As part of the accelerated development of vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), we report a dose-finding and adjuvant justification study of SCB-2019, a ...protein subunit vaccine candidate containing a stabilised trimeric form of the spike (S)-protein (S-Trimer) combined with two different adjuvants.
Our study is a phase 1, randomised, double-blind placebo-controlled trial at a specialised clinical trials centre in Australia. We enrolled healthy adult volunteers in two age groups: younger adults (aged 18–54 years) and older adults (aged 55–75 years). Participants were randomly allocated either vaccine or placebo using a list prepared by the study funder. Participants were to receive two doses of SCB-2019 (either 3 μg, 9 μg, or 30 μg) or a placebo (0·9% NaCl) 21 days apart. SCB-2019 either had no adjuvant (S-Trimer protein alone) or was adjuvanted with AS03 or CpG/Alum. The assigned treatment was administered in opaque syringes to maintain masking of assignments. Reactogenicity was assessed for 7 days after each vaccination. Humoral responses were measured as SCB-2019 binding IgG antibodies and ACE2-competitive blocking IgG antibodies by ELISA and as neutralising antibodies by wild-type SARS-CoV-2 microneutralisation assay. Cellular responses to pooled S-protein peptides were measured by flow-cytometric intracellular cytokine staining. This trial is registered with ClinicalTrials.gov, NCT04405908; this is an interim analysis and the study is continuing.
Between June 19 and Sept 23, 2020, 151 volunteers were enrolled; three people withdrew, two for personal reasons and one with an unrelated serious adverse event (pituitary adenoma). 148 participants had at least 4 weeks of follow-up after dose two and were included in this analysis (database lock, Oct 23, 2020). Vaccination was well tolerated, with two grade 3 solicited adverse events (pain in 9 μg AS03-adjuvanted and 9 μg CpG/Alum-adjuvanted groups). Most local adverse events were mild injection-site pain, and local events were more frequent with SCB-2019 formulations containing AS03 adjuvant (44–69%) than with those containing CpG/Alum adjuvant (6–44%) or no adjuvant (3–13%). Systemic adverse events were more frequent in younger adults (38%) than in older adults (17%) after the first dose but increased to similar levels in both age groups after the second dose (30% in older and 34% in younger adults). SCB-2019 with no adjuvant elicited minimal immune responses (three seroconversions by day 50), but SCB-2019 with fixed doses of either AS03 or CpG/Alum adjuvants induced high titres and seroconversion rates of binding and neutralising antibodies in both younger and older adults (anti-SCB-2019 IgG antibody geometric mean titres at day 36 were 1567–4452 with AS03 and 174–2440 with CpG/Alum). Titres in all AS03 dose groups and the CpG/Alum 30 μg group were higher than were those recorded in a panel of convalescent serum samples from patients with COVID-19. Both adjuvanted SCB-2019 formulations elicited T-helper-1-biased CD4+ T-cell responses.
The SCB-2019 vaccine, comprising S-Trimer protein formulated with either AS03 or CpG/Alum adjuvants, elicited robust humoral and cellular immune responses against SARS-CoV-2, with high viral neutralising activity. Both adjuvanted vaccine formulations were well tolerated and are suitable for further clinical development.
Clover Biopharmaceuticals and the Coalition for Epidemic Preparedness Innovations.
Abiotic stresses, such as heat, drought, salinity, low temperature, and heavy metals, inhibit plant growth and reduce crop productivity. Abiotic stresses are becoming increasingly extreme worldwide ...due to the ongoing deterioration of the global climate and the increase in agrochemical utilization and industrialization. Plants grown in fields are affected by one or more abiotic stresses. The consequent stress response of plants induces reactive oxygen species (ROS), which are then used as signaling molecules to activate stress‐tolerance mechanism. However, under extreme stress conditions, ROS are overproduced and cause oxidative damage to plants. In such conditions, plants produce anthocyanins after ROS signaling via the transcription of anthocyanin biosynthesis genes. These anthocyanins are then utilized in antioxidant activities by scavenging excess ROS for their sustainability. In this review, we discuss the physiological, biochemical, and molecular mechanisms underlying abiotic stress‐induced anthocyanins in plants and their role in abiotic stress tolerance. In addition, we highlight the current progress in the development of anthocyanin‐enriched transgenic plants and their ability to increase abiotic stress tolerance. Overall, this review provides valuable information that increases our understanding of the mechanisms by which anthocyanins respond to abiotic stress and protect plants against it. This review also provides practical guidance for plant biologists who are engineering stress‐tolerant crops using anthocyanin biosynthesis or regulatory genes.
Opisthorchis viverrini is endemic in the South East Asian region, especially in Cambodia, Lao People's Democratic Republic, Vietnam and Thailand, but there have been no previous records from Myanmar. ...During stool surveys of rural populations in three regions of Lower Myanmar, Opisthorchis-like eggs were found in 34 out of 364 (9.3%) participants by stool microscopy after using the modified formalin-ether concentration technique. DNA was extracted from these positive stool samples and a portion of the mitochondrial cytochrome c oxidase subunit I (cox1) gene was amplified using the polymerase chain reaction and then sequenced. DNA sequences, successfully obtained from 18 of 34 positive samples (Bago Region, n = 13; Mon State, n = 3; Yangon Region, n = 2), confirmed that the eggs were of O. viverrini. Sequences showed 99.7% identity with O. viverrini mitochondrial cox1 (GenBank accession no. JF739555) but 95%, 88.7%, 82.6% and 81.4% identities with those of Opisthorchis lobatus from Lao People's Democratic Republic (GenBank accession nos. HQ328539-HQ328541), Metorchis orientalis from China (KT239342), Clonorchis sinensis from China (JF729303) and Opisthorchis felineus from Russia (EU921260), respectively. When alignement with other Opisthorchiidae trematodes, 81% similarity with Metorchis bilis from Czech Republic (GenBank accession nos. KT740966, KT740969, KT740970) and Slovakia (GenBank accession nos. KT740971-KT740973), 84.6% similarity with Metorchis xanthosomus from Czech Republic (GenBank accession no. KT740974), 78.6% similarity with M. xanthosomus from Poland (GenBank accession no. KT740968) and 82.2% similarity with Euamphimerus pancreaticus from Czech Republic (GenBank accession no. KT740975) were revealed. This study demonstrated, for the first time, O. viverrini from rural people in Myanmar using molecular methods and is an urgent call for surveillance and control activities against opisthorchiasis in Myanmar.
Zika virus, a flavivirus transmitted by Aedes aegypti and Aedes albopictus mosquitoes, is associated with cases of congenital malformations and neurological complications. Absence of specific ...treatment makes a prophylactic Zika virus vaccine an unmet medical need. We assessed safety and immunogenicity of three doses of a purified, inactivated, Zika virus vaccine candidate in healthy flavivirus-naive and flavivirus-primed adults.
This two-part, multicentre, observer-blind, randomised, placebo-controlled, phase 1 trial was done at seven medical clinics in the USA and two in Puerto Rico. Eligible participants were healthy adults aged 18–49 years. Participants were randomly assigned (1:1:1:1), using a sponsor-supplied randomisation scheme, to four groups to receive two intramuscular injections, 28 days apart, of saline placebo or TAK-426 containing 2 μg, 5 μg, or 10 μg antigen. Participants, investigators, and vaccine administrating personnel were masked to group assignment. Part 1 of the study assessed flavivirus-naive participants and part 2 assessed flavivirus-primed participants. The primary outcomes were safety, tolerability, and immunogenicity based on solicited local reactions and solicited systemic adverse events in the 7 days after each dose; unsolicited adverse events and serious adverse events in the 28 days after each dose; and geometric mean titres (GMTs) of neutralising anti-Zika virus antibodies at 28 days after the second dose. Safety assessments were done in all participants who received at least one dose of vaccine. Immunogenicity assessments were in the per-protocol set, comprising all participants who received at least one dose of vaccine and provided valid serology results at baseline and at least one post-vaccination timepoint, with no major protocol violations. The trial is ongoing and is registered at ClinicalTrials.gov (NCT03343626).
Between Nov 13, 2017, and Oct 24, 2018, 894 volunteers were screened and 271 enrolled (125 flavivirus-naive and 146 flavivirus-primed participants). All TAK-426 doses were well tolerated with no deaths, no vaccine-related serious adverse events, and similar rates of mainly mild to moderate adverse events. TAK-426 elicited dose-dependent increases in antibody GMTs in both flavivirus-naive and flavivirus-primed participants. 28 days after dose 2, plaque-reduction neutralisation test GMTs in flavivirus-naive participants were 1130 (95% CI 749–1703) in the 2 μg TAK-426 group, 1992 (1401–2833) in the 5 μg TAK-426 group, and 3690 (2677–5086) in the 10 μg TAK-426 group. In pairwise comparisons, responses after two vaccinations in the 10 μg group were significantly greater than in the 2 μg group (GMT ratio 3·27 95% CI 1·98–5·39, p<0·0001) and the 5 μg group (GMT ratio 1·85 1·15–2·98, p=0·012).
TAK-426 was well tolerated, with an acceptable safety profile, and was immunogenic in both flavivirus-naive and flavivirus-primed adults. Based on the safety and immunogenicity profiles of all TAK-426 doses assessed, the 10 μg TAK-426 dose was selected for further clinical development.
Takeda Vaccines and the US Biomedical Advanced Research and Development Authority.
For the Spanish translation of the abstract see Supplementary Materials section.
Key message
This review contains functional roles of MYB transcription factors in the transcriptional regulation of anthocyanin biosynthesis in horticultural plants. This review describes potential ...uses of MYB TFs as tools for metabolic engineering for anthocyanin production.
Anthocyanins (ranging from red to blue) are controlled by specific branches of the anthocyanin biosynthetic pathway and are mostly visible in ornamentals, fruits, and vegetables. In the present review, we describe which R2R3-MYB transcription factors (TFs) control the transcriptional regulation of anthocyanin structural genes involved in the specific branches of the anthocyanin biosynthetic pathway in various horticultural plants (e.g., ornamentals, fruits, and vegetables). In addition, some MYBs responsible for anthocyanin accumulation in specific tissues are described. Moreover, we highlight the phylogenetic relationships of the MYBs that suppress or promote anthocyanin synthesis in horticultural crops. Enhancement of anthocyanin synthesis via metabolic genetic engineering of anthocyanin MYBs, which is described in the review, is indicative of the potential use of the mentioned anthocyanin-related MYBs as tools for anthocyanin production. Therefore, the MYBs would be suitable for metabolic genetic engineering for improvement of flower colors, fruit quality, and vegetable nutrients.
In 2017, the Myanmar National Action Plan for Containment of Antimicrobial Resistance (AMR) (2017–2022) was endorsed by the Ministry of Health and Sports, Myanmar; one of its objectives was to ...increase public awareness of AMR to accelerate appropriate antibiotic use. This survey aimed to assess the public knowledge, practices and awareness concerning antibiotics and AMR awareness among adults in Myanmar. We conducted a nationwide cross-sectional mobile phone panel survey in January and February 2020. Participants were randomly selected from the mobile phone panel in each of three groups stratified by gender, age group, and residential area urbanity; they were interviewed using a structured questionnaire. Collected data were weighted based on the population of each stratum from the latest national census and analyzed using descriptive and inferential statistics. Two thousand and forty-five adults from 12 regions and states participated in this survey. Overall, 89.5% of participants had heard about antibiotics; however, only 0.9% provided correct answers to all five questions about antibiotics, whereas 9.7% provided all incorrect answers. More than half of participants (58.5%) purchased antibiotics without a prescription, mainly from medical stores or pharmacies (87.9%); this was more frequent in age group (18–29 years) and those in rural areas (p = 0.004 and p < 0.001, respectively). Only 56.3% were aware of antibiotic resistance and received their information from medical professionals (46.3%), family members or friends (38.9%), or the media (26.1%). Less than half (42.4%) knew that antibiotics were used in farm animals. Most did not know that using antibiotics in farm animals could develop resistance (73.2%) and is banned for the purposes of growth stimulation (64.1%). This survey identifies considerable gaps in the knowledge, practices, and awareness about antibiotics among the general population in Myanmar. Continuous public education and awareness campaigns must be urgently conducted to fulfill these gaps, which would aid in promoting antibiotic stewardship, leading to combating AMR in Myanmar.
Rotaviruses are the most important cause of severe acute gastroenteritis worldwide in children <5 years of age. The human, G1P8 rotavirus vaccine Rotarix™ significantly reduced severe rotavirus ...gastroenteritis episodes in a Phase III clinical trial conducted in infants in South Africa and Malawi. This paper examines rotavirus vaccine efficacy in preventing severe rotavirus gastroenteritis, during infancy, caused by the various G and P rotavirus types encountered during the first rotavirus-season.
Healthy infants aged 5-10 weeks were enrolled and randomized into three groups to receive either two (10 and 14 weeks) or three doses of Rotarix™ (together forming the pooled Rotarix™ group) or three doses of placebo at a 6,10,14-week schedule. Weekly home visits were conducted to identify gastroenteritis episodes. Rotaviruses were detected by ELISA and genotyped by RT-PCR and nucleotide sequencing. The percentage of infants with severe rotavirus gastroenteritis caused by the circulating G and P types from 2 weeks post-last dose until one year of age and the corresponding vaccine efficacy was calculated with 95% CI.
Overall, 4939 infants were vaccinated and 4417 (pooled Rotarix™ = 2974; placebo = 1443) were included in the per protocol efficacy cohort. G1 wild-type was detected in 23 (1.6%) severe rotavirus gastroenteritis episodes from the placebo group. This was followed in order of detection by G12 (15 1% in placebo) and G8 types (15 1% in placebo). Vaccine efficacy against G1 wild-type, G12 and G8 types were 64.1% (95% CI: 29.9%; 82%), 51.5% (95% CI:-6.5%; 77.9%) and 64.4% (95% CI: 17.1%; 85.2%), respectively. Genotype P8 was the predominant circulating P type and was detected in 38 (2.6%) severe rotavirus gastroenteritis cases in placebo group. The remaining circulating P types comprised of P4 (20 1.4% in placebo) and P6 (13 0.9% in placebo). Vaccine efficacy against P8 was 59.1% (95% CI: 32.8%; 75.3%), P4 was 70.9% (95% CI: 37.5%; 87.0%) and P6 was 55.2% (95% CI: -6.5%; 81.3%)
Rotarix™ vaccine demonstrated efficacy against severe gastroenteritis caused by diverse circulating rotavirus types. These data add to a growing body of evidence supporting heterotypic protection provided by Rotarix™.
NCT00241644.
We previously reported the efficacy of the adjuvanted-protein COVID-19 vaccine candidate S-Trimer (SCB-2019) in adults who showed no evidence of previous exposure to SARS-CoV-2. In this study, we ...aimed to investigate the extent of protection afforded by previous exposure to SARS-CoV-2 on subsequent COVID-19 infection, as well as the efficacy, safety, and reactogenicity of SCB-2019 in participants who were enrolled in the Study evaluating Protective-Efficacy and safety of Clover's Trimeric Recombinant protein-based and Adjuvanted COVID-19 vaccine (SPECTRA) trial who had already been exposed to SARS-CoV-2 before vaccination.
In a phase 2 and 3 multicentre, double-blind, randomised, placebo-controlled trial (SPECTRA) done at 31 sites in five countries, participants were randomly assigned 1:1 using the Cenduit Interactive Response Technology system (IQVIA, Durham, NC, USA), with a block size of six, to receive two doses of either SCB-2019 or placebo 21 days apart. The primary outcomes of the SPECTRA trial were vaccine efficacy, measured by real-time PCR (rtPCR)-confirmed COVID-19 of any severity, with onset from 14 days after the second vaccine dose, as well as the safety and solicited local and systemic adverse events in the phase 2 subset. Here, we present secondary analyses to calculate the protective efficacy due to previous exposure to SARS-CoV-2 against reinfection with COVID-19 according to severity in SPECTRA participants who had evidence of exposure to SARS-CoV-2 at baseline, including efficacy against identified viral variants, as well as efficacy of SCB-2019 vaccination in this population.
We enrolled 30 174 participants between March 24, 2021, and Aug 10, 2021. In the 14 670 participants who were randomly assigned to receive placebo, there were 418 (2·8%) confirmed cases of COVID-19; 65 (0·9%) of 7339 SARS-CoV-2-exposed participants, and 353 (4·8%) of 7331 SARS-CoV-2-naive participants (attack rates of 5·5 cases per 100 person-years for SARS-CoV-2-exposed participants and 32·4 cases per 100 person-years for SARS-CoV-2-naive participants). Protective efficacy due to previous exposure to SARS-CoV-2 was 83·2% (95% CI 78·0–87·3) against any COVID-19, 92·5% (82·9–97·3) against moderate-to-severe COVID-19, and 100% (59·3–100) against severe COVID-19; no SARS-CoV-2-exposed participants had hospitalisation associated with COVID-19. Protective efficacy against variants were 100% for alpha (B.1.1.7) and lambda (C.37) variants, 88·6% (14·9–99·7) for B.1.623, 93·6% (80·1–98·7) for gamma (P.1), and 92·4% (81·2–97·6) for mu (B.1.621) variants, and lowest against beta (B.1.351; 72·2% 33·1–89·9) and delta (B.1.617.2; 77·2% 61·3–87·2) variants. In addition, one dose of SCB-2019 had 49·9% (1·5–75·6) efficacy against any symptomatic COVID-19, and two doses had 64·2% (26·5–83·8) efficacy. SCB-2019 was well tolerated in SARS-CoV-2-exposed participants, but was associated with higher rates of injection site pain (89 33·8% of 263 participants) than placebo (16 6·7% of 239 participants). Rates of solicited systemic adverse events, severe adverse events, and serious adverse events were similar between vaccine and placebo groups, and with rates in SARS-CoV-2-naive vaccine recipients.
Previous exposure to SARS-CoV-2 decreased the risk and severity of subsequent COVID-19 infection, even against newly emerging variants. Protection is further enhanced by one or two doses of SCB-2019.
Clover Biopharmaceuticals, The Coalition for Epidemic Preparedness Innovations (CEPI).
Anxiety is associated with poor health outcomes among chronic kidney disease (CKD) patients. This review summarizes the prevalence and risk factors associated with elevated anxiety symptoms and ...disorders among CKD patients.
Articles evaluating the prevalence and risk factors associated with elevated anxiety symptoms and disorders among CKD patients, as diagnosed via DSM 4th or 5th edition criteria, clinical interviews or validated questionnaires, were searched in Medline®, Embase®, PsychINFO® and CINAHL®. Using random-effects meta-analyses, the prevalence of elevated anxiety symptoms and disorders were estimated. A narrative review on the risk factors associated with elevated anxiety symptoms and disorders was presented.
From 4941 articles, 61 studies were included. The pooled prevalence of anxiety disorders (9 studies, n = 1071) among CKD patients across studies was 19% while that of elevated anxiety symptoms (52 studies, n = 10,739) was 43%. Across continents, prevalence of elevated anxiety symptoms was highest in Europe and Asia. Between pre-dialysis and dialysis patients, the prevalence of elevated anxiety symptoms was not statistically different at 31% and 42% respectively. Common risk factors associated with elevated anxiety symptoms included concomitant depression, lower parathyroid hormone levels, increased comorbidities, increased duration of hospitalization, reduced perceived quality of life, and decreased vitality levels.
Given the high prevalence of anxiety disorders and elevated anxiety symptoms, more studies are required to assess the role and outcomes of anxiety screening among CKD patients. This could facilitate early identification of at-risk patients and potentially improve their clinical outcomes.
•SCB-2019 is a protein subunit vaccine candidate against COVID-19.•SCB-2019 contains the SARS-CoV-2 spike protein adjuvanted with CpG-1018/alum.•A single dose of SCB-2019 was immunogenic in ...SARS-CoV-2-exposed individuals.•Two doses are required to induce immune response in SARS-CoV-2-naïve individuals.•SCB-2019 induced cross-reactive neutralizing antibodies to SARS-CoV-2 variants.
We evaluated immunogenicity of SCB-2019, a subunit vaccine candidate containing a pre-fusion trimeric form of the SARS-CoV-2 spike (S)-protein adjuvanted with CpG-1018/alum.
The phase 2/3, double-blind, randomized SPECTRA trial was conducted in five countries in participants aged ≥ 18 years, either SARS-CoV-2-naïve or previously exposed. Participants were randomly assigned to receive two doses of SCB-2019 or placebo administered intramuscularly 21 days apart. In the phase 2 part of the study, on days 1, 22, and 36, neutralizing antibodies were measured by pseudovirus and wild-type virus neutralization assays to SARS-CoV-2 prototype and variants, and ACE2-receptor-binding antibodies and SCB-2019–binding antibodies were measured by ELISA. Cell-mediated immunity was measured by intracellular cytokine staining via flow cytometry.
1601 individuals were enrolled between 24 March and 13 September 2021 and received at least one vaccine dose. Immunogenicity analysis was conducted in a phase 2 subset of 691 participants, including 428 SARS-CoV-2-naïve (381 vaccine and 47 placebo recipients) and 263 SARS-CoV-2-exposed (235 vaccine and 28 placebo recipients). In SARS-CoV-2-naïve participants, GMTs of neutralizing antibodies against prototype virus increased 2 weeks post-second dose (day 36) compared to baseline (224 vs 12.7 IU/mL). Seroconversion rate was 82.5 %. In SARS-CoV-2-exposed participants, one SCB-2019 dose increased GMT of neutralizing antibodies by 48.3-fold (1276.1 IU/mL on day 22) compared to baseline. Seroconversion rate was 92.4 %. Increase was marginal post-second dose. SCB-2019 also showed cross-neutralization capability against nine variants, including Omicron, in SARS-CoV-2-exposed participants at day 36. SCB-2019 stimulated Th1-biased cell-mediated immunity to the S-protein in both naïve and exposed participants. The vaccine was well tolerated, no safety concerns were raised from the study.
A single dose of SCB-2019 was immunogenic in SARS-CoV-2-exposed individuals, whereas two doses were required to induce immune response in SARS-CoV-2-naïve individuals. SCB-2019 elicited a cross-neutralizing response against emergent SARS-CoV-2 variants at antibody levels associated with clinical protection, underlining its potential as a booster.
Clinicaltrials.gov: NCT04672395; EudraCT: 2020-004272-17.
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