In the heterologous vs homologous prime/boost experiment (Experiment 2), homologous ChulaCov19 and homologous AZD1222 immunizations elicited comparable levels of S-specific IFN- positive T cells responses which was 2482 and 2210 SFC/106 splenocytes, respectively. Folegatti, P. M. et al. The ethics committee waived the need for formal written informed consent from patients, as this study was performed on clinical data retrieved from routine tests; thus, no patient was specifically included in this study. Experiment 3: antibody durability and effect of 3rd dose of ChulaCov19 study, mice were immunized twice with 3 weeks interval with 5g of ChulaCov19 (1/10 of human dose used in clinical trial) then boosted again at week 20. The signal was amplified using a specific set of amplifiers (AMP1-6) as recommended by the manufacturer and was detected using a Fast Red solution for 5min at room temperature. doi:10.1371/journal.pone.0281257, Editor: Deniz Can Guven, Elazg Fethi Sekin City Hospital: Elazig Fethi Sekin Sehir Hastanesi, TURKEY, Received: November 17, 2022; Accepted: January 18, 2023; Published: April 28, 2023. This result implied that the decrease in Nab titers against BA.4/5 may be improved with higher mRNA vaccine doses. In a heterologous prime-boost study, ChulaCov19 booster dose generates a 7-fold increase of NAb against Wuhan-Hu1 WT virus and also significantly increases NAb response against Omicron (BA.1 and BA.4/5) when compared to homologous CoronaVac or AZD1222 vaccination. on this website is designed to support, not to replace the relationship News-Medical, viewed 01 May 2023, https://www.news-medical.net/news/20230427/Neurological-phenotypes-induced-by-SARS-CoV-2-spike-protein-in-neurons.aspx. Lancet Infect Dis 21, 13521354 (2021). CK was also funded by emerging Infectious Diseases and Vaccines Cluster, Ratchadapisek Sompoch Endowment Fund (2021), Chulalongkorn University (764002-HE04), and the Second Century Fund (C2F), Chulalongkorn University and Ratchadapiseksompotch Fund. This candidate vaccine has now completed non-clinical toxicity and biodistribution studies and has entered Phase 1 and 2 human trials. A table of quantitative anti-spike levels for otherwise healthy, recently vaccinated individuals by week of vaccination to aid in interpretation of test results is available in Table 3 in this pre-print. Detailed amino sequence was shown in Supplementary File1. Feikin, D.R. 1a). While neurological signs have been documented in some, not all, coronavirus disease 2019 (COVID-19) patients, the precise mechanism by which viruses affect neuronal cells is still unknown and, thus, a subject of investigation. Bowen, J. E. et al. Each dot represents an individual animal. Available from: https://covid19.trackvaccines.org/agency/who (2022). The purified mRNA-S (ChulaCov19) with undetectable endotoxin was tested for protein expression in VERO E6 cells. Her educational background allowed her to foster an interest in anatomical and physiological sciences. The geometric mean titers (GMTs) of NAb against wild-type (WT, Wuhan-Hu1) virus are 1,280, 11,762, 54,047, and 62,084, respectively. NAb measurements in mice sera from Experiment 1 against WT (Wuhan-Hu1) live-virus (micro-VNT50) at 2-week after each dose showed NAb response in a dose-dependent manner. After SARS-CoV-2 challenge, there was no measurable decline in body weight among vaccinated groups. During the experiments, mice were maintained at 2022C and a relative humidity of 4510% on a 12h light/dark cycle. 2a). The 4-week gap was used according to the preclinical study protocol of ChAdOX-vectored vaccines65,66. Safety and immunogenicity of the ChAdOx1 nCoV-19 vaccine against SARS-CoV-2: a preliminary report of a phase 1/2, single-blind, randomised controlled trial. They were widely available in these countries for approximately a year before being accessible on other continents. First bivalent COVID-19 booster vaccine approved by UK medicines regulator). Ma, Q. et al. However, there was no discernible difference in burst activity between S1-treated and the control wells. Bars represent the meanSD of S-specific IFN- positive T cells after stimulated with overlapping peptide pools spanning the SARS-CoV-2 S1 (pooled #1-5) and S2 (pooled #6-10). Do ketogenic diets elevate low-density lipoprotein cholesterol levels? J. Clin. Even though most COVID-19 patients are asymptomatic or only mildly symptomatic2,3,4, the virus is still eminently transmissible even during the early phases of the illness. The bands corresponding to S1, S2 and intact S (S0) were detected. demonstrated that only Th2-dominant but not Th1/Th2 balanced response enhanced lung pathology in adjuvanted recombinant RSV immunized mice45. Nat Commun 12, 372 (2021). Percentage of virus infectivity in virus control (VC) and samples were calculated based on OD of cell control (CC), infectivity (%) = (OD of CC OD of sample) x 100. The Abbott Architect SARS-CoV-2 IgG II assay, run under an emergency use authorization from the FDA, is quantitative test designed to detect IgG antibodies to the spike protein of SARS-CoV-2 in serum and plasma from individuals with an adaptive immune response to SARS-CoV-2, indicating recent or prior infection. ];V^srE]DwCyTPre_fyG;Cb@*\d$ j '-|,!]jF/J9r\s%3! KR, DW, MGA, CK, EP, and SB are co-inventors of the submitted ChulaCov19 mRNA vaccines Patent. The investigators strictly adhered to the principles and guidelines of the Institute of Animals for Scientific Purposes Development, National Research Council of Thailand. Laboratoires Oriade NovialeBiogroup, Grenoble, France, Affiliation: Funding: The author(s) received no specific funding for this work. The micro-VNT50 titers was calculated as the reciprocal serum dilution that neutralized 50% of virus observed in virus control wells using probit analysis, SPSS program71. This study was performed using sera collected between October 2021 and December 2021 from a real life cohort of 69 individuals attending internal medicine and infectious diseases department of the European Hospital (Marseille). About the study. By continuing to browse this site you agree to our use of cookies. Front Immunol 11, 1673 (2020). Elecsys Anti-SARS-CoV-2 serology assay is intended for the detection of IgM and IgG antibodies to SARS-CoV-2 in human serum and plasma. Median time between last vaccination and sampling was 5.2 months (3.16.4). Jiang, R. D. et al. The study identified the number of pulses per electrode as the most prominent characteristic that differentiated the spike protein-treated wells from the control wells. Thank you for visiting nature.com. Science 368, 489493 (2020). Neurological phenotypes induced by SARS-CoV-2 spike protein in neurons. Similar findings were also observed in BA.4/5 subvariant (Fig. Antibodies against the SARS-CoV-2 viral spike protein have been shown to have neutralizing effects.1-3Current vaccines have been developed to elicit antibodies to the spike protein. Kairat Tabynov, Nurkeldi Turebekov, Kaissar Tabynov, James Logue, Robert M. Johnson, Matthew B. Frieman, Yi-Jiun Lin, Meei-Yun Lin, Chia-En Lien, Susanne Rauch, Nicole Roth, Benjamin Petsch, Felicity C. Stark, Bassel Akache, Martin Handfield, Maarten Swart, Joan van der Lubbe, Roland Zahn, Jessica Andries, Wildriss Viranaicken, Philippe Despres, Nature Communications Voysey, M. et al. Hence, in this study, although the NAb was displayed in a dose-dependent fashion, in-depth analysis of T cell quality induced by different vaccine dosage is also needed to investigate the controversy of viremia after challenge. https://www.news-medical.net/news/20230427/Neurological-phenotypes-induced-by-SARS-CoV-2-spike-protein-in-neurons.aspx. Additional quality control to ensure the absence of double-stranded RNA (dsRNA) and endotoxin contamination prior to encapsulation into lipid nanoparticles (LNPs) were performed as described previously60. Use the Previous and Next buttons to navigate the slides or the slide controller buttons at the end to navigate through each slide. More info. With such promising results from animal studies, the same formulation of ChulaCov19 vaccine that had been tested in animals is currently in phase 1-2 of clinical trials and can be manufactured locally for later clinical development. Please note that medical information found Vaccines (Basel) 10, 613 (2022). By Day 4 after challenge, two mice in PBS-receiving group (control) began to show clinical signs of anorexia, lethargy, and rough hair coat. Among the 1g group, only one tissue had very few positive cells, the nasal epithelium. Virus titers were quantified by RT-qPCR and by determined the log10TCID50 values. Cevik, M. et al. Six-day post challenge, wk5+6 days, mice were sacrificed to determine virus titers in different tissues (nasal turbinate, brain, lung, and kidney) and for histopathology. The results resembled those observed in the panel that used a commercial recombinant S-trimer instead of transfected supernatant. In these preclinical studies in mice, we have demonstrated that ChulaCov19, a secreted, prefusion non-stabilized ectodomain spike mRNA vaccine, elicited robust Spike-specific antibody and T-cell responses which has also translated into efficacy in protecting transgenic mice from SARS-CoV-2. Alene, M. et al. Recombinant S protein with S1/S2 cleavage site abolished (ACROBioSystems, China) was used as positive control both in HEK293T-hACE-2 binding assay and western blot. Characteristics like the number of bursts per electrode, their duration, frequency, and the number of spikes per burst according to the treatment condition were also quantified. The RT-qPCR data showed that both doses of vaccine prevented the expression of SARS-CoV-2 viremia at 5 or 6 days after viral inoculation. Bars represent the GMTs and 95% CI for each group. At 24h before transfection, 1105 Vero E6 cells were seeded in a 24-well plate (Thermo Fisher Scientific, MA, USA). Contact: commserv@uw.edu | ACS Cent Sci 7, 594602 (2021). SARS-CoV-2 delta variant infection in domestic dogs and cats, Thailand. Negative test results do not rule out the possibility of an infection with SARS-CoV-2. By using immunofluorescent assay, employing RBD-, S1-, S2-specific antibodies or PCS, the S proteins were observed within the cytoplasm of transfected cells while untransfected cells were negative for fluorescent signal (Fig. Ying, B. et al. These services aid in identifying a relative . Source data are provided as a source data file. Therefore, during the surge of Omicron globally, there is a need of a boosting dose even with a first-generation vaccine or ideally with a second-generation vaccine such as a bivalent immunogen containing or encoding of Omicrons spike protein49,50. The National Library of Medicine is running a pilotto include preprints that result from research funded by NIH in PMC and PubMed. The primary components of the SARS-CoV-2 structure are envelope (E), spike (S), membrane (M), and nucleocapsid (N) proteins. According to French regulations, the study was approved by the French ethics committee (Health Data Hub, approval number: F20211217094518). Neurological phenotypes induced by SARS-CoV-2 spike protein in neurons. Boosting with ChulaCov19, although not statistically significant, it could enhance the IFN- positive T cells by approximately 6.5 folds (p=0.1523) of the magnitude of T cells response in CoronaVac-primed mice (273 SFC/106 splenocytes). Results from antibody testing should not be used as the sole basis to diagnose or exclude SARS-CoV-2 infection or to inform infection status. Goat-anti-human IgG, goat-anti-mouse IgG, or goat-anti-rabbit IgG antibodies (all were diluted 1:10,000) conjugated with horseradish peroxidase (HRP) were used as secondary antibodies (all were from KPL, MD, USA) and detected by chemiluminescence substrate (Immobilon western, Millipore, CA, USA) then exposed to an X-ray film. At week 5 (2 weeks after the second dose), all mice in both vaccinated groups showed increased NAb levels. In contrast, a higher dose vaccination not only induced the mixture of low and high avidity T cells responses, but also induced the clonal deletion of high avidity CD8 T cells29,30,31. Prefusion RSV F Immunization Elicits Th2-Mediated Lung Pathology in Mice When Formulated With a Th2 (but Not a Th1/Th2-Balanced) Adjuvant Despite Complete Viral Protection. Article The total volume of 50l of viral RNA was obtained from each sample. mSphere 7, e0024322 (2022). Science 377, 890894 (2022). To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. N Engl J Med 384, 403416 (2021). A recent randomized efficacy trial of the ChAdOx1 nCoV-19 (AZD1222) vaccine conducted in more than 8,500 patients in the United Kingdom, analyzed the antibody levels associated with protection against SARS-CoV-2 [7]. The NT50 titers against WT and Delta variants increased 7- to 14-fold when using the heterologous approach with ChulaCov19 as compared to the homologous immunizations with CoronaVac or AZD1222 (Fig. PLOS is a nonprofit 501(c)(3) corporation, #C2354500, based in San Francisco, California, US. Bloomberg. Previous studies reported that low-dose vaccination induced only high avidity T cells. 4d). Tian, J. H. et al. Rotshild, V., Hirsh-Raccah, B., Miskin, I., Muszkat, M. & Matok, I. Whether differences in response impact vaccine efficacy needs further study. Source data are provided as a Source Data file. xA 0 @L 200 0 obj <>]/Filter/FlateDecode/BitsPerComponent 8/Length 2211/Height 275>>stream Overall concordance increased consistently after applying new thresholds, i.e., 148 BAU/ml (Abbott), 48 (Beckman), 559 (Roche), and 270 (Siemens). Jairak, W. et al. FITC-tagged 2nd Abs (green) were used for detection of RBD, S1, and S2 while AlexaFluor647-tagged 2nd Ab (red) was used following PCS staining. If material is not included in the articles Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. Zhang, L. et al. As with many viral respiratory infections, knowledge of the immune response to SARS-CoV-2 after a natural infection or vaccination, that could be predictive of the protection conferred, is challenging and not well established [14]. An mRNA Vaccine against SARS-CoV-2 - Preliminary Report. These results reflect the real S protein dynamic as shedding of S1 could be detected in viral infection33,34. Stained cells were visualized under confocal microscope (ZEISS LSM 800, Carl Zeiss, Germany). The optimal cutoff was analyzed for each antibody binding assay (Table 3). Some must be performed in a laboratory by trained personnel, some can be performed at the point of care, and others can be . PLOS ONE promises fair, rigorous peer review, Developing highly effective vaccine platforms like mRNA technology in low- and middle-income countries (LMICs) is therefore an important goal21. Since the outbreak of COVID-19, the world has raced to understand and accurately diagnose infection caused by SARS-CoV-2. Each dot represents an individual animal. Statistical significance was set at P < 0.05. Immunogenicity and Safety of ChulaCov19 BNA159 Vaccine as a Booster Dose in Adults). Zheng, J. et al. Mice sera were further analyzed for NAb by psVNT50 test against the important recent VOCs, including Delta (B.1.617.2) variant and Omicron (BA.1 and BA.4/5) variants, and titers significantly decreased for all VOCs. Overall, all assays showed good agreement with the Genscript sVNT. Li, R. et al. mRNA encapsulation was performed by Genevant Sciences Corporation (Vancouver, British Columbia, Canada). DNA Vaccine Administered by Cationic Lipoplexes or by In Vivo Electroporation Induces Comparable Antibody Responses against SARS-CoV-2 in Mice. Source data are provided with this paper. Before administering S1 to neurons on day zero, a human monoclonal anti-S1 antibody was sampled and neutralized using the antibody. Owned and operated by AZoNetwork, 2000-2023. In brief, mouse splenocytes at 5105 cells/well were cultured with SARS-CoV-2 spike peptide pools spanning the entire sequence of spike protein, 25 peptides/pool (Mimotopes, Mulgrave, Victoria, Australia) at a final concentration of 2g/mL at 37C, 5% CO2 for 40h. Pools 15 and 610 corresponded to S1 and S2 regions of spike protein, respectively. Safety and Immunogenicity of Two RNA-Based Covid-19 Vaccine Candidates. Using a serologic test in combination with a NAAT to detect IgG or total antibodies 3 to 4 weeks after symptom onset maximizes the sensitivity and specificity to detect past SARS-CoV-2 infection. More importantly, in partnering with a domestic vaccine manufacture, BioNet Asia, ChulaCov19 can now be manufactured and formulated locally54. Google Scholar. Some tests provide results rapidly (within minutes); others require 1-3 days for processing. b S-specific IgG2a/IgG1 ratio measured at 2 weeks after the 2nd dose. This demonstrated the significant protective efficacy of ChulaCov19 in the preclinical phase. PubMed Central This assay detects antibodies that block the interaction of SARS-CoV-2 with its entry receptor angiotensin-converting enzyme 2. All authors reviewed the results and approved the final version of the manuscript.
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