Risk factors for severe Covid-19 breakthrough infections: an observational longitudinal study

Abstract Background The drive to vaccinate large populations is nowadays the main instrument for combating the pandemic and preventing serious disease and death. However, breakthrough infection (post-vaccination infection) still happens after vaccination among fully vaccinated people. We aimed to assess the severity outcomes and to determine its associated factors among vaccinated COVID-19 cases in the governorate of Sousse, Tunisia. Methods We carried out a five-month observational longitudinal study including all the population of Sousse. Confirmed infections of SARS-CoV-2 and the vaccination status are recorded in the daily COVID- 19 database of the Regional Office of the Tunisian Ministry of Health. We included all post-vaccination COVID-19 cases for the analysis of the COVID-19 serious outcomes. Data were collected via 15-min telephonic call interviews conducted by trained interviewers. Descriptive analysis with calculating incidence rates of confirmed COVID-19 cases per 100,000 inhabitants was conducted. In binary logistic regression, adjusted odds ratios along with 95% intervals confidence were performed to determine factors related to severe or critical COVID-19. Results As of 31 July 2021, 107,545 persons over 19 years old have received at least one dose of COVID-19 vaccination. Among the vaccinated population, we traced and included 765 breakthrough infection cases, and the incidence rate was 711.3 per week. The majority were female (sex-ratio = 0.8), and the average age of the overall cases was 55.7 years. The prevalence of severe or critical cases in vaccinated COVID-19 patients occurs in 10.8% of cases. Patients with a medical history of cardiovascular diseases had more than two times increased odds to have a severe or critical disease. We also found the highest self-estimation of adherence to preventive measures was inversely correlated to serious cases and having an incomplete vaccination schema was strongly associated with complications. Conclusions We tried to provide evidence about the breakthrough infections to improve measures of prevention and control of COVID-19. Boosting immunity for vulnerable patients added to maintaining and promoting preventive measures are not only essential to prevent severe cases of breakthrough infections of COVID-19, but also other influenza-like diseases

A new mechanistic model for an O 2-protected electron-bifurcating hydrogenase, Hnd from Desulfovibrio fructosovorans

International audienceThe genome of the sulfate-reducing and anaerobic bacterium Desulfovibrio fructosovorans encodes different hydrogenases. Among them is Hnd, a tetrameric cytoplasmic [FeFe] hydrogenase that has previously been described as an NADP-specific enzyme (Malki et al., 1995). In this study, we purified and characterized a recombinant Strep-tagged form of Hnd and demonstrated that it is an electron-bifurcating enzyme. Flavin-based electron-bifurcation is a mechanism that couples an exergonic redox reaction to an endergonic one allowing energy conservation in anaerobic microorganisms. One of the three ferredoxins of the bacterium, that was named FdxB, was also purified and characterized. It contains a low-potential (E m =-450 mV) [4Fe4S] cluster. We found that Hnd was not able to reduce NADP + , and that it catalyzes the simultaneous reduction of FdxB and NAD +. Moreover, Hnd is the first electron-bifurcating hydrogenase that retains activity when purified aerobically due to formation of an inactive state of its catalytic site protecting against O 2 damage (H inact). Hnd is highly active with the artificial redox partner (methyl viologen) and can perform the electron-bifurcation reaction to oxidize H 2 with a specific activity of 10 µmol of NADH/min/mg of enzyme. Surprisingly, the ratio between NADH and reduced FdxB varies over the reaction 2 with a decreasing amount of FdxB reduced per NADH produced, indicating a more complex mechanism than previously described. We proposed a new mechanistic model in which the ferredoxin is recycled at the hydrogenase catalytic subunit

Rare predicted loss-of-function variants of type I IFN immunity genes are associated with life-threatening COVID-19

BackgroundWe previously reported that impaired type I IFN activity, due to inborn errors of TLR3- and TLR7-dependent type I interferon (IFN) immunity or to autoantibodies against type I IFN, account for 15-20% of cases of life-threatening COVID-19 in unvaccinated patients. Therefore, the determinants of life-threatening COVID-19 remain to be identified in similar to 80% of cases.MethodsWe report here a genome-wide rare variant burden association analysis in 3269 unvaccinated patients with life-threatening COVID-19, and 1373 unvaccinated SARS-CoV-2-infected individuals without pneumonia. Among the 928 patients tested for autoantibodies against type I IFN, a quarter (234) were positive and were excluded.ResultsNo gene reached genome-wide significance. Under a recessive model, the most significant gene with at-risk variants was TLR7, with an OR of 27.68 (95%CI 1.5-528.7, P=1.1x10(-4)) for biochemically loss-of-function (bLOF) variants. We replicated the enrichment in rare predicted LOF (pLOF) variants at 13 influenza susceptibility loci involved in TLR3-dependent type I IFN immunity (OR=3.70[95%CI 1.3-8.2], P=2.1x10(-4)). This enrichment was further strengthened by (1) adding the recently reported TYK2 and TLR7 COVID-19 loci, particularly under a recessive model (OR=19.65[95%CI 2.1-2635.4], P=3.4x10(-3)), and (2) considering as pLOF branchpoint variants with potentially strong impacts on splicing among the 15 loci (OR=4.40[9%CI 2.3-8.4], P=7.7x10(-8)). Finally, the patients with pLOF/bLOF variants at these 15 loci were significantly younger (mean age [SD]=43.3 [20.3] years) than the other patients (56.0 [17.3] years; P=1.68x10(-5)).ConclusionsRare variants of TLR3- and TLR7-dependent type I IFN immunity genes can underlie life-threatening COVID-19, particularly with recessive inheritance, in patients under 60 years old

Correction: Rare predicted loss-of-function variants of type I IFN immunity genes are associated with life-threatening COVID-19

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