunosorbent assay [ELISA] and wild-type virus neutralization [microneutralization and plaque reduction neutralization assays]). Cell-mediated responses were also evaluated. Results: Reactogenicity was absent in the majority of participants, with mild events. The majority of adverse events were mild and were resolved. One serious adverse event was reported, which was found to be unrelated to vaccination. All three vaccine formulations resulted in robust immune responses comparable to a panel of convalescent serum. No significant differences were observed between the 3-μg and 6-μg Algel-IMDG groups. Neutralizing responses to homologous and heterologous SARS-CoV-2 strains were detected in all vaccinated individuals. Cell-mediated responses were biased to a Th-1 phenotype. Conclusions BBV152 induced binding and neutralising antibody responses and with the inclusion of the Algel-IMDG adjuvant, this is the first inactivated SARS-CoV-2 vaccine that has been reported to induce a Th1-biased response. Vaccine-induced neutralizing antibody titers were reported with two divergent SARS-CoV-2 strains. BBV152 is stored between 2°C and 8°C, which is compatible with all national immunization program cold chain requirements. Both Algel-IMDG formulations were selected for the phase 2 immunogenicity trials. Further efficacy trials are underway.

scholarly journals Multiple Indirect ELISAs for Serological Detection of SARS-CoV-2 Antibodies

2020 ◽  
Author(s):  
Abdullah Algaissi ◽  
Mohamed A. Alfaleh ◽  
Sherif Hala ◽  
Turki S. Abujamel ◽  
Sawsan S. Alamari ◽  
...  
Keyword(s):  
Antibody Response ◽  
Large Scale ◽  
Disease Onset ◽  
High Specificity ◽  
Epidemiological Studies ◽  
Cross Reactivity ◽  
Enzyme Linked Immunosorbent Assay ◽  
Serological Tests ◽  
Specificity And Sensitivity ◽  
Novel Coronavirus

As the coronavirus disease 2019 (COVID-19), which is caused by the novel coronavirus SARS-CoV-2, continues to spread rapidly around the world, there is an urgent need for validated serological assays to evaluate viral specific antibody responses in COVID-19 patients or recovered individuals. In this study, we established and used indirect Enzyme Linked Immunosorbent Assay (ELISA)-based serological tests to study the antibody response in COVID-19 patients. In order to validate the assays, we determined the cut-off values, sensitivity and specificity of the developed assays using sera collected from COVID-19 patients in Saudi Arabia at different time points after disease onset, as well as sera that are seropositive to other human CoVs; namely MERS-CoV, hCoV-OC43, hCoV-NL63, hCoV-229E, and hCoV-HKU1. The SARS-CoV-2 S1 subunit of the spike glycoprotein and nucleocapsid (N) ELISAs that we developed here not only showed high specificity and sensitivity, but also did not show any cross-reactivity with other CoVs. We also showed that all RT-PCR confirmed COVID-19 patients included in our study developed both virus specific IgM and IgG as early as one week after the onset of disease. The availability of these validated assays will enable us to determine the nature and duration of the antibody response mounted in response to SARS-CoV-2 infection. It will also allow conducting large-scale epidemiological studies to determine evidence of previous exposure to the virus and assess the true extent of virus spread within communities.

scholarly journals Serological Correlates of Protection against a GII.4 Norovirus

2015 ◽  
Vol 22 (8) ◽  
pp. 923-929 ◽  
Author(s):  
Robert L. Atmar ◽  
David I. Bernstein ◽  
G. Marshall Lyon ◽  
John J. Treanor ◽  
Mohamed S. Al-Ibrahim ◽  
...  
Keyword(s):  
Controlled Trial ◽  
Phase 1 ◽  
Serum Antibody ◽  
Vaccine Dose ◽  
Enzyme Linked Immunosorbent Assay ◽  
Double Blind ◽  
Live Virus ◽  
Monophosphoryl Lipid A ◽  
Antibody Levels ◽  
The Impact

ABSTRACTNoroviruses are the leading cause of acute gastroenteritis worldwide, and norovirus vaccine prevention strategies are under evaluation. The immunogenicity of two doses of bivalent genogroup 1 genotype 1 (GI.1)/GII.4 (50 μg of virus-like particles [VLPs] of each strain adjuvanted with aluminum hydroxide and 3-O-desacyl-4′monophosphoryl lipid A [MPL]) norovirus vaccine administered to healthy adults in a phase 1/2 double-blind placebo-controlled trial was determined using virus-specific serum total antibody enzyme-linked immunosorbent assay (ELISA), IgG, IgA, and histoblood group antigen (HBGA)-blocking assays. Trial participants subsequently received an oral live virus challenge with a GII.4 strain, and the vaccine efficacy results were reported previously (D. I. Bernstein et al., J Infect Dis 211:870–878, 2014, doi:10.1093/infdis/jiu497). This report assesses the impact of prechallenge serum antibody levels on infection and illness outcomes. Serum antibody responses were observed in vaccine recipients by all antibody assays, with first-dose seroresponse frequencies ranging from 88 to 100% for the GI.1 antigen and from 69 to 84% for the GII.4 antigen. There was little increase in antibody levels after the second vaccine dose. Among the subjects receiving the placebo, higher prechallenge serum anti-GII.4 HBGA-blocking and IgA antibody levels, but not IgG or total antibody levels, were associated with a lower frequency of virus infection and associated illness. Notably, some placebo subjects without measurable serum antibody levels prechallenge did not become infected after norovirus challenge. In vaccinees, anti-GII.4 HBGA-blocking antibody levels of >1:500 were associated with a lower frequency of moderate-to-severe vomiting or diarrheal illness. In this study, prechallenge serum HBGA antibody titers correlated with protection in subjects receiving the placebo; however, other factors may impact the likelihood of infection and illness after virus exposure. (This study is registered at ClinicalTrials.gov under registration number NCT1609257.)

scholarly journals N-acetyl galactosamine-conjugated antisense drug to APOC3 mRNA, triglycerides and atherogenic lipoprotein levels

2019 ◽  
Vol 40 (33) ◽  
pp. 2785-2796 ◽  
Author(s):  
Veronica J Alexander ◽  
Shuting Xia ◽  
Eunju Hurh ◽  
Steven G Hughes ◽  
Louis O’Dea ◽  
...  
Keyword(s):  
Single Dose ◽  
Multiple Dose ◽  
Phase 1 ◽  
Low Density Lipoprotein ◽  
Injection Site Reaction ◽  
Density Lipoprotein ◽  
Lipoprotein Cholesterol ◽  
Tolerability Profile ◽  
Double Blind ◽  
Favourable Safety

Abstract Aims Elevated apolipoprotein C-III (apoC-III) levels are associated with hypertriglyceridaemia and coronary heart disease. AKCEA-APOCIII-LRx is an N-acetyl galactosamine-conjugated antisense oligonucleotide targeted to the liver that selectively inhibits apoC-III protein synthesis. Methods and results The safety, tolerability, and efficacy of AKCEA-APOCIII-LRx was assessed in a double-blind, placebo-controlled, dose-escalation Phase 1/2a study in healthy volunteers (ages 18–65) with triglyceride levels ≥90 or ≥200 mg/dL. Single-dose cohorts were treated with 10, 30, 60, 90, and 120 mg subcutaneously (sc) and multiple-dose cohorts were treated with 15 and 30 mg weekly sc for 6 weeks or 60 mg every 4 weeks sc for 3 months. In the single-dose cohorts treated with 10, 30, 60, 90, or 120 mg of AKCEA-APOCIII-LRx, median reductions of 0, −42%, −73%, −81%, and −92% in apoC-III, and −12%, −7%, −42%, −73%, and −77% in triglycerides were observed 14 days after dosing. In multiple-dose cohorts of 15 and 30 mg weekly and 60 mg every 4 weeks, median reductions of −66%, −84%, and −89% in apoC-III, and −59%, −73%, and −66% in triglycerides were observed 1 week after the last dose. Significant reductions in total cholesterol, apolipoprotein B, non-high-density lipoprotein cholesterol (HDL-C), very low-density lipoprotein cholesterol, and increases in HDL-C were also observed. AKCEA-APOCIII-LRx was well tolerated with one injection site reaction of mild erythema, and no flu-like reactions, platelet count reductions, liver, or renal safety signals. Conclusion Treatment of hypertriglyceridaemic subjects with AKCEA-APOCIII-LRx results in a broad improvement in the atherogenic lipid profile with a favourable safety and tolerability profile. ClinicalTrials.gov Identifier: NCT02900027.

scholarly journals A randomized, double-blind, placebo-controlled, single and multiple ascending dose Phase 1 study to determine the safety, pharmacokinetics and food and faecal microbiome effects of ibezapolstat administered orally to healthy subjects

2020 ◽  
Vol 75 (12) ◽  
pp. 3635-3643 ◽  
Author(s):  
Kevin W Garey ◽  
Khurshida Begum ◽  
Chris Lancaster ◽  
Anne Gonzales-Luna ◽  
Dinh Bui ◽  
...  
Keyword(s):  
Phase 1 ◽  
Plasma Concentrations ◽  
Systemic Exposure ◽  
Controlled Study ◽  
Systemic Absorption ◽  
Double Blind ◽  
Shotgun Metagenomics ◽  
Double Blind Placebo ◽  
Α Diversity

Abstract Background Clostridioides difficile infection is the most common cause of healthcare-associated infections in the USA, with limited treatment options. Ibezapolstat is a novel DNA polymerase IIIC inhibitor with in vitro activity against C. difficile. Objectives and methods Randomized, double-blind, placebo-controlled study to assess the safety, tolerability and pharmacokinetics of ibezapolstat in healthy volunteers. Microbiome changes associated with ibezapolstat were compared with vancomycin over a 10 day course using shotgun metagenomics. Results A total of 62 subjects aged 31 ± 7 years (45% female; average BMI: 25 ± 3 kg/m2) were randomized. Ibezapolstat was well tolerated with a safety signal similar to placebo. Ibezapolstat had minimal systemic absorption with the majority of plasma concentrations less than 1 µg/mL. In the multiday, ascending dose study, ibezapolstat concentrations of 2000 µg/g of stool were observed by Day 2 and for the remainder of the dosing time period. In the multiday, multiple-dose arm, baseline microbiota was comparable between subjects that received ibezapolstat compared with vancomycin. At Day 10 of dosing, differential abundance analysis and β-diversity demonstrated a distinct difference between the microbiome in subjects given vancomycin compared with either dose of ibezapolstat (P = 0.006). α-Diversity changes were characterized as an increase in the Actinobacteria phylum in subjects that received ibezapolstat and an increase in Proteobacteria in subjects given vancomycin. Conclusions Ibezapolstat was shown to be safe and well tolerated, with minimal systemic exposure, high stool concentrations and a distinct microbiome profile compared with oral vancomycin. These results support further clinical development of ibezapolstat for patients with C. difficile infection.

Favorable Immunologic Response to Recombinant Thrombin Application in Surgery among Subjects with Pre-Existing Antibodies to Bovine Thrombin.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3390-3390
Author(s):  
Gregory Moneta ◽  
Jeffrey Ballard ◽  
Carlton Randleman ◽  
Kenneth Renkens ◽  
Neil Singla ◽  
...  
Keyword(s):  
Adverse Events ◽  
Phase 1 ◽  
Prior Exposure ◽  
Enzyme Linked Immunosorbent Assay ◽  
Immunologic Response ◽  
Open Label ◽  
Double Blind ◽  
Bovine Thrombin ◽  
Increased Risk ◽  
Study Results

Abstract Recombinant thrombin (rThrombin) is an active topical hemostat that is approved by the FDA as an aid to hemostasis. The safety, immunogenicity, and efficacy of rThrombin have been demonstrated in 1 Phase 1 study, 5 Phase 2 studies, and 1 randomized, double-blind Phase 3 study. No safety observations have been deemed clearly causally related to exposure to rThrombin; favorable immunologic response to rThrombin was observed in these trials. Treatment with thrombin derived from bovine sources has occasionally been associated with adverse events which appear to be related to the formation of antibodies against bovine thrombin and/or Factor V. A boxed product warning indicates that patients with antibodies to bovine thrombin preparations should not be re-exposed to these products. Secondary immune responses to bovine thrombin re-exposure may occur in patients with antibodies to bovine thrombin product. This Phase 3b open-label, single-group, multisite study was designed to evaluate the immunogenicity and safety of rThrombin among subjects at increased risk for having anti-bovine thrombin product antibodies as a result of prior surgery with a high likelihood of bovine thrombin exposure (N=209). Topical rThrombin was applied during a single spinal or vascular surgical procedure. Immunogenicity was evaluated by enzyme-linked immunosorbent assay at baseline and Day 29; safety measures were evaluated through Day 29. Subjects were eligible for participation if they had definite or highly likely prior exposure to bovine thrombin within the previous 3 years. Preliminary results from 162 subjects enrolled and evaluated as of the cut-off date (28 July 2008) are presented herein; complete study results will be available at the meeting. Of the subjects evaluated to date, 78 (48%) had definite prior exposure to bovine thrombin; prior exposure was highly likely for 85 subjects (52%) and unknown for 1 subject. At baseline, 139 subjects (86%) were seronegative and 23 (14%) were seropositive for anti-bovine thrombin product antibodies. Anti-rThrombin product antibodies did not develop through Day 29 post-treatment in any subject; thus, the rate of antibody formation to rThrombin was the same regardless of anti-bovine thrombin product antibody status. Of the 4 subjects who had anti-rThrombin product antibodies at baseline, none had a change in titer ≥1.0 unit at Day 29. Common adverse events (AEs; reported by ≥10% of subjects) were consistent with the post-surgical setting and with prior studies of rThrombin in these surgical populations. Common AEs included incision site pain, procedural pain, nausea, constipation, anemia, muscle spasms, hypotension, and pyrexia. Topical application of rThrombin was well tolerated, and there was no difference in the formation of antibodies to rThrombin at Day 29 in subjects with or without pre-existing antibodies to bovine thrombin product. The results from this study provide additional information about the immunologic safety of rThrombin and suggest that rThrombin can be safely applied as an aid to hemostasis in patients with pre-existing antibodies to bovine thrombin.

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