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Background: Nirsevimab, a long-acting monoclonal antibody, has been approved for the prevention of respiratory syncytial virus (RSV) infection in infants. In France, more than 210 000 single doses were administered in infants younger than 1 year during the 2023-24 season. In this context, the selection and spread of escape variants might be a concern. Here, we aimed to characterise RSV associated with breakthrough infection., Methods: We did a multicentre, national, observational study in France during the 2023-24 RSV season in RSV-infected infants (aged <1 year) who either received or did not receive a dose of nirsevimab before their first RSV season. We excluded infants with insufficient information about nirsevimab treatment or without parental consent. We used respiratory samples collected in each laboratory for full-length RSV RNA sequencing to analyse changes in the nirsevimab binding site Ø. We tested clinical RSV isolates for neutralisation by nirsevimab. We analysed F candidate substitutions by fusion-inhibition assay., Findings: Of the 695 RSV infected infants, we analysed 545 (78%) full-length RSV genome sequences: 260 (48%) from nirsevimab-treated breakthrough infections (236 [91%] RSV-A and 24 [9%] RSV-B) and 285 (52%) from untreated RSV-infected infants (236 [83%] RSV-A and 49 [17%] RSV-B). Analysis of RSV-A did not reveal any substitution in site Ø known to be associated with resistance to nirsevimab. Two (8%) of 24 RSV-B breakthrough infections had resistance-associated substitutions: F:N208D (dominant resistance-associated substitution) and a newly described F:I64M plus F:K65R combination (minority resistance-associated substitution), both of which induced high levels of resistance in the fusion-inhibition assay., Interpretation: This study is, to the best of our knowledge, the largest genotypic and phenotypic surveillance study of nirsevimab breakthrough infections to date. Nirsevimab breakthrough variants remain very rare despite the drug's widespread use. The detection of resistance-associated substitutions in the RSV-B F protein highlights the importance of active molecular surveillance., Funding: ANRS Maladies Infectieuses Emergentes and the French Ministry of Health and Prevention., Competing Interests: Declaration of interests SF has served as a speaker for GlaxoSmithKline, AstraZeneca, MSD, Pfizer, Cepheid, and Moderna. IE received support by R-Biopharm for attending meetings. CR has served as a speaker for Pfizer and received support by Tecan for attending meetings. J-MP has served as an advisor or speaker for Abbott, Abbvie, Gilead, and GlaxoSmithKline. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Introduction: Due to the COVID-19 pandemic, France underwent several lockdown periods during 2020. Our aim was to evaluate its clinical and social impact on lung transplant (LT) patients treated at Strasbourg University Hospital, by comparing three periods: first lockdown (T1: March-May 2020), end of the first lockdown (T2: May-October 2020), and second lockdown (T3: November-December 2020) and the incidence of COVID-19 infections. A cohort of patients with rare lung disease (RLD) was also studied during T2., Methods: We used clinical and paraclinical data collected during routine follow-up. A questionnaire was submitted to each patient at each period to assess their lifestyle, adherence to protective measures against COVID-19, contacts with their family and friends, and contagion risk. The incidence of new COVID-19 cases was also assessed., Results: Overall, 283 LT and 57 RLD patients were included. We observed only eight COVID-19 cases over the three periods (n = 4 during T1, n = 0 during T2, and n = 4 during T3) in LT patients, with 37.5 % of patients hospitalized, no ICU transfers, and 100 % favorable outcomes. No case of COVID-19 was diagnosed in the RLD cohort. When comparing the three periods in the LT group, fewer patients limited their out-of-home activities during T2 (p < 0.0001). The frequency of these activities increased after the first lockdown, for the purchase of basic necessities (p < 0.0001), and professional activity continued (p = 0.008). We observed a significant increase in unscheduled medical consultations and in the prescription of anti-infective treatments during the end of the lockdown (p = 0.0002 and p = 0.005, respectively). Adherence to lockdown and to protective measures was high in both groups of patients., Conclusion: COVID-19 incidence remained low in both groups and there were significant lifestyle evolutions in LT patients and in those with RLD between first and second lockdown., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Transplant recipients display poor responses to SARS-CoV-2 mRNA vaccines. In this retrospective study, we investigate torque teno virus (TTV) viral load (VL), a ubiquitous virus reflecting global immune response levels, as a predictive factor of vaccine response in kidney transplant recipients (KTR). Four hundred and fifty-nine KTR having received two SARS-CoV-2 mRNA vaccine doses were enrolled, and 241 of them subsequently received a third vaccine dose. Antireceptor-binding domain (RBD) IgG response was assessed after each vaccine dose and TTV VL was measured in pre-vaccine samples. Prevaccine TTV VL > 6.2 log 10 copies (cp)/mL was independently associated with nonresponse to two doses (odds ratio (OR) = 6.17, 95% confidence interval (CI95) = 2.42-15.78) as well as to three doses (OR = 3.62, 95% CI95 = 1.55-8.49). In nonresponders to the second dose, high TTV VL in prevaccine samples or measured before the third dose were equally predictive of lower seroconversion rates and antibody titers. High TTV VL before and during SARS-CoV-2 vaccination schedules are predictive of poor vaccine response in KTR. This biomarker should be further evaluated regarding other vaccine responses., (© 2023 Wiley Periodicals LLC.)

Question Addressed by the Study: Do three coronavirus disease 2019 (COVID-19) vaccine doses induce a serological response in lung transplant recipients?, Methods: We retrospectively included 1071 adults (551 (52%) males) at nine transplant centres in France. Each had received three COVID-19 vaccine doses in 2021, after lung transplantation. An anti-spike protein IgG response, defined as a titre >264 BAU·mL -1 after the third dose (median (interquartile range (IQR)) 3.0 (1.7-4.1) months), was the primary outcome and adverse events were the secondary outcomes. Median (IQR) age at the first vaccine dose was 54 (40-63) years and median (IQR) time from transplantation to the first dose was 64 (30-110) months., Results: Median (IQR) follow-up after the first dose was 8.3 (6.7-9.3) months. A vaccine response developed in 173 (16%) patients. Factors independently associated with a response were younger age at vaccination, longer time from transplantation to vaccination and absence of corticosteroid or mycophenolate therapy. After vaccination, 51 (5%) patients (47 non-responders (47/898 (5%)) and four (4/173 (2%)) responders) experienced COVID-19, at a median (IQR) of 6.6 (5.1-7.3) months after the third dose. No responders had severe COVID-19 compared with 15 non-responders, including six who died of the disease., Conclusions: Few lung transplant recipients achieved a serological response to three COVID-19 vaccine doses, indicating a need for other protective measures. Older age and use of mycophenolate or corticosteroids were associated with absence of a response. The low incidence of COVID-19 might reflect vaccine protection via cellular immunity and/or good adherence to shielding measures., Competing Interests: Conflict of interest: None for any authors., (Copyright ©The authors 2023.)

The recent and sudden outbreak of monkeypox in numerous non-endemic countries requires expanding its surveillance immediately and understanding its origin and spread. As learned from the COVID-19 pandemic, appropriate detection techniques are crucial to achieving such a goal. Mass spectrometry has the advantages of a rapid response, low analytical interferences, better precision, and easier multiplexing to detect various pathogens and their variants. In this proteomic dataset, we report experimental data on the proteome of the monkeypox virus (MPXV) recorded by state-of-the-art shotgun proteomics, including data-dependent and data-independent acquisition for comprehensive coverage. We highlighted 152 viral proteins, corresponding to an overall proteome coverage of 79.5 %. Among the 1371 viral peptides detected, 35 peptides with the most intense signals in mass spectrometry were selected, representing a subset of 13 viral proteins. Their relevance as potential candidate markers for virus detection by targeted mass spectrometry is discussed. This report should assist the rapid development of mass spectrometry-based tests to detect a pathogen of increasing concern., (© 2022 Wiley-VCH GmbH.)

Background: Previous studies have reported that lung transplant recipients (LTR) develop a poor response to two doses of COVID-19 vaccine, but data regarding the third dose are lacking. We investigated the antibody response after three doses of mRNA vaccine in LTR and its predictive factors., Methods: A total of 136 LTR, including 10 LTR previously infected and 126 COVID-19-naive LTR, were followed during and after three doses of mRNA vaccine. We retrospectively measured anti-receptor-binding domain (RBD) IgG response and neutralizing antibodies. In a posthoc analysis, we used a multivariate logistic regression model to assess the association between vaccine response and patient characteristics, including viral DNA load (VL) of the ubiquitous Torque teno virus (TTV) (optimal cut-off set by ROC curve analysis), which reflects the overall immunosuppression., Results: After 3 doses, 47/126 (37.3%) COVID-19-naive LTR had positive anti-RBD IgG (responders) and 14/126 (11.1%) had antibody titers above 264 Binding Antibody Units/mL. None neutralized the omicron variant versus 7 of the 10 previously infected LTR. Nonresponse was associated with TTV VL ≥6.2 log 10 copies/mL before vaccination (Odds Ratio (OR) = 17.87, 95% confidence interval (CI95) = 3.02-105.72), mycophenolate treatment (OR = 4.73, CI95 = 1.46-15.34) and BNT162b2 (n = 34; vs mRNA-1273, n = 101) vaccine (OR = 6.72, CI95 = 1.75-25.92). In second dose non-responders, TTV VL ≥6.2 or <3.2 log 10 copies/mL before the third dose was associated with low (0/19) and high (9/10) rates of seroconversion., Conclusion: COVID-19-naive LTR respond poorly to three doses of mRNA vaccine, especially those with high TTV VL. Future studies could further evaluate this biomarker as a guide for vaccine strategies., Competing Interests: Declaration of Competing Interest None., (Copyright © 2022 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Background: Since December 2019, the SARS-CoV-2 pandemic significantly has impacted the medical community. When infected with SARS-CoV-2, most of the patients developed bilateral pneumonia. We have herein presented the atypical case of a patient who developed unilateral SARS-CoV-2 pneumonia, affecting only the second lung allograft re-transplanted (re-LTX)., Case Presentation: A SARS-CoV-2 infection occurred in a 2-dose vaccinated patient with LTx with a history of second unilateral lung transplantation performed after an end-stage bronchiolitis obliterans syndrome. The first symptoms started with a flu-like syndrome, and the patient's clinical condition worsened with nonsevere acute respiratory failure requiring conventional oxygen therapy. Treatment consisted in administrating specific anti-SARS-CoV-2 monoclonal antibodies along with probabilistic antibiotherapy, anticoagulation, and steroids. On day 7, the patient was discharged from hospital. We aimed to assess this atypical unilateral pneumonia based on different explorations. A ventilation scintigraphy showed a severe ventilation decrease owing to end-stage bronchiolitis obliterans syndrome within the left first allograft, which may be associated with asymmetrical virus diffusion between the 2 lungs. We did not identify any other relevant differences with respect to the 2 donors' clinical characteristics. Using specific immunohistochemistry staining against angiotensin converting enzyme-2 receptor, the main known receptor for SARS-CoV-2 binding on airway epithelial cells, no staining difference was observed between the 2 lung biopsies that were collected at re-LTx from each lung., Conclusions: With the present case report, we aimed to highlight how this kind of unusual presentation may be caused by the difference of ventilation between the 2 lungs., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Transplant recipients, who receive therapeutic immunosuppression to prevent graft rejection, are characterized by high coronavirus disease 2019 (COVID-19)-related mortality and defective response to vaccines. We observed that previous infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), but not the standard two-dose regimen of vaccination, provided protection against symptomatic COVID-19 in kidney transplant recipients. We therefore compared the cellular and humoral immune responses of these two groups of patients. Neutralizing anti-receptor-binding domain (RBD) immunoglobulin G (IgG) antibodies were identified as the primary correlate of protection for transplant recipients. Analysis of virus-specific B and T cell responses suggested that the generation of neutralizing anti-RBD IgG may have depended on cognate T-B cell interactions that took place in germinal center, potentially acting as a limiting checkpoint. High-dose mycophenolate mofetil, an immunosuppressive drug, was associated with fewer antigen-specific B and T follicular helper (T FH ) cells after vaccination; this was not observed in patients recently infected with SARS-CoV-2. Last, we observed that, in two independent prospective cohorts, administration of a third dose of SARS-CoV-2 mRNA vaccine restored neutralizing titers of anti-RBD IgG in about 40% of individuals who had not previously responded to two doses of vaccine. Together, these findings suggest that a third dose of SARS-CoV-2 mRNA vaccine improves the RBD-specific responses of transplant patients treated with immunosuppressive drugs.

Rationale/objectives: SARS-CoV-2 is the cause of worldwide COVID-19, which severity has been linked to the immune and inflammatory response. Here, we investigate Torquetenovirus (TTV) DNA load - a marker reflecting the intensity of the overall immune response - as well as SARS-CoV-2 RNAemia and IgM/IgG antibodies in COVID-19-positive patients., Methods: Two hundred and fifteen COVID-19-positive patients were enrolled, including 87 severe cases and 128 mild-moderate cases. SARS-CoV-2 RNAemia and IgM/IgG antibodies, as well as TTV DNA loads, were measured on longitudinal plasma samples., Results: The rate of severe cases was higher in patients with low TTV DNA load in plasma considering a threshold of 700 copies/mL. In severe patients, SARS-CoV-2 RNAemia positivity rates were higher than those in mild-moderate cases at any timepoint. When combined, TTV DNA load and SARS-CoV-2 RNAemia allowed to predict the outcome of COVID-19 infection, with a higher risk (HR=12.4) of ICU admission in patients with low TTV DNA load and positive SARS-CoV-2 RNAemia., Conclusions: TTV DNA load and SARS-CoV-2 RNAemia may be effective, non-invasive markers reflecting disease severity and poor outcome that could be conveniently measured in a clinical laboratory setting, as soon as COVID-19 diagnosis is made., (Copyright © 2022. Published by Elsevier B.V.)

Objectives: Strasbourg University Hospital faced an important COVID-19 first wave from early March 2020. We performed a longitudinal prospective cohort study to describe clinical and virological data, exposure history to COVID-19, and adherence to strict hygiene standards during the first pandemic wave in 1497 workers undergoing a SARS-CoV-2 serological test at our hospital, with a follow up of serology result three months later., Patients and Methods: A total of 1497 patients were enrolled from April 6 to May 7, 2020. Antibody response to SARS-CoV-2 was measured, and COVID-19 exposure routes were analyzed according to SARS-CoV-2 serological status., Results: A total of 515 patients (34.4%) were seropositive, mainly medical students (13.2%) and assistant nurses (12.0%). A history of COVID-19 exposure in a professional and/or private setting was mentioned by 83.1% of seropositive subjects (P<0.05; odds ratio [OR]: 2.5; 95% confidence interval [CI]: 1.8-3.4). COVID-19 exposure factors associated with seropositive status were non-professional exposure (OR: 1.9, 95% CI: 1.3-2.7), especially outside the immediate family circle (OR: 2.2, 95% CI: 1.2-3.9) and contact with a COVID-19 patient (OR: 1.6; 95% CI: 1.1-2.2). Among professionally exposed workers, systematic adherence to strict hygiene standards was well observed, except for the use of a surgical mask (P<0.05, OR: 1.9, 95% CI: 1.3-2.8). Of those who reported occasionally or never wearing a surgical mask, nurses (25.7%), assistant nurses (16.2%), and medical students (11.7%) were predominant., Conclusion: Infection of staff members during the first pandemic wave in our hospital occurred after both professional and private COVID-19 exposure, underlining the importance of continuous training in strict hygiene standards., (Copyright © 2021 Elsevier Masson SAS. All rights reserved.)

Here, we report the molecular engineering of nanobodies that bind with picomolar affinity to both SARS-CoV-1 and SARS-CoV-2 receptor-binding domains (RBD) and are highly neutralizing. We applied deep mutational engineering to VHH72, a nanobody initially specific for SARS-CoV-1 RBD with little cross-reactivity to SARS-CoV-2 antigen. We first identified all the individual VHH substitutions that increase binding to SARS-CoV-2 RBD and then screened highly focused combinatorial libraries to isolate engineered nanobodies with improved properties. The corresponding VHH-Fc molecules show high affinities for SARS-CoV-2 antigens from various emerging variants and SARS-CoV-1, block the interaction between ACE2 and RBD, and neutralize the virus with high efficiency. Its rare specificity across sarbecovirus relies on its peculiar epitope outside the immunodominant regions. The engineered nanobodies share a common motif of three amino acids, which contribute to the broad specificity of recognition. Our results show that deep mutational engineering is a very powerful method, especially to rapidly adapt existing antibodies to new variants of pathogens.

Competing Interests: There was no funding for this study. LA declares consulting fees from AstraZeneca, Janssen, and BMS, unrelated to the current work. All other authors declare no competing interests. RF and FG contributed equally and have directly accessed and verified the underlying data. All authors contributed to the concept, design and drafting of the study and have approved the final version.

COVID-19 is the most disturbing pandemic of the past hundred years. Its causative agent, the SARS-CoV-2 virus, has been the subject of an unprecedented investigation to characterize its molecular structure and intimate functioning. While markers for its detection have been proposed and several diagnostic methodologies developed, its propensity to evolve and evade diagnostic tools and the immune response is of great concern. The recent spread of new variants with increased infectivity requires even more attention. Here, we document how shotgun proteomics can be useful for rapidly monitoring the evolution of the SARS-CoV-2 virus. We evaluated the heterogeneity of purified SARS-CoV-2 virus obtained after culturing in the Vero E6 cell line. We found that cell culture induces significant changes that are translated at the protein level, such changes being detectable by tandem mass spectrometry. Production of viral particles requires careful quality control which can be easily performed by shotgun proteomics. Although considered relatively stable so far, the SARS-CoV-2 genome turns out to be prone to frequent variations. Therefore, the sequencing of SARS-CoV-2 variants from patients reporting only the consensus genome after its amplification would deserve more attention and could benefit from more in-depth analysis of low level but crystal-clear signals, as well as complementary and rapid analysis by shotgun proteomics., (© 2021. The Author(s).)

We measured anti-spike (S), nucleoprotein (N), and neutralizing antibodies in sera from 308 healthcare workers with a positive reverse-transcription quantitative polymerase chain reaction result for severe acute respiratory syndrome coronavirus 2 and with mild disease, collected at 2 timepoints up to 6 months after symptom onset. At month 1, anti-S and -N antibody levels were higher in male participants aged >50 years and participants with a body mass index (BMI) >25 kg/m2. At months 3-6, anti-S and anti-N antibodies were detected in 99% and 59% of individuals, respectively. Anti-S antibodies and neutralizing antibodies declined faster in men than in women, independent of age and BMI, suggesting an association of sex with evolution of the humoral response., (© The Author(s) 2021. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Introduction: COVID-19 long-haulers, also decribed as having "long-COVID" or post-acute COVID-19 syndrome, represent 10% of COVID-19 patients and remain understudied., Methods: In this prospective study, we recruited 30 consecutive patients seeking medical help for persistent symptoms (> 30 days) attributed to COVID-19. All reported a viral illness compatible with COVID-19. The patients underwent a multi-modal evaluation, including clinical, psychologic, virologic and specific immunologic assays and were followed longitudinally. A group of 17 convalescent COVID-19 individuals without persistent symptoms were included as a comparison group., Results: The median age was 40 [interquartile range: 35-54] years and 18 (60%) were female. At a median time of 152 [102-164] days after symptom onset, fever, cough and dyspnea were less frequently reported compared with the initial presentation, but paresthesia and burning pain emerged in 18 (60%) and 13 (43%) patients, respectively. The clinical examination was unremarkable in all patients, although the median fatigue and pain visual analog scales were 7 [5-8] and 5 [2-6], respectively. Extensive biologic studies were unremarkable, and multiplex cytokines and ultra-sensitive interferon-α2 measurements were similar between long-haulers and convalescent COVID-19 individuals without persistent symptoms. Using SARS-CoV-2 serology and IFN-γ ELISPOT, we found evidence of a previous SARS-CoV-2 infection in 50% (15/30) of patients, with evidence of a lack of immune response, or a waning immune response, in two patients. Finally, psychiatric evaluation showed that 11 (36.7%), 13 (43.3%) and 9 (30%) patients had a positive screening for anxiety, depression and post-traumatic stress disorder, respectively., Conclusions: Half of patients seeking medical help for post-acute COVID-19 syndrome lack SARS-CoV-2 immunity. The presence of SARS-CoV-2 immunity, or not, had no consequence on the clinical or biologic characteristics of post-acute COVID-19 syndrome patients, all of whom reported severe fatigue, altered quality of life and psychologic distress., (© 2021. The Author(s).)

Background: Assessment of the kinetics of SARS-CoV-2 antibodies is essential in predicting risk of reinfection and durability of vaccine protection., Methods: This is a prospective, monocentric, longitudinal, cohort clinical study. Healthcare workers (HCW) from Strasbourg University Hospital were enrolled between April 6th and May 7th, 2020 and followed up to 422 days. Serial serum samples were tested for antibodies against the Receptor Binding Domain (RBD) of the spike protein and nucleocapsid protein (N) to characterize the kinetics of SARS-CoV-2 antibodies and the incidence of reinfection. Live-neutralization assays were performed for a subset of samples before and after vaccination to analyze sensitivity to SARS-CoV-2 variants., Findings: A total of 4290 samples from 393 convalescent COVID-19 and 916 COVID-19 negative individuals were analyzed. In convalescent individuals, SARS-CoV-2 antibodies followed a triphasic kinetic model with half-lives at month (M) 11-13 of 283 days (95% CI 231-349) for anti-N and 725 days (95% CI 623-921) for anti-RBD IgG, which stabilized at a median of 1.54 log BAU/mL (95% CI 1.42-1.67). The incidence of SARS-CoV-2 infections was 12.22 and 0.40 per 100 person-years in COVID-19-negative and COVID-19-positive HCW, respectively, indicating a relative reduction in the incidence of SARS-CoV-2 reinfection of 96.7%. Live-virus neutralization assay revealed that after one year, variants D614G and B.1.1.7, but less so B.1.351, were sensitive to anti-RBD antibodies at 1.4 log BAU/mL, while IgG ≥ 2.0 log BAU/mL strongly neutralized all three variants. These latter anti-RBD IgG titers were reached by all vaccinated HCW regardless of pre-vaccination IgG levels and type of vaccine., Interpretation: Our study demonstrates a long-term persistence of anti-RBD antibodies that may reduce risk of reinfection. By significantly increasing cross-neutralizing antibody titers, a single-dose vaccination strengthens protection against variants. FUN1DING: None., Competing Interests: Declaration of Competing Interest The authors have declared no potential conflicts of interest., (Copyright © 2021 The Author(s). Published by Elsevier B.V. All rights reserved.)

The SARS-CoV-2 B.1.617 lineage was identified in October 2020 in India 1-5 . Since then, it has become dominant in some regions of India and in the UK, and has spread to many other countries 6 . The lineage includes three main subtypes (B1.617.1, B.1.617.2 and B.1.617.3), which contain diverse mutations in the N-terminal domain (NTD) and the receptor-binding domain (RBD) of the SARS-CoV-2 spike protein that may increase the immune evasion potential of these variants. B.1.617.2-also termed the Delta variant-is believed to spread faster than other variants. Here we isolated an infectious strain of the Delta variant from an individual with COVID-19 who had returned to France from India. We examined the sensitivity of this strain to monoclonal antibodies and to antibodies present in sera from individuals who had recovered from COVID-19 (hereafter referred to as convalescent individuals) or who had received a COVID-19 vaccine, and then compared this strain with other strains of SARS-CoV-2. The Delta variant was resistant to neutralization by some anti-NTD and anti-RBD monoclonal antibodies, including bamlanivimab, and these antibodies showed impaired binding to the spike protein. Sera collected from convalescent individuals up to 12 months after the onset of symptoms were fourfold less potent against the Delta variant relative to the Alpha variant (B.1.1.7). Sera from individuals who had received one dose of the Pfizer or the AstraZeneca vaccine had a barely discernible inhibitory effect on the Delta variant. Administration of two doses of the vaccine generated a neutralizing response in 95% of individuals, with titres three- to fivefold lower against the Delta variant than against the Alpha variant. Thus, the spread of the Delta variant is associated with an escape from antibodies that target non-RBD and RBD epitopes of the spike protein., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)

Ibrutinib is indicated for the treatment of chronic lymphocytic leukemia (CLL). Absolute lymphocyte count (ALC) is a clinical criterion used for the monitoring of CLL. Ibrutinib has several effects on lymphocytes, and has highly variable pharmacokinetics (PK). The objective of this work was to build a PK-pharmacodynamic (PD) model describing ALC dynamics under ibrutinib treatment in patients with CLL. ALC observations before and after ibrutinib treatment initiation in patients with CLL were included in the analysis. A population PK-PD model was developed based on physio-pharmacological knowledge. Individual PK concentrations at each hospital visit were included in the model. The association between PD parameters and lymphocytosis, and between PD parameters and response to treatment were assessed. A total of 94 patients, 658 ALC and 1,501 PK observations were included in model development. The final PK-PD model accurately described ALC dynamics for different patient profiles. It consisted in two compartments (tissues and blood circulation) with ibrutinib plasmatic concentration inducing two drug effects: stimulation of lymphocyte redistribution and death. Patients with hyperlymphocytosis had significantly higher tissues to circulation baseline lymphocyte count ratio, and lower death effect. Patients who progressed under ibrutinib had significantly lower baseline lymphocyte counts in tissues (2-fold lower) and blood (3-fold lower). The first PK-PD model for ALC in patients with CLL under ibrutinib treatment was developed. This model suggests that estimated lymphocyte counts in tissues and blood could be used as an early predictor of response in patients with CLL., (© 2021 The Authors Clinical Pharmacology & Therapeutics © 2021 American Society for Clinical Pharmacology and Therapeutics.)

Background: High-dose methotrexate is used for treating several types of cancer. However, it is associated with a high risk of acute kidney injury (AKI), especially in patients with high MTX concentrations. Although therapeutic drug monitoring is performed to monitor MTX concentrations, it is unclear what concentration should be considered critical, thus requiring rescue protocols to prevent nephrotoxicity., Methods: Patients treated with high-dose methotrexate for lymphoma or acute lymphoblastic leukemia and those benefited from therapeutic drug monitoring were included. The relationship between MTX concentrations and the presence or absence of AKI was assessed. MTX concentrations were analyzed using a population pharmacokinetic approach. Specific attention was given to morphological covariates because MTX doses are individualized according to body surface area (BSA)., Results: In total, 328 patients and 657 cycles of treatment were analyzed. Higher MTX concentrations were observed in the AKI+ group. For cycle 1, all patients showing an MTX concentration >6 µM at 36 hours or >2 µM at 48 hours after infusion developed nephrotoxicity. The final pharmacokinetic model had 2 compartments and included the effect of age on clearance (CL) and of body weight on peripheral distribution volume. None of the morphological covariates tested on CL led to significant improvement in the model. Higher MTX concentrations were observed in patients with extreme BSA values (≥2 m2) or body mass index (≥25 kg/m2). Patients with AKI who received at least 1 cycle had higher BSA and BMI., Conclusions: The results from this study provide additional information on the relationship between MTX concentration and nephrotoxicity. Patients with a plasma MTX concentration >6 µM at 36 hours were more likely to manifest AKI. In addition, the results suggest that overweight patients have a high AKI risk and that BSA-based adjustment of MTX dose is not appropriate., Competing Interests: The authors declare no conflict of interest., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Therapeutic drug monitoring of ibrutinib is based on the area under the curve of concentration vs. time (AUC IBRU ) instead of trough concentration (C min,ss ) because of a limited accumulation in plasma. Our objective was to identify a limited sampling strategy (LSS) to estimate AUC IBRU associated with Bayesian estimation. The actual AUC IBRU of 85 patients was determined by the Bayesian analysis of the full pharmacokinetic profile of ibrutinib concentrations (pre-dose T0 and 0.5, 1, 2, 4 and 6 h post-dose) and experimental AUC IBRU were derived considering combinations of one to four sampling times. The T0-1-2-4 design was the most accurate LSS (root-mean-square error RMSE = 11.0%), and three-point strategies removing the 1 h or 2 h points (RMSE = 22.7% and 14.5%, respectively) also showed good accuracy. The correlation between the actual AUC IBRU and C min,ss was poor ( r 2 = 0.25). The joint analysis of dihydrodiol-ibrutinib metabolite concentrations did not improve the predictive performance of AUC IBRU . These results were confirmed in a prospective validation cohort ( n = 27 patients). At least three samples, within the pre-dose and 4 h post-dose period, are necessary to estimate ibrutinib exposure accurately.

Alternative methods to RT-PCR for SARS-CoV-2 detection are investigated to provide complementary data on viral proteins, increase the number of tests performed, or identify false positive/negative results. Here, we have developed a simple mass spectrometry assay for SARS-CoV-2 in nasopharyngeal swab samples using common laboratory reagents. The method employs high sensitivity and selectivity targeted mass spectrometry detection, monitoring nine constitutive peptides representative of the three main viral proteins and a straightforward pellet digestion protocol for convenient routine applications. Absolute quantification of N, M, and S proteins was achieved by addition of isotope-labeled versions of best peptides. Limit of detection, recovery, precision, and linearity were thoroughly evaluated in four representative viral transport media (VTM) containing distinct total protein content. The protocol was sensitive in all swab media with limit of detection determined at 2 × 10 3 pfu/mL, corresponding to as low as 30 pfu injected into the LC-MS/MS system. When tested on VTM-stored nasopharyngeal swab samples from positive and control patients, sensitivity was similar to or better than rapid immunoassay dipsticks, revealing a corresponding RT-PCR detection threshold at Ct ∼ 24. The study represents the first thorough evaluation of sensitivity and robustness of targeted mass spectrometry in nasal swabs, constituting a promising SARS-CoV-2 antigen assay for the first-line diagnosis of COVID-19 and compatible with the constraints of clinical settings. The raw files generated in this study can be found on PASSEL (Peptide Atlas) under data set identifier PASS01646.

We investigated severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-specific antibodies and T-cell responses against SARS-CoV-2 and human coronavirus (HCoV) 229E and OC43 in 11 SARS-CoV-2 serodiscordant couples in Strausbourg, France, in which 1 partner had evidence of mild coronavirus disease (COVID-19) and in 10 unexposed healthy controls. Patients with confirmed COVID-19 were considered index patients and their partners close contacts. All index patients displayed positive SARS-CoV-2-specific antibody and T-cell responses that lasted up to 102 days after symptom onset. All contacts remained seronegative for SARS-CoV-2; however, 6 reported COVID-19 symptoms within a median of 7 days after their partners, and 4 of those showed a positive SARS-CoV-2-specific T-cell response against 3 or 4 SARS-CoV-2 antigens that lasted up to 93 days after symptom onset. The 11 couples and controls displayed positive T-cell responses against HCoV-229E or HCoV-OC43. These data suggest that exposure to SARS-CoV-2 can induce virus-specific T-cell responses without seroconversion.

BK virus (BKV) replication occurs frequently in kidney transplant recipients (KTR), potentially leading to BKV-associated nephropathy (BKVAN) and graft loss. Patients with high titers of BKV-neutralizing antibodies (NAbs) are protected against BKV replication, and intravenous immunoglobulin (IVIg) infusion can increase NAb titers. We investigated whether early IVIg administration prevents BKV replication in patients with low NAb titers (<4 log 10 against the BKV-specific genotype). Based on NAb titers on the day of transplantation, KTR followed in the Strasbourg University Hospital (n = 174) were retrospectively divided into the following 3 risk categories for BKV replication: (1) patients with low NAb titers ("high-risk") who received IVIg for the first 3 posttransplant months (n = 44), (2) patients with low NAb titers ("high-risk") who did not undergo IVIg treatment (n = 41), and (3) patients with high NAb titers ("low-risk") who did not receive IVIg (n = 89). At 12 posttransplant months, the incidence of BKV viremia in the high-risk group treated with IVIg (6.8%) was similar to that observed in the low-risk group (10.1%) and markedly lower than that of the untreated high-risk group (36.6%; P < .001). Similar results were observed with regard to BKVAN. We conclude that IVIg may be a valuable strategy for preventing BKV replication., (© 2020 The American Society of Transplantation and the American Society of Transplant Surgeons.)