Vaccine breakthrough hypoxemic COVID-19 pneumonia in patients with auto-Abs neutralizing type I IFNs

Life-threatening `breakthrough' cases of critical COVID-19 are attributed to poor or waning antibody response to the SARS- CoV-2 vaccine in individuals already at risk. Pre-existing autoantibodies (auto-Abs) neutralizing type I IFNs underlie at least 15% of critical COVID-19 pneumonia cases in unvaccinated individuals; however, their contribution to hypoxemic breakthrough cases in vaccinated people remains unknown. Here, we studied a cohort of 48 individuals ( age 20-86 years) who received 2 doses of an mRNA vaccine and developed a breakthrough infection with hypoxemic COVID-19 pneumonia 2 weeks to 4 months later. Antibody levels to the vaccine, neutralization of the virus, and auto- Abs to type I IFNs were measured in the plasma. Forty-two individuals had no known deficiency of B cell immunity and a normal antibody response to the vaccine. Among them, ten (24%) had auto-Abs neutralizing type I IFNs (aged 43-86 years). Eight of these ten patients had auto-Abs neutralizing both IFN-a2 and IFN-., while two neutralized IFN-omega only. No patient neutralized IFN-ss. Seven neutralized 10 ng/mL of type I IFNs, and three 100 pg/mL only. Seven patients neutralized SARS-CoV-2 D614G and the Delta variant (B.1.617.2) efficiently, while one patient neutralized Delta slightly less efficiently. Two of the three patients neutralizing only 100 pg/mL of type I IFNs neutralized both D61G and Delta less efficiently. Despite two mRNA vaccine inoculations and the presence of circulating antibodies capable of neutralizing SARS-CoV-2, auto-Abs neutralizing type I IFNs may underlie a significant proportion of hypoxemic COVID-19 pneumonia cases, highlighting the importance of this particularly vulnerable population

In vitro bactericidal activity of amoxicillin combined with different cephalosporins against endocarditis-associated Enterococcus faecalis clinical isolates

International audienceBackground - The combination of amoxicillin with cefazolin could be an interesting regimen for the empirical therapy of severe infective endocarditis, but its activity against enterococci is unknown. Objectives - To evaluate in vitro the bactericidal activity of the combination of amoxicillin with different cephalosporins including cefazolin. Methods - Combinations of amoxicillin (at MIC×¼) with cefazolin, cefotaxime, ceftriaxone, cefepime, ceftaroline or ceftobiprole (at the mean free plasma concentration) were studied using time-kill experiments for 10 endocarditis-associated Enterococcus faecalis strains and 2 reference strains. Results - The combinations amoxicillin/cefazolin, amoxicillin/cefotaxime, amoxicillin/ceftriaxone and amoxicillin/cefepime were synergistic at 12 and 24 h against 12/12 strains and amoxicillin/ceftobiprole and amoxicillin/ceftaroline against 10/12 strains. The combination amoxicillin/cefepime was bactericidal at 24 h against 9/12 strains, the combination amoxicillin/cefazolin against 8/12 strains, the combinations amoxicillin/ceftaroline, amoxicillin/cefotaxime and amoxicillin/ceftobiprole against 7/12 strains and the combination amoxicillin/ceftriaxone against 6/12 strains. Conclusions - The combination amoxicillin/cefazolin is as synergistic and bactericidal in vitro as amoxicillin/cefotaxime or amoxicillin/ceftriaxone against E. faecalis

MOSAIC: A cohort study of human mpox virus disease

Background: Human mpox is a viral disease caused by an Orthopoxvirus, human mpox virus (hMPXV), typically causing fever and a rash. Mpox has historically been endemic to parts of Central and West Africa, with small numbers of imported cases reported elsewhere, but starting May 2022 an unprecedented global outbreak caused by clade IIb hMPXV was reported outside traditionally endemic countries. This prompted the initiation of MOSAIC, a cohort study implemented in Europe and Asia that aims to describe clinical and virologic outcomes of PCR-confirmed hMPXV disease, including those who receive antiviral therapy. The study is ongoing. Methods: MOSAIC recruits participants of any age with laboratory-confirmed mpox disease who provide informed consent. Participants enrol in the cohort for a total of six months. Blood, lesion and throat samples are collected at several timepoints from the day of diagnosis or the first day of treatment (Day 1) until Day 28 for PCR detection of hMPXV. Clinical data are collected by clinicians and participants ( via a self-completion questionnaire) for six months to characterize the signs and symptoms associated with the illness, as well as short- and more long-term outcomes. Discussion: The design and prompt implementation of clinical research response is key in addressing emerging outbreaks. MOSAIC began enrolment within two months of the start of the international mpox epidemic. While the number of cases is now low, the study remains open for inclusion. Ictrp registration: EU CT number: 2022-501132-42-00 (22/06/2022)

Hydroxychloroquine use against SARS-CoV-2 infection in non-human primates

International audienceCoronavirus disease 2019 (COVID-19) has rapidly become a global pandemic and no antiviral drug or vaccine is yet available for the treatment of this disease1-3. Several clinical studies are ongoing to evaluate the efficacy of repurposed drugs that have demonstrated antiviral efficacy in vitro. Among these candidates, hydroxychloroquine (HCQ) has been given to thousands of individuals infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-the virus that causes COVID-19-worldwide but there is no definitive evidence that HCQ is effective for treating COVID-194-7. Here we evaluated the antiviral activity of HCQ both in vitro and in SARS-CoV-2-infected macaques. HCQ showed antiviral activity in African green monkey kidney cells (Vero E6) but not in a model of reconstituted human airway epithelium. In macaques, we tested different treatment strategies in comparison to a placebo treatment, before and after peak viral load, alone or in combination with azithromycin (AZTH). Neither HCQ nor the combination of HCQ and AZTH showed a significant effect on viral load in any of the analysed tissues. When the drug was used as a pre-exposure prophylaxis treatment, HCQ did not confer protection against infection with SARS-CoV-2. Our findings do not support the use of HCQ, either alone or in combination with AZTH, as an antiviral drug for the treatment of COVID-19 in humans

Silent Cerebral Small-Vessel Disease Is Twice as Prevalent in Middle-Aged Individuals With Well-Controlled, Combination Antiretroviral Therapy–Treated Human Immunodeficiency Virus (HIV) Than in HIV-Uninfected Individuals

International audienc