INTRODUCTION:HIV reservoir is the main barrier to HIV cure but its size dynamics on antiretroviral therapy (ART) in various clinical settings is poorly characterized. METHODS:Responders to a dolutegravir-based regimen (DBR) enrolled in the DRONE study were analyzed for longitudinal total HIV DNA and immune activation biomarkers (sCD14, sCD163, IL-6, IP-10). RESULTS:Overall, 169 participants were allocated to various groups: ART-naive acute infections (AI, n = 20) or chronic infections (CI, n = 21), and ART-treated individuals in virological success (VS, n = 116) or failure (VF, n = 12). HIV DNA significantly decreased at W48 of successful DBR in the AI (median: -1.3log10copies/million PBMCs), CI (-0.6), and VF (-0.5) groups, but not in the VS group. Activation biomarkers decreased on DBR only for individuals with ongoing HIV replication at baseline. CONCLUSION:Successful DBR was associated with rapid HIV DNA decline in ART-naive and ART-failing individuals but not in the context of ART switch.

Post-transplant lymphoproliferative disorders (PTLD) represent a heterogeneous group of complications with rising complexity, particularly as EBV-negative forms are increasingly recognized in adult recipients. While early EBV-driven PTLD was historically monitored by viral load, this approach fails to detect EBV-negative disease and lacks specificity even in EBV-positive cases. Recent advances in tumor immunology, virology, and liquid biopsy technologies have led to the emergence of novel biomarkers that offer improved diagnostic precision. These include plasma soluble ZEBRA antigen, reflecting lytic EBV activation; EBV DNA methylation status, which may distinguish latent from benign viral replication; and LMP1 sequence variants that influence immune evasion through the NKG2A/HLA-E axis. For EBV-negative PTLD, circulating tumor DNA profiling has shown promise for early, non-invasive detection. These innovations are complemented by preventive strategies such as anti-CD20 therapy in high-risk EBV-seronegative transplant recipients and ongoing trials of EBV-targeted vaccines. However, such approaches remain limited to EBV-naïve patients. Moving forward, integrating viral, immune, and tumor-derived markers—alongside host genetic factors—may enable more personalized surveillance and preemptive interventions. This review outlines the evolving paradigm of PTLD monitoring and highlights key areas where viro-immunologic precision medicine may reshape clinical practice.

In medicine, virological diagnosis is mainly based on the detection of the viral genome and antigens, or on the identification of specific antibodies produced in response to infection. These strategies are suitable for characterizing an active infection or past contact with an already known virus. The recent development of tests for evaluating the host's cellular immune response opens new perspectives for personalized patient care based on immunomonitoring. The IGRA tests (Interferon Gamma Release Assay), measuring interferon gamma produced by T lymphocytes stimulated in vitro by antigenic peptides specific to infectious agents and the quantification of the blood viral load of Torque teno virus (TTV) thus constitute tools for assessing infectious risk, particularly usable to predict opportunistic viral reactivations in immunocompromised patients. The characterization of the expression profile of interferon stimulated genes (IGS) in a respiratory sample is also likely to provide significant assistance in diagnosis, discriminating a viral infection from a bacterial infection, an acute infection from a persistence of nucleic acids from non-replicating microorganisms or allowing, in case of viral emergence, to quickly identify infected subjects in the absence of specific PCR tests available. All of these new approaches, described in this review, have the potential to considerably improve patient care with the objective to correctly prescribe medical virology tests and anti-infective treatments.

BACKGROUND:As new SARS-CoV-2 variants emerge and as treatment of COVID-19 ARDS remains exclusively supportive, there is an unmet need to better characterize its different phenotypes to tailor personalized treatments. Clinical, biological, spirometric and CT data hardly allow deciphering of Heavy (H), Intermediate (I) and Light (L) phenotypes of COVID-19 ARDS and the implementation of tailored specific strategies (prone positioning, PEEP settings, recruitment maneuvers). We hypothesized that the ratio of two pivotal COVID-19 biomarkers (interleukin 6 [IL-6] and Krebs von den Lungen 6 [KL-6], related to inflammation and pneumocyte repair, respectively) would provide a biologic insight into the disease timeline allowing 1) to differentiate H, I and L phenotypes, 2) to predict outcome and 3) to reflect some of CT findings. METHODS AND FINDINGS:This was a retrospective analysis of prospectively acquired data (COVID HUS cohort). Inclusion concerned any patient with severe COVID-19 pneumonia admitted to two intensive care units between March 1st and May 1st, 2020, in a high-density cluster of the first epidemic wave (Strasbourg University Hospital, France). Demographic, clinical, biological (standard, IL-6 [new generation ELISA], KL-6 [CLEIA technique]), spirometric (driving pressure, respiratory system compliance) and CT data were collected longitudinally. CT analysis included semi-automatic and automatic lung measurements and allowed segmentation of lung volumes into 4 (poorly aerated, non-aerated, overinflated and normally aerated) and 3 (ground-glass, restricted normally aerated, and overinflated) zones, respectively. The primary outcome was to challenge the IL-6/KL-6 ratio capacity to decipher the three COVID-19 ARDS phenotypes (H, I and L) defined on clinical, spirometric and radiologic grounds. Secondary outcomes were the analysis of the prognostic value of the IL-6/KL-6 ratio and its correlates with CT-acquired data. Multivariate analysis was based on principal component analysis. One hundred and forty-eight ventilated COVID-19 ICU patients from the COVID HUS cohort were assessed for eligibility and 77 were included in the full analysis. Most were male, all were under invasive mechanical ventilation and vasopressor therapy and displayed high severity scores (SAPSII: 48 [42-56]; SOFA: 8 [7-10]). The L, I and H COVID ARDS phenotypes were identified in 11, 15 and 48 patients, respectively. In three patients, the phenotype could not be defined precisely. Thirty patients (39%) died in the ICU and the number of ventilator-free days was 2 [0-2] days. The IL-6/KL-6 ratio was not significantly different between the L, I and H phenotypes and evolved according to similar patterns over time. Surviving and deceased patients displayed an inverse kinetic of KL-6. IL-6 and the IL-6/KL-6 ratio were linearly associated with ground-glass volume on semi-automatic and automatic CT lung measurements. CONCLUSIONS:In our population of severe ventilated COVID ARDS patients, the IL-6/KL-6 ratio was not clue to differentiate the H, I and L phenotypes and tailor a personalized ventilatory approach. There was an interesting correlation between IL-6/KL-6 ratio and ground-glass volume as determined by automated lung CT analysis. Such correlation deserves more in-depth pathophysiological study, at best gathered from a prospective cohort with a larger sample size and histological analysis. TRIAL REGISTRATION:COVID HUS Trial registration number: NCT04405726.

The MTOR inhibitors have demonstrated antiviral properties, and prior non-randomized studies have suggested they may have a suppressive effect on BKPyV replication. Here, in this randomized, multicenter, controlled trial (BKEVER study), we sought to evaluate the impact of everolimus (EVR) in facilitating the clearance of BKPyV compared to simply reducing immunosuppression among kidney transplant recipients (KTRs). All together, 130 KTRs presenting with BKPyV DNAemia were randomized 1:1 into two groups. The EVR group, in which mycophenolate mofetil (MMF) was replaced by EVR along with a decrease in calcineurin inhibitor trough levels and secondly the MMF group, in which the MMF dose was decreased by half along with a similar lowering of calcineurin inhibitor levels. The primary endpoint was the proportion of patients achieving viral clearance at six months. Secondary endpoints included the kinetics of BKPyV replication over time, the incidence of BKPyV-associated nephropathy, kidney graft function, the incidence of kidney graft rejection, and medication tolerability over two years. Significantly, BKPyV clearance was achieved in 55.7% of patients in the EVR group compared to 81.3% of patients in the MMF group at six months. The reduction in BKPyV DNA load was significantly more rapid in the MMF group. Calcineurin inhibitor trough levels were within expected target ranges and did not differ meaningfully between the two groups from randomization through month six. Two grafts were lost, and four patients died. Eleven patients in the EVR group and six patients in the MMF group developed biopsy-proven BKPyV nephropathy. Thus, in KTRs with BKPyV DNAemia, replacing MMF with EVR along with lowering calcineurin inhibitor levels did not lead to more frequent or faster clearance of BKPyV.

Neutralizing antibodies (NAbs) have been proposed as biomarkers for stratifying BK polyomavirus (BKPyV) replication risk, while torque teno virus (TTV) viral load is recognized as a global immunomarker in kidney transplantation. This study investigates their combined utility to improve BKPyV DNAemia risk assessment in 187 patients within 12 months posttransplant. BKPyV DNAemia occurred in 19% of recipients. Donor seronegativity was protective, whereas in case of seropositive donor, replication risk varied according to recipient NAb titers. Indeed, patients with low NAbs faced a high risk of BKPyV DNAemia regardless of TTV load, whereas in those with high NAbs, replication was influenced by TTV load at 1 month posttransplant. These findings provide a deeper understanding of BKPyV infection in kidney transplant recipients. In patients with low humoral immunity, the risk of early replication is high, whereas in those with adequate humoral immunity, replication appears to be primarily driven by the overall burden of immunosuppression. Donor status and cold ischemia time were also associated with BKPyV DNAemia, suggesting an influence of transplant characteristics and related injury. Our findings support a multifactorial BKPyV risk assessment integrating immune markers to enable personalized prevention and potentially reduce BKPyV risk.

BackgroundHepatitis Delta virus (HDV) infection is a major cause of liver-related morbidity and mortality in patients infected with HBV, with a global HDV prevalence uncertain. In France, 2 to 5 % of HBs antigen (HBsAg) carriers present anti-HDV antibodies (anti-HDV). The EASL recommends testing for anti-HDV in all HBsAg-positive patients. Since January 2022, we have systematically carried out anti-HDV serology when a positive HBsAg is discovered (new HBsAg carriers).ObjectivesWe evaluated the benefit of anti-HDV reflex testing after one year of practice by comparing anti-HDV and HBsAg serology data over the last six years, among the new HBsAg carriers and all the HBsAg carriers.Study designHBsAg and anti-HDV were screened using the Abbott Architect HBsAg quanti kit and the DIA.PRO HDVAb kit. Serological, demographic, virological, and clinical data were analyzed.ResultsImplementing anti-HDV reflex testing leads to more than a 2-fold increase in diagnoses of HDV infection among all HBsAg carriers. If the anti-HDV positive rate remains stable among the new HBsAg carriers, a significant increase in the anti-HDV positive rate from 6.8 % to 10.3 % was observed considering all HBsAg carriers. Interestingly, the discovery of anti-HDV carriage increased from 3.9 % to 6.5 % in 2022, allowing earlier identification of HBV-HDV-infected patients and a fast referral to hepatologists for adequate clinical management and, in some cases, the introduction of bulevirtide-based therapy.ConclusionsOur preliminary results at one year seem promising and evaluating the cost-effectiveness of reflex tests in real life with feedback would be helpful.

Background: Vector-borne diseases such as malaria and arboviruses are common etiologies of post-travel fever. Methods: After excluding malaria, we retrospectively analyzed the diagnosis of dengue virus (DENV), chikungunya virus (CHIKV), and zika virus (ZIKV) infections following recent travel by patients treated at the Strasbourg University Hospital between 2014 and 2023. Available serums (n = 35) sampled in 2023 were retrospectively tested for DENV, CHIKV, and ZIKV infections. Results: Our results showed that 78% of the 915 malaria-negative patients without changes over the course of ten years had not undergone arbovirus infection testing. Retrospective testing revealed missing arbovirus infections: two DENV infections and one CHIKV infection, representing 8.6% (3/35) of patients for whom no mandatory declaration or vector control could be undertaken. Conclusion: Our results highlight the need for early case detection, particularly in the context of the upcoming 2024 Olympic Games.

Background: Throughout HIV infection, productively infected cells generate billions of viral particles and are thus responsible for body-wide HIV dissemination, but their phenotype during AIDS is unknown. As AIDS is associated with immunological changes, analyzing the phenotype of productively infected cells can help understand HIV production during this terminal stage. Methods: Blood samples from 15 untreated viremic participants (recent infection, n=5; long-term infection, n=5; active opportunistic AIDS-defining disease, n=5) and 5 participants virologically controlled on antiretroviral therapy (ART) enrolled in the Analysis of the Persistence, Reservoir and HIV Latency (APRIL) study (NCT05752318) were analyzed. Cells expressing the capsid protein p24 (p24+ cells) after 18 hours of resting or 24 hours of stimulation (HIV-Flow) revealed productively infected cells from viremic participants or translation-competent reservoir cells from treated participants, respectively. Results: The frequency of productively infected cells tended to be higher during AIDS in comparison with recent and long-term infections (median, 340, 72, and 32/million CD4+ T cells, respectively) and correlated with the plasma viral load at all stages of infection. Altogether, these cells were more frequently CD4low, HLA-ABClow, CD45RA-, Ki67+, PD-1+, with a non-negligible contribution from pTfh (CXCR5+PD-1+) cells, and were not significantly enriched in HIV coreceptors CCR5 nor CXCR4 expression. The comparison markers expression between stages showed that productively infected cells during AIDS were enriched in memory and exhausted cells. In contrast, the frequencies of infected pTfh were lower during AIDS compared to non-AIDS stages. A UMAP analysis revealed that total CD4+ T cells were grouped in 7 clusters and that productive p24+ cells were skewed to given clusters throughout the course of infection. Overall, the preferential targets of HIV during the latest stages seemed to be more frequently highly differentiated (memory, TTD-like) and exhausted cells and less frequently pTfh-like cells. In contrast, translation-competent reservoir cells were less frequent (5/million CD4+ T cells) and expressed more frequently HLA-ABC and less frequently PD-1. Conclusions: In long-term infection and AIDS, productively infected cells were differentiated and exhausted. This could indicate that cells with these given features are responsible for HIV production and dissemination in an immune dysfunction environment occurring during the last stages of infection.

Dolutegravir/lamivudine (DTG/3TC) has a high genetic barrier against the development of human immunodeficiency virus drug resistance. We report 2 cases of R263K + M184V mutations during DTG/3TC failure followed by viral suppression after adherence intervention without treatment change that we attribute to residual drug activity, reduced viral fitness, and robust immune competence.

Tick-borne encephalitis (TBE) is a vector-borne disease caused by the TBE virus (TBEV). Although TBEV infection in children seems to lead to a milder clinical presentation, data in pediatrics are scarce. We aimed to determine the incidence of TBE among pediatric patients presenting with neurological symptoms from January 2020 to December 2022 at the University Hospital of Strasbourg (HUS), France. 462 Patients for whom cerebrospinal fluid (CSF) samples were available were included and categorized by age group: 0–4 years, 5–9 years, and 10–15 years. Serological tests and RT-PCR were carried out on the CSF samples, and the positive results were confirmed by seroneutralization test (SNT). A CSF IL-6 assay was performed for confirmed cases. We retrospectively detected four TBE-confirmed cases. We found an incidence of 1.51 cases per 100,000 inhabitants in the pediatric population over 2020–2022. The four cases were girls, with a median age of 10.4 years. The symptoms appeared in two cases in October 2022, outside the seasonal peak. Signs of encephalitis were present in two patients, and persistent sequelae were reported in three patients and two more than a year after hospitalization. None of the confirmed cases were vaccinated against TBEV despite frequent exposure to ticks. Intrathecal concentrations of IL-6 were increased for two patients; for one patient, the concentration was significantly higher than the values found in control cases. Our data highlight the need for early diagnosis and long-term follow-up of affected children and raise questions about the evolution of vaccination recommendations.

We read with considerable interest the paper by Sato et al,1 titled "Preemptive intravenous human immunoglobulin G suppresses BK polyomavirus replication and spread of infection in vitro." This study demonstrates, through an in vitro model, that BK polyomavirus (BKPyV) infection can be effectively curtailed by intravenous immunoglobulin (IVIG) treatment, provided it is administered within a 3-hour window postinfection. However, the effectiveness of IVIG wanes when given beyond this time frame because it only partially inhibits viral spread by neutralizing the released virus without preventing BKPyV replication.

Kidney transplant recipients (KTRs) are highly vulnerable to COVID-19. An intensified scheme of vaccination offers short-term protection to the 50%-75% of KTRs able to develop a germinal center reaction, required for the generation of neutralizing titers of antibodies (NAbs). However, the duration of this vaccinal protection is unknown. In-depth longitudinal analysis of the immune response to vaccination of 33 KTRs demonstrates that the low peak of IgGs, the progressive decline in antibody titers, and the emergence of a variant of concerns (VOC) of SARS-CoV2, synergize to let 2/3 of responders to vaccine without NAbs after only a few months. Yet, a retrospective study of an independent cohort of 274 KTRs, revealed that the risk of severe COVID-19 in the latter was low, similar to that of patients with serum neutralizing capacity against VOC. Our work links this late vaccine protection with the presence of memory B cells, which are generated during the initial vaccine-induced germinal center reaction, have a wide repertoire directed against conserved spike epitopes, and rapidly differentiate into IgG-producing plasma cells upon antigenic rechallenge. We conclude that in contrast with a serological layer that goes fading rapidly, the cellular layer of humoral memory provides an efficient long-term protection against VOC to KTRs. This illustration of the complementary roles of the two layers of the humoral memory has implications in immunopathology beyond the COVID-19 in KTRs.

Tick-borne encephalitis (TBE) virus (TBEV) is transmitted to humans via tick bites. Infection is benign in >90% of the cases but can cause mild (<5%), moderate (<4%), or severe (<1%) encephalitis. We show here that ∼10% of patients hospitalized for severe TBE in cohorts from Austria, Czech Republic, and France carry auto-Abs neutralizing IFN-α2, -β, and/or -ω at the onset of disease, contrasting with only ∼1% of patients with moderate and mild TBE. These auto-Abs were found in two of eight patients who died and none of 13 with silent infection. The odds ratios (OR) for severe TBE in individuals with these auto-Abs relative to those without them in the general population were 4.9 (95% CI: 1.5-15.9, P < 0.0001) for the neutralization of only 100 pg/ml IFN-α2 and/or -ω, and 20.8 (95% CI: 4.5-97.4, P < 0.0001) for the neutralization of 10 ng/ml IFN-α2 and -ω. Auto-Abs neutralizing type I IFNs accounted for ∼10% of severe TBE cases in these three European cohorts.

Response to: Yi Zhang et al. Intra-host SARS-CoV-2 single-nucleotide variants emerged during the early stage of COVID-19 pandemic forecast population fixing mutations, J Infect 2022;84:722–746. We read with interest the article by Zhang et al.1Zhang Y. Jiang N. Qi W. Li T. Zhang Y. Zhang H. et al.Intra-host SARS-CoV-2 single-nucleotide variants emerged during the early stage of COVID-19 pandemic forecast population fixing mutations.J Infect. 2022; 84 (May): 722-746Abstract Full Text Full Text PDF Scopus (3) Google Scholar who reported the emergence of numerous SARS-CoV-2 variants during the early stages of the COVID-19 pandemic. The authors forecast these variants’ potential ability to evade immune responses. Research investigating the occurrence of prolonged SARS-CoV-2 shedding from the upper respiratory tract has detected that this phenomenon is common2Gallais F. Gantner P. Planas D. Solis M. Bruel T. Pierre F. et al.Case report: evolution of humoral and cellular immunity in two COVID-19 breakthrough infections after BNT162b2 vaccine.Front Immunol. 2022; 13 (Feb 23)790212Crossref PubMed Scopus (2) Google Scholar and associated with the emergence of de novo mutations in the viral genome. Here, we describe the emergence of SARS-CoV-2 mutations in a cohort of kidney transplant recipients (KTRs) who experienced prolonged viral shedding despite being treated with anti-SARS-CoV-2 monoclonal antibodies. Several of the 197 KTRs who were diagnosed with COVID-19 at our center between December 20, 2021 and April 15, 2022 (i.e., throughout the omicron wave in France) experienced a late clinical deterioration. We identified 15 KTRs (8%) who had detectable viral loads in nasopharyngeal swabs for more than 21 days. Of them, eight harbored the BA.2 variant and had at least two specimens collected during the course of infection (i.e., the first at diagnosis and the second after day 21 [D21] or at the time of clinical deterioration). Quantification of both viral loads and anti-RBD IgG as well as Spike gene sequencing was carried out in the available specimens according to a previously described methodology.3Benotmane I. Risch S. Doderer-Lang C. Caillard S. Fafi-Kremer S. Long-term shedding of viable SARS-CoV-2 in kidney transplant recipients with COVID-19.Am J Transplant. 2021; 21 (Aug): 2871-2875Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar All of the eight patients received between two and four mRNA vaccine doses in the year preceding the diagnosis of COVID-19. Prophylactic injections of casirivimab–imdevimab were given to three participants. In addition, four received pre-exposure prophylaxis with tixagevimab–cilgavimab (300 mg) between 36 and 76 days prior to the onset of COVID-19. Symptoms at presentation were mild in all cases (Table 1). Tixagevimab–cilgavimab (600 mg) was administered with curative intent to five participants, and four received sotrovimab infusions (500 mg). Consequently, all patients received tixagevimab–cilgavimab in either a prophylactic or curative setting.Table 1General characteristics of the eight kidney transplant recipients (P1–P8) with COVID-19 who showed prolonged SARS-CoV-2 shedding.VariableP1P2P3P4P5P6P7P8Age (years)5457738071465973SexMMFMMFMMInterval from TX (years)270.226150.10.1Number of mRNA vaccine doses34433233Prophylactic casirivimab–imdevimabNoNoYesYesYesNoNoNoProphylactic tixagevimab–cilgavimabNoYesYesYesYesYesNoNoAdministration delay until diagnosis (days)-55364476---Anti-Spike IgG titers at diagnosis (BAU/mL)219222456853405356717923297Symptoms at presentationRhinitisCough, rhinitisCough, rhinitisCough, anosmia, ageusia, diarrhea, astheniaRhinitisNoneCough, rhinitisNoneCurative tixagevimab–cilgavimabYesNoNoNoYesNoYesYesCurative sotrovimabNoYesYesYesNoNoNoYesDuration of viral shedding (days)3049532642722870Clinical worseningYesYesYesYesYesNoNoNoInterval from diagnosis to worsening (days)3044351427---Symptoms at the time of worseningSevere asthenia, coughDyspnea, lung involvement (10–25%)Asthenia, fever, myalgia, cough, pneumopathy (10–25%)Dyspnea, fever, lung involvement (10–25%)ARDS---HospitalizationNoYesYesYesYes (ICU)---TreatmentNoneHigh steroid dosesHigh steroid dosesHigh steroid dosesNon-invasive ventilation---Abbreviations: M, male, F, female; TX, transplantation; ARDS, acute respiratory distress syndrome; ICU, intensive care unit. Open table in a new tab Abbreviations: M, male, F, female; TX, transplantation; ARDS, acute respiratory distress syndrome; ICU, intensive care unit. A total of 36 nasopharyngeal swabs were collected between D0 and D72 post infection. All tested specimens remained positive by real-time PCR for a median of 36 days (interquartile range [IQR]: 28–46 days; Fig. 1A). The SARS-CoV-2 Spike gene was analyzed in 29 samples and 22 were exploitable. One deletion and 11 non-synonymous nucleotide substitutions were identified between D11 and D72 post-infection (Fig. 1A). Early mutations—which included K147E (n = 1), E340D (n = 2), E340K (n = 1), R346T (n = 3), K356T (n = 2), and K444R (n = 5)—emerged after a median of 28 days from symptom onset (IQR: 24–30 days). Conversely, we identified the following late mutations between D70 and D72 post infection (Fig. 1B): K147N (n = 1), H245N (n = 1), Y449S (n = 1), L452R (n = 1), T547K (n = 1), and KN187–188del (n = 1). Five patients (P1–P5) showed an unusual symptom worsening as of 21 days after the diagnosis of COVID-19. Hospitalization was required in four cases and one was admitted to an intensive care unit (ICU). Table 1 summarizes patient characteristics both at baseline and at the time of clinical deterioration. It is worth noting that the mutation burden observed in SARS-CoV-2 isolates at the beginning of the infection—when symptoms were mild—was markedly lower. Conversely, the number of mutations tended to increase during the course of follow-up, being evident between 11 and 72 days from symptom onset. The most potently neutralizing antibodies to SARS-CoV-2—which are directed against the RBD of the viral Spike protein—act by blocking the RBD−ACE2 interactions. Interestingly, six (E340, R346, K356, K444, Y449, and L452) of the eleven mutations identified during the course of follow-up are known to affect the RBD region4Lan J. Ge J. Yu J. Shan S. Zhou H. Fan S. et al.Structure of the SARS-CoV-2 spike receptor-binding domain bound to the ACE2 receptor.Nature. 2020; 581 (May): 215-220Crossref PubMed Scopus (3368) Google Scholar and can act as escape mutations to neutralizing antibodies.5Greaney A.J. Starr T.N. Barnes C.O. Weisblum Y. Schmidt F. Caskey M. et al.Mapping mutations to the SARS-CoV-2 RBD that escape binding by different classes of antibodies.Nat Commun. 2021; 12 (Jul 7): 4196Crossref PubMed Scopus (162) Google Scholar, 6Starr T.N. Czudnochowski N. Liu Z. Zatta F. Park Y.J. Addetia A. et al.SARS-CoV-2 RBD antibodies that maximize breadth and resistance to escape.Nature. 2021; 597 (Sep): 97-102Crossref PubMed Scopus (187) Google Scholar Previous studies have shown that SARS-CoV-2 can evolve to respond to immune pressures conferred by specific mAbs. For example, the E340K substitution confers reduced susceptibility to sotrovimab (>297-fold change in EC50 value), whereas mutations at R346 and K444 not only confer resistance to cilgavimab but may also facilitate transmission primarily by enhancing binding to ACE2.7Li L. Liao H. Meng Y. Li W. Han P. Liu K. et al.Structural basis of human ACE2 higher binding affinity to currently circulating Omicron SARS-CoV-2 sub-variants BA.2 and BA.1.1.Cell. 2022; 185 (Aug 4): 2952-2960Abstract Full Text Full Text PDF PubMed Scopus (26) Google Scholar The R346K and K444R mutations have been previously reported in nine immunocompromised patients who had been treated with tixagevimab–cilgavimab; however, differently from our study, no significant clinical deterioration was observed at follow-up.8Vellas C. Kamar N. Izopet J. Resistance mutations in SARS-CoV-2 omicron variant after tixagevimab-cilgavimab treatment.J Infect. 2022; S0163–4453: 00422-00424https://doi.org/10.1016/j.jinf.2022.07.014Abstract Full Text Full Text PDF Scopus (11) Google Scholar The question as to whether the prophylactic or therapeutic use of tixagevimab–cilgavimab could have increased viral mutation rates remains unanswered. While all patients in our study had received tixagevimab–cilgavimab, this association does not prove a causative link between the use of mAbs and the emergence of mutations. Notably, prolonged viral shedding did not occur in any of the 120 KTRs with COVID-19 who were followed at our center and had not been treated with tixagevimab–cilgavimab. There are at least two potential reasons to link the use of this mAbs combination with the onset of mutations. First, the ability of tixagevimab–cilgavimab to neutralize any omicron sublineage is limited—with cilgavimab being the only ingredient of the cocktail with some effectiveness.9Takashita E. Kinoshita N. Yamayoshi S. Sakai-Tagawa Y. Fujisaki S. Ito M. et al.Efficacy of antibodies and antiviral drugs against covid-19 omicron variant.N Engl J Med. 2022; 386 (Mar 10): 995-998Crossref PubMed Scopus (177) Google Scholar Second, the use of low-dose cilgavimab–tixagevimab (150 mg of each antibody)—as generally performed in France at the beginning of the omicron wave—does not confer an adequate protection in a high proportion of KTRs.10Benotmane I. Velay A. Gautier-Vargas G. Olagne J. Obrecht A. Cognard N. et al.Breakthrough COVID-19 cases despite prophylaxis with 150 mg of tixagevimab and 150 mg of cilgavimab in kidney transplant recipients.Am J Transplant. 2022; 22: 2675-2681https://doi.org/10.1111/ajt.17121Abstract Full Text Full Text PDF PubMed Scopus (23) Google Scholar This may ultimately lead to the possible emergence of escape mutations to evade immune responses. Despite its rarity, prolonged SARS-CoV-2 shedding in KTRs with COVID-19 may result in adverse molecular (i.e., onset of escape mutations) and clinical (i.e., symptom deterioration) consequences—even in patients with an initially mild presentation. Further research is needed to clarify the potential causative role of neutralizing mAbs given in either a prophylactic or curative setting. It can be anticipated that their potential detrimental effects may be more pronounced when given at suboptimal doses and/or to patients infected with resistant variants of concern. Sophie Caillard received honoraria from Astra Zeneca (board expert). Other authors have no conflict of interest.