The COVID-19 pandemic led to significantly disrupted tuberculosis case detection and management. Additionally, overlapping symptoms, radiological findings and risk factors make differentiating tuberculosis and COVID-19 disease difficult. We conducted a prospective multicentre diagnostic accuracy study to determine sensitivity, specificity and operational characteristics of the Truenat MTB Ultima/COVID-19 assay, using a combined sputum plus nasopharyngeal swab specimen, in a single multiplex molecular assay. Participants were consenting adults with presumptive tuberculosis enrolled via convenience sampling from Uganda, Peru, South Africa, and India between August 2022 and December 2023. A microbiological reference standard of sputum GeneXpert MTB/RIF Ultra and culture was used for tuberculosis, whereas national RT-PCR was used for COVID-19. Wilson's score method was used to determine the sensitivity and specificity. Of 1,928 participants enrolled, median age was 38 years (IQR 28-50), 359/1928 (18.6%) previously had TB, and 287/1928 (14.9%) were HIV-positive. Overall prevalence of tuberculosis was 24.8% [95% CI 22.9-26.8%]. Prevalence of COVID-19 was 3.8% [3.1-4.8%] overall, and 4.7% [3.1-7.0%] in those with confirmed tuberculosis. Overall sensitivity of Truenat MTB Ultima/COVID-19 for tuberculosis was 79.8% [95% CI 76.0-83.2%]. When comparing paired samples, Truenat MTB Ultima/COVID-19 had a 9.5% [6.5-13.1%] decreased sensitivity against sputum TB culture, compared to GeneXpert Ultra; (82.8% [78.9-86.1%] vs 92.4% [89.4-94.5%]). Overall specificity of Truenat MTB Ultima/COVID-19 for tuberculosis was 98.9% [98.2-99.3%]. For COVID-19 detection, sensitivity of Truenat MTB Ultima/COVID-19 was 64.4% [52.9-74.4%], with specificity of 99.2% [98.7-99.5%]. Although optimal diagnostic performance was not demonstrated, the potential and need for rapid development of tests that integrate tuberculosis diagnosis with detection of other relevant respiratory infections is highlighted. The study was registered on ClinicalTrials.gov (NCT05405296).

Background Favipiravir has shown efficacy against SARS-CoV-2 in patients <60 years old, but data linking plasma concentrations to clinical outcomes are limited. This study investigated whether favipiravir plasma concentrations influence clinical efficacy and outcomes in patients hospitalised with COVID-19. The main research question was, How can antiviral dosing strategies be optimised to improve pandemic preparedness and treatment efficacy? Methods Adult participants were drawn from the PIONEER trial, in which patients received oral favipiravir (1800 mg twice daily for 1 day, then 800 mg twice daily for 9 days) plus standard care. This analysis included patients with confirmed COVID-19 and ≥75% study adherence. Samples were collected between days 5 and 10 post-treatment initiation. The primary outcome was time to clinical improvement. Secondary outcomes included achievement of clinical improvement and mortality risk. Results Out of 140 patients (50% male; mean± sd age 59.5±14.8 years), target plasma concentrations were reached in 29 (21%). Mean time to improvement was 7.7±5.9 days in target achievers versus 9.1±7.2 days in non-achievers (p=0.26). The target was more often achieved in female (34%) than male (7%) participants (p=0.0002). Plasma concentration inversely correlated with body mass index (r= –0.4, p<0.0001), and with lower body mass index in achievers (26.0±5.1 kg·m −2 versus 30.5±6.9 kg·m −2 , p=0.003). Alkaline phosphatase and alanine aminotransferase levels were also lower in achievers (p=0.004 and p=0.02, respectively). Conclusion Most patients did not reach target favipiravir levels. Concentrations were influenced by sex, body mass index and liver function, confirming the need for pharmacokinetically guided dosing and therapeutic monitoring to optimise antiviral efficacy in future pandemic responses.

BACKGROUND: Tuberculosis is the main cause of death among hospitalised people living with HIV. Non-sputum-based diagnostics could improve patient outcomes. The EXULTANT trial aims to evaluate an expanded tuberculosis screening strategy among people with HIV in two African countries with a high tuberculosis and HIV burden. METHODS: This pragmatic, individually randomised controlled superiority trial was conducted across 11 hospitals in Tanzania and Mozambique. We consecutively enrolled adults living with HIV (aged ≥18 years) without an existing tuberculosis diagnosis or recent tuberculosis treatment, within 24 h of admission. The intervention group underwent Xpert MTB/RIF Ultra (Xpert Ultra) testing from sputum, stool, and urine, plus lateral flow urine lipoarabinomannan (LF-LAM) testing (Determine TB LAM Ag assay), irrespective of symptoms. The control group followed standard-of-care, symptom-based, WHO-recommended sputum Xpert Ultra and LF-LAM testing. The primary endpoint was the proportion of participants with microbiologically confirmed tuberculosis starting treatment within 72 h. Secondary endpoints included 8-week all-cause mortality and time to tuberculosis diagnosis. The trial is registered at ClinicalTrials.gov (NCT04568967) and is completed. FINDINGS: From Sept 25, 2022, to March 15, 2024, we screened 1534 participants, and randomly assigned 1172 (76·6%) to either the intervention group (n=582) or the control group (n=590). At admission, 715 participants (61·0%) were female, 845 (75·4%) were on antiretroviral therapy (ART), and median CD4 count was 232 cells per μL (IQR 87-490). In the control group, 505 (85·6%) had tuberculosis-compatible symptoms and were eligible for sputum Xpert Ultra testing (306 of them [60·6%] provided a sample) and 538 (91·2%) met WHO criteria for LF-LAM testing. In the intention-to-treat analysis, 93 (16·0%) of 582 participants in the intervention group and 90 (15·3%) of 590 in the control group had microbiologically confirmed tuberculosis and started treatment within 72 h (difference 0·7%, 95% CI -3·4 to 4·8, p=0·73). 8-week all-cause mortality was 25·8% (150 of 582) in the intervention group and 28·8% (170 of 590) in the control group (hazard ratio 0·86, 95% CI 0·69 to 1·07, p=0·18). Median time to tuberculosis treatment initiation was 0·98 days (IQR 0·83-1·92) and 0·92 days (0·79-1·86) in the intervention and control groups, respectively (hazard ratio 1·05, 95% CI 0·82 to 1·33, p=0·72). INTERPRETATION: An expanded screening strategy among people living with HIV admitted to hospital did not increase the proportion of individuals with microbiologically confirmed tuberculosis starting treatment or reduce 8-week mortality. FUNDING: EDCTP2 programme, supported by the EU.

PURPOSE:To quantify the impact of noncanonical FBN1 splice site variants in undiagnosed Marfan syndrome (MFS), a connective tissue disorder associated with skeletal abnormalities and familial thoracic aortic aneurysm disease (FTAAD). METHODS:A systematic analysis of ultrarare FBN1 variants was performed using genome sequencing data from the 100,000 Genomes Project. Variants were annotated with SpliceAI and the significance of enrichment among individuals with FTAAD was assessed using Fisher's exact test. Experimental validation used RNA sequencing, reverse transcriptase polymerase chain reaction, minigene constructs, and replication analysis was with data from UK Biobank. RESULTS:Using aggregate data for 78,195 individuals, we identified 13,864 singleton single-nucleotide variants in FBN1 of which 21 were predicted to affect splicing (SpliceAI > 0.5). Incidence of candidate splice variants in individuals recruited with FTAAD (9/703) was significantly elevated compared with that seen in non-FTAAD participants (12/77,492; odds ratio = 84, P = 9.7 × 10-14). Additional analysis uncovered a further 14 families harboring 11 different FBN1 splice variants. A total of 20 candidate splice variants in 23 families were identified, of which 70% lay beyond the ±8 splice regions. RNA testing confirmed the predicted splice aberration in 16 of 20 and for 9 of 20, pseudoexonization was the likely splicing anomaly. CONCLUSION:Our findings indicate that noncanonical splice variants may account for approximately 3% of families with undiagnosed FTAAD, highlighting the importance of incorporating analysis of introns and confirmatory RNA testing into genetic testing for Marfan syndrome.

Background Multidrug resistant or rifampicin-resistant tuberculosis (MDR/RR-TB) poses a significant global public health challenge. While most people with RR-TB have MDR-TB (resistance to isoniazid and rifampicin), rifampicin mono-resistant tuberculosis (RmR-TB, rifampicin resistance, isoniazid susceptibility) is prevalent in certain regions. We aimed to compare mortality between patients with RmR-TB and MDR-TB and assess potential effect modification by HIV status during treatment. Methods We conducted an individual patient data meta-analysis involving 16,651 individuals with confirmed drug-resistant tuberculosis, all of whom had drug susceptibility test results for at least rifampicin, isoniazid, and fluoroquinolones and had initiated TB treatment. Mixed-effects logistic regression was used to estimate mortality during two-year treatment, adjusting for age, sex, history of TB, disease site, and HIV status. Stratified analyses explored effect modification by HIV status. Results Among 16,568 patients, 2878 (17.4%) were classified as having RmR-TB, 11,236 (67.8%) as MDR-TB, 2384 (14.4%) as pre-XDR-TB, and 70 (0.4%) as XDR-TB. During the first four months of treatment, the cumulative incidence of mortality was higher among patients with RmR-TB compared to those with MDR-TB, pre-XDR-TB and XDR-TB. Patients with RmR-TB had 14% higher odds of mortality compared to patients with MDR-TB (32.2% vs 23.7%; aOR 1.14; 95% CI: 1.02–1.27), but a lower mortality compared to patients with pre-XDR or XDR-TB. Although HIV status did not significantly modify the effect (p-value interaction = 0.362), the odds of mortality was only higher among RmR-TB patients with HIV co-infection (aOR 1.17; 95% CI:1.03–1.33). Conclusion Using a large individual patient data meta-analysis, this study confirmed the counterintuitive finding of prior smaller studies that the odds of mortality are higher among patients with RmR-TB compared to MDR-TB. While HIV co-infection was not an effect modifier, the higher odds of mortality were only observed among RmR TB patients living with HIV. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This study did not receive any funding ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Not Applicable The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Studies included in this article received ethical approval from relevant authorities. Further information is obtained from respective databases where data was sought. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Not Applicable I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Not Applicable I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Not Applicable We have no authority to share the data however, this data can be accessed from the TBIPD platform and the TB Consortium portal. Individual datasets used can be accessed from individual authors upon request.

Background Tuberculosis (TB) remains a major public health problem globally, as reflected in persistently high morbidity and mortality rates. Current control efforts have been further complicated by the ongoing SARS-CoV-2 (COVID-19) pandemic. Rapid molecular diagnostics remain crucial to identifying the millions of people with undiagnosed TB. Objectives The study aimed to determine the diagnostic accuracy of Truenat MTB Ultima/COVID-19 for the detection of COVID-19 and TB among presumptive TB participants, using a microbiological reference standard (MRS) and a country-approved real-time reverse transcription polymerase chain reaction (RT-PCR) COVID-19 assay. Methods This prospective cohort study assessed the diagnostic accuracy of the Truenat MTB Ultima/COVID-19 multiplex test among adults with presumptive TB, enrolled from healthcare facilities in four countries, aiming to reach 270 confirmed TB cases. The inclusion criteria were as follows: adults who self-reported at least one symptom suggestive of pulmonary TB, were willing to return for a day 2 visit, and agreed to provide oral swab samples for bio-banking. Patients were excluded from enrolment in the study if they had started anti-TB treatment within 60 days or TB preventive therapy within 6 months prior to enrolment or if they were unable to provide 3 mL of sputum or nasopharyngeal (NP) and tongue swab samples. Expected outcome This study expected to obtain point estimates of the sensitivity and specificity of the Truenat MTB Ultima/COVID-19 multiplex test for TB and COVID-19 detection, compared to Xpert Ultra, among presumptive TB participants using an MRS and pre-defined COVID-19 assay.

Background: High levels of multidrug and rifampicin resistant tuberculosis (MDR/RR-TB) are a global concern, although they have declined over the last decade. TB patients are at increased risk of acquired rifampicin resistance if they have HIV coinfection, especially at low CD4 counts, but this dynamic has not previously been modelled. Methods: We extended a previously-developed model that simulates HIV and TB in South African adults, to include the acquisition and transmission of rifampicin resistance. In line with systematic reviews, the risk of acquiring RR with TB treatment is modelled as being negatively associated with patients' CD4 counts. We allow for temporal changes in drug susceptibility testing, both before treatment initiation and at treatment failure, as well as other changes in TB prevention and treatment. The model is calibrated to data from national TB drug-resistance surveys, and recorded numbers of MDR/RR-TB laboratory diagnoses and patients initiating second-line TB treatment, using a Bayesian approach. Results: The model estimates that the proportion of South African TB patients with rifampicin resistance at diagnosis increased from 2.0% (95% CI: 1.7-2.3%) in 1986 to 5.9% (5.2-6.9%) in 2013, in line with survey data. In the absence of HIV, the prevalence of MDR/RR-TB would have increased to 4.1% (2.7-5.1%) in 2013, suggesting a third of rifampicin resistance in 2013 was attributable to HIV. In the absence of antiretroviral treatment (ART), the prevalence of rifampicin resistance would have been higher (6.5% [5.6-7.6%] in 2013, rising to 6.9% [5.7-8.2%] in 2019). ART reduced the prevalence of rifampicin resistance in 2019 by 17%. Conclusions: In countries with high HIV prevalence, HIV may be a major driver of rifampicin resistance in people with TB. ART programmes have the potential to reduce the emergence of resistance substantially. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This work was supported, in part, by the Bill & Melinda Gates Foundation (INV-019496 and INV-063625). The conclusions and opinions expressed in this work are those of the authors alone and shall not be attributed to the Foundation. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The Human Research Ethics Committee of the University of Cape Town gave approval for this work (ref. 740/2025). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors. Most of the data used in the model calibration are from publicly available sources cited in the paper.

BackgroundMulti-drug or rifamycin-resistant tuberculosis (MDR/RR-TB) is an important public health concern, including in settings with high HIV prevalence. TB drug resistance can be directly transmitted or arise through resistance acquisition during first-line TB treatment. Limited evidence suggests that people living with HIV (PLHIV) might have an increased risk of acquired rifamycin-resistance (ARR).MethodsTo assess HIV as a risk factor for ARR during first-line TB treatment, a systematic review and meta-analysis was conducted. ARR was defined as rifamycin-susceptibility at treatment start with rifamycin-resistance diagnosed during or at the end of treatment, or at recurrence. PubMed/MEDLINE, CINAHL, Cochrane Library, and Google Scholar databases were searched from inception to 23 May 2024 for articles in English; conference abstracts were also searched from 2004 to 2021. The Mantel-Haenszel random-effects model was used to estimate the pooled odds ratio of any association between HIV and ARR among individuals receiving first-line TB treatment.ResultsTen studies that included data collected between 1990 and 2014 were identified: five from the United States, two from South Africa and one each from Uganda, India and Moldova. A total of 97,564 individuals were included across all studies, with 13,359 (13.7%) PLHIV. Overall, 312 (0.32%) acquired rifamycin-resistance, among whom 115 (36.9%) were PLHIV. The weighted odds of ARR were 4.57 (95% CI, 2.01-10.42) times higher among PLHIV compared to HIV-negative individuals receiving first-line TB treatment.ConclusionThe available data, suggest that PLHIV have an increased ARR risk during first-line TB treatment. Further research is needed to clarify specific risk factors, including advanced HIV disease and TB disease severity. Given the introduction of shorter, 4-month rifamycin-based regimens, there is an urgent need for additional data on ARR, particularly for PLHIV.Systematic review registrationPROSPERO CRD42022327337.

There has been an exponential increase in the diagnosis of transthyretin amyloid cardiomyopathy (ATTR-CA). In response, the Midlands Amyloidosis Service was launched with the aim of providing patients with a timely diagnosis, remote expertise from the National Amyloidosis Centre and access to emerging transthyretin (TTR)-directed therapies. This was a descriptive study of a pilot hub-and-spoke model of delivering specialist amyloidosis care. Patients with suspected amyloidosis were referred from the wider Midlands region, and seen in a consultant-led multidisciplinary clinic. The diagnosis of ATTR-CA was established according to either the validated non-biopsy criteria or histological confirmation of ATTR deposits with imaging evidence of amyloid. Study endpoints were the volume of service provision and the time to diagnosis from the receipt of referral. Patients (n=173, age 75±2 years; male 72 %) were referred between 2019 and 2021. Eighty patients (46 %) were found to have cardiac amyloidosis, of whom 68 (85 %) had ATTR-CA. The median time from referral to diagnosis was 43 days. By removing the need for patients to travel to London, an average of 187 patient-miles was saved. Fifteen (9 %) patients with wild-type ATTR-CA received tafamidis under the Early Access to Medicine scheme; 10 (6 %) were enrolled into phase 3 clinical trials of RNA interference or antisense oligonucleotide therapies. Our results suggest that implementing a UK amyloidosis network appears feasible and would enhance equity of access to specialised amyloidosis healthcare for the increasing numbers of older patients found to have ATTR-CA.

Favipiravir (FVP) and remdesivir (RDV) have demonstrable antiviral activity against SARS-CoV-2. Here, the efficacy of FVP, RDV, and FVP with RDV (FVP + RDV) in combination was assessed in Syrian golden hamsters challenged with SARS-CoV- 2 (B.1.1.7) following intraperitoneal administration. At day 4 post infection, viral RNA and viral antigen expression were significantly lower in lungs for all three treatment groups compared to the sham treatment. Similarly, viral titres in the lungs were lower in all treatment groups compared to the sham treatment. The FVP + RDV combination was the only treatment group where viral RNA in nasal turbinate and lung, virus titres in lung, and viral antigen expression (lung) were all lower than those for the sham treatment group. Moreover, lower viral titre values were observed in the FVP + RDV group compared to other treatment groups, albeit only significantly lower in comparison to those in the RDV-only-treated group. Further assessment of the potential utility of FVP in combination with RDV may be warranted. Future studies should also consider whether the combination of these two drugs may reduce the speed at which drug resistance mutations are selected.

Drug-resistant tuberculosis (DR-TB) threatens to derail tuberculosis control efforts, particularly in Africa where the disease remains out of control. The dogma that DR-TB epidemics are fueled by unchecked rates of acquired resistance in inadequately treated or non-adherent individuals is no longer valid in most high DR-TB burden settings, where community transmission is now widespread. A large burden of DR-TB in Africa remains undiagnosed due to inadequate access to diagnostic tools that simultaneously detect tuberculosis and screen for resistance. Furthermore, acquisition of drug resistance to new and repurposed drugs, for which diagnostic solutions are not yet available, presents a major challenge for the implementation of novel, all-oral, shortened (6-9 months) treatment. Structural challenges including poverty, stigma, and social distress disrupt engagement in care, promote poor treatment outcomes, and reduce the quality of life for people with DR-TB. We reflect on the lessons learnt from the South African experience in implementing state-of-the-art advances in diagnostic solutions, deploying recent innovations in pharmacotherapeutic approaches for rapid cure, understanding local transmission dynamics and implementing interventions to curtail DR-TB transmission, and in mitigating the catastrophic socioeconomic costs of DR-TB. We also highlight globally relevant and locally responsive research priorities for achieving DR-TB control in South Africa.

Neurodevelopmental disorders are major indications for genetic referral and have been linked to more than 1500 loci including genes encoding transcriptional regulators. The dysfunction of transcription factors often results in characteristic syndromic presentations; however, at least half of these patients lack a genetic diagnosis. The implementation of machine learning approaches has the potential to aid in the identification of new disease genes and delineate associated phenotypes.Next generation sequencing was performed in seven affected individuals with neurodevelopmental delay and dysmorphic features. Clinical characterization included reanalysis of available neuroimaging datasets and 2D portrait image analysis with GestaltMatcher. The functional consequences of ZSCAN10 loss were modelled in mouse embryonic stem cells (mESCs), including a knockout and a representative ZSCAN10 protein truncating variant. These models were characterized by gene expression and western blot analyses, chromatin immunoprecipitation and quantitative PCR (ChIP-qPCR) and immunofluorescence staining. Zscan10 knockout mouse embryos were generated and phenotyped.We prioritized bi-allelic ZSCAN10 loss-of-function variants in seven affected individuals from five unrelated families as the underlying molecular cause. RNA-sequencing analyses in Zscan10-/- mESCs indicated dysregulation of genes related to stem cell pluripotency. In addition, we established in mESCs the loss-of-function mechanism for a representative human ZSCAN10 protein truncating variant by showing alteration of its expression levels and subcellular localization, interfering with its binding to DNA enhancer targets. Deep phenotyping revealed global developmental delay, facial asymmetry and malformations of the outer ear as consistent clinical features. Cerebral MRI showed dysplasia of the semicircular canals as an anatomical correlate of sensorineural hearing loss. Facial asymmetry was confirmed as a clinical feature by GestaltMatcher and was recapitulated in the Zscan10 mouse model along with inner and outer ear malformations.Our findings provide evidence of a novel syndromic neurodevelopmental disorder caused by bi-allelic loss-of-function variants in ZSCAN10. Laugwitz et al. describe a novel syndromic neurodevelopmental disorder with characteristic malformations of the face and of the inner and outer ear. The autosomal recessive disorder is caused by biallelic loss-of-function variants in the ZSCAN10 gene.

Background:Ronapreve demonstrated clinical application in post-exposure prophylaxis, mild/moderate disease and in the treatment of seronegative patients with severe COVID19 prior to the emergence of the Omicron variant in late 2021. Numerous reports have described loss of in vitro neutralisation activity of Ronapreve and other monoclonal antibodies for BA.1 Omicron and subsequent sub-lineages of the Omicron variant. With some exceptions, global policy makers have recommended against the use of existing monoclonal antibodies in COVID19. Gaps in knowledge regarding the mechanism of action of monoclonal antibodies are noted, and further preclinical study will help understand positioning of new monoclonal antibodies under development. Objectives:The purpose of this study was to investigate the impact of Ronapreve on compartmental viral replication as a paradigm for a monoclonal antibody combination. The study also sought to confirm absence of in vivo activity against BA.1 Omicron (B.1.1.529) relative to the Delta (B.1.617.2) variant. Methods:Virological efficacy of Ronapreve was assessed in K18-hACE2 mice inoculated with either the SARS-CoV-2 Delta or Omicron variants. Viral replication in tissues was quantified using qRT-PCR to measure sub-genomic viral RNA to the E gene (sgE) as a proxy. A histological examination in combination with staining for viral antigen served to determine viral spread and associated damage. Results:Ronapreve reduced sub-genomic viral RNA levels in lung and nasal turbinate, 4 and 6 days post infection, for the Delta variant but not the Omicron variant of SARS-CoV-2 at doses 2-fold higher than those shown to be active against previous variants of the virus. It also appeared to block brain infection which is seen with high frequency in K18-hACE2 mice after Delta variant infection. At day 6, the inflammatory response to lung infection with the Delta variant was altered to a mild multifocal granulomatous inflammation in which the virus appeared to be confined. A similar tendency was also observed in Omicron infected, Ronapreve-treated animals. Conclusions:The current study provides evidence of an altered tissue response to the SARS-CoV-2 after treatment with a monoclonal antibody combination that retains neutralization activity. These data also demonstrate that experimental designs that reflect the treatment use case are achievable in animal models for monoclonal antibodies deployed against susceptible variants. Extreme caution should be taken when interpreting prophylactic experimental designs when assessing plausibility of monoclonal antibodies for treatment use cases.