ABSTRACT
BackgroundSARS-CoV-2 ongoing pandemic and heterologous immunization approaches implemented worldwide for booster doses call for diversified vaccines portfolio. We report safety and immunogenicity of GRAd-COV2, a novel gorilla adenovirus-based COVID-19 vaccine, in a phase 2 trial aimed at identifying the appropriate dose and schedule. Method917 eligible adults aged 18 years or older, including participants with co-morbidities, were randomised to receive, 21 days apart, a single vaccine administration at 2x1011 viral particles (vp) followed by placebo, or repeated vaccine administration at 1x1011 vp, or two doses of placebo. Primary endpoints were the incidence of local and systemic solicited AEs for 7 days post each dose and the post-treatment (35 days after the first dose), geometric mean titers (GMTs) and geometric mean fold rise (GMFRs) of ELISA antibody responses to Spike protein. Additional humoral and cellular immune response parameters were monitored for up to six months. ResultsThe safety profile of GRAd-COV2 was characterized by short-term, mild-to-moderate pain and tenderness at injection site, fatigue, headache, malaise, and myalgia. Neither related SAEs nor deaths were reported. Humoral (binding and neutralizing) Ab responses peaked at day 35 after a single administration, were boosted by a second vaccination, were sustained until day 57 to then decline at day 180. Potent, VOC cross-reactive T cell responses peaked already after first dose with high frequencies of long-lived CD8 T cells. ConclusionGRAd-COV2 was safe, and induced robust immune responses after a single immunization; the second administration increased humoral but not cellular immune responses. Trial RegistrationClinicalTrials.gov NCT04791423. FundingReiThera Srl
ABSTRACT
Given the highly variable clinical phenotype of Coronavirus disease 2019 (COVID-19), a deeper analysis of the host genetic contribution to severe COVID-19 is important to improve our understanding of underlying disease mechanisms. Here, we describe an extended GWAS meta-analysis of a well-characterized cohort of 3,260 COVID-19 patients with respiratory failure and 12,483 population controls from Italy, Spain, Norway and Germany/Austria, including stratified analyses based on age, sex and disease severity, as well as targeted analyses of chromosome Y haplotypes, the human leukocyte antigen (HLA) region and the SARS-CoV-2 peptidome. By inversion imputation, we traced a reported association at 17q21.31 to a highly pleiotropic [~]0.9-Mb inversion polymorphism and characterized the potential effects of the inversion in detail. Our data, together with the 5th release of summary statistics from the COVID-19 Host Genetics Initiative, also identified a new locus at 19q13.33, including NAPSA, a gene which is expressed primarily in alveolar cells responsible for gas exchange in the lung.
ABSTRACT
BackgroundAnakinra may represent an important therapy to improve the prognosis of COVID-19 patients. This meta-analysis using individual patient data was designed to assess the efficacy and safety of anakinra treatment in patients with COVID-19. MethodsBased on a pre-specified protocol (PROSPERO: CRD42020221491), a systematic literature search was performed in MEDLINE (PubMed), Cochrane, medRxiv.org, bioRxiv.org and clinicaltrials.gov databases for trials in COVID-19 comparing administration of anakinra with standard-of-care and/or placebo. Individual patient data from eligible trials were requested. The primary endpoint was the mortality rate and the secondary endpoint was safety. FindingsLiterature search yielded 209 articles, of which 178 articles fulfilled screening criteria and were full-text assessed. Aggregate data on 1185 patients from 9 studies were analyzed and individual patient data on 895 patients from 6 studies were collected. Most studies used historical controls. Mortality was significantly lower in anakinra-treated patients (38/342 [11{middle dot}1%]) as compared with 137/553 (24{middle dot}8%) observed in patients receiving standard-of-care and/or placebo on top of standard-of-care (137/553 [24{middle dot}8%]); adjusted odds ratio (OR), 0{middle dot}32; 95% CI, 0{middle dot}20 to 0{middle dot}51; p <0{middle dot}001. The mortality benefit was similar across subgroups regardless of diabetes mellitus, ferritin concentrations, or baseline P/F ratio. The effect was more profound in patients exhibiting CRP levels >100 mg/L (OR 0{middle dot}28,95%CI 0{middle dot}27-1{middle dot}47). Safety issues, such as increase of secondary infections, did not emerge. InterpretationAnakinra may be a safe anti-inflammatory treatment option in patients hospitalized with moderate-to-severe COVID-19 pneumonia to reduce mortality, especially in the presence of hyperinflammation signs such as CRP>100mg /L. FundingSobi. Research in contextO_ST_ABSEvidence before this studyC_ST_ABSSince the emergence of the COVID-19 pandemic, numerous drugs have been tried in an effort to prevent major detrimental consequences, such as respiratory and multiorgan failure and death. Early during the pandemic, it was realized that drugs aiming to regulate the immune host reaction may play an important role in the treatment of COVID-19. Evidence from a small number of patients with moderate or severe COVID-19 treated with anakinra, and interleukin-1 receptor antagonist, has suggested therapeutic efficacy. We systematically searched all available literature and aimed to present cumulative evidence of anakinra treatment in COVID-19 and the related effect on mortality. Added value of this studyThis is the first patient-level analysis on the effect of anakinra treatment in COVID-19 patients, which, on the one hand, suggests a significant benefit in the reduction of mortality and on the other hand, reassures safety of the treatment. Most importantly, the current study identifies a subgroup of patients with CRP>100mg/L, that may benefit most from treatment with anakinra. Confirmation of these effects in larger randomized clinical trials (RCTs) is urgently needed. Implications of all the available evidenceAnakinra may be an effective and safe immunomodulatory treatment in moderate-to-severe cases of pneumonia due to COVID-19 to prevent unfavorable outcomes. Anakinra may be helpful to avoid adverse events, such as breakthrough infections observed often with dexamethasone use, and may be considered an alternative in specific subgroups of patients e.g. diabetics. Larger trials, summarized in the Table, are ongoing and their results are urgently needed to investigate anakinras best place in the treatment of COVID-19. O_TBL View this table: org.highwire.dtl.DTLVardef@37134borg.highwire.dtl.DTLVardef@1d3ca11org.highwire.dtl.DTLVardef@1774b08org.highwire.dtl.DTLVardef@df281borg.highwire.dtl.DTLVardef@c2188d_HPS_FORMAT_FIGEXP M_TBL C_TBL
