C910 chemical compound inhibits the traffiking of several bacterial AB toxins with cross-protection against influenza virus.

The development of anti-infectives against a large range of AB-like toxin-producing bacteria includes the identification of compounds disrupting toxin transport through both the endolysosomal and retrograde pathways. Here, we performed a high-throughput screening of compounds blocking Rac1 proteasomal degradation triggered by the Cytotoxic Necrotizing Factor-1 (CNF1) toxin, which was followed by orthogonal screens against two toxins that hijack the endolysosomal (diphtheria toxin) or retrograde (Shiga-like toxin 1) pathways to intoxicate cells. This led to the identification of the molecule C910 that induces the enlargement of EEA1-positive early endosomes associated with sorting defects of CNF1 and Shiga toxins to their trafficking pathways. C910 protects cells against eight bacterial AB toxins and the CNF1-mediated pathogenic Escherichia coli invasion. Interestingly, C910 reduces influenza A H1N1 and SARS-CoV-2 viral infection in vitro. Moreover, parenteral administration of C910 to mice resulted in its accumulation in lung tissues and a reduction in lethal influenza infection.

Targeting SARS-CoV-2 receptor-binding domain to cells expressing CD40 improves protection to infection in convalescent macaques.

Achieving sufficient worldwide vaccination coverage against SARS-CoV-2 will require additional approaches to currently approved viral vector and mRNA vaccines. Subunit vaccines may have distinct advantages when immunizing vulnerable individuals, children and pregnant women. Here, we present a new generation of subunit vaccines targeting viral antigens to CD40-expressing antigen-presenting cells. We demonstrate that targeting the receptor-binding domain (RBD) of the SARS-CoV-2 spike protein to CD40 (αCD40.RBD) induces significant levels of specific T and B cells, with long-term memory phenotypes, in a humanized mouse model. Additionally, we demonstrate that a single dose of the αCD40.RBD vaccine, injected without adjuvant, is sufficient to boost a rapid increase in neutralizing antibodies in convalescent non-human primates (NHPs) exposed six months previously to SARS-CoV-2. Vaccine-elicited antibodies cross-neutralize different SARS-CoV-2 variants, including D614G, B1.1.7 and to a lesser extent B1.351. Such vaccination significantly improves protection against a new high-dose virulent challenge versus that in non-vaccinated convalescent animals.

Adjuvant Effect of Orally Applied Preparations Containing Non-Digestible Polysaccharides on Influenza Vaccination in Healthy Seniors: A Double-Blind, Randomised, Controlled Pilot Trial.

Senior individuals can suffer from immunosenescence and novel strategies to bolster the immune response could contribute to healthy ageing. In this double-blind, randomised, controlled pilot trial, we investigated the ability of non-digestible polysaccharide (NPS) preparations to enhance the immune response in a human vaccination model. In total, 239 subjects (aged 50-79 years) were randomised to consume one of five different NPS (yeast ß-glucan (YBG), shiitake ß-glucan (SBG), oat ß-glucan (OBG), arabinoxylan (AX), bacterial exopolysaccharide (EPS)) or control (CTRL) product daily for five weeks. After two weeks of intervention, subjects were vaccinated with seasonal influenza vaccine. The post-vaccination increases in haemagglutination inhibition antibody titres and seroprotection rate against the influenza strains were non-significantly enhanced in the NPS intervention groups compared to CTRL. Specifically, a trend towards a higher mean log2 fold increase was observed in the AX group (uncorrected p = 0.074) combined with a trend for an increased seroprotection rate, AX group (48.7%) compared to CTRL (25.6%) (uncorrected p = 0.057), for the influenza A H1N1 strain. Subjects consuming AX also had a reduced incidence of common colds compared to CTRL (1 vs. 8; p = 0.029 in Fisher exact test). No adverse effects of NPS consumption were reported. The findings of this pilot study warrant further research to study AX as an oral adjuvant to support vaccine efficacy.

Nationwide Seroprevalence of SARS-CoV-2 IgG Antibodies among Four Groups of Primary Health-Care Workers and Their Household Contacts 6 Months after the Initiation of the COVID-19 Vaccination Campaign in France: SeroPRIM Study Protocol.

BACKGROUND: The protocol study will focus on the seroprevalence of IgG antibodies to SARS-CoV-2 achieved by vaccination and/or natural protection as well as the history, symptoms, and risk factors for SARS-CoV-2 in four primary health-care workers (PHCWs) and their household contacts in metropolitan France. METHODS: Here, we propose a protocol for a nationwide survey to determine the seroprevalence of IgG antibodies to SARS-CoV-2 achieved by vaccination and/or natural protection in four PHCW populations (general practitioners, pediatricians, pharmacists and assistants, and dentists and assistants) and their household contacts. Participants will be included from June to July 2021 (Phase 1) among PHCW populations located throughout metropolitan France. They will be asked to provide a range of demographic and behavioral information since the first SARS-CoV-2 wave and a self-sampled dried blood spot. Phase 1 will involve also a questionnaire and serological study of PHCWs' household contacts. Seroprevalence will be estimated using two ELISAs designed to detect specific IgG antibodies to SARS-CoV-2 in humoral fluid, and these results will be confirmed using a virus neutralization test. This study will be repeated from November to December 2021 (Phase 2) to evaluate the evolution of immune status achieved by vaccination and/or natural protection of PHCWs and to describe the history of exposure to SARS-CoV-2.

Humoral immunity to SARS-CoV-2 and seasonal coronaviruses in children and adults in north-eastern France.

BACKGROUND: Children are underrepresented in the COVID-19 pandemic and often experience milder disease than adolescents and adults. Reduced severity is possibly due to recent and more frequent seasonal human coronaviruses (HCoV) infections. We assessed the seroprevalence of SARS-CoV-2 and seasonal HCoV specific antibodies in a large cohort in north-eastern France. METHODS: In this cross-sectional seroprevalence study, serum samples were collected from children and adults requiring hospital admission for non-COVID-19 between February and August 2020. Antibody responses to SARS-CoV-2 and seasonal HCoV (229E, HKU1, NL63, OC43) were assessed using a bead-based multiplex assay, Luciferase-Linked ImmunoSorbent Assay, and a pseudotype neutralisation assay. FINDINGS: In 2,408 individuals, seroprevalence of SARS-CoV-2-specific antibodies was 7-8% with three different immunoassays. Antibody levels to seasonal HCoV increased substantially up to the age of 10. Antibody responses in SARS-CoV-2 seropositive individuals were lowest in adults 18-30 years. In SARS-CoV-2 seronegative individuals, we observed cross-reactivity between antibodies to the four HCoV and SARS-CoV-2 Spike. In contrast to other antibodies to SARS-CoV-2, specific antibodies to sub-unit 2 of Spike (S2) in seronegative samples were highest in children. Upon infection with SARS-CoV-2, antibody levels to Spike of betacoronavirus OC43 increased across the whole age spectrum. No SARS-CoV-2 seropositive individuals with low levels of antibodies to seasonal HCoV were observed. INTERPRETATION: Our findings underline significant cross-reactivity between antibodies to SARS-CoV-2 and seasonal HCoV, but provide no significant evidence for cross-protective immunity to SARS-CoV-2 infection due to a recent seasonal HCoV infection. In particular, across all age groups we did not observe SARS-CoV-2 infected individuals with low levels of antibodies to seasonal HCoV. FUNDING: This work was supported by the « URGENCE COVID-19 ¼ fundraising campaign of Institut Pasteur, by the French Government's Investissement d'Avenir program, Laboratoire d'Excellence Integrative Biology of Emerging Infectious Diseases (Grant No. ANR-10-LABX-62-IBEID), and by the REACTing (Research & Action Emerging Infectious Diseases), and by the RECOVER project funded by the European Union's Horizon 2020 research and innovation programme under grant agreement No. 101003589, and by a grant from LabEx IBEID (ANR-10-LABX-62-IBEID).

Factors associated with non-persistence to oral and inhaled antiviral therapies for seasonal influenza: a secondary analysis of a double-blind, multicentre, randomised clinical trial.

OBJECTIVES: We aimed to evaluate and compare non-adherence to oral and inhaled antiviral therapies prescribed of a randomised clinical trial in outpatients with influenza A infection. DESIGN: A parallel, three-arm, double-blinded trial randomly allocated antiviral therapies twice daily for 5 days: (1) oral oseltamivir plus inhaled zanamivir (arm OZ); (2) oseltamivir plus inhaled placebo (arm Opz); or (3) oral placebo plus inhaled zanamivir (arm poZ). Analysis of non-adherence was a secondary objective of the trial. SETTINGS: Outpatients were enrolled by 145 general practitioners throughout France during the 2008-2009 seasonal influenza epidemics. PARTICIPANTS: A total of 541 adults presenting with influenza-like illness for less than 36 hours. PRIMARY OUTCOMES: Non-persistence, the time between inclusion and the last dose treated as a failure time, was used as the primary endpoint. RESULTS: The proportions of patients who persisted on treatment until the end of prescription were estimated at 85.73% (±3.28%) for the oral route and 82.73% (±3.44%) for the inhaled route. Based on multivariable models, non-persistence was associated with a PCR confirmation of influenza for both the oral (HR=0.54, p=0.010) and inhaled (HR=0.59, p=0.018) drugs and antibiotic coprescriptions (HR=2.07, p=0.007; and HR=1.88, p=0.017, respectively) and active combination treatment (HR=1.71, p=0.035; and HR=1.58, p=0.035, respectively). The hazard of non-persistence of the inhaled therapy was increased compared with that of the oral therapy (HR=1.23, p=0.043). CONCLUSION: In addition to the clinical and virological profiles of influenza infection, non-persistence may have been influenced by an active combination and the route of administration. RCT REGISTRATION NUMBER: NCT00799760. This is a post-result analysis.