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AbstractBackgroundHigh-risk patients, often immunocompromised and not responding to vaccine, continue to experience severe COVID-19 and death. Monoclonal antibodies (mAbs) were shown effective to prevent severe COVID-19 for these patients. Nevertheless, concerns about the emergence of resistance mutations were raised.MethodsWe conducted a multicentric prospective cohort study, including 264 patients with mild-to moderate COVID-19 at high risk for progression to severe COVID-19 and treated early with Casirivimab/Imdevimab, Sotrovimab or Tixagevimab/Cilgavimab. We sequenced the SARS-CoV-2 genome during follow-up and searched for emerging Spike mutations.ResultsImmunocompromised patients have a 6-fold increased risk of developing mutations, which are associated with a prolonged duration of viral clearance but no clinical worsening. Emerging P337S/R/L/H, E340D/K/A/Q/V/G and K356T/R substitutions in patients treated with Sotrovimab are associated with higher viral RNA loads for up to 14 days post-treatment initiation. Tixagevimab/Cilgavimab is associated with a 5-fold increased risk of developing mutations. R346K/I/T/S and K444R/N/M substitutions associated with Tixagevimab/Cilgavimab have been identified in multiple SARS-CoV-2 lineages, including BQ.1 and XBB.ConclusionsIn conclusion, the probability of emerging mutations arising in response to mAbs is significant, emphasizing the crucial need to investigate these mutations thoroughly and assess their impact on patients and the evolutionary trajectory of the SARS-CoV-2.

Journal of Medical Virology, Volume 95, Issue 8, August 2023.

AbstractBackgroundWe report spike protein-based lineage and AZD7442 (tixagevimab/cilgavimab) neutralizing activity of SARS-CoV-2 variants identified from breakthrough infections in the PROVENT pre-exposure prophylaxis trial (NCT04625725).MethodsVariants identified from PROVENT participants with reverse-transcription polymerase chain reaction–positive symptomatic illness were phenotypically assessed to determine neutralization susceptibility of variant-specific pseudotyped virus-like particles.ResultsAt completion of 6 months’ follow-up, no AZD7442-resistant variants were observed in breakthrough COVID-19 cases. SARS-CoV-2 neutralizing antibody titers were similar in breakthrough and non-breakthrough cases.ConclusionSymptomatic COVID-19 breakthrough cases in PROVENT were not due to resistance-associated substitutions in AZD7442 binding sites or lack of AZD7442 exposure.

Some proportions of populations, such as immunocompromised patients and organ transplant recipients might have inadequate immune responses to the vaccine for coronavirus disease 2019 (COVID‐19). For these groups of populations, administering monoclonal antibodies might offer some additional protection. This review sought to analyze the effectiveness and safety of tixagevimab‐cilgavimab (Evusheld) as pre‐exposure prophylaxis against COVID‐19. We used specific keywords to comprehensively search for potential studies on PubMed, Scopus, Europe PMC, and sources until 3 September 2022. We collected all published articles that analyzed tixagevimab‐cilgavimab on the course of COVID‐19. Review Manager 5.4 was utilized for statistical analysis. Six studies were included. Our pooled analysis revealed that tixagevimab‐cilgavimab prophylaxis may decrease the rate of SARS‐CoV‐2 infection (OR: 0.24; 95% CI: 0.15–0.40,  …

Abstract Purpose Lung transplant (LTx) recipients are at risk for poor outcomes from coronavirus disease 2019 (COVID-19). The aim of the study was to assess the outcome of patients receiving pre-exposure prophylaxis (PrEP) with tixagevimab and cilgavimab after LTx. Methods All LTx recipients with outpatient visits from February 28th to October 31st, 2022 at two German centers were included. Baseline characteristics were recorded and patients followed until November 30rd, 2022. Infections with SARS-CoV-2, disease severity, and COVID-19-associated death were compared between patients with and without PrEP. Results In total, 1438 patients were included in the analysis, and 419 (29%) received PrEP. Patients receiving PrEP were older and earlier after transplantation, had lower glomerular filtration rates, and lower levels of SARS-CoV-2-S antibodies. In total, 535 patients (37%) developed SARS-CoV-2 infection during a follow-up of median of 209 days. Fewer infections occurred in patients with PrEP during the study period (31% vs. 40%, p = 0.004). Breakthrough SARS-CoV-2 infections after PrEP occurred in 77 patients (19%). In total, 37 infections (8%) were severe or critical. No difference in severity of COVID-19 was observed between patients with and without PrEP. There were 15 COVID-19-associated deaths (n = 1 after PrEP). Compared to matched controls, there was a non-significant difference towards a lower risk for moderate to critical COVID-19 (p 0.184). Conclusion The number of SARS-CoV-2 infections was lower in LTx recipients with PrEP. Despite being at higher risk for worse outcome severity of COVID-19 and associated mortality were similar in patients with and without PrEP. …

In late January, the US Food and Drug Administration announced that Evusheld (the combined monoclonal antibodies tixagevimab and cilgavimab) is not currently authorized for emergency use because it’s likely ineffective against more than 90% of SARS-CoV-2 variants now circulating in the US. Evusheld had been used as COVID-19 preexposure prophylaxis among certain patients who are immunocompromised.

AbstractBackgroundAZD7442 is a combination of extended half-life, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)−specific neutralizing monoclonal antibodies (tixagevimab/cilgavimab).MethodsThis phase 1, first-in-human, randomized, double-blind, placebo-controlled, dose-escalation study evaluated AZD7442 administered intramuscularly (300 mg) or intravenously (300, 1000, 3000 mg) in healthy adults (aged 18–55 years). The primary endpoint was safety and tolerability. Secondary endpoints included pharmacokinetics and anti-drug antibodies.ResultsBetween August 18–October 16, 2020, 60 participants enrolled; 50 received AZD7442 and 10 received placebo. Adverse events (all of mild/moderate intensity) occurred in 26 (52.0%) and 8 (80.0%) participants (AZD7442 and placebo groups, respectively). No infusion- or injection-site, or hypersensitivity reactions occurred. Tixagevimab and cilgavimab had mean half-lives of approximately 90 days (range: 87.0–95.3 [tixagevimab], 79.8–­91.1 [cilgavimab]) and similar pharmacokinetic profiles over the 361-day study period. SARS-CoV-2–specific neutralizing antibody titers provided by AZD7442 were maintained above those in plasma from convalescent coronavirus disease-19 (COVID-19) patients.ConclusionsAZD7442 was well tolerated in healthy adults, showing a favorable safety profile across all doses. Depending on the SARS-CoV-2 variant, pharmacokinetic analyses suggest AZD7442 could offer protection for at least 6 months against symptomatic COVID-19 following a single 300 mg intramuscular administration.Clinical trials registrationNCT04507256 (https://clinicaltrials.gov/ct2/show/NCT04507256).

Since in two phase 3 clinical trials, there were a disproportion of number of thromboembolic events in the tixagevimab/cilgavimab group than in placebo group, there is a cardiovascular safety concerns with the use of this Anti-SARS-COV-2 Monoclonal Antibody. Whether tixagevimab/cilgavimab use in real life context increases the risk for of thromboembolic events is unclear.

AbstractBackgroundWe report primary results of a phase 3 trial of AZD7442 (tixagevimab/cilgavimab) for post-exposure prophylaxis to prevent symptomatic coronavirus disease 2019 (COVID-19)MethodsAdults without prior SARS-CoV-2 infection or COVID-19 vaccination were enrolled within 8 days of exposure to a SARS-CoV-2–infected individual and randomized 2:1 to a single 300-mg AZD7442 dose (one 1.5-mL intramuscular injection each of tixagevimab and cilgavimab consecutively) or placebo. Primary endpoints were safety and first post-dose SARS-CoV-2 reverse-transcription–polymerase-chain-reaction (RT-PCR)–positive symptomatic COVID-19 event before day 183.Results1121 participants were randomized and dosed (mean age 46 years; 49% females; AZD7442, n=749; placebo, n=372). Median (range) follow-up was 49 (5–115) and 48 (20–113) days for AZD7442 and placebo, respectively. Adverse events occurred in 162/749 (21.6%) and 111/372 (29.8%) participants with AZD7442 and placebo, respectively, mostly mild/moderate. RT-PCR–positive symptomatic COVID-19 occurred in 23/749 (3.1%) and 17/372 (4.6%) AZD7442- and placebo-treated participants, respectively (relative risk reduction 33.3%; 95% confidence interval [CI] –25.9 to 64.7; P=.21). In predefined subgroup analyses of 1073 (96%) participants who were SARS-CoV-2 RT-PCR–negative (n=974 [87%]) or missing an RT-PCR result (n=99 [9%]) at baseline, AZD7442 reduced RT-PCR–positive symptomatic COVID-19 by 73.2% (95% CI 27.1 to 90.1) versus placebo.ConclusionsThis study did not meet the primary efficacy endpoint of post-exposure prevention of symptomatic COVID-19 with AZD7442 versus placebo. However, predefined analysis of participants who were SARS-CoV-2 RT-PCR–negative or missing an RT-PCR result at baseline support a role for AZD7442 in preventing symptomatic COVID-19.

AbstractTixagevimab and cilgavimab treatment was associated with higher rates of cardiovascular events in a post-hoc analysis of a phase 3 trial. In this large population-based propensity-matched study, we found no increased risk of cardiovascular events up to 90 days after tixagevimab and cilgavimab administration, including in patients with pre-existing cardiovascular disease.

Monoclonal antibodies that neutralise SARS-CoV-2 have consistently reduced hospitalisation or death in outpatients with mild to moderate COVID-19.1–3 Conversely, results of randomised trials in patients who are hospitalised are mixed.4–8 In The Lancet Respiratory Medicine, Thomas L Holland and colleagues present results of the ACTIV-3 trial comparing intravenous tixagevimab−cilgavimab with placebo for patients hospitalised with COVID-19.8 Although tixagevimab−cilgavimab did not improve the primary outcome of time to sustained recovery (rate ratio [RR] 1·08 [95% CI 0·97–1·20]; p=0·21), it was associated with improved 28-day (6% vs 9%; p=0·02) and 90-day (9% vs 12%; p=0·03) mortality.

Among patients hospitalised with COVID-19 receiving remdesivir and other standard care, tixagevimab–cilgavimab did not improve the primary outcome of time to sustained recovery but was safe and mortality was lower.

A single intramuscular tixagevimab–cilgavimab dose provided statistically and clinically significant protection against progression to severe COVID-19 or death versus placebo in unvaccinated individuals and safety was favourable. Treating mild to moderate COVID-19 earlier in the disease course with tixagevimab–cilgavimab might lead to more favourable outcomes.