Interindividual clinical variability in the course of SARS-CoV-2 infection is immense. We report that at least 101 of 987 patients with life-threatening COVID-19 pneumonia had neutralizing IgG auto-Abs against IFN-ω (13 patients), the 13 types of IFN-α (36), or both (52), at the onset of critical disease; a few also had auto-Abs against the other three type I IFNs. The auto-Abs neutralize the ability of the corresponding type I IFNs to block SARS-CoV-2 infection in vitro. These auto-Abs were not found in 663 individuals with asymptomatic or mild SARS-CoV-2 infection and were present in only 4 of 1,227 healthy individuals. Patients with auto-Abs were aged 25 to 87 years and 95 were men. A B cell auto-immune phenocopy of inborn errors of type I IFN immunity underlies life-threatening COVID-19 pneumonia in at least 2.6% of women and 12.5% of men.

Clinical outcome upon infection with SARS-CoV-2 ranges from silent infection to lethal COVID-19. We have found an enrichment in rare variants predicted to be loss-of-function (LOF) at the 13 human loci known to govern TLR3- and IRF7-dependent type I interferon (IFN) immunity to influenza virus, in 659 patients with life-threatening COVID-19 pneumonia, relative to 534 subjects with asymptomatic or benign infection. By testing these and other rare variants at these 13 loci, we experimentally define LOF variants in 23 patients (3.5%), aged 17 to 77 years, underlying autosomal recessive or dominant deficiencies. We show that human fibroblasts with mutations affecting this pathway are vulnerable to SARS-CoV-2. Inborn errors of TLR3- and IRF7-dependent type I IFN immunity can underlie life-threatening COVID-19 pneumonia in patients with no prior severe infection.

In patients who are receiving prolonged antiretroviral treatment (ART), HIV can persist within a small pool of long-lived resting memory CD4+ T cells infected with integrated latent virus. This latent reservoir involves distinct memory subsets. Here we provide results that suggest a progressive reduction of the size of the blood latent reservoir around a core of less-differentiated memory subsets (central memory and stem cell-like memory (TSCM) CD4+ T cells). This process appears to be driven by the differences in initial sizes and decay rates between latently infected memory subsets. Our results also suggest an extreme stability of the TSCM sub-reservoir, the size of which is directly related to cumulative plasma virus exposure before the onset of ART, stressing the importance of early initiation of effective ART. The presence of these intrinsic dynamics within the latent reservoir may have implications for the design of optimal HIV therapeutic purging strategies.

Significance There is growing evidence that preexisting autoantibodies neutralizing type I interferons (IFNs) are strong determinants of life-threatening COVID-19 pneumonia. It is important to estimate their quantitative impact on COVID-19 mortality upon SARS-CoV-2 infection, by age and sex, as both the prevalence of these autoantibodies and the risk of COVID-19 death increase with age and are higher in men. Using an unvaccinated sample of 1,261 deceased patients and 34,159 individuals from the general population, we found that autoantibodies against type I IFNs strongly increased the SARS-CoV-2 infection fatality rate at all ages, in both men and women. Autoantibodies against type I IFNs are strong and common predictors of life-threatening COVID-19. Testing for these autoantibodies should be considered in the general population.

Objectives Molecular assays on nasopharyngeal swabs remain the cornerstone of COVID-19 diagnostic. The high technicalities of nasopharyngeal sampling and molecular assays, as well as scarce resources of reagents, limit our testing capabilities. Several strategies failed, to date, to fully alleviate this testing process (e.g. saliva sampling or antigen testing on nasopharyngeal samples). We assessed the clinical performances of SARS-CoV-2 nucleocapsid antigen (N-antigen) ELISA detection in serum or plasma using the COVID-19 Quantigene® (AAZ, France) assay. Methods Performances were determined on 63 sera from 63 non-COVID patients and 227 serum samples (165 patients) from the French COVID and CoV-CONTACT cohorts with RT-PCR confirmed SARS-CoV-2 infection, including 142 serum (114 patients) obtained within 14 days after symptoms’ onset. Results Specificity was 98.4% (95% confidence interval [CI], 95.3 to 100). Sensitivity was 79.3% overall (180/227, 95% CI, 74.0 to 84.6) and 93.0% (132/142, 95% CI, 88.7 to 97.2) within 14 days after symptoms onset. 91 included patients had a sera and nasopharyngeal swabs collected in the same 24 hours. Among those with high nasopharyngeal viral loads, i.e. Ct value below 30 and 33, only 1/50 and 4/67 tested negative for N-antigenemia, respectively. Among those with a negative nasopharyngeal RT-PCR, 8/12 presented positive N-antigenemia; the lower respiratory tract was explored for 6 of these 8 patients, showing positive RT-PCR in 5 cases. Conclusion This is the first evaluation of a commercially available serum N-antigen detection assay. It presents a robust specificity and sensitivity within the first 14 days after symptoms onset. This approach provides a valuable new option for COVID-19 diagnosis, only requiring a blood draw and easily scalable in all clinical laboratories.

Background The ISARIC prospective multinational observational study is the largest cohort of hospitalized patients with COVID-19. We present relationships of age, sex, and nationality to presenting symptoms. Methods International, prospective observational study of 60 109 hospitalized symptomatic patients with laboratory-confirmed COVID-19 recruited from 43 countries between 30 January and 3 August 2020. Logistic regression was performed to evaluate relationships of age and sex to published COVID-19 case definitions and the most commonly reported symptoms. Results ‘Typical’ symptoms of fever (69%), cough (68%) and shortness of breath (66%) were the most commonly reported. 92% of patients experienced at least one of these. Prevalence of typical symptoms was greatest in 30- to 60-year-olds (respectively 80, 79, 69%; at least one 95%). They were reported less frequently in children (≤ 18 years: 69, 48, 23; 85%), older adults (≥ 70 years: 61, 62, 65; 90%), and women (66, 66, 64; 90%; vs. men 71, 70, 67; 93%, each P < 0.001). The most common atypical presentations under 60 years of age were nausea and vomiting and abdominal pain, and over 60 years was confusion. Regression models showed significant differences in symptoms with sex, age and country. Interpretation This international collaboration has allowed us to report reliable symptom data from the largest cohort of patients admitted to hospital with COVID-19. Adults over 60 and children admitted to hospital with COVID-19 are less likely to present with typical symptoms. Nausea and vomiting are common atypical presentations under 30 years. Confusion is a frequent atypical presentation of COVID-19 in adults over 60 years. Women are less likely to experience typical symptoms than men.

During the primary immune response, CD8 memory emerges from an environment of strong immune activation. The FoxP3+ regulatory CD4 T-cell subset (Treg) is known as a key suppressive component of the immune system. Here we report that Tregs are required for the generation of functional CD8 memory. In the absence of Tregs during priming, the resulting memory cells proliferate poorly and fail to differentiate into functional cytotoxic secondary effectors following antigen reactivation. We find that the Tregs act early, during the expansion phase of primary CD8 effectors, by fine tuning interleukin-2 exposure of CD8 memory precursors. This crucial new role of Tregs has implications for optimal vaccine development.

Background Humoral response to SARS-CoV-2 occurs within the first weeks after COVID-19. Those antibodies exert a neutralizing activity against SARS-CoV-2, whose evolution overtime after COVID-19 as well as efficiency against novel variants are however poorly characterized. Methods In this prospective study, sera of 107 patients hospitalized with COVID-19 were collected at 3- and 6-months post-infection. We performed quantitative neutralization experiments on top of high-throughput serological assays evaluating anti-Spike (S) and anti-Nucleocapsid (NP) IgG. Findings Levels of sero-neutralization and IgG rates against the ancestral strain decreased significantly over time. After 6 months, 2.8% of the patients had a negative serological status for both anti-S and anti-NP IgG. However, all sera had a persistent and effective neutralizing effect against SARS-CoV-2. IgG levels correlated with sero-neutralization and this correlation was stronger for anti-S than for anti-NP antibodies. The level of sero-neutralization quantified at 6 months correlated with markers of initial severity, notably admission in intensive care units and the need for mechanical invasive ventilation. In addition, sera collected at 6 months were tested against multiple SARS-CoV-2 variants and showed efficient neutralizing effects against D614G, B.1.1.7 and P.1 variants but a significantly weaker activity against B.1.351 variant. Interpretation Decrease of IgG rates and serological assays becoming negative did not imply loss of neutralizing capacity. Our results indicate a sustained humoral response against the ancestral strain and the D614G, B.1.1.7 and P.1 variants for at least 6 months in patients previously hospitalized for COVID-19. A weaker protection was however observed for the B.1.351 variant.