Human endogenous retrovirus-R envelope is a host restriction factor against severe acute respiratory syndrome-coronavirus-2

Coronavirus induced disease-19 (COVID-19), caused by the SARS-CoV-2 remains a major global health challenge. Human endogenous retroviruses (HERVs) represent retroviral elements that got integrated into the ancestral human genome. HERVs are important in development and diseases, including cancer, inflammation and viral infections. Here, we analyzed the expression of several HERVs in SARS-CoV-2 infected cells and observed increased activity of HERV-E, HERV-V, HERV-FRD, HERV-MER34, HERV-W and HERV-KHML2. In contrast, HERV-R-envelope was downregulated in cell-based models and COVID-19 patient PBMCs. HERV-R overexpression inhibited SARS-CoV-2 replication, suggesting its antiviral action. Further studies demonstrated the role of extracellular signal-regulated kinase (ERK) in regulating HERV-R antiviral activity. Cross-talk between the ERK and p38 MAPK controls HERV-R envelope synthesis, which in turn modulates the replication of SARS-CoV-2. These findings establish the importance of HERV-R envelope as a host restriction factor against SARS-CoV-2 and illustrate the advantage of integration and evolutionary maintenance of retroviral-elements in the human genome.

Safety, tolerability and immunogenicity of Biological Es CORBEVAX vaccine in children and adolescents: A Prospective, Randomised, Double-blind, Placebo controlled, Phase-2/3 Study.

BackgroundAfter establishing safety and immunogenicity of Biological Es CORBEVAX vaccine in adult population (18-80 years) in Phase 1-3 studies, vaccine is further tested in children and adolescents in this study. MethodsThis is a phase-2/3 prospective, randomised, double-blind, placebo controlled, study evaluating safety, reactogenicity, tolerability and immunogenicity of CORBEVAX vaccine in children and adolescents of either gender between <18 to [≥]12 years of age in Phase-II and <18 to [≥]5 years of age in Phase-III with placebo as a control. This study has two age sub groups; age subgroup-1 with subjects <18 to [≥]12 years of age and age subgroup-2 with subjects <12 to [≥]5 years of age. In both age sub groups eligible subjects (SARS-CoV-2 RT-PCR negative and seronegative at baseline) were randomized to receive either CORBEVAX vaccine or Placebo in 3: 1 ratio. FindingsThe safety profile of CORBEVAX vaccine in both pediatric cohorts was comparable to the placebo control group. Majority of reported adverse events (AEs) were mild in nature. No severe or serious AEs, medically attended AEs (MAAEs) or AEs of special interest (AESI) were reported during the study period and all the reported AEs resolved without any sequelae. In both pediatric age groups, CORBEVAX vaccinated subjects showed significant improvement in humoral immune-responses in terms of anti-RBD-IgG concentrations, anti-RBD-IgG1 titers, neutralizing antibody (nAb)-titers against Ancestral Wuhan and Delta strains. Significantly high interferon gamma immune response (cellular) was elicited by CORBEVAX vaccinated subjects with minimal effect on IL-4 cytokine secretion. InterpretationsThe safety profile of CORBEVAX vaccine in <18 to [≥]5 years children and adolescents was found to be safe and tolerable. The adverse event profile was also found to be acceptable. Significant increase in anti-RBD IgG and nAb titers and IFN-gamma immune responses were observed post vaccination in both pediatric age sub groups. Both humoral and cellular immune responses were found to be non-inferior to the immune responses induced by CORBEVAX vaccine in adult population. This study shows that CORBEVAX vaccine is highly immunogenic and can be safely administered to pediatric population as young as 5 years old. The study was prospectively registered with clinical trial registry of India-CTRI/2021/10/037066

SARS-CoV-2 and its variants, but not Omicron, induces thymic atrophy and impaired T cell development

Pathogenic infections cause thymic atrophy, perturb thymic-T cell development and alter immunological response. Previous studies reported dysregulated T cell function and lymphopenia in coronavirus disease-19 (COVID-19) patients. However, immune-pathological changes, in the thymus, post severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection have not been elucidated. Here, we report SARS-CoV-2 infects thymocytes, depletes CD4+CD8+ (double positive; DP) T cell population associated with an increased apoptosis of thymocytes, which leads to severe thymic atrophy in K18-hACE2-Tg mice. CD44+CD25-T cells were found to be enriched in infected thymus, indicating an early arrest in the T cell developmental pathway. Further, Interferon gamma (IFN-{gamma}) was crucial for thymic atrophy, as anti-IFN-{gamma} antibody neutralization rescued the loss of thymic involution. Therapeutic use of remdesivir (prototype anti-viral drug) was also able to rescue thymic atrophy. While Omicron variant of SARS-CoV2 caused marginal thymic atrophy, delta variant of SARS-CoV-2 exhibited most profound thymic atrophy characterized by severely depleted DP T cells. Recently characterized broadly SARS-CoV-2 neutralizing monoclonal antibody P4A2 was able to rescue thymic atrophy and restore thymic developmental pathway of T cells. Together, we provide the first report of SARS-CoV-2 associated thymic atrophy resulting from impaired T cell developmental pathway and also explains dysregulated T cell function in COVID-19.

Innate immune response and distinct metabolomic signatures together drive and shape the SARS-CoV-2-specific T cell response during COVID-19

The underlying factors contributing to the evolution of SARS-CoV-2-specific T cell responses during COVID-19 infection remain unidentified. To address this, we characterized innate and adaptive immune responses with metabolomic profiling longitudinally at three different time points (0-3, 7-9, and 14-16 days post-COVID-19 positivity) from young mildly symptomatic active COVID-19 patients infected during the first wave in mid-2020. We observed that anti-RBD IgG and viral neutralization are significantly reduced against the Delta variant compared to the ancestral strain. In contrast, compared to the ancestral strain, T cell responses remain preserved against the delta and omicron variants. We determined innate immune responses during the early stage of active infection in response to TLR 3/7/8 mediated activation in PBMCs and serum metabolomic profiling. Correlation analysis indicated PBMCs-derived proinflammatory cytokines, IL-18, IL-1{beta}, and IL-23, and the abundance of plasma metabolites involved in arginine biosynthesis were predictive of a robust SARS-CoV-2-specific Th1 response at a later stage (two weeks after PCR positivity). These observations may contribute to designing effective vaccines and adjuvants that promote innate immune responses and metabolites to induce long-lasting anti-SARS-CoV-2 specific T cells response.

Immunogenic superiority and safety of Biological E CORBEVAX vaccine compared to COVISHIELD (ChAdOx1 nCoV-19) vaccine studied in a phase III, single blind, multicenter, randomized clinical trial

BackgroundOptimum formulation of Biological Es CORBEVAX vaccine that contains protein sub unit of Receptor Binding Domain (RBD) from the spike protein of SARS-COV-2 formulated with aluminum hydroxide (Al3+) and CpG1018 as adjuvants was selected in phase-1 and 2 studies and proven to be safe, well tolerated and immunogenic in healthy adult population. In the current study, additional data was generated to determine immunogenic superiority of CORBEVAX vaccine over COVISHIELD vaccine and safety in larger and older population. MethodsThis is a phase III prospective, single blinded, randomized, active controlled study (CTRI/2021/08/036074) conducted at 20 sites across India in healthy adults aged between 18-80 years. This study has two arms; immunogenicity arm and safety arm. Participants in immunogenicity arm were randomized equally to either CORBEVAX or COVISHIELD vaccination groups to determine the immunogenic superiority. Healthy adults without a history of Covid-19 vaccination or SARS-CoV-2 infection, were enrolled. FindingsThe safety profile of CORBEVAX vaccine was comparable to the comparator vaccine COVISHIELD in terms of overall AE rates, related AE rates and medically attended AEs. Majority of reported AEs were mild in nature, and overall CORBEVAX appeared to cause fewer local and systemic adverse reactions/events. Overall, two grade-3 serious AEs (Dengue fever and femur fracture) were reported and they are unrelated to study vaccine. Neutralizing Antibody titers, against both Ancestral and Delta strain, induced post two-dose vaccination regimen were higher in the CORBEVAX arm as compared to COVISHIELD and the analysis of GMT ratios demonstrated immunogenic superiority of CORBEVAX in comparison with COVISHIELD. Both CORBEVAX and COVISHIELD vaccines showed comparable seroconversion post vaccination when assessed against anti-RBD IgG response. The subjects in CORBEVAX cohort also exhibited higher Interferon-gamma secreting PBMCs post stimulation with SARS-COV-2 RBD peptides than the subjects in COVISHIELD cohort. InterpretationsNeutralizing antibody titers induced by CORBEVAX vaccine against Delta and Ancestral strains were protective, indicative of vaccine effectiveness of >90% for prevention of symptomatic infections based on the Correlates of Protection assessment performed during Moderna and Astra-Zeneca vaccine Phase III studies. Safety findings revealed that CORBEVAX vaccine has excellent safety profile when tested in larger and older population. FundingBIRAC-division of Department of Biotechnology, Government of India, and the Coalition for Epidemic Preparedness Innovations funded the study.