Safety and immunogenicity of SII-NVX-CoV2373 (COVID-19 vaccine) in adults in a phase 2/3, observer-blind, randomised, controlled study.

Background: NVX-CoV2373, a Covid-19 vaccine was developed in the USA with ∼90% efficacy. The same vaccine is manufactured in India after technology transfer (called as SII-NVX-CoV2373), was evaluated in this phase 2/3 immuno-bridging study. Methods: This was an observer-blind, randomised, phase 2/3 study in 1600 adults. In phase 2, 200 participants were randomized 3:1 to SII-NVX-CoV2373 or placebo. In phase 3, 1400 participants were randomized 3:1 to SII-NVX-CoV2373 or NVX-CoV2373 (940 safety cohort and 460 immunogenicity cohort). Two doses of study products (SII-NVX-CoV2373, NVX-CoV2373 or placebo) were given 3 weeks apart. Primary objectives were to demonstrate non-inferiority of SII-NVX-CoV2373 to NVX-CoV2373 in terms of geometric mean ELISA units (GMEU) ratio of anti-S IgG antibodies 14 days after the second dose (day 36) and to determine the incidence of causally related serious adverse events (SAEs) through 180 days after the first dose. Anti-S IgG response was assessed using an Enzyme-Linked Immunosorbent Assay (ELISA) and neutralizing antibodies (nAb) were assessed by a microneutralization assay using wild type SARS CoV-2 in participants from the immunogenicity cohort at baseline, day 22, day 36 and day 180. Cell mediated immune (CMI) response was assessed in a subset of 28 participants from immunogenicity cohort by ELISpot assay at baseline, day 36 and day 180. The total follow-up was for 6 months. Trial registration: CTRI/2021/02/031554. Findings: Total 1596 participants (200 in Phase 2 and 1396 in Phase 3) received the first dose. SII-NVX-CoV2373 was found non-inferior to NVX-CoV2373 (anti-S IgG antibodies GMEU ratio 0.91; 95% CI: 0.79, 1.06). At day 36, there was more than 58-fold rise in anti-S IgG and nAb titers compared to baseline in both the groups. On day 180 visit, these antibody titers declined to levels slightly lower than those after the first dose (13-22 fold-rise above baseline). Incidence of unsolicited and solicited AEs was similar between the SII-NVX-CoV2373 and NVX-CoV2373 groups. No adverse event of special interest (AESI) was reported. No causally related SAE was reported. Interpretation: SII-NVX-CoV2373 induced a non-inferior immune response compared to NVX-CoV2373 and has acceptable safety profile. Funding: SIIPL, Indian Council of Medical Research, Novavax.

Study of Association of Leptin and Leucocyte Telomere Length with Body Mass Index in Adult Indian Population a One Year Cross Sectional Study.

Obesity is a leading preventable cause of death and a growing health problem worldwide with increasing rate in both adults and children. Obesity is an important factor causing accelerated aging and various metabolic syndromes. Leptin role as proinflammatory adipokine in obesity is well established. Telomere length acts as a biological clock and a marker for cellular senescence. This study is aimed to quantify leucocyte telomere length & its association with biochemical and anthropometric surrogates of obesity. MATERIAL: This cross-sectional study was conducted for a duration of 1yr on patients admitted in the wards or attending OPD, fulfilling the inclusion criteria. After a written informed consent and a thorough history, patient's anthropometric measurements were taken following all guidelines. Based on the values obtained the participants were divided into categories based on age and BMI. Blood samples are collected for the assessment of Leucocyte Telomere length through qPCR technique, Leptin through ELIZA method and HBA1c through HPLC method. OBSERVATION: In our present study, a total of 90 patients were included. These patients are equally divided in age groups of 25-39yrs, 40-54yrs and >=55yrs of age. The mean age of the patients was 48.84±16.84yrs. The patients were further categorized equally in each age group into normal, overweight and obese. The mean BMI of the study subjects was 24.20±3.32 kg/m2. Age is found to have a negative correlation with telomere length (r=-0.205). A significant negative correlation of BMI with telomere length is observed (r=-0.20, p<0.05). No significant correlation between leptin with telomere length (r=0.092, p=0.386) or other anthropometric variables is observed. Waist circumference has a positive correlation with waist/hip ratio (r=0.281) (p=0.007), BMI (r=0.640), weight (r=0.677) and neck circumference(r=0.687). Whereas Telomere length has a negative correlation with waist circumference (r= -0.171), neck circumference (r=--0.2266) (p=0.0318) and positive correlation with waist/hip ratio (r=0.043). In our study a negative correlation was observed between waist/ height ratio and telomere length. Waist hip ratio had a positive correlation with BMI (r= 0.138) and telomere length (r=0.232). CONCLUSION: Telomere length showed a negative correlation with all anthropometric measures except WHR which showed a positive correlation. Leptin did not show any association with telomere length or anthropometric measures in our study. Our study shows that WHR is a better marker of central obesity than BMI. The notion of metabolically healthy obese also holds true in our study results.

Safety and immunogenicity of a single dose, live-attenuated 'tetravalent dengue vaccine' in healthy Indian adults; a randomized, double-blind, placebo controlled phase I/II trial.

BACKGROUND: Dengue fever is the most prevalent mosquito-borne viral disease in the world, with 390 million dengue infections occurring every year. There is an unmet medical need to develop a safe, effective and affordable dengue vaccine against all four Dengue serotype viruses-DENV1, DENV-2, DENV-3 and DENV-4. Panacea Biotec Ltd (PBL) has developed a cell culture-derived, live-attenuated, lyophilized Tetravalent Dengue Vaccine (TDV). Here, in phase I/II study we assessed the safety and immunogenicity of single dose 'Dengue Tetravalent Vaccine' in healthy Indian adults. METHODS: In the study, 100 healthy adult volunteers aged 18-60 years were enrolled. The participants were allocated to TDV and placebo groups in 3:1 ratio, i.e. 75 participants to TDV group and 25 participants to the placebo group. Enrolled participants were administered a single dose of 0.5 ml of the test vaccine / placebo by subcutaneous route. Primary outcome for safety included all solicited AEs up to 21 days, unsolicited AEs up to 28 days and all AEs/serious adverse events (SAEs) till day 90 post-vaccination. For immunogenicity assessment the primary outcome was seroconversion & seropositivity rate by PRNT50 to all four serotype till 90 days. RESULTS: Overall, 100 subjects were vaccinated out of which 8 subjects (5 subjects in vaccine group and 3 subjects in placebo group) dropped out from the study. The most commonly reported solicited local AE was pain and most common solicited systemic AE was headache and fever. No SAE was reported during the study. There was no statistically significant difference between TDV and placebo groups in terms of AEs. Of the 92 subjects who completed all scheduled visits in the study, 59 (81.9%) achieved seroconversion for DENV-1, 56 (77.8%) for DENV-2; 59 (81.9%) for DENV-3 and 57 (79.2%) for DENV-4 in TDV group. The seroconversion rate in the TDV group was statistically significant (p < 0.001) compared to placebo.Clinical trial registration: CTRI/2017/02/007923.

Conventional Risk Factors, Telomere Length, and Ischemic Heart disease: Insights into the Mediation Analysis.

Telomere length is regarded as a potential biomarker of biological ageing and is associated with various age-related diseases, such as ischemic heart disease (IHD), myocardial infarction, peripheral vascular disease, and cancer. As there is a paucity of study that deals with this influence, this study aimed to assess how the cardiovascular risk factors influence the risk of IHD by performing mediation analysis. A total of 407 males were included in the study. IHD was diagnosed through echocardiography and coronary angiography by determining the number of coronary vessels involved. Demographic data, clinical history, and laboratory investigations such as random blood sugar (RBS), fasting lipid profile, serum creatinine, and serum urea levels of all the subjects were measured and recorded. Serum uric acid and blood urea nitrogen (BUN) levels were significantly higher in IHD subjects compared to non-IHD subjects (P < 0.05). Body mass index (BMI), glycosylated hemoglobin (HbA1c), RBS, serum uric acid, serum creatinine, BUN, total cholesterol, triglycerides, and telomere length significantly differed between subjects with and without IHD (P < 0.05). Further, telomere length (P < 0.001), BMI (P < 0.001), and total cholesterol level (P < 0.001) were risk factors that significantly affected the incidence of IHD, as proved by logistic regression. It indicates that shorter telomeres contribute to increased risk of IHD, influenced by BMI, HbA1c, BUN, total cholesterol levels, and RBS (P < 0.001). The study established a link between telomere shortening, conventional risk factors, and IHD; moreover, the study takes care in the role of mediation analysis which is a novel idea as little is done in this area of biostatistics with telomere length. Overall, this further establishes that telomeres length might serve as the promising biomarkers in predicting the risk of IHD.

Resuscitative Effect of Centhaquine (Lyfaquin®) in Hypovolemic Shock Patients: A Randomized, Multicentric, Controlled Trial.

INTRODUCTION: Centhaquine (Lyfaquin®) showed significant efficacy as a resuscitative agent in animal models of haemorrhagic shock. Its safety and tolerability were confirmed in healthy human volunteers. In this study, our primary objective was to determine the safety, and the secondary objective was to assess the efficacy of centhaquine in patients with hypovolemic shock. METHODS: A prospective, multicentre, randomized phase II study was conducted in male and female patients aged 18-70 years with hypovolemic shock having systolic BP ≤ 90 mmHg. Patients were randomized in a 1:1 ratio to either the control or centhaquine group. The control group received 100 ml of normal saline infusion over 1 h, while the centhaquine group received 0.01 mg/kg of centhaquine in 100 ml normal saline infusion over 1 h. Every patient received standard of care (SOC) and was followed for 28 days. RESULTS: Fifty patients were included, and 45 completed the trial: 22 in the control group and 23 in the centhaquine group. The demographics of patients in both groups were comparable. No adverse event related to centhaquine was recorded in the 28-day observation period. The baseline, Injury Scoring System score, haemoglobin, and haematocrit were similar in both groups. However, 91% of the patients in the centhaquine group needed major surgery, whereas only 68% in the control group (p = 0.0526). Twenty-eight-day all-cause mortality was 0/23 in the centhaquine group and 2/22 in the control group. The percent time in ICU and ventilator support was less in the centhaquine group than in the control group. The total amount of vasopressors needed in the first 48 h of resuscitation was lower in the centhaquine group than in the control group (3.12 ± 2.18 vs. 9.39 ± 4.28 mg). An increase in systolic and diastolic BP from baseline through 48 h was more marked in the centhaquine group than in the control group. Compared with the control group, blood lactate level was lower by 1.75 ± 1.07 mmol/l in the centhaquine group on day 3 of resuscitation. Improvements in base deficit, multiple organ dysfunction syndrome (MODS) score and adult respiratory distress syndrome (ARDS) were greater in the centhaquine group than in the control group. CONCLUSION: When added to SOC, centhaquine is a well-tolerated and effective resuscitative agent. It improves the clinical outcome of patients with hypovolemic shock. TRIAL REGISTRATION: ClinicalTrials.gov identifier number: NCT04056065.

Association of Telomere Length and Serum Vitamin D Levels with Type 2 Diabetes Mellitus and its Related Complications: A Possible Future Perspective.

Evidence show that shortened telomere length (TL) and low Vitamin D levels can increase the risk of type 2 diabetes mellitus (T2DM) and its associated complications. T2DM has been considered as an age-related disease, it may be associated with TL. The study aimed to evaluate the association of TL and Vitamin D levels with complications of T2DM and the impact of Vitamin D on TL in patients with T2DM. This 1-year cross-sectional study was conducted at a tertiary care hospital on 90 patients. Height, weight, body mass index, waist-hip ratio was calculated. Fasting blood sugars, postprandial blood sugar, and glycated hemoglobin (HbA1c) were analyzed. Absolute TL was obtained from quantitative real-time polymerase chain reaction (qPCR). Vitamin D estimation was done by chemiluminescent immunoassay. Descriptive analysis of the data was done using R i386 3.6.3. The study found a positive correlation between TL and Vitamin D levels (r = 0.64; P < 0.0001). The interaction with high HbA1c levels and lower levels of Vitamin D led to the shortening of TL (P = 0.0001). The median of TL and mean of Vitamin D levels were significantly less in the diabetic group (P < 0.0001). Vitamin D levels positively affected the TL and its levels had an inverse relation with the HbA1c levels. This association had a significant effect on the shortening of TL. Vitamin D also had a significant association with other diabetic complications that instigated the shortening of TL. Therefore, assessing the role of Vitamin D levels on the shortening of TL can prove to be crucial biomarkers in managing optimal glycemic levels in T2DM patients.

Correlation of the telomere length with type 2 diabetes mellitus in patients with ischemic heart disease.

OBJECTIVE: The study aimed to explore the relationship of the telomere length with type 2 diabetes mellitus (DM) among patients with ischemic heart disease (IHD). METHOD: This 2-year cross-sectional study included 130 male patients diagnosed with IHD through echocardiography and coronary angiography, wherein consecutive IHD patients with type 2 DM (65) and without type 2 DM (65) were selected. Baseline characteristics including age, gender, body mass index, and blood pressure were recorded. Laboratory investigations such as random blood sugar (RBS), fasting lipid profile, serum creatinine, and serum urea levels were measured. Quantitative real-time polymerase chain reaction was used for the measurement of the telomere length. The logistic regression analysis was used to predict the relationship of the telomere length with age and type 2 DM among patients with IHD. RESULTS: All the patients in the study were men, and most of them (diabetics = 22; nondiabetics = 20) were aged between 56 and 65 years. Age (p = 0.003), telomere length (p < 0.001), RBS (p < 0.001), serum creatinine (p < 0013), and serum urea (p < 0.04) were significantly higher in the diabetic subset than in the nondiabetic subset. No significant relationship was observed between age and the telomere length (p = 0.813); however, the mean telomere length was significantly high among the patients with type 2 DM than those without type 2 DM (p = 0.005). The logistic regression analysis showed that the telomere shortening (p = 0.00019) and RBS (p < 0.0001) were the significant risk factors for type 2 DM in patients with IHD. CONCLUSION: The telomere shortening was significantly correlated with type 2 DM among the patients with IHD. However, multicentric studies with larger samples are required to validate the current observation.