Publications by authors named "Slim Fourati"

102 Publications

Persistent SARS-CoV-2 Alpha Variant Infection in Immunosuppressed Patient, France, February 2022.

Emerg Infect Dis 2022 May 6;28(7). Epub 2022 May 6.

We describe persistent circulation of SARS-CoV-2 Alpha variant in an immunosuppressed patient in France during February 2022. The virus had a new pattern of mutation accumulation. The ongoing circulation of previous variants of concern could lead to reemergence of variants with the potential to propagate future waves of infection.
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http://dx.doi.org/10.3201/eid2807.220467DOI Listing
May 2022

Analysis of mRNA vaccination-elicited RBD-specific memory B cells reveals strong but incomplete immune escape of the SARS-CoV-2 Omicron variant.

Immunity 2022 Apr 7. Epub 2022 Apr 7.

Institut Necker Enfants Malades (INEM), INSERM U1151/CNRS UMR 8253, Université Paris Cité, Paris, France; INSERM U955, équipe 2, Institut Mondor de Recherche Biomédicale (IMRB), Université Paris-Est Créteil, Créteil, France. Electronic address:

The SARS-CoV-2 Omicron variant can escape neutralization by vaccine-elicited and convalescent antibodies. Memory B cells (MBCs) represent another layer of protection against SARS-CoV-2, as they persist after infection and vaccination and improve their affinity. Whether MBCs elicited by mRNA vaccines can recognize the Omicron variant remains unclear. We assessed the affinity and neutralization potency against the Omicron variant of several hundred naturally expressed MBC-derived monoclonal IgG antibodies from vaccinated COVID-19-recovered and -naive individuals. Compared with other variants of concern, Omicron evaded recognition by a larger proportion of MBC-derived antibodies, with only 30% retaining high affinity against the Omicron RBD, and the reduction in neutralization potency was even more pronounced. Nonetheless, neutralizing MBC clones could be found in all the analyzed individuals. Therefore, despite the strong immune escape potential of the Omicron variant, these results suggest that the MBC repertoire generated by mRNA vaccines still provides some protection against the Omicron variant in vaccinated individuals.
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http://dx.doi.org/10.1016/j.immuni.2022.04.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8986479PMC
April 2022

Characteristics of hepatitis C virus resistance in an international cohort after a decade of direct-acting antivirals.

JHEP Rep 2022 May 24;4(5):100462. Epub 2022 Feb 24.

CIBER de Enfermedades Infecciosas (CIBERINFEC), Hospital Universitario Clinico San Cecilio, Instituto de Investigacion Ibs.Granada, Granada, Spain.

Background & Aims: Direct-acting antiviral (DAA) regimens provide a cure in >95% of patients with chronic HCV infection. However, in some patients in whom therapy fails, resistance-associated substitutions (RASs) can develop, limiting retreatment options and risking onward resistant virus transmission. In this study, we evaluated RAS prevalence and distribution, including novel NS5A RASs and clinical factors associated with RAS selection, among patients who experienced DAA treatment failure.

Methods: SHARED is an international consortium of clinicians and scientists studying HCV drug resistance. HCV sequence linked metadata from 3,355 patients were collected from 22 countries. NS3, NS5A, and NS5B RASs in virologic failures, including novel NS5A substitutions, were examined. Associations of clinical and demographic characteristics with RAS selection were investigated.

Results: The frequency of RASs increased from its natural prevalence following DAA exposure: 37% to 60% in NS3, 29% to 80% in NS5A, 15% to 22% in NS5B for sofosbuvir, and 24% to 37% in NS5B for dasabuvir. Among 730 virologic failures, most were treated with first-generation DAAs, 94% had drug resistance in ≥1 DAA class: 31% single-class resistance, 42% dual-class resistance (predominantly against protease and NS5A inhibitors), and 21% triple-class resistance. Distinct patterns containing ≥2 highly resistant RASs were common. New potential NS5A RASs and adaptive changes were identified in genotypes 1a, 3, and 4. Following DAA failure, RAS selection was more frequent in older people with cirrhosis and those infected with genotypes 1b and 4.

Conclusions: Drug resistance in HCV is frequent after DAA treatment failure. Previously unrecognized substitutions continue to emerge and remain uncharacterized.

Lay Summary: Although direct-acting antiviral medications effectively cure hepatitis C in most patients, sometimes treatment selects for resistant viruses, causing antiviral drugs to be either ineffective or only partially effective. Multidrug resistance is common in patients for whom DAA treatment fails. Older patients and patients with advanced liver diseases are more likely to select drug-resistant viruses. Collective efforts from international communities and governments are needed to develop an optimal approach to managing drug resistance and preventing the transmission of resistant viruses.
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http://dx.doi.org/10.1016/j.jhepr.2022.100462DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9010635PMC
May 2022

Impact of donor vaccination on recipient response to early SARS-CoV-2 mRNA vaccination after allogeneic HSCT.

Lancet Haematol 2022 05 1;9(5):e318-e321. Epub 2022 Apr 1.

Haematology Department, Assistance Publique-Hôpitaux de Paris (AP-HP), Fédération Hospitalo-Universitaire TRUE innovative therapy for immune disorders, Henri Mondor Hospital, Creteil 94000, France; INSERM U955, Paris Est Créteil University UPEC, Créteil, France. Electronic address:

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http://dx.doi.org/10.1016/S2352-3026(22)00097-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8975260PMC
May 2022

Determinants of SARS-CoV-2 waning immunity in allogeneic hematopoietic stem cell transplant recipients.

J Hematol Oncol 2022 03 18;15(1):27. Epub 2022 Mar 18.

Hematology Department, Fédération Hospitalo-Universitaire TRUE InnovaTive theRapy for immUne disordErsHenri Mondor Hospital, Assistance Publique-Hôpitaux de Paris (AP-HP), 51 avenue du Mal de Lattre de Tassigny, 94010, Créteil Cedex, France.

Hematopoietic stem cell transplant (HSCT) recipients are at high-risk for severe COVID-19 and have altered immune responses to vaccination. We sought to evaluate the dynamics of immune response to BNT162b2 mRNA vaccine in HSCT recipients. We systematically proposed vaccination with BNT162b2 to HSCT recipients and gave a third vaccine dose to those showing titers of IgG(S-RBD) below 4160 AU/mL 1 month following the second dose. We then quantified anti-SARS-CoV-2 antibodies dynamics in 133 of these HSCT recipients (88 after two and 45 after three vaccine doses) 6 months after the first vaccine dose. Mean IgG(S-RBD) titer at 6 months was significantly lower than the peak value measured 1 month after a second (p < 0.001) or third (p < 0.01) vaccine dose. IgG(S-RBD) titers at 6 months were strongly correlated to peak values (p < 0.001) and a peak titer above 10,370 AU/mL predicted persistent protection at 6 months. Seventy-two percent (96/133) of patients retained protective antibody levels at 6 months. Immunosuppressive drugs and low lymphocyte counts in peripheral blood correlated with lower IgG(S-RBD) titers at 6 months. Four patients (3%) developed PCR-documented SARS-CoV-2 infection and one died.
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http://dx.doi.org/10.1186/s13045-022-01250-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8931584PMC
March 2022

Fusogenicity and neutralization sensitivity of the SARS-CoV-2 Delta sublineage AY.4.2.

EBioMedicine 2022 Mar 13;77:103934. Epub 2022 Mar 13.

Virus & Immunity Unit, Department of Virology, Institut Pasteur; CNRS UMR 3569, Paris, France; Vaccine Research Institute, Creteil, France. Electronic address:

Background: SARS-CoV-2 lineages are continuously evolving. As of December 2021, the AY.4.2 Delta sub-lineage represented 20 % of sequenced strains in the UK and had been detected in dozens of countries. It has since then been supplanted by Omicron. The AY.4.2 spike displays three additional mutations (T95I, Y145H and A222V) in the N-terminal domain when compared to the original Delta variant (B.1.617.2) and remains poorly characterized.

Methods: We compared the Delta and the AY.4.2 spikes, by assessing their binding to antibodies and ACE2 and their fusogenicity. We studied the sensitivity of an authentic AY.4.2 viral isolate to neutralizing antibodies.

Findings: The AY.4.2 spike exhibited similar binding to all the antibodies and sera tested, and similar fusogenicity and binding to ACE2 than the ancestral Delta spike. The AY.4.2 virus was slightly less sensitive than Delta to neutralization by a panel of monoclonal antibodies; noticeably, the anti-RBD Imdevimab showed incomplete neutralization. Sensitivity of AY.4.2 to sera from vaccinated individuals was reduced by 1.3 to 3-fold, when compared to Delta.

Interpretation: Our results suggest that mutations in the NTD remotely impair the efficacy of anti-RBD antibodies. The spread of AY.4.2 was not due to major changes in spike fusogenicity or ACE2 binding, but more likely to a partially reduced neutralization sensitivity.

Funding: The work was funded by Institut Pasteur, Fondation pour la Recherche Médicale, Urgence COVID-19 Fundraising Campaign of Institut Pasteur, ANRS, the Vaccine Research Institute, Labex IBEID, ANR/FRM Flash Covid PROTEO-SARS-CoV-2 and IDISCOVR.
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http://dx.doi.org/10.1016/j.ebiom.2022.103934DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8917961PMC
March 2022

Case Report: Evolution of Humoral and Cellular Immunity in Two COVID-19 Breakthrough Infections After BNT162b2 Vaccine.

Front Immunol 2022 23;13:790212. Epub 2022 Feb 23.

CHU de Strasbourg, Laboratoire de Virologie, Strasbourg, France.

Background: SARS-CoV-2 breakthrough infections after complete vaccination are increasing whereas their determinants remain uncharacterized.

Methods: We analyzed two cases of post-vaccination SARS-CoV-2 infections by α and β variants, respectively. For each participant both humoral (binding and neutralizing antibodies) and cellular (activation markers and cytokine expression) immune responses were characterized longitudinally.

Results: The first participant (P1) was infected by an α variant and displayed an extended and short period of viral excretion and symptom. Analysis of cellular and humoral response 72 h post-symptom onset revealed that P1 failed at developing neutralizing antibodies and a potent CD4 memory response (lack of SARS-CoV-2 specific CD4IL-2 cells) and CD8 effector response (CD8IFNγ cells). The second participant (P2) developed post-vaccination SARS-CoV-2 infection by a β variant, associated with a short period of viral excretion and symptoms. Despite displaying initially high levels and polyfunctional T cell responses, P2 lacked initial β-directed neutralizing antibodies. Both participants developed and/or increased their neutralization activity and cellular responses against all variants, namely, β and δ variants that lasts up to 3 months after breakthrough infection.

Conclusions: An analysis of cellular and humoral response suggests two possible mechanisms of breakthrough infection: a poor immune response to vaccine and viral evasion to neutralizing antibodies.
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http://dx.doi.org/10.3389/fimmu.2022.790212DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8905643PMC
March 2022

Anti-SARS-CoV-2 antibody response after 2 and 3 doses of BNT162b2 mRNA vaccine in patients with lymphoid malignancies.

Clin Microbiol Infect 2022 Mar 5. Epub 2022 Mar 5.

AP-HP, Groupe Hospitalo-universitaire Chenevier Mondor, Service Unité Hémopathies Lymphoides, Créteil, France; Univ Paris Est Créteil, INSERM, IMRB, Créteil, France. Electronic address:

Objectives: COVID-19 patients affected by haematological malignancies have a more severe course of the disease and higher mortality, prompting for effective prophylaxis. The present study aims to evaluate the humoral response after mRNA vaccination as well as the impact of a third vaccine dose in patients with lymphoid malignancies.

Methods: We conducted a single-centre study, evaluating the serological responses of mRNA vaccination amongst a cohort of 200 patients affected by lymphoid malignancies after two or three doses using an industrial SARS-CoV-2 serology assay for anti-receptor binding domain (RBD) Spike IgG detection and quantification.

Results: Among patients with plasma cell disorders, 59 of 96 (61%) had seroconversion (anti-RBD >50 AU/mL), and recent anti-CD38 therapies were associated with lower serological anti-RBD IgG concentrations (median IgG concentration 137 (IQR 0-512) AU/mL vs. 543 (IQR 35-3496) AU/mL; p < 0.001). Patients with B-cell malignancies had a lower seroconversion rate (20/84, 24%) mainly due to the broad usage of anti-CD20 monoclonal antibodies; only 2 of 53 (4%) patients treated by anti-CD20 antibodies during the last 12 months experienced a seroconversion. A total of 78 patients (44 with plasma cell disorders, 27 with B-cell malignancies, and 7 with other lymphomas) received a third dose of vaccine. The seroconversion rate and antibody concentrations increased significantly, especially in patients with plasma cell disorders, where an increment of anti-RBD IgG concentrations was observed in 31 of 44 (70%) patients, with an anti-RBD concentration median-fold increase of 10.6 (IQR 2.4-25.5). Its benefit in B-cell malignancies is uncertain, with only 2 of 25 (8%) patients having seroconverted after the vaccine booster, without increased median antibody concentration.

Discussion: A third mRNA vaccine dose significantly improved humoral responses among patients with plasma cell disorders, whereas the effect was limited among patients with B-cell malignancies.
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http://dx.doi.org/10.1016/j.cmi.2022.02.029DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8897197PMC
March 2022

Epidemiological and clinical insights from SARS-CoV-2 RT-PCR crossing threshold values, France, January to November 2020.

Euro Surveill 2022 Feb;27(6)

French Society of Microbiology (SFM), https://www.sfm-microbiologie.org.

BackgroundThe COVID-19 pandemic has led to an unprecedented daily use of RT-PCR tests. These tests are interpreted qualitatively for diagnosis, and the relevance of the test result intensity, i.e. the number of quantification cycles (Cq), is debated because of strong potential biases.AimWe explored the possibility to use Cq values from SARS-CoV-2 screening tests to better understand the spread of an epidemic and to better understand the biology of the infection.MethodsWe used linear regression models to analyse a large database of 793,479 Cq values from tests performed on more than 2 million samples between 21 January and 30 November 2020, i.e. the first two pandemic waves. We performed time series analysis using autoregressive integrated moving average (ARIMA) models to estimate whether Cq data information improves short-term predictions of epidemiological dynamics.ResultsAlthough we found that the Cq values varied depending on the testing laboratory or the assay used, we detected strong significant trends associated with patient age, number of days after symptoms onset or the state of the epidemic (the temporal reproduction number) at the time of the test. Furthermore, knowing the quartiles of the Cq distribution greatly reduced the error in predicting the temporal reproduction number of the COVID-19 epidemic.ConclusionOur results suggest that Cq values of screening tests performed in the general population generate testable hypotheses and help improve short-term predictions for epidemic surveillance.
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http://dx.doi.org/10.2807/1560-7917.ES.2022.27.6.2100406DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8832522PMC
February 2022

SARS-CoV-2 Antibody Response to 2 or 3 Doses of the BNT162b2 Vaccine in Patients Treated With Anticancer Agents.

JAMA Oncol 2022 Apr;8(4):612-617

University Paris Est Créteil, INSERM U955, IMRB, Créteil, France.

Importance: Patients with solid cancer are more susceptible to develop SARS-CoV-2 infection and severe complications; the immunogenicity in patients treated with anticancer agents remains unknown.

Objective: To assess the immune humoral response to 2 or 3 doses of the BNT162b2 (BioNTech; Pfizer) vaccine in patients treated with anticancer agents.

Design, Setting, And Participants: A prospective observational cohort study was conducted between February 1 and May 31, 2021. Adults treated with anticancer agents who received 2 or 3 doses of vaccine were included; of these, individuals with a weak humoral response 1 month after the second dose received a third injection.

Interventions: Quantitative serologic testing of antibodies specific for SARS-CoV-2 was conducted before vaccination and during follow-up.

Main Outcomes And Measures: Humoral response was evaluated with a threshold of anti-SARS-CoV-2 spike protein antibody levels at 1000 arbitrary units (AU)/mL to neutralize less-sensitive COVID-19 variants.

Results: Among 163 patients (median [range] age, 66 [27-89] years, 86 men [53%]) with solid tumors who received 2 or 3 doses of vaccine, 122 individuals (75%) were treated with chemotherapy, 15 with immunotherapy (9%), and 26 with targeted therapies (16%). The proportions of patients with an anti-S immunoglobulin G titer greater than 1000 AU/mL were 15% (22 of 145) at the time of the second vaccination and 65% (92 of 142) 28 days after the second vaccination. Humoral response decreased 3 months after the second dose. Treatment type was associated with humoral response; in particular, time between vaccine and chemotherapy did not interfere with the humoral response. Among 36 patients receiving a third dose of vaccine, a serologic response greater than 1000 AU/mL occurred in 27 individuals (75%).

Conclusions And Relevance: The results of this cohort study appear to support the use of a third vaccine dose among patients with active cancer treatment for solid tumors.
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http://dx.doi.org/10.1001/jamaoncol.2021.7777DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8742219PMC
April 2022

Performance of a high-throughput, automated enzyme immunoassay for the detection of SARS-CoV-2 antigen, including in viral "variants of concern": Implications for clinical use.

J Clin Virol 2022 01 29;146:105048. Epub 2021 Nov 29.

Department of Virology, Henri Mondor Hospital, AP-HP (Assistance Publique-Hôpitaux de Paris), Université Paris-Est, Créteil, F-94010 France; INSERM U955, Institut Mondor de Recherche Biomédicale, Créteil, F-94010 France.

Direct detection of SARS-CoV-2 viral antigens could replace RT-PCR, provided that its clinical performance is validated in different epidemiological settings. Here, we evaluated the performance of the VITROS Antigen test, an enzyme immunoassay detecting a SARS-CoV-2 antigen, in NPSs from 3 cohorts of patients.

Methods: Three cohorts including SARS-CoV-2 RNA-positive samples collected during the first and second wave of the French epidemic between March 2020 and February 2021 (including variant B.1.1.7/α and variant B.1.351/β).

Results: Among the 1763 prospectively tested subjects, 8.2% (145/1763) were SARS-CoV-2 RNA-positive by RT-PCR. Using Ct ≤ 30 and Ct ≤ 35 as thresholds, the sensitivities of the antigen assay were 98.8% (93.6-100%) and 93.5% (87.0-97.3%), respectively. The overall specificity of the assay was 100% (1614/1614; 99.8-100%). In a retrospective cohort of subjects infected with variants of concern, 90.4% (47/52) of NPSs containing B. B.1.1.7/α (Ct ≤ 35) and 100% (7/7) of those containing B.1.351/β were positive with the VITROS EIA SARS-CoV-2 Antigen test.

Conclusion: The excellent performance of the EIA Antigen test reported here, including in patients infected with viral "variants of concern", support the use of high-throughput, EIA-based SARS-CoV-2 antigen assays as an alternative or complement to nucleic acid testing in order to scale-up laboratory screening and diagnostic capacities.
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http://dx.doi.org/10.1016/j.jcv.2021.105048DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8628626PMC
January 2022

mRNA vaccination of naive and COVID-19-recovered individuals elicits potent memory B cells that recognize SARS-CoV-2 variants.

Immunity 2021 12 21;54(12):2893-2907.e5. Epub 2021 Sep 21.

Institut Necker Enfants Malades (INEM), INSERM U1151/CNRS UMS 8253, Université de Paris, Paris, France; Service de Médecine Interne, Centre Hospitalier Universitaire Henri-Mondor, Assistance Publique-Hôpitaux de Paris (AP-HP), Université Paris-Est Créteil (UPEC), Créteil, France; INSERM U955, Équipe 2, Institut Mondor de Recherche Biomédicale (IMRB), Université Paris-Est Créteil (UPEC), Créteil, France. Electronic address:

In addition to serum immunoglobulins, memory B cell (MBC) generation against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is another layer of immune protection, but the quality of MBC responses in naive and coronavirus disease 2019 (COVID-19)-recovered individuals after vaccination remains ill defined. We studied longitudinal cohorts of naive and disease-recovered individuals for up to 2 months after SARS-CoV-2 mRNA vaccination. We assessed the quality of the memory response by analysis of antibody repertoires, affinity, and neutralization against variants of concern (VOCs) using unbiased cultures of 2,452 MBCs. Upon boosting, the MBC pool of recovered individuals expanded selectively, matured further, and harbored potent neutralizers against VOCs. Although naive individuals had weaker neutralizing serum responses, half of their RBD-specific MBCs displayed high affinity toward multiple VOCs, including delta (B.1.617.2), and one-third retained neutralizing potency against beta (B.1.351). Our data suggest that an additional challenge in naive vaccinees could recall such affinity-matured MBCs and allow them to respond efficiently to VOCs.
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http://dx.doi.org/10.1016/j.immuni.2021.09.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8452492PMC
December 2021

The transcription factor CREB1 is a mechanistic driver of immunogenicity and reduced HIV-1 acquisition following ALVAC vaccination.

Nat Immunol 2021 10 23;22(10):1294-1305. Epub 2021 Sep 23.

Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, OH, USA.

Development of effective human immunodeficiency virus 1 (HIV-1) vaccines requires synergy between innate and adaptive immune cells. Here we show that induction of the transcription factor CREB1 and its target genes by the recombinant canarypox vector ALVAC + Alum augments immunogenicity in non-human primates (NHPs) and predicts reduced HIV-1 acquisition in the RV144 trial. These target genes include those encoding cytokines/chemokines associated with heightened protection from simian immunodeficiency virus challenge in NHPs. Expression of CREB1 target genes probably results from direct cGAMP (STING agonist)-modulated p-CREB1 activity that drives the recruitment of CD4 T cells and B cells to the site of antigen presentation. Importantly, unlike NHPs immunized with ALVAC + Alum, those immunized with ALVAC + MF59, the regimen in the HVTN702 trial that showed no protection from HIV infection, exhibited significantly reduced CREB1 target gene expression. Our integrated systems biology approach has validated CREB1 as a critical driver of vaccine efficacy and highlights that adjuvants that trigger CREB1 signaling may be critical for efficacious HIV-1 vaccines.
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http://dx.doi.org/10.1038/s41590-021-01026-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8525330PMC
October 2021

Evaluation of prognostic scores for respiratory syncytial virus infection in a French multicentre cohort of allogeneic haematopoietic stem cell transplantation recipients.

Bone Marrow Transplant 2021 12 21;56(12):3032-3041. Epub 2021 Sep 21.

Université de Paris, Service de Pneumologie, Hôpital Saint-Louis, AP-HP -, Paris, France.

Haematopoietic stem cell transplantation (HSCT) recipients are at risk for severe respiratory syncytial virus (RSV) infection. Two prognostic scores have been proposed to predict the risk of progression from upper respiratory tract infection (URTI) to lower respiratory tract infection (LRTI) and death. This was a multicentre study of allogeneic HSCT recipients diagnosed with an RSV infection between 2010 and 2019 who were retrospectively stratified by the immunodeficiency scoring index (ISI) and the severe immunodeficiency (SID) score. Endpoints were overall survival, RSV-attributable mortality and progression to LRTI after URTI. Prognostic analyses were performed using Cox regression models. We included 147 consecutive patients, including 94 (63.9%) initially diagnosed with URTI and 53 (36.1%) with LRTI. At 90 days, 14 patients had died (survival rate, 90.5%; 95% CI: 85.9-95.3), and nine deaths were attributable to RSV (attributable mortality rate, 5.4%; 95% CI: 2.5-10.0). The cumulative 90-day incidence of LRTI after URTI was 13.8% (95% CI: 7.8-21.6). Neither score showed prognostic value for mortality, while the ISI allowed the prediction of progression to LRTI (p = 0.0008). Our results do not fully replicate the results previously reported in cohorts of HSCT recipients. This may reflect the recent epidemiology of RSV infections in this HSCT cohort.
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http://dx.doi.org/10.1038/s41409-021-01462-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8454013PMC
December 2021

Monocyte-derived transcriptome signature indicates antibody-dependent cellular phagocytosis as a potential mechanism of vaccine-induced protection against HIV-1.

Elife 2021 09 17;10. Epub 2021 Sep 17.

US Military HIV Research Program (MHRP), Walter Reed Army Institute of Research, Silver Spring, United States.

A gene signature was previously found to be correlated with mosaic adenovirus 26 vaccine protection in simian immunodeficiency virus and simian-human immunodeficiency virus challenge models in non-human primates. In this report, we investigated the presence of this signature as a correlate of reduced risk in human clinical trials and potential mechanisms of protection. The absence of this gene signature in the DNA/rAd5 human vaccine trial, which did not show efficacy, strengthens our hypothesis that this signature is only enriched in studies that demonstrated protection. This gene signature was enriched in the partially effective RV144 human trial that administered the ALVAC/protein vaccine, and we find that the signature associates with both decreased risk of HIV-1 acquisition and increased vaccine efficacy (VE). Total RNA-seq in a clinical trial that used the same vaccine regimen as the RV144 HIV vaccine implicated antibody-dependent cellular phagocytosis (ADCP) as a potential mechanism of vaccine protection. CITE-seq profiling of 53 surface markers and transcriptomes of 53,777 single cells from the same trial showed that genes in this signature were primarily expressed in cells belonging to the myeloid lineage, including monocytes, which are major effector cells for ADCP. The consistent association of this transcriptome signature with VE represents a tool both to identify potential mechanisms, as with ADCP here, and to screen novel approaches to accelerate the development of new vaccine candidates.
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http://dx.doi.org/10.7554/eLife.69577DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8514236PMC
September 2021

Antibody response after third BNT162b2 dose in recipients of allogeneic HSCT.

Lancet Haematol 2021 Oct 3;8(10):e681-e683. Epub 2021 Sep 3.

Haematology Department, Assistance Publique, Hôpitaux de Paris, Henri Mondor Hospital, Créteil 94000, France; INSERM U955, Université Paris Est Créteil Val de Marne, Créteil, France. Electronic address:

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http://dx.doi.org/10.1016/S2352-3026(21)00274-XDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8415894PMC
October 2021

Performance of six rapid diagnostic tests for SARS-CoV-2 antigen detection and implications for practical use.

J Clin Virol 2021 09 25;142:104930. Epub 2021 Jul 25.

Department of Virology, Hôpital Henri Mondor, Créteil, France; INSERM U955, Créteil, France. Electronic address:

Background: Direct detection of SARS-CoV-2 viral proteins in nasopharyngeal swabs using lateral flow immunoassays is a simple, fast and cheap approach to diagnose the infection.

Aims And Methods: The performance of 6 SARS-CoV-2 antigen rapid diagnostic tests has been assessed in 634 hospitalized patients or outpatients including 297 patients found to be positive for SARS-CoV-2 RNA by means of RT-PCR and 337 patients presumed to be SARS-CoV-2 RNA-negative.

Results: The specificity of SARS-CoV-2 RDTs was generally high (398.5%). One assay had a lower specificity of 93.2%. The overall sensitivity of the 6 RDTs was variable, from 32.3% to 61.7%. Sensitivity correlated with the delay of sampling after the onset of symptoms and the viral load estimated by the Ct value in RT-PCR. Four out of 6 RDTs tested achieved sensitivities 380% when clinical specimens were collected during the first 3 days following symptom onset or with a Ct value ≤25.

Conclusions: The present study shows that SARS-CoV-2 antigen can be easily and reliably detected by RDTs. These tests are easy and rapid to perform. However, the specificity and sensitivity of COVID-19 antigen RDTs may widely vary across different tests and must therefore be carefully evaluated before releasing these assays for realworld applications.
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http://dx.doi.org/10.1016/j.jcv.2021.104930DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8310570PMC
September 2021

The Potential Role of Clinical Metagenomics in Infectious Diseases: Therapeutic Perspectives.

Drugs 2021 Sep 30;81(13):1453-1466. Epub 2021 Jul 30.

Université de Paris, IAME, INSERM, 75018, Paris, France.

Clinical metagenomics (CMg) is the process of sequencing nucleic acid of clinical samples to obtain clinically relevant information such as the identification of microorganisms and their susceptibility to antimicrobials. Over the last decades, sequencing and bioinformatic solutions supporting CMg have much evolved and an increasing number of case reports and series covering various infectious diseases have been published. Metagenomics is a new approach to infectious disease diagnosis that is currently being developed and is certainly one of the most promising for the coming years. However, most CMg studies are retrospective, and few address the potential impact CMg could have on patient management, including initiation, adaptation, or cessation of antimicrobials. In this narrative review, we have discussed the potential role of CMg in bacteriology, virology, mycology, and parasitology. Several reports and case-series confirm that CMg is an innovative tool with which one can (i) identify more microorganisms than with conventional methods in a single test, (ii) obtain results within hours, and (iii) tailor the antimicrobial regimen of patients. However, the cost-efficiency of CMg and its real impact on patient management are still to be determined.
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http://dx.doi.org/10.1007/s40265-021-01572-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8323086PMC
September 2021

Antibody response after second BNT162b2 dose in allogeneic HSCT recipients.

Lancet 2021 07 13;398(10297):298-299. Epub 2021 Jul 13.

Hopital Henri Mondor, 94000 Créteil, France. Electronic address:

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http://dx.doi.org/10.1016/S0140-6736(21)01594-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8277189PMC
July 2021

Single cell RNA sequencing of AML initiating cells reveals RNA-based evolution during disease progression.

Leukemia 2021 10 9;35(10):2799-2812. Epub 2021 Jul 9.

Department of Pathology, Case Western Reserve University, Cleveland, OH, USA.

The prognosis of most patients with AML is poor due to frequent disease relapse. The cause of relapse is thought to be from the persistence of leukemia initiating cells (LIC's) following treatment. Here we assessed RNA based changes in LICs from matched patient diagnosis and relapse samples using single-cell RNA sequencing. Previous studies on AML progression have focused on genetic changes at the DNA mutation level mostly in bulk AML cells and demonstrated the existence of DNA clonal evolution. Here we identified in LICs that the phenomenon of RNA clonal evolution occurs during AML progression. Despite the presence of vast transcriptional heterogeneity at the single cell level, pathway analysis identified common signaling networks involving metabolism, apoptosis and chemokine signaling that evolved during AML progression and become a signature of relapse samples. A subset of this gene signature was validated at the protein level in LICs by flow cytometry from an independent AML cohort and functional studies were performed to demonstrate co-targeting BCL2 and CXCR4 signaling may help overcome therapeutic challenges with AML heterogeneity. It is hoped this work will facilitate a greater understanding of AML relapse leading to improved prognostic biomarkers and therapeutic strategies to target LIC's.
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http://dx.doi.org/10.1038/s41375-021-01338-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8807029PMC
October 2021

Translocated microbiome composition determines immunological outcome in treated HIV infection.

Cell 2021 07 7;184(15):3899-3914.e16. Epub 2021 Jul 7.

Department of Pediatrics, Miller School of Medicine, University of Miami, Miami, FL 33124, USA.

The impact of the microbiome on HIV disease is widely acknowledged although the mechanisms downstream of fluctuations in microbial composition remain speculative. We detected rapid, dynamic changes in translocated microbial constituents during two years after cART initiation. An unbiased systems biology approach revealed two distinct pathways driven by changes in the abundance ratio of Serratia to other bacterial genera. Increased CD4 T cell numbers over the first year were associated with high Serratia abundance, pro-inflammatory innate cytokines, and metabolites that drive Th17 gene expression signatures and restoration of mucosal integrity. Subsequently, decreased Serratia abundance and downregulation of innate cytokines allowed re-establishment of systemic T cell homeostasis promoting restoration of Th1 and Th2 gene expression signatures. Analyses of three other geographically distinct cohorts of treated HIV infection established a more generalized principle that changes in diversity and composition of translocated microbial species influence systemic inflammation and consequently CD4 T cell recovery.
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http://dx.doi.org/10.1016/j.cell.2021.05.023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8316372PMC
July 2021

Interleukin-15 response signature predicts RhCMV/SIV vaccine efficacy.

PLoS Pathog 2021 07 6;17(7):e1009278. Epub 2021 Jul 6.

Department of Pathology, Case Western Reserve University, Cleveland, Ohio, United States of America.

Simian immunodeficiency virus (SIV) challenge of rhesus macaques (RMs) vaccinated with strain 68-1 Rhesus Cytomegalovirus (RhCMV) vectors expressing SIV proteins (RhCMV/SIV) results in a binary outcome: stringent control and subsequent clearance of highly pathogenic SIV in ~55% of vaccinated RMs with no protection in the remaining 45%. Although previous work indicates that unconventionally restricted, SIV-specific, effector-memory (EM)-biased CD8+ T cell responses are necessary for efficacy, the magnitude of these responses does not predict efficacy, and the basis of protection vs. non-protection in 68-1 RhCMV/SIV vector-vaccinated RMs has not been elucidated. Here, we report that 68-1 RhCMV/SIV vector administration strikingly alters the whole blood transcriptome of vaccinated RMs, with the sustained induction of specific immune-related pathways, including immune cell, toll-like receptor (TLR), inflammasome/cell death, and interleukin-15 (IL-15) signaling, significantly correlating with subsequent vaccine efficacy. Treatment of a separate RM cohort with IL-15 confirmed the central involvement of this cytokine in the protection signature, linking the major innate and adaptive immune gene expression networks that correlate with RhCMV/SIV vaccine efficacy. This change-from-baseline IL-15 response signature was also demonstrated to significantly correlate with vaccine efficacy in an independent validation cohort of vaccinated and challenged RMs. The differential IL-15 gene set response to vaccination strongly correlated with the pre-vaccination activity of this pathway, with reduced baseline expression of IL-15 response genes significantly correlating with higher vaccine-induced induction of IL-15 signaling and subsequent vaccine protection, suggesting that a robust de novo vaccine-induced IL-15 signaling response is needed to program vaccine efficacy. Thus, the RhCMV/SIV vaccine imparts a coordinated and persistent induction of innate and adaptive immune pathways featuring IL-15, a known regulator of CD8+ T cell function, that support the ability of vaccine-elicited unconventionally restricted CD8+ T cells to mediate protection against SIV challenge.
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http://dx.doi.org/10.1371/journal.ppat.1009278DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8284654PMC
July 2021

Neutralization Heterogeneity of UK and South African Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Variants in BNT162b2-Vaccinated or Convalescent Coronavirus Disease 2019 (COVID-19) Healthcare Workers.

Clin Infect Dis 2022 03;74(4):707-710

Sorbonne Université, Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Pierre Louis d'Epidémiologie et de Santé Publique (iPLESP), Assistance Publique-Hôpitaux de Paris (AP-HP), Pitié Salpêtrière Hospital, Department of Virology, Paris, France.

There are concerns about neutralizing antibodies' (NAbs') potency against severe acute respiratory syndrome coronavirus 2 variants. Despite decreased NAb titers elicited by BNT162b2 vaccine against VOC202012/01 and 501Y.V2 strains, 28/29 healthcare workers (HCWs) had an NAb titer ≥1:10. In contrast, 6 months after coronavirus disease 2019 mild forms, only 9/15 (60%) of HCWs displayed detectable NAbs against 501Y.V2 strain.
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http://dx.doi.org/10.1093/cid/ciab492DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8244299PMC
March 2022

BNT162b2 Messenger RNA Vaccination Did Not Prevent an Outbreak of Severe Acute Respiratory Syndrome Coronavirus 2 Variant 501Y.V2 in an Elderly Nursing Home but Reduced Transmission and Disease Severity.

Clin Infect Dis 2022 02;74(3):517-520

Virology Unit, Department of Prevention, Diagnosis and Treatment of Infections, Hôpital Henri Mondor (AP-HP), Université Paris-Est, Créteil, France.

We report an outbreak of severe acute respiratory syndrome coronavirus 2 501Y.V2 in a nursing home. All nonvaccinated residents (5/5) versus half of those vaccinated with BNT162b2 (13/26) were infected. Two of 13 vaccinated versus 4 of 5 nonvaccinated residents presented severe disease. BNT162b2 did not prevent the outbreak, but reduced transmission and disease severity.
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http://dx.doi.org/10.1093/cid/ciab446DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8241482PMC
February 2022

Novel SARS-CoV-2 Variant Derived from Clade 19B, France.

Emerg Infect Dis 2021 05;27(5):1540-1543

We report a novel severe acute respiratory syndrome coronavirus 2 variant derived from clade 19B (HMN.19B variant or Henri Mondor variant). This variant is characterized by the presence of 18 amino acid substitutions, including 7-8 substitutions in the spike protein and 2 deletions. These variants actively circulate in different regions of France.
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http://dx.doi.org/10.3201/eid2705.210324DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8084519PMC
May 2021

Performance of 30 commercial SARS-CoV-2 serology assays in testing symptomatic COVID-19 patients.

Eur J Clin Microbiol Infect Dis 2021 Oct 29;40(10):2235-2241. Epub 2021 Mar 29.

Service de Microbiologie, Hôpital Robert-Debré, Université de Paris, Paris, France.

We report evaluation of 30 assays' (17 rapid tests (RDTs) and 13 automated/manual ELISA/CLIA assay (IAs)) clinical performances with 2594 sera collected from symptomatic patients with positive SARS-CoV-2 rRT-PCR on a respiratory sample, and 1996 pre-epidemic serum samples expected to be negative. Only 4 RDT and 3 IAs fitted both specificity (> 98%) and sensitivity (> 90%) criteria according to French recommendations. Serology may offer valuable information during COVID-19 pandemic, but inconsistent performances observed among the 30 commercial assays evaluated, which underlines the importance of independent evaluation before clinical implementation.
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http://dx.doi.org/10.1007/s10096-021-04232-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8007057PMC
October 2021

Viral genomic, metagenomic and human transcriptomic characterization and prediction of the clinical forms of COVID-19.

PLoS Pathog 2021 03 29;17(3):e1009416. Epub 2021 Mar 29.

Department of Microbiology, Hôpitaux Universitaires Henri Mondor, Assistance Publique-Hôpitaux de Paris (AP-HP), Créteil, France.

COVID-19 is characterized by respiratory symptoms of various severities, ranging from mild upper respiratory signs to acute respiratory failure/acute respiratory distress syndrome associated with a high mortality rate. However, the pathophysiology of the disease is largely unknown. Shotgun metagenomics from nasopharyngeal swabs were used to characterize the genomic, metagenomic and transcriptomic features of patients from the first pandemic wave with various forms of COVID-19, including outpatients, patients hospitalized not requiring intensive care, and patients in the intensive care unit, to identify viral and/or host factors associated with the most severe forms of the disease. Neither the genetic characteristics of SARS-CoV-2, nor the detection of bacteria, viruses, fungi or parasites were associated with the severity of pulmonary disease. Severe pneumonia was associated with overexpression of cytokine transcripts activating the CXCR2 pathway, whereas patients with benign disease presented with a T helper "Th1-Th17" profile. The latter profile was associated with female gender and a lower mortality rate. Our findings indicate that the most severe cases of COVID-19 are characterized by the presence of overactive immune cells resulting in neutrophil pulmonary infiltration which, in turn, could enhance the inflammatory response and prolong tissue damage. These findings make CXCR2 antagonists, in particular IL-8 antagonists, promising candidates for the treatment of patients with severe COVID-19.
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http://dx.doi.org/10.1371/journal.ppat.1009416DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8032121PMC
March 2021

Kinetics of Anti-SARS-CoV-2 IgG Antibodies in Hemodialysis Patients Six Months after Infection.

J Am Soc Nephrol 2021 05 26;32(5):1033-1036. Epub 2021 Feb 26.

Assistance Publique des Hôpitaux de Paris, Hôpitaux Universitaires Henri Mondor, Department of Nephrology, Centre de Référence Maladie Rare « Syndrome Néphrotique Idiopathique », Fédération Hospitalo-Universitaire « Innovative therapy for immune disorders », Créteil, France

Background: The humoral response against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in the hemodialysis population, including its dynamics over time, remains poorly understood.

Methods: To analyze initial and long-term humoral responses against SARS-CoV-2 in a hemodialysis population, we retrospectively evaluated findings from SARS-CoV-2 IgG serologic assays targeting the nucleocapsid antigen or spike antigen up to 6 months of follow-up in patients on hemodialysis in the Paris, France, region who had recovered from coronavirus disease 2019 (COVID-19).

Results: Our analysis included 83 patients (median age 65 years); 59 (71%) were male and 28 (34%) had presented with severe COVID-19. We observed positive initial SARS-CoV-2 IgG antinucleocapsid serology in 74 patients (89%) at a median of 67 days postdiagnosis. By multivariable analysis, immunocompromised status was the only factor significantly associated with lack of an IgG antinucleocapsid antibody response. Follow-up data were available at 6 months postdiagnosis for 60 of 74 patients (81%) with positive initial antinucleocapsid serology, and 15 (25%) of them had negative antinucleocapsid serology at month 6. In total, 14 of 15 sera were tested for antispike antibodies, 3 of 14 (21%) of which were also negative. Overall, 97% of antinucleocapsid-antibody-positive specimens were also antispike-antibody positive. Female sex, age >70 years, and nonsevere clinical presentation were independently associated with faster IgG antinucleocapsid titer decay in multivariable analysis. After adjustment for sex and age >70 years, nonsevere clinical presentation was the only factor associated with faster decay of IgG antispike antibodies.

Conclusions: This study characterizes evolution of the SARS-CoV-2 antibody response in patients on hemodialysis and identifies factors that are associated with lack of seroconversion and with IgG titer decay.
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http://dx.doi.org/10.1681/ASN.2020111618DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8259690PMC
May 2021
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