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Objective To describe the clinical efficacy of tixagevimab/cilgavimab in pre-exposure prophylaxis in patients at risk of severe coronavirus disease 2019 (COVID-19) and unresponsive to vaccination (anti-severe acute respiratory syndrome coronavirus 2 antibodies <260 binding antibody units/ml) in rheumatology. Methods In this multicentre observational study we included patients with autoimmune or inflammatory diseases who received pre-exposure prophylaxis with tixagevimab/cilgavimab between December 2021 and August 2022. The endpoint was incidence of COVID-19 and its severity. Results Tixagevimab/cilgavimab was administered to 115 patients with a median age of 62 years [interquartile range (IQR) 52–71], chronic arthritis (n  = 53), connective tissue disease (n  = 38) or vasculitis (n  = 11). The main background immunosuppressants were rituximab (n  = 98), corticosteroids [ n  = 62; median dose 5 mg (95% CI 5–8)] and methotrexate (n  = 48). During a median follow-up of 128 days (IQR 93–173), COVID-19 occurred in 23/115 patients (20%) and the omicron variant was identified for the eight genotyped patients. During the study period, the average weekly incidence was 1071/100 000 inhabitants in Île-de-France vs 588/100 000 in our patients. Patients who received a two-injection regimen had a lower risk of infection than those with a single injection [16/49 (33%) vs 5/64 (8%), P  = 0.0012]. The COVID-19-positive patients did not differ from uninfected patients concerning age, comorbidities, underlying rheumatic disease and immunosuppressants. All COVID-19 cases were non-severe. The tolerance of injections was excellent. Conclusion In a population with autoimmune or inflammatory diseases at risk of severe COVID-19 unresponsive to vaccination, pre-exposure prophylaxis withy tixagevimab/cilgavimab was associated with a lower incidence of COVID-19 and no severe infections. [ABSTRACT FROM AUTHOR]

Monoclonal antibodies, as tixagevimab/cilgavimab, have been introduced as prophylaxis against COVID-19 infections in high-risk populations. However, data on efficacy are limited. This study investigates efficacy and tolerability of tixagevimab/cilgavimab in hematological patients under real-life conditions. Tixagevimab/cilgavimab was administered to 155 hematological patients (March-August 2022) at two Austrian centres. S/RBD-antibody assessments were performed before (T0), four weeks (T1), and six months (T2) after application. Side effects, the occurrence of COVID-19 infections, and the course of S/RBD-antibody titres were analysed retrospectively in relation to clinical variables. 155 hematological patients, who refused tixagevimab/cilgavimab, were included as a control group to compare the frequency of COVID-19 infections. Of all immunised patients (52.3% males; 91% triple vaccinated), 25.8% had a COVID-19 breakthrough infection (76% mild) compared to 43.9% in the control group. Patients with chronic lymphocytic leukaemia (CLL)/lymphoma were at highest risk of a COVID-19 infection (OR = 2.21; 95% CI 1.05–4.65; p = 0.037). After immunisation, a steep increase in median antibody levels (1193.4BAU/ml, IQR 0–2318.94) was observed in 67.8%, followed by a rapid decrease between T1 and T2 (465.95BAU/ml, IQR 0–1900.65.3) with the greatest declines in CLL/lymphoma (848.7BAU/ml, IQR 0–1949.6, p = 0.026). Side-effects occurred in 21.2% (CTCAE I/II). These real-world data indicate that S/RBD antibodies respond rapidly after passive immunisation in all hematological patients without safety concerns. Given the rapid decline in S/RBD antibodies, early booster immunisations should be considered for future scenarios in this vulnerable group. [ABSTRACT FROM AUTHOR]

Antiviral therapies are integral in the fight against SARS‐CoV‐2 (i.e. severe acute respiratory syndrome coronavirus 2), the causative agent of COVID‐19. Antiviral therapeutics can be divided into categories based on how they combat the virus, including viral entry into the host cell, viral replication, protein trafficking, post‐translational processing, and immune response regulation. Drugs that target how the virus enters the cell include: Evusheld, REGEN‐COV, bamlanivimab and etesevimab, bebtelovimab, sotrovimab, Arbidol, nitazoxanide, and chloroquine. Drugs that prevent the virus from replicating include: Paxlovid, remdesivir, molnupiravir, favipiravir, ribavirin, and Kaletra. Drugs that interfere with protein trafficking and post‐translational processing include nitazoxanide and ivermectin. Lastly, drugs that target immune response regulation include interferons and the use of anti‐inflammatory drugs such as dexamethasone. Antiviral therapies offer an alternative solution for those unable or unwilling to be vaccinated and are a vital weapon in the battle against the global pandemic. Learning more about these therapies helps raise awareness in the general population about the options available to them with respect to aiding in the reduction of the severity of COVID‐19 infection. In this 'A Guide To' article, we provide an in‐depth insight into the development of antiviral therapeutics against SARS‐CoV‐2 and their ability to help fight COVID‐19. [ABSTRACT FROM AUTHOR]

Background: Patients treated with hemato-oncological malignancies (HO) or undergoing cellular therapies such as hematopoietic stem cell transplantation (HSCT) or chimeric antigen receptor T cells (CAR-T) were significantly affected by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Despite the success of SARS-CoV-2 vaccination, immunocompromised patients remain at increased risk for severe coronavirus disease (COVID-19), rendering this group of population a high priority for additional prevention and treatment options. Tixagevimab and Cilgavimab (TIXA/CILGA, AZD7442, Evusheld®) is a combination of two fully human, long-acting monoclonal antibodies. TIXA/CILGA have been approved as pre-exposure prophylaxis and treatment in patients at risk of severe disease with impaired vaccine response. Our objective was to describe the efficacy and safety among immunocompromised pediatric patients. Methods: This was an observational multicenter cohort study of immunocompromised pediatric patients receiving TIXA/CILGA conducted at nine Polish centers of Pediatric Oncology, Hematology and Bone Marrow Transplantation. We analyzed patients in two groups; those treated with HO and those undergoing cellular therapies: HSCT or CAR-T cells. In addition, two other cohorts were identified: patients given TIXA/CILGA as pre-exposure prophylactic and therapeutic intervention. Results: A total of 78 patients were evaluated during the study period: 69 (88.5%) received TIXA/CILGA as pre-exposure prophylaxis and 9 (11.5%) as a treatment strategy. A total of 52 (66.6%) patients were treated with standard chemotherapy at HO departments; 21 (27%) underwent HSCT, and 5 (6.4%) received CAR-T cell therapy. All children with COVID-19 receiving TIXA/CILGA presented a mild degree of severity. The most common clinical manifestations were fever, cough and coryza. At least one adverse event (AE) was reported in two (3.8%) patients excluding standard injection site reactions. Reported AEs were mild or moderate in intensity. One child reported mild myalgia and one reported moderate bone pain and weakness. Conclusions: In our observational multicenter cohort study, we explored the use of TIXA/CILGA as pre-exposure prophylaxis and treatment for COVID-19 among immunocompromised pediatric patients. While our findings suggest a potential benefit in preventing and managing COVID-19 in this vulnerable population, it is important to note the study's non-comparative design. Our results highlight the need for well-designed clinical trials to confirm these observations and further assess the efficacy and safety of TIXA/CILGA in immunocompromised children. [ABSTRACT FROM AUTHOR]

Abstract Background During the COVID-19 pandemic, some populations, including immunocompromised patients, could not tolerate COVID-19 vaccination or had low responses. Evusheld is a combined neutralizing monoclonal antibody containing tixagevimab and cilgavimab. The World Health Organization (WHO) has approved this combination as pre-exposure prophylaxis (PrEP) and treatment for immunocompromised patients. With the new variant, the (WHO) recommended an increase in dose from 300 to 600 mg with a booster dose after 6 months. The target of this review was to compare the efficacy of the two doses, 300 mg and 600 mg of tixagevimab/cilgavimab (Evusheld) as prophylaxis for higher-risk individuals to reveal if there is a significant difference in efficacy between those two doses of the drug. Methods In this study, electronic databases (PubMed, Web of Science core collection, Scopus, and Cochran) were investigated for articles up to 31/12/2022 in English using a well-established search strategy. We included studies conducted in immunocompromised patients (aged ≥ 12 years) (WHO) received Evusheld as prophylaxis or treatment for COVID-19. After excluding studies inconsistent with the selection criteria, 24 were involved, 22 of which were included in the meta-analysis. We analyzed the data by using RevMan 5.4 program software. Results In the double-arm subgroup analysis, Evusheld 600 mg, administered as prophylaxis, showed no significant difference in the COVID-19 infection rate, mortality rate, or needed hospitalization rate compared with the dose of 300 mg (p = 0.13, p = 0.29, and p = 0.25, respectively). In the single-arm subgroup analysis, Evusheld 600 mg, administered as prophylaxis, showed a significant decrease in the COVID-19 infection rate and the hospitalization rate compared with the dose of 300 mg (p = 0.0001, p = 0.007, respectively). As a treatment, Evusheld showed a significant decrease in the mortality rate over the placebo group (p = 0.01) in COVID-19 patients. Conclusion This result indicated that Evusheld was an effective prophylactic and therapeutic drug for COVID-19 infection, especially for immunocompromised patients, but there was no considerable variation between the high and low doses. Further prospective and randomized controlled trials (RCTs) with increased population sizes are necessary to show the valuable benefit of the high dose of Evusheld in COVID-19 prevention and treatment and to compare the difference between the two doses within adverse events.

Background. COVID-19 (COrona VIrus Disease 2019) is a serious threat to cancer patients, who are at an increased risk of severe infection complications. Pre-exposure prophylaxis with a combination of monoclonal antibodies, tixagevimab-cilgavimab (Evusheld), has been shown to be effective in preventing COVID-19, reducing hospital admission rate and mortality in immunocompromised individuals. Aim. To describe the experience of using tixagevimab-cilgavimab for pre-exposure prophylaxis of COVID-19 in the Russian population of patients with solid tumors receiving antitumor drug therapies. Materials and methods. The retrospective analysis included case histories of 79 patients (57% females and 43% males) with solid tumors treated at the Moscow City Clinical Oncology Hospital No. 1 from October 2022 to June 2023. All patients received tixagevimab-cilgavimab for COVID-19 pre-exposure prophylaxis. Results. The mean age was 64±11 years (32 to 83 years). Seventy-three percent of patients received cytotoxic therapy, associated with an increased risk of infectious complications, including COVID-19. No immediate or delayed adverse events related to tixagevimab-cilgavimab were reported. During the observation period since the drug injection, 3 (3.8%) new mild cases of COVID-19 were reported. Conclusion. Tixagevimab-cilgavimab (Evusheld) is safe and effective for pre-exposure prophylaxis of COVID-19 in the Russian population of patients with solid tumors receiving antitumor drug therapy.

Tixagevimab/cilgavimab (tix/cil) received emergency use authorization in December 2021 for pre‐exposure prophylaxis against COVID‐19 in moderately to severely immunocompromised patients. Our study aimed to describe the incidence of COVID‐19 infection and assess the immunologic risks associated with tix/cil in kidney, pancreas, liver, and heart transplant recipients. Retrospective chart review was completed to provide descriptive analysis. Outcomes data included COVID‐19 infection, severity of COVID‐19 infection, graft function, and rejection. Safety outcomes included cardiovascular (CV) and hypersensitivity events post tix/cil administration. A total of 410 transplant patients were included in the analysis: 20 heart, 92 liver, 243 kidney, 25 simultaneous pancreas/kidney, 23 simultaneous liver/kidney, and seven simultaneous heart/kidney. Twenty‐seven (6.5%) patients tested positive for COVID‐19 via PCR or antigen test post tix/cil. No apparent difference was observed in patients testing positive for COVID‐19 by type of organ transplant (p =.122). Twenty‐five of the 27 patients testing positive for COVID‐19 reported symptomatic infection, only nine of whom were hospitalized. No patients were mechanically ventilated and no deaths due to COVID‐19 occurred. No significant changes in graft function were observed. Clinically significant rejection was diagnosed and treated in four patients. COVID‐19 breakthrough infection rates remained low in immunocompromised solid organ transplant recipients who received tix/cil. No significant immunologic risks were observed. [ABSTRACT FROM AUTHOR]

Background: During the COVID-19 pandemic, some populations, including immunocompromised patients, could not tolerate COVID-19 vaccination or had low responses. Evusheld is a combined neutralizing monoclonal antibody containing tixagevimab and cilgavimab. The World Health Organization (WHO) has approved this combination as pre-exposure prophylaxis (PrEP) and treatment for immunocompromised patients. With the new variant, the (WHO) recommended an increase in dose from 300 to 600 mg with a booster dose after 6 months. The target of this review was to compare the efficacy of the two doses, 300 mg and 600 mg of tixagevimab/cilgavimab (Evusheld) as prophylaxis for higher-risk individuals to reveal if there is a significant difference in efficacy between those two doses of the drug. Methods: In this study, electronic databases (PubMed, Web of Science core collection, Scopus, and Cochran) were investigated for articles up to 31/12/2022 in English using a well-established search strategy. We included studies conducted in immunocompromised patients (aged ≥ 12 years) (WHO) received Evusheld as prophylaxis or treatment for COVID-19. After excluding studies inconsistent with the selection criteria, 24 were involved, 22 of which were included in the meta-analysis. We analyzed the data by using RevMan 5.4 program software. Results: In the double-arm subgroup analysis, Evusheld 600 mg, administered as prophylaxis, showed no significant difference in the COVID-19 infection rate, mortality rate, or needed hospitalization rate compared with the dose of 300 mg (p = 0.13, p = 0.29, and p = 0.25, respectively). In the single-arm subgroup analysis, Evusheld 600 mg, administered as prophylaxis, showed a significant decrease in the COVID-19 infection rate and the hospitalization rate compared with the dose of 300 mg (p = 0.0001, p = 0.007, respectively). As a treatment, Evusheld showed a significant decrease in the mortality rate over the placebo group (p = 0.01) in COVID-19 patients. Conclusion: This result indicated that Evusheld was an effective prophylactic and therapeutic drug for COVID-19 infection, especially for immunocompromised patients, but there was no considerable variation between the high and low doses. Further prospective and randomized controlled trials (RCTs) with increased population sizes are necessary to show the valuable benefit of the high dose of Evusheld in COVID-19 prevention and treatment and to compare the difference between the two doses within adverse events. [ABSTRACT FROM AUTHOR]

Background and Objectives: In addition to a suboptimal and rapidly diminishing response to the coronavirus disease 2019 (COVID-19) vaccine, hemodialysis (HD) patients are at risk for developing a severe COVID-19 infection. In 2022, the combination of cilgavimab and tixagevimab (Evusheld, AstraZeneca) was approved for COVID-19 preexposure prophylaxis in high-risk groups. The purpose of this study was to evaluate the humoral response and short-term safety of this antibody combination in a group of HD patients. Materials and Methods: Seventy-three adult maintenance hemodialysis patients were recruited from a tertiary-care hospital for this double-blinded, non-randomized, placebo-controlled study. Patients were placed into two groups: the intervention group (n = 43) received a single 300 mg dosage of cilgavimab and tixagevimab, while the control group (n = 30) received a saline placebo. The titer of COVID-19-neutralizing antibodies was measured at baseline and after 1 and 6 months. The patients were evaluated for any drug-related adverse effects and monitored for six months for the emergence of any COVID-19-related events. Results: Patients in the intervention group were substantially older and had been on HD for longer (p = 0.002 and 0.006, respectively). The baseline antibody levels were higher in the Evusheld group. The antibody level in the intervention group increased significantly after 1 month and remained consistent for 6 months, whereas the antibody level in the control group fell significantly after 6 months during the study period (Wald χ2 = 30.620, p < 0.001). The drug-related adverse effects were modest and well-tolerated, and only seven patients experienced them. Six months after study enrollment, 10 patients in the intervention group and 6 patients in the control group had been infected with COVID-19, respectively. In the control group, ICU admission and mortality were observed, but in the intervention group, the infection was milder with no aggressive consequences. Conclusions: This study demonstrated the short-term safety and efficacy of tixagevimab–cilgavimab for COVID-19 preexposure prophylaxis in HD patients. These findings require more studies with more HD patients and longer follow-up periods. [ABSTRACT FROM AUTHOR]

Background: Evusheld (EVS) was authorized by FDA and EMA as pre-exposure prophylaxis (PrEP) in people at high risk of severe Covid-19 outcomes, including people with Multiple Sclerosis (pwMS) on B-cell depleting (BCD) therapies—such as Ocrelizumab (OCR). In this population, no data on possible adverse drug reactions (ADRs) to EVS, B-lymphocytes (CD20 +) counts pre- and post-EVS injection, and comparison of percentage increase of IgG antibodies directed against SARS-CoV-2 trimeric spike protein (anti-TSP IgG) post-EVS and Covid-19 vaccine was available. The aim of this study was to better characterize the efficacy and safety profile of EVS in pwMS on BCD agents. Methods: 17 pwMS on OCR agreed to receive EVS as PrEP for Covid-19. Sera samples were collected before the first dose of Covid-19 vaccine (T0), 4 weeks after the second dose (T1), 4 weeks after third dose (T2), immediately before (T3) and 4 weeks after (T4) EVS. Results: Covid-19 vaccine ADRs were mild-to-moderate, whereas no ADRs were reported after EVS injection. A significant increase of anti-TSP IgG was found only at T0-T1 (Z = -3.059, p =.002) and T3-T4 (Z = -3.621, p <.001) time-points. The median percentage increase between T3-T4 was significantly higher with respect to the T0-T1(Z = -3.296, p =.001) and T1-T2 (Z = -3.059, p =.002) time-points. Conclusions: These results further support EVS safety and efficacy in boosting anti-TSP IgG titers in pwMS on OCR, with a statistically greater increase than that observed after completion of a full Covid-19 vaccine cycle, plus a booster dose. [ABSTRACT FROM AUTHOR]

Background Patients on B-cell-depleting agents may have a suboptimal response to vaccination, placing them at a higher risk of contracting severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) or suffering from a more severe prognosis. Indeed, available data on pre-exposure prophylaxis with tixagevimab/cilgavimab (Evusheld) in subjects with glomerular diseases (GDs) who received rituximab are limited. Methods We conducted a prospective study analysing the safety and efficacy of tixagevimab/cilgavimab for pre-exposure prophylaxis in patients with GDs who received rituximab in the previous 12 months. The rates of symptomatic infections and hospitalizations were compared with those for patients with GD treated with rituximab who refused to receive tixagevimab/cilgavimab. Results Tixagevimab/cilgavimab was administered to 22 patients (12 females, mean age 58.4 ± 19.6 years) with GD diagnoses including membranous nephropathy, lupus nephritis, anti-neutrophil cytoplasmic antibody–associated vasculitis and focal segmental glomerulosclerosis. No patient treated with tixagevimab/cilgavimab experienced symptomatic infection with SARS-CoV-2 during the follow-up (mean observation time of follow-up was 112 ± 23 days), while 11 of 28 controls (39.3%) reported a symptomatic infection (P  = .0001), requiring hospitalization in 2 cases. Reported adverse events were mild, namely self-limiting headache [ 4 ], discomfort at the injection site [ 3 ], flu-like symptoms/myalgia [ 3 ] and fever [ 1 ]. No serious adverse events (e.g. cardiac events, anaphylaxis) were reported. Conclusion Pre-exposure prophylaxis with tixagevimab/cilgavimab seems safe and lowered the risk of symptomatic SARS-CoV-2 infection by ≈40% in vaccinated subjects with GD who received anti-CD20 therapy. Possible applications in the subset of patients who need immunosuppressive therapy, especially with rituximab, in a pandemic setting might be envisaged. [ABSTRACT FROM AUTHOR]

Background: tixagevimab/cilgavimab, distributed under the name "Evusheld", was the first available pre-exposure prophylaxis for COVID-19 other than vaccination. It received an EUA from the FDA after sufficient trial data showed efficacy in preventing SARS-CoV-2 infections and subsequent severe disease. Its potential benefits for high-risk immunocompromised patients generated a lot of interest. Individuals with multiple myeloma fall into this category, as they are characterized by attenuated immune responses and, in some cases, vaccines have limited efficacy. Methods: this single-center, prospective study included consecutive patients with multiple myeloma. All individuals were considered high-risk for COVID-19 due to their underlying disease. Baseline demographic and clinical characteristics, as well as data regarding COVID-19 infection and antibodies, were collected. Patients were administered two intramuscular 150 mg doses of Evusheld and were monitored during the follow-up period. Results: one hundred and eleven multiple myeloma patients were included in this analysis, with a median age of 64 years (range 58–69) and fifty-three were females (47.7%). Fourteen patients (12.6%) had a prior history of COVID-19 and all patients were vaccinated with either three or four doses of mRNA-based vaccines. An increase was observed in the median neutralizing-antibody levels before and after tixagevimab/cilgavimab administration, from 92.6% to 97.3%. The high levels were sustainable, with a median neutralizing-antibody level of 95.4% at 3 months post Evusheld administration. Overall, nine patients (8.1%) were diagnosed with COVID-19 during the follow-up period, at a median of 31 days. There were no SARS-CoV-2- infection-related hospitalizations or deaths. The monoclonal antibody combination was well tolerated, with no infusion-related reactions or major adverse events, and pain at the injection site only was reported by 33 patients (30%). Conclusions: tixagevimab/cilgavimab (Evusheld) seemed beneficial for patients with multiple myeloma, who presented high neutralizing-antibody levels and a low incidence of COVID-19 during the initial Omicron wave. No new safety concerns emerged. However, novel combinations of monoclonal antibodies against the new circulating variants of SARS-CoV-2 are deemed necessary in view of the emergence of immune tolerance. [ABSTRACT FROM AUTHOR]

Evusheld is a combination injection of tixagevimab and cilgavimab and is indicated for the pre-exposure prophylaxis of COVID-19 in adults and adolescents aged 12 years and older. Its use has been advocated for immunosuppressed individuals, such as blood cancer patients, although uptake varies significantly between countries. Despite extensive use internationally, there has been limited analysis of potential psychological benefits that vulnerable patients might gain from receiving this prophylactic medication. In this study we have quantified four key psychological health parameters in blood cancer patients who received Evusheld (EQ5D-3L quality of life score, DSM5 Agoraphobia score, Duke’s Social Support Index and the hospital anxiety and depression score) and compared their responses with a control group of patients who did not receive Evusheld. We show that patients who opted for treatment had higher baseline markers of psychological stress and ill-health compared with non-treated individuals but that treatment with Evusheld significantly improved the psychological health of recipients and increased the level of physical social/work interactions over that of control patients. Although there are limitations with this small study, the findings strongly suggest that Evusheld prophylaxis can provide significant psychological benefits for vulnerable blood cancer patients who have significant anxiety about COVID-19 infection.

Drug appropriateness is a pillar of modern evidence-based medicine, but the turnaround times of genomic sequencing are not compatible with the urgent need to deliver treatments against microorganisms. Massive worldwide genomic surveillance has created an unprecedented landscape for exploiting viral sequencing for therapeutic purposes. When it comes to therapeutic antiviral antibodies, using IC50 against specific polymorphisms of the target antigen can be calculated in vitro, and a list of mutations leading to drug resistance (immune escape) can be compiled. The author encountered this type of knowledge (available from the Stanford University Coronavirus Antiviral Resistance Database,) in a publicly accessible repository of SARS-CoV-2 sequences. The author used a custom function of the CoV-Spectrum.org web portal to deliver up-to-date, regional prevalence estimates of baseline efficacy for each authorized anti-spike mAb across all co-circulating SARS-CoV-2 sublineages at a given time point. This publicly accessible tool can inform therapeutic choices that would otherwise be blind. [ABSTRACT FROM AUTHOR]

Evusheld is a combination injection of tixagevimab and cilgavimab and is indicated for the pre-exposure prophylaxis of COVID-19 in adults and adolescents aged 12 years and older. Its use has been advocated for immunosuppressed individuals, such as blood cancer patients, although uptake varies significantly between countries. Despite extensive use internationally, there has been limited analysis of potential psychological benefits that vulnerable patients might gain from receiving this prophylactic medication. In this study we have quantified four key psychological health parameters in blood cancer patients who received Evusheld (EQ5D-3L quality of life score, DSM5 Agoraphobia score, Duke's Social Support Index and the hospital anxiety and depression score) and compared their responses with a control group of patients who did not receive Evusheld. We show that patients who opted for treatment had higher baseline markers of psychological stress and ill-health compared with non-treated individuals but that treatment with Evusheld significantly improved the psychological health of recipients and increased the level of physical social/work interactions over that of control patients. Although there are limitations with this small study, the findings strongly suggest that Evusheld prophylaxis can provide significant psychological benefits for vulnerable blood cancer patients who have significant anxiety about COVID-19 infection. [ABSTRACT FROM AUTHOR]

Tixagevimab 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. [ABSTRACT FROM AUTHOR]

Background: Tixagevimab and Cilgavimab (T + C) is authorized for pre‐exposure prophylaxis (PrEP) against Coronavirus Disease 2019 (COVID‐19) in solid organ transplant recipients (SOTRs), yet patient‐reported outcomes after injection are not well described. Furthermore, changes in risk tolerance after T + C PrEP have not been reported, of interest given uncertain activity against emerging Omicron sublineages. Methods: Within a national prospective observational study, SOTRs who reported receiving T + C were surveyed for 3 months to ascertain: (1) local and systemic reactogenicity, (2) severe adverse events with focus on cardiovascular and alloimmune complications, and (3) breakthrough COVID‐19, contextualized through (4) changes in attitudes regarding COVID‐19 risk and behaviors. Results: At 7 days postinjection, the most common reactions were mild fatigue (29%), headache (20%), and pain at injection sites (18%). Severe adverse events were uncommon; over 3 months of follow‐up, 4/392 (1%) reported acute rejection and one (.3%) reported a myocardial infarction. Breakthrough COVID‐19 occurred in 9%, 16–129 days after receiving full dose (300/300 mg) T + C, including two non‐ICU hospitalizations. Most surveyed SOTRs (65%) felt T + C PrEP was likely to reduce their COVID‐19 risk, and 70% reported increased willingness to engage in social activities such as visiting friends. However, few felt safe to return to in‐person work (20%) or cease public mask‐wearing (15%). Conclusions: In this prospective study of patient‐reported outcomes, T + C was well tolerated with few serious events. Several COVID‐19 breakthroughs were reported, notable as most SOTRs reported changes in risk tolerance after T + C. These results aid counseling of SOTRs regarding real‐world safety and effectiveness of T + C. [ABSTRACT FROM AUTHOR]

Background Tixagevimab and cilgavimab, a combined monoclonal antibody (Evusheld), was granted emergency use authorization for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) preexposure prophylaxis in individuals with immunocompromising conditions. In this study we used population-based real-world data to evaluate the effectiveness of Evusheld in immunocompromised patients. Methods Using the computerized database of the largest healthcare provider in Israel, we identified all adult immunocompromised patients who were eligible to receive Evusheld (150 mg tixagevimab and 150 mg cilgavimab) on 15 February 2022. Patients with a documentation of a prior SARS-CoV-2 infection were excluded. A total of 703 patients who received Evusheld were propensity score matched, using a ratio of 1:4, with 2812 patients who had not received Evusheld (control group). Patients were followed through 30 June 2022 for up to 90 days for the first documentation of SARS-CoV-2 infection and coronavirus disease 2019 (COVID-19)–related hospitalization. Results Overall, 72 patients in the Evusheld group and 377 patients in the control group had SARS-CoV-2 infection, reflecting an incidence rate of 4.18 and 5.64 per 100 person-months, respectively. The hazard ratios were 0.75 (95% confidence interval [CI]:.58–.96) for SARS-CoV-2 infection and 0.41 (95% CI:.19–.89) for COVID-19–related hospitalization in the Evusheld group compared to the control group. The magnitude of relative risk reduction of each outcome was greater in nonobese patients (P for interaction =.020 and.045, respectively). Conclusions This study suggests that Evusheld is effective in reducing the risk of SARS-CoV-2 infection and COVID-19 hospitalization in immunocompromised patients. The effectiveness of this dose appears to be greater in nonobese patients. [ABSTRACT FROM AUTHOR]

Introduction: The effect of tixagevimab/cilgavimab (Evusheld™; AstraZeneca, UK) should be evaluated in the context of concurrent outbreak situations. Methods: For serologic investigation of tixagevimab/cilgavimab during the BA.5 outbreak period, sera of immunocompromised (IC) hosts sampled before and one month after tixagevimab/cilgavimab administration and those of healthcare workers (HCWs) sampled one month after a 3rd shot of COVID-19 vaccines, five months after BA.1/BA.2 breakthrough infection (BI), and one month after BA.5 BI were investigated. Semi-quantitative anti-spike protein antibody (Sab) test and plaque reduction neutralizing test (PRNT) against BA.5 were performed. Results: A total of 19 IC hosts (five received tixagevimab/cilgavimab 300 mg and 14 received 600 mg) and 41 HCWs (21 experienced BA.1/BA.2 BI and 20 experienced BA.5 BI) were evaluated. Baseline characteristics did not differ significantly between IC hosts and HCWs except for age and hypertension. Sab significantly increased after tixagevimab/cilgavimab administration (median 130.2 BAU/mL before tixagevimab/cilgavimab, 5,665.8 BAU/mL after 300 mg, and 10,217 BAU/mL after 600 mg; both P < 0.001). Sab of one month after the 3rd shot (12,144.2 BAU/mL) or five months after BA.1/BA.2 BI (10,455.8 BAU/mL) were comparable with that of tixagevimab/cilgavimab 600 mg, while Sab of one month after BA.5 BI were significantly higher (22,216.0 BAU/mL; P < 0.001). BA.5 PRNT ND50 significantly increased after tixagevimab/cilgavimab administration (median ND50 29.6 before tixagevimab/cilgavimab, 170.8 after 300 mg, and 298.5 after 600 mg; both P < 0.001). The ND50 after tixagevimab/cilgavimab 600 mg was comparable to those of five months after BA.1 BI (ND50 200.9) while ND50 of one month after the 3rd shot was significantly lower (ND50 107.6; P = 0.019). The ND50 of one month after BA.5 BI (ND50 1,272.5) was highest among tested groups, but statistical difference was not noticed with tixagevimab/cilgavimab 600 mg. Conclusion: Tixagevimab/cilgavimab provided a comparable neutralizing activity against the BA.5 with a healthy adult population who were vaccinated with a 3rd shot and experienced BA.1/BA.2 BI. [ABSTRACT FROM AUTHOR]

Background and Objectives: In addition to a suboptimal and rapidly diminishing response to the coronavirus disease 2019 (COVID-19) vaccine, hemodialysis (HD) patients are at risk for developing a severe COVID-19 infection. In 2022, the combination of cilgavimab and tixagevimab (Evusheld, AstraZeneca) was approved for COVID-19 preexposure prophylaxis in high-risk groups. The purpose of this study was to evaluate the humoral response and short-term safety of this antibody combination in a group of HD patients. Materials and Methods: Seventy-three adult maintenance hemodialysis patients were recruited from a tertiary-care hospital for this double-blinded, non-randomized, placebo-controlled study. Patients were placed into two groups: the intervention group (n = 43) received a single 300 mg dosage of cilgavimab and tixagevimab, while the control group (n = 30) received a saline placebo. The titer of COVID-19-neutralizing antibodies was measured at baseline and after 1 and 6 months. The patients were evaluated for any drug-related adverse effects and monitored for six months for the emergence of any COVID-19-related events. Results: Patients in the intervention group were substantially older and had been on HD for longer (p = 0.002 and 0.006, respectively). The baseline antibody levels were higher in the Evusheld group. The antibody level in the intervention group increased significantly after 1 month and remained consistent for 6 months, whereas the antibody level in the control group fell significantly after 6 months during the study period (Wald χ2 = 30.620, p < 0.001). The drug-related adverse effects were modest and well-tolerated, and only seven patients experienced them. Six months after study enrollment, 10 patients in the intervention group and 6 patients in the control group had been infected with COVID-19, respectively. In the control group, ICU admission and mortality were observed, but in the intervention group, the infection was milder with no aggressive consequences. Conclusions: This study demonstrated the short-term safety and efficacy of tixagevimab–cilgavimab for COVID-19 preexposure prophylaxis in HD patients. These findings require more studies with more HD patients and longer follow-up periods.

Background: The past 2 years of the COVID-19 pandemic brought with it many unknowns for patients with immunodeficiency. Because of the concern for severe infection in those with immunocompromise, patients have been eager for effective prevention, vaccination, and treatment strategies. Preexposure prophylaxis provides another means of prevention in those with immunocompromise. A combination of tixagevimab and cilgavimab (Evusheld [AstraZeneca Cambridge, United Kingdom]) was granted emergency use authorization for preexposure prophylaxis at the end of 2021, but questions remained regarding how this would be tolerated and the side effects associated with its use. Objectives: Our aim was to evaluate the safety and tolerability of Evusheld in patients with CVID from our tri-site institution. Methods: We performed an institutional review board–approved, retrospective chart review of patients with common variable immunodeficiency (CVID) who received Evusheld before March 26, 2022. Results: Of the 45 patients with CVID who received Evusheld, 41 (91%) received the recommended full dose of 600 mg. The majority of patients (39 of 45 [87%]) tolerated Evusheld without adverse events. The adverse events reported included immediate injection site pain, fatigue and cough, an episode of shingles, and chest pain. Conclusions: This is an initial report on the safety and tolerability of Evusheld injections in patients with CVID. The majority of patients tolerated the injections without adverse events. For patients with reported chest pain, the results of a subsequent cardiac workup were negative. The efficacy of Evusheld could not be evaluated owing to the short median follow-up of this study (19 days).

Background Intramuscular AZD7442 (tixagevimab–cilgavimab [Evusheld; AstraZeneca]) has been found effective among immunocompromised individuals (ICIs) in reducing SARS-CoV-2 infection and severe disease in ICIs. We evaluated the association between AZD7442 administration and SARS-CoV-2 infection and severe disease (COVID-19 hospitalization and all-cause mortality) among selected ICIs, during a fifth Omicron-dominated wave of COVID-19 (December 2021–April 2022) in Israel. Methods ICIs aged ≥12 years identified in the Maccabi HealthCare Services database were invited by SMS/e-mail to receive AZD7442. Demographic information, comorbidities, coronavirus vaccination, and prior SARS-CoV-2 infection and COVID-19 outcome data (infection, severe disease) were extracted from the database. Rates of infection and severe disease were compared between those administered AZD7442 and those who did not respond to the invitation over a 3-month period. Results Of all 825 ICIs administered AZD7442, 29 (3.5%) became infected with SARS-CoV-2 compared with 308 (7.2%) of 4299 ICIs not administered AZD7442 (P <.001). After adjustment, the AZD7442 group was half as likely to become infected with SARS-CoV-2 than the nonadministered group (OR:.51; 95% CI:.30–.84). One person in the AZD7442 group (0.1%) was hospitalized for COVID-19 compared with 27 (0.6%) in the nonadministered group (P =.07). No mortality was recorded among the AZD7442 group compared with 40 deaths (0.9%) in the nonadministered group (P =.005). After adjustment, ICIs administered AZD7442 were 92% less likely to be hospitalized/die than those not administered AZD7442 (OR:.08; 95% CI:.01–.54). Conclusions AZD7442 among ICIs may protect against Omicron variant infection and severe disease and should be considered for pre-exposure prophylactic AZD7442. [ABSTRACT FROM AUTHOR]

Background: Persons with neuroinflammatory diseases (pwNID) treated with potent immunosuppressives are at risk of severe COVID-19 outcomes and reduced vaccine seroconversion. We aimed at determining the real-world efficacy of tixagevimab and cilgavimab (Evusheld™) in immunosuppressed pwNID in preventing breakthrough COVID-19 infections. Methods: 31 immunosuppressed pwNID were followed for 6 months after administration of tixagevimab and cilgavimab as a prophylactic COVID-19 medication (January 2022–July 2022). Only pwNID treated with anti-CD20 monoclonal antibodies and sphingosine-1-phosphate modulators were considered eligible for the study. A control group of 126 immunosuppressed pwNID (38 seropositive and 88 seronegative after SARS-CoV-2 vaccination) were included. Breakthrough COVID-19 infections rate and their severity was determined over the follow-up. Results: The pwNID treated with tixagevimab and cilgavimab had more comorbidities when compared with the total and seronegative pwNID control group (54.8% vs. 30.2% vs. 27.3%, p = 0.02 and p = 0.005, respectively). After a 6-month follow-up, significantly lower numbers of pwNID treated with tixagevimab and cilgavimab had breakthrough COVID-19 when compared with the control pwNID group (6.5% vs. 34.1%, p = 0.002) and seronegative control pwNID group (6.5% vs. 38.6%, p < 0.001). All COVID-19 infections in Evusheld-treated pwNID were mild, whereas 9/43 COVID-19 infections in the control group were moderate/severe. No side effects to tixagevimab and cilgavimab were recorded. Conclusion: In pwNID treated with immunosuppressive therapies, tixagevimab and cilgavimab (Evusheld™) significantly reduced the numbers and severity of breakthrough COVID-19 infections during the Omicron (BA.2–BA.5 variants) wave. [ABSTRACT FROM AUTHOR]

Effective treatments and vaccines against COVID-19 used in clinical practice have made a positive impact on controlling the spread of the pandemic, where they are available. Nevertheless, even if fully vaccinated, immunocompromised patients still remain at high risk of adverse outcomes. This has driven the largely expanding field of monoclonal antibodies, with variable results. Tixagevimab/Cilgavimab (AZD7442), a long-acting antibody combination that inhibits the attachment of the SARS-CoV-2 spike protein to the surface of cells, has proved promising in reducing the incidence of symptomatic COVID-19 or death in high-risk individuals without major adverse events when given as prophylaxis, as well as early treatment. Real-world data confirm the antibody combination's prophylaxis efficacy in lowering the incidence, hospitalization, and mortality associated with COVID-19 in solid organ transplant recipients, patients with immune-mediated inflammatory diseases and hematological malignancies, and patients in B-cell-depleting therapies. Data suggest a difference in neutralization efficiency between the SARS-CoV-2 subtypes in favor of the BA.2 over the BA.1. In treating COVID-19, AZD7442 showed a significant reduction in severe COVID-19 cases and mortality when given early in the course of disease, and within 5 days of symptom onset, without being associated with severe adverse events, even when it is used in addition to standard care. The possibility of the development of spike-protein mutations that resist monoclonal antibodies has been reported; therefore, increased vigilance is required in view of the evolving variants. AZD7442 may be a powerful ally in preventing COVID-19 and the mortality associated with it in high-risk individuals. Further research is required to include more high-risk groups and assess the concerns limiting its use, along the SARS-CoV-2 evolutionary trajectory. [ABSTRACT FROM AUTHOR]

Background: Tixagevimab/cilgavimab (TGM/CGM) are neutralizing monoclonal antibodies (mAbs) directed against different epitopes of the receptor-binding domain of the SARS-CoV-2 spike protein that have been considered as pre-exposure prophylaxis (PrEP). Objectives: This study seeks to assess the efficacy and safety of TGM/CGM to prevent COVID-19 in patients at high risk for breakthrough and severe SARS-CoV-2 infection who never benefited maximally from SARS-CoV-2 vaccination and for those who have a contraindication to SARS-CoV-2 vaccines. Design: This study is a systematic review and meta-analysis. The Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) statement was followed. Methods: Electronic databases (PubMed, CINAHL, Embase, medRxiv, ProQuest, Wiley online library, Medline, and Nature) were searched from 1 December 2021 to 30 November 2022 in the English language using the following keywords alone or in combination: 2019-nCoV, 2019 novel coronavirus, COVID-19, coronavirus disease 2019, SARS-CoV-2, severe acute respiratory syndrome coronavirus 2, tixagevimab, cilgavimab, combination, monoclonal, passive, immunization, antibody, efficacy, clinical trial, cohort, pre-exposure, prophylaxis, and prevention. We included studies in moderate to severe immunocompromised adults (aged ≥18 years) and children (aged ≥12 years) who cannot be vaccinated against COVID-19 or may have an inadequate response to SARS-CoV-2 vaccination. The effect sizes of the outcome of measures were pooled with 95% confidence intervals (CIs) and risk ratios (RRs). Results: Of the 76 papers that were identified, 30 articles were included in the qualitative analysis and 13 articles were included in the quantitative analysis (23 cohorts, 5 case series, 1 care report, and 1 randomized clinical trial). Studies involving 27,932 patients with high risk for breakthrough and severe COVID-19 that reported use of TGM/CGM combination were analyzed (all were adults (100%), 62.8% were men, and patients were mainly immunocompromised (66.6%)). The patients' ages ranged from 19.7 years to 79.8 years across studies. TGM/CGM use was associated with lower COVID-19-related hospitalization rate (0.54% vs. 1.2%, p = 0.27), lower ICU admission rate (0.6% vs. 5.2%, p = 0.68), lower mortality rate (0.2% vs. 1.2%, p = 0.67), higher neutralization of COVID-19 Omicron variant rate (12.9% vs. 6%, p = 0.60), lower proportion of patients who needed oxygen therapy (8% vs. 41.2%, p = 0.27), lower RT-PCR SARS-CoV-2 positivity rate (2.1% vs. 5.8%, p < 0.01), lower proportion of patients who had severe COVID-19 (0% vs. 0.5%, p = 0.79), lower proportion of patients who had symptomatic COVID-19 (1.8% vs. 6%, p = 0.22), and higher adverse effects rate (11.1% vs. 10.7%, p = 0.0066) than no treatment or other alternative treatment in the prevention of COVID-19. Conclusion: For PrEP, TGM/CGM-based treatment can be associated with a better clinical outcome than no treatment or other alternative treatment. However, more randomized control trials are warranted to confirm our findings and investigate the efficacy and safety of TGM/CGM to prevent COVID-19 in patients at risk for breakthrough or severe SARS-CoV-2 infection. [ABSTRACT FROM AUTHOR]

Background : Infection by SARS-CoV2 has become a challenge, especially for immunocompromised patients who show a weaker humoral response to COVID-19 vaccine. Tixagevimab+cilgavimab (Evusheld) is a combination of human monoclonal antibodies that can be used for pre-exposure prophylaxis to prevent infection or disease by SARS-CoV2. Objectives : Our study aimed to investigate the effectiveness of Evusheld by comparing an Exposed and an Unexposed group. Study design : Immunocompromised patients were enrolled in the Evusheld Group between March and September 2022. All patients had anti-spike IgG antibody levels <260 BAU/ml before administration of Evusheld. Blood samples for serological evaluations were collected, and anti-Spike antibodies were tested. For the Unexposed Group, a serologic test was performed at enrollment and a questionnaire was performed after 6 months. Results : 43 patients received Evusheld pre-exposure prophylaxis and 45 patients not receiving Evusheld were enrolled in the Unexposed group. The median age was 59.0 years in the Evusheld group, and 63.0 in the unexposed group. In the Evusheld group, during the Omicron wave in Italy, 23.3% of subjects developed symptomatic infection compared to 42.2% in the unexposed group. A majority of infections was seen in male respect to female patients. No difference in length of infection between the groups was seen. Antibody level remained higher than the basal threshold at 180 days from enrollment. Conclusions : Evusheld seems to reduce the rate of symptomatic infection in immunocompromised patients. Further data are required to determine whether this prophylaxis may have a longer-lasting effect over time. • Immunocompromised patients: weaker humoral response to Sars-CoV-2 vaccine. • Human monoclonal antibodies for pre-exposure prophylaxis. • Difference Sars-CoV-2 infection rate between males and females • Likely effectiveness of tixagevimab+cilgavimab in reducing symptomatic infection rate in immunocompromised patients. [ABSTRACT FROM AUTHOR]

Background: tixagevimab/cilgavimab, distributed under the name “Evusheld”, was the first available pre-exposure prophylaxis for COVID-19 other than vaccination. It received an EUA from the FDA after sufficient trial data showed efficacy in preventing SARS-CoV-2 infections and subsequent severe disease. Its potential benefits for high-risk immunocompromised patients generated a lot of interest. Individuals with multiple myeloma fall into this category, as they are characterized by attenuated immune responses and, in some cases, vaccines have limited efficacy. Methods: this single-center, prospective study included consecutive patients with multiple myeloma. All individuals were considered high-risk for COVID-19 due to their underlying disease. Baseline demographic and clinical characteristics, as well as data regarding COVID-19 infection and antibodies, were collected. Patients were administered two intramuscular 150 mg doses of Evusheld and were monitored during the follow-up period. Results: one hundred and eleven multiple myeloma patients were included in this analysis, with a median age of 64 years (range 58–69) and fifty-three were females (47.7%). Fourteen patients (12.6%) had a prior history of COVID-19 and all patients were vaccinated with either three or four doses of mRNA-based vaccines. An increase was observed in the median neutralizing-antibody levels before and after tixagevimab/cilgavimab administration, from 92.6% to 97.3%. The high levels were sustainable, with a median neutralizing-antibody level of 95.4% at 3 months post Evusheld administration. Overall, nine patients (8.1%) were diagnosed with COVID-19 during the follow-up period, at a median of 31 days. There were no SARS-CoV-2- infection-related hospitalizations or deaths. The monoclonal antibody combination was well tolerated, with no infusion-related reactions or major adverse events, and pain at the injection site only was reported by 33 patients (30%). Conclusions: tixagevimab/cilgavimab (Evusheld) seemed beneficial for patients with multiple myeloma, who presented high neutralizing-antibody levels and a low incidence of COVID-19 during the initial Omicron wave. No new safety concerns emerged. However, novel combinations of monoclonal antibodies against the new circulating variants of SARS-CoV-2 are deemed necessary in view of the emergence of immune tolerance.

Evusheld® (tixagevimab + cilgavimab; AZD7442) was the first anti-Spike monoclonal antibody (mAb) cocktail designed not only for treatment but also with pre-exposure prophylaxis in mind. The immunoglobulins were engineered for prolonged half-life by modifying the Fc fragment, thus creating a long-acting antibody (LAAB). We review here preclinical development, baseline and treatment-emergent resistance, clinical efficacy from registration trials, and real-world post-marketing evidence. The combination was initially approved for pre-exposure prophylaxis at the time of the SARS-CoV-2 Delta VOC wave based on a trial conducted in unvaccinated subjects when the Alpha VOC was dominant. Another trial also conducted at the time of the Alpha VOC wave proved efficacy as early treatment in unvaccinated patients and led to authorization at the time of the BA.4/5 VOC wave. Tixagevimab was ineffective against any Omicron sublineage, so cilgavimab has so far been the ingredient which has made a difference. Antibody monotherapy has a high risk of selecting for immune escape variants in immunocompromised patients with high viral loads, which nowadays represent the main therapeutic indication for antibody therapies. Among Omicron sublineages, cilgavimab was ineffective against BA.1, recovered efficacy against BA.2 and BA.2.12.1, but lost efficacy again against BA.4/BA.5 and BA.2.75. Our analysis indicated that Evusheld® has been used during the Omicron VOC phase without robust clinical data of efficacy against this variant and suggested that several regulatory decisions regarding its use lacked consistency. There is an urgent need for new randomized controlled trials in vaccinated, immunocompromised subjects, using COVID-19 convalescent plasma as a control arm. [ABSTRACT FROM AUTHOR]

The current pandemic due to the SARS-CoV-2 virus has caused irreparable damage globally. High importance is placed on defining current therapeutics for Coronavirus Disease 2019 (COVID-19). In this review, we discuss the evidence from pivotal trials that led to the approval of effective therapeutics in the treatment and prevention of COVID-19. We categorize them as effective outpatient and inpatient management strategies The review also attempts to contextualize the efficacy of therapeutics to the emerging variants. Vaccines, which remain the most effective prevention against hospitalization and deaths is not included in this review. [ABSTRACT FROM AUTHOR]

• Sixty-one percent of patients who were offered Evusheld chose to receive it. • Evusheld was largely well-tolerated among multiple sclerosis patients. • There were fewer COVID-19 infections in those who received Evusheld. • Antibody prophylaxis for viruses must consider evolving variants. In December 2021, the U.S. Food and Drug Administration issued emergency use authorization for the combination monoclonal antibodies tixagevimab and cilgavimab (Evusheld – AstraZeneca) for COVID-19 pre-exposure prophylaxis. While COVID-19 vaccination is recommended for multiple sclerosis (MS) patients, there is concern for insufficient antibody response in patients receiving B-cell depleting therapies. The literature is sparse regarding the safety and efficacy of Evusheld use in MS patients. We sought to investigate the administration, safety, and efficacy of Evusheld in MS patients. Participants were consecutively recruited from the UCSD MS Center from July 2022 to October 2022. We conducted both a review of medical records and a prospective cohort study. Inclusion criteria included prior diagnosis of MS and eligibility for Evusheld injection due to use of B-cell depleting disease modifying therapy (DMT). All eligible patients were evaluated to determine uptake of Evusheld use. Participant surveys were distributed to Evusheld recipients that evaluated for potential Evusheld side effects and COVID-19 vaccination and infection history. The proportion of COVID-19 infections among participants with or without Evusheld use were compared using Fisher's exact test, and a negative binomial regression analysis was used to evaluate risk for COVID-19 infection after Evusheld administration. A review of medical records showed that 79 MS patients were offered Evusheld by their clinicians during the recruitment period; 48 patients ultimately received the injection. Forty-two participants consented to the prospective cross-sectional study (mean age 46.4 years, 71.8 % female), of which 33 individuals received Evusheld. All participants received at least one COVID-19 vaccination dose, with 92.3 % receiving the initial series and at least one booster dose. One-third (30.8 %) of participants had a previous COVID-19 infection. DMTs included ocrelizumab, rituximab, and ofatumumab. Of the 33 participants who received Evusheld, 10 (30.3 %) reported experiencing at least one side effect. Injection site reactions included pain (most common), itchiness, and redness. General side effects included fatigue (most common), headache, muscle pain, and weakness. Of the 33 participants who received Evusheld, seven participants (21.2 %) tested positive for COVID-19 within 6 months of Evusheld injection. In an unadjusted binomial regression analysis, Evusheld administration was associated with a reduction in COVID-19 infection risk (OR 0.22, 95 % CI 0.05 – 1.02, p = 0.05). After adjusting for age and sex, Evusheld administration was still associated with a lower COVID-19 infection risk though it did not achieve nominal significance (OR 0.21, 95 % CI 0.04 - 1.09, p = 0.06). Of the 9 participants who were offered but did not receive Evusheld, five (55.6 %) tested positive for COVID-19 (p = 0.04 with Pearson's chi square test and p = 0.09 on Fisher's exact test). Our medical records data demonstrated that only 61 % of MS patients offered Evusheld received the injection. Evusheld seems to be largely well-tolerated. No serious adverse effects were reported. The use of Evusheld was associated with fewer COVID-19 infections, but this did not reach nominal statistical significance in the modest sample size. The lessons learned from the initial Evusheld experience may be applied to future interventions directed at infection prevention in MS patients on immunomodulatory therapies. [ABSTRACT FROM AUTHOR]

Drug appropriateness is a pillar of modern evidence-based medicine, but the turnaround times of genomic sequencing are not compatible with the urgent need to deliver treatments against microorganisms. Massive worldwide genomic surveillance has created an unprecedented landscape for exploiting viral sequencing for therapeutic purposes. When it comes to therapeutic antiviral antibodies, using IC50 against specific polymorphisms of the target antigen can be calculated in vitro, and a list of mutations leading to drug resistance (immune escape) can be compiled. The author encountered this type of knowledge (available from the Stanford University Coronavirus Antiviral Resistance Database,) in a publicly accessible repository of SARS-CoV-2 sequences. The author used a custom function of the CoV-Spectrum.org web portal to deliver up-to-date, regional prevalence estimates of baseline efficacy for each authorized anti-spike mAb across all co-circulating SARS-CoV-2 sublineages at a given time point. This publicly accessible tool can inform therapeutic choices that would otherwise be blind.

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Background: Persons with neuroinflammatory diseases (pwNID) treated with potent immunosuppressives are at risk of severe COVID-19 outcomes and reduced vaccine seroconversion. We aimed at determining the real-world efficacy of tixagevimab and cilgavimab (Evusheld™) in immunosuppressed pwNID in preventing breakthrough COVID-19 infections. Methods: 31 immunosuppressed pwNID were followed for 6 months after administration of tixagevimab and cilgavimab as a prophylactic COVID-19 medication (January 2022–July 2022). Only pwNID treated with anti-CD20 monoclonal antibodies and sphingosine-1-phosphate modulators were considered eligible for the study. A control group of 126 immunosuppressed pwNID (38 seropositive and 88 seronegative after SARS-CoV-2 vaccination) were included. Breakthrough COVID-19 infections rate and their severity was determined over the follow-up. Results: The pwNID treated with tixagevimab and cilgavimab had more comorbidities when compared with the total and seronegative pwNID control group (54.8% vs. 30.2% vs. 27.3%, p = 0.02 and p = 0.005, respectively). After a 6-month follow-up, significantly lower numbers of pwNID treated with tixagevimab and cilgavimab had breakthrough COVID-19 when compared with the control pwNID group (6.5% vs. 34.1%, p = 0.002) and seronegative control pwNID group (6.5% vs. 38.6%, p < 0.001). All COVID-19 infections in Evusheld-treated pwNID were mild, whereas 9/43 COVID-19 infections in the control group were moderate/severe. No side effects to tixagevimab and cilgavimab were recorded. Conclusion: In pwNID treated with immunosuppressive therapies, tixagevimab and cilgavimab (Evusheld™) significantly reduced the numbers and severity of breakthrough COVID-19 infections during the Omicron (BA.2–BA.5 variants) wave.

Background: Tixagevimab/cilgavimab (TGM/CGM) are neutralizing monoclonal antibodies (mAbs) directed against different epitopes of the receptor-binding domain of the SARS-CoV-2 spike protein that have been considered as pre-exposure prophylaxis (PrEP). Objectives: This study seeks to assess the efficacy and safety of TGM/CGM to prevent COVID-19 in patients at high risk for breakthrough and severe SARS-CoV-2 infection who never benefited maximally from SARS-CoV-2 vaccination and for those who have a contraindication to SARS-CoV-2 vaccines. Design: This study is a systematic review and meta-analysis. The Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) statement was followed. Methods: Electronic databases (PubMed, CINAHL, Embase, medRxiv, ProQuest, Wiley online library, Medline, and Nature) were searched from 1 December 2021 to 30 November 2022 in the English language using the following keywords alone or in combination: 2019-nCoV, 2019 novel coronavirus, COVID-19, coronavirus disease 2019, SARS-CoV-2, severe acute respiratory syndrome coronavirus 2, tixagevimab, cilgavimab, combination, monoclonal, passive, immunization, antibody, efficacy, clinical trial, cohort, pre-exposure, prophylaxis, and prevention. We included studies in moderate to severe immunocompromised adults (aged ≥18 years) and children (aged ≥12 years) who cannot be vaccinated against COVID-19 or may have an inadequate response to SARS-CoV-2 vaccination. The effect sizes of the outcome of measures were pooled with 95% confidence intervals (CIs) and risk ratios (RRs). Results: Of the 76 papers that were identified, 30 articles were included in the qualitative analysis and 13 articles were included in the quantitative analysis (23 cohorts, 5 case series, 1 care report, and 1 randomized clinical trial). Studies involving 27,932 patients with high risk for breakthrough and severe COVID-19 that reported use of TGM/CGM combination were analyzed (all were adults (100%), 62.8% were men, and patients were mainly immunocompromised (66.6%)). The patients’ ages ranged from 19.7 years to 79.8 years across studies. TGM/CGM use was associated with lower COVID-19-related hospitalization rate (0.54% vs. 1.2%, p = 0.27), lower ICU admission rate (0.6% vs. 5.2%, p = 0.68), lower mortality rate (0.2% vs. 1.2%, p = 0.67), higher neutralization of COVID-19 Omicron variant rate (12.9% vs. 6%, p = 0.60), lower proportion of patients who needed oxygen therapy (8% vs. 41.2%, p = 0.27), lower RT-PCR SARS-CoV-2 positivity rate (2.1% vs. 5.8%, p < 0.01), lower proportion of patients who had severe COVID-19 (0% vs. 0.5%, p = 0.79), lower proportion of patients who had symptomatic COVID-19 (1.8% vs. 6%, p = 0.22), and higher adverse effects rate (11.1% vs. 10.7%, p = 0.0066) than no treatment or other alternative treatment in the prevention of COVID-19. Conclusion: For PrEP, TGM/CGM-based treatment can be associated with a better clinical outcome than no treatment or other alternative treatment. However, more randomized control trials are warranted to confirm our findings and investigate the efficacy and safety of TGM/CGM to prevent COVID-19 in patients at risk for breakthrough or severe SARS-CoV-2 infection.

Effective treatments and vaccines against COVID-19 used in clinical practice have made a positive impact on controlling the spread of the pandemic, where they are available. Nevertheless, even if fully vaccinated, immunocompromised patients still remain at high risk of adverse outcomes. This has driven the largely expanding field of monoclonal antibodies, with variable results. Tixagevimab/Cilgavimab (AZD7442), a long-acting antibody combination that inhibits the attachment of the SARS-CoV-2 spike protein to the surface of cells, has proved promising in reducing the incidence of symptomatic COVID-19 or death in high-risk individuals without major adverse events when given as prophylaxis, as well as early treatment. Real-world data confirm the antibody combination’s prophylaxis efficacy in lowering the incidence, hospitalization, and mortality associated with COVID-19 in solid organ transplant recipients, patients with immune-mediated inflammatory diseases and hematological malignancies, and patients in B-cell-depleting therapies. Data suggest a difference in neutralization efficiency between the SARS-CoV-2 subtypes in favor of the BA.2 over the BA.1. In treating COVID-19, AZD7442 showed a significant reduction in severe COVID-19 cases and mortality when given early in the course of disease, and within 5 days of symptom onset, without being associated with severe adverse events, even when it is used in addition to standard care. The possibility of the development of spike-protein mutations that resist monoclonal antibodies has been reported; therefore, increased vigilance is required in view of the evolving variants. AZD7442 may be a powerful ally in preventing COVID-19 and the mortality associated with it in high-risk individuals. Further research is required to include more high-risk groups and assess the concerns limiting its use, along the SARS-CoV-2 evolutionary trajectory.

Evusheld® (tixagevimab + cilgavimab; AZD7442) was the first anti-Spike monoclonal antibody (mAb) cocktail designed not only for treatment but also with pre-exposure prophylaxis in mind. The immunoglobulins were engineered for prolonged half-life by modifying the Fc fragment, thus creating a long-acting antibody (LAAB). We review here preclinical development, baseline and treatment-emergent resistance, clinical efficacy from registration trials, and real-world post-marketing evidence. The combination was initially approved for pre-exposure prophylaxis at the time of the SARS-CoV-2 Delta VOC wave based on a trial conducted in unvaccinated subjects when the Alpha VOC was dominant. Another trial also conducted at the time of the Alpha VOC wave proved efficacy as early treatment in unvaccinated patients and led to authorization at the time of the BA.4/5 VOC wave. Tixagevimab was ineffective against any Omicron sublineage, so cilgavimab has so far been the ingredient which has made a difference. Antibody monotherapy has a high risk of selecting for immune escape variants in immunocompromised patients with high viral loads, which nowadays represent the main therapeutic indication for antibody therapies. Among Omicron sublineages, cilgavimab was ineffective against BA.1, recovered efficacy against BA.2 and BA.2.12.1, but lost efficacy again against BA.4/BA.5 and BA.2.75. Our analysis indicated that Evusheld® has been used during the Omicron VOC phase without robust clinical data of efficacy against this variant and suggested that several regulatory decisions regarding its use lacked consistency. There is an urgent need for new randomized controlled trials in vaccinated, immunocompromised subjects, using COVID-19 convalescent plasma as a control arm.

• No antiCD20-treated MS/NMOSD patients developed COVID-19 after receiving evusheld. • Three antiCD20-treated patients in the matched control group developed COVID-19. • Evusheld group's risk of COVID-19 is 20.2 % of the control group's risk. • Bayesian statistics has ability to handle complex real-world data effectively. AntiCD20 therapy, such as rituximab, ocrelizumab, or ofatumumab, effectively treats patients with multiple sclerosis (pwMS) or neuromyelitis optica spectrum disorder (pwNMOSD) but negatively affects the humoral immune response to COVID-19 vaccination. One strategy to protect these patients is using tixagevimab/cilgavimab (T/C) as pre-exposure prophylaxis. This study aimed to evaluate the effect of T/C on the incidence of COVID-19 in pwMS and pwNMOSD. Data in this observational cohort study were collected in two Czech MS centres through ReMuS registry between March 1, 2020 and December 31, 2022. Adult pwMS and pwNMOSD who were (1) treated with antiCD20 therapy at least six months before T/C administration, or at least from February 1, 2022 in the control group; (2) were already on antiCD20 therapy at the time of vaccination or COVID-19 infection; and (3) were on antiCD20 therapy at least 100 days after T/C, or at least 90 days after August 1, 2022 in the control group, were included. Analysis was performed using frequency-based (propensity score matching) and Bayesian statistical methods (informative and non-informative priors). Using propensity score matching 1:1, 47 patients who received T/C (mean age 45.7 years, median disease duration 12.5 years) were matched with those who did not receive T/C (n = 341; mean age 46.6 years, median disease duration 11.4 years) based on age, MS/NMOSD duration, and number of vaccine doses. None of the T/C patients and three in the control matched group, developed COVID-19 between 10 and 100 days after receiving T/C, August 1, 2022, respectively. The frequency of COVID-19 was not significantly different between groups (p = 0.242). Due to the low number of patients, a Bayesian analysis was also added. Using a non-informative Bayesian prior, the median relative risk of COVID-19 after T/C was 7.6 % (95 % CrI 0.02–115.9 %). The posterior probability of risk difference lower than zero was 96.4 %. Using an informative prior (based on the registration study of Evusheld), the median relative risk of COVID-19 after T/C was 20.2 % (95 % CI 8.4–43.8 %). The posterior probability of the risk difference lower than zero was 100 %. This work highlights the possible good efficacy of T/C in antiCD20-treated pwMS and pwNMSOD. Based on Bayesian analysis with an informative prior, the T/C group's risk of COVID-19 infection was approximately 20.2 % of the control group's risk. However, given the low frequency of COVID-19, the results of this pilot analysis must be interpreted with caution. [ABSTRACT FROM AUTHOR]

B-cell-depleting treatments, such as ocrelizumab and rituximab (anti-CD20), reduce humoral response to SARS-CoV-2 in people with Multiple Sclerosis (pwMS) and Neuromyelitis Optica Spectrum Disorder (NMOSD) and are associated with an increased risk of a more severe course of COVID-19 disease. The combination of tixagevimab and cilgavimab was authorized for COVID-19 prevention in immunocompromised subjects at high risk of severe COVID-19 disease, including patients treated with anti-CD20. Few real-world studies are available regarding the use of tixagevimab/cilgavimab in pwMS/NMOSD. In the present study, we describe the use of tixagevimab/cilgavimab for SARS-CoV-2 pre-exposure prophylaxis in a cohort of pwMS and NMOSD, treated with ocrelizumab and rituximab respectively. 26 subjects were treated with tixagevimab/cilgavimab, while we used 18 patients as the control group. We collected clinical data at baseline in all patients and during scheduled follow up evaluations. SARS-CoV-2 serological status pre- and post-tixagevimab/cilgavimab treatment was available for 10 patients. We observed no adverse events following tixagevimab/cilgavimab treatment. Post-tixagevimab/cilgavimab anti-Spike-1-RBD IgG were significantly higher when compared to baseline values. No difference was found when comparing the percentage of COVID-19 infections between groups. All patients infected with SARS-CoV-2 had mild disease which did not require hospitalization. In patients treated with tixagevimab/cilgavimab, the rate of infection among patients exposed to SARS-CoV-2 was lower, without reaching statistical significance. We observed a significantly longer negativization time in the treated group. Our results are not consistent with what was observed in the registration trial and some more recent studies. We did not observe a difference in COVID-19 incidence nor in disease severity in MS and NMOSD between treated and untreated patients. Our different results may be partially explained by the change in SARS-CoV-2 variants epidemiology (i.e. reduced efficacy of tixagevimab and cilgavimab against the currently dominant variants) as well as different patient selection included in the trial and different dose of tixagevimab/cilgavimab used in other studies. The present report provides a real-life experience with tixagevimab/cilgavimab in pwMS and NMOSD treated with anti-CD20, with findings that are in line with the current SARS-CoV-2 epidemiology and the recent evidence regarding SARS-CoV-2 variants. Our results warrant further research to best treat patients in the present and future pandemic scenario. [ABSTRACT FROM AUTHOR]

Background: Tixagevimab and cilgavimab (Evusheld) administration is a recommended strategy for unvaccinated patients with immunocompromised conditions and severe allergic reaction conditions to protect high-risk individuals and control the coronavirus disease 2019 (COVID-19) epidemic. We estimated the cost-effectiveness of Evusheld in key risk populations: 1) immunocompromised (vaccinated/unvaccinated), 2) severe allergic reaction, and 3) unvaccinated elderly high-risk groups., Methods: Based on the estimated target risk group population, we used a model of COVID-19 transmission to estimate the size of the risk group population for whom Evusheld treatment may help prevent symptomatic COVID-19 (and deaths) in 2022. We projected Evusheld intervention costs, quality-adjusted life year (QALY) lost, cost averted and QALY gained by reduced COVID-19 incidence, and incremental cost-effectiveness (cost per QALY gained) in each modeled population from the healthcare system perspective., Results: Our study demonstrated that Evusheld treatment for COVID-19 infection in South Korea is highly cost-effective for unvaccinated risk groups ($18,959 per QALY gained for immunocompromised and $23,978 per QALY gained for high-risk elderly groups) and moderately cost-effective among individuals who are vaccinated immunocompromised ($46,494 per QALY gained), or have severe allergic reactions ($45,996 per QALY gained). Evusheld's cost-effectiveness may be subject to risk-group-specific COVID-19 disease progression and Evusheld efficacy and cost, which may change in future epidemic scenarios., Conclusion: As the COVID-19 variants and risk group-specific durable efficacy, toxicity (and/or resistance) and optimal dosing of Evusheld remain uncertain, better empirical estimates to inform these values in different epidemiological contexts are needed. These results may help decision-makers prioritize resources toward more equitable and effective COVID-19 control efforts., Competing Interests: The authors have no potential conflicts of interest to disclose., (© 2023 The Korean Academy of Medical Sciences.)

Tixagevimab/cilgavimab is a monoclonal antibody used to prevent coronavirus disease 2019 among immunocompromised hosts and maintained neutralizing activity against early omicron variants. Omicron BN.1 became a dominant circulating strain in Korea early 2023, but its susceptibility to tixagevimab/cilgavimab is unclear. We conducted plaque reduction neutralization test (PRNT) against BN.1 in a prospective cohort (14 patients and 30 specimens). BN.1 PRNT was conducted for one- and three-months after tixagevimab/cilgavimab administration and the average PRNT ND 50 of each point was lower than the positive cut-off value of 20 (12.9 ± 4.5 and 13.2 ± 4.2, respectively, P = 0.825). In the paired analyses, tixagevimab/cilgavimab-administered sera could not actively neutralize BN.1 (PRNT ND 50 11.5 ± 2.9, P = 0.001), compared with the reserved activity against BA.5 (ND 50 310.5 ± 180.4). Unlike virus-like particle assay, tixagevimab/cilgavimab was not active against BN.1 in neutralizing assay, and would not be effective in the present predominance of BA.2.75 sublineages., Competing Interests: The authors have no potential conflicts of interest to disclose., (© 2023 The Korean Academy of Medical Sciences.)

Introduction:  Hemodialysis patients are deemed to be immunosuppressed and may not be able to mount an adequate response to vaccination against the SARS-CoV-2 virus. Due to the higher morbidity and mortality in this vulnerable group, pre-exposure prophylaxis with monoclonal antibodies was introduced as an additional measure for protection in selected community-based hemodialysis patients in Singapore. Tixagevimab and cilgavimab, available as Evusheld, were used for this purpose., Methods:  A government-sponsored clinical administration program with the provision of 200 doses of Evusheld at no cost to the patients was implemented. Patient selection criteria to further risk-stratify this vulnerable hemodialysis patient cohort was developed and 200 patients were finally selected. Evusheld administration was done over a period of two months, as two consecutive injections were given at two separate intramuscular sites, which constituted one administration. Data were collected as part of a retrospective clinical audit, as part of a routine quality monitoring process for this patient care program. Real-world evidence was generated to assess the impact on mortality, hospitalization rate, reason for hospitalization, and any associated morbidity., Results:  No adverse events from the Evusheld administration were noted. All recipients had received COVID-19 vaccinations prior to Tixa-Cilga, with a range of one to five doses. A total of 198 (99%) completed two doses and 189 (95%) completed three doses, out of which, 14 (7%) patients contracted COVID-19 infection over three months. The overall hospitalization rate was 2% (four out of 200 patients). Severe illness that required intensive care unit stay was therefore seen in only 2 (1%) out of 200 patients. None of the infected patients died., Discussion:  A significant reduction in severity of illness, hospitalization rate, and mortality was found with pre-exposure prophylaxis with tixagevimab and cilgavimab, in this real-world experience from Singapore. Evusheld administration reduced the hospitalization rate from 42.5% to 2%, which is a reduction of 95.3% (p<0.0001). Symptoms in infected patients were mild, with only 1% being admitted to the intensive care unit. The mortality rate from COVID-19 infection was reduced from 2.5% to 0% with Evusheld.  Conclusion: Mass administration of prophylactic treatments for vulnerable populations can be challenging in community-based settings and the successful implementation of such a program has been described. The findings can have health policy implications for the protection of such immunocompromised patients in the future. The combination of tixagevimab and cilgavimab, available as Evusheld in Singapore, was safe to use in hemodialysis patients, with no adverse events noted. There was a significant reduction in hospitalization rates and intensive care unit admissions with a zero-mortality rate due to COVID-19 infection, after pre-exposure prophylaxis., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2023, Khan et al.)

Background: The past 2 years of the COVID-19 pandemic brought with it many unknowns for patients with immunodeficiency. Because of the concern for severe infection in those with immunocompromise, patients have been eager for effective prevention, vaccination, and treatment strategies. Preexposure prophylaxis provides another means of prevention in those with immunocompromise. A combination of tixagevimab and cilgavimab (Evusheld [AstraZeneca Cambridge, United Kingdom]) was granted emergency use authorization for preexposure prophylaxis at the end of 2021, but questions remained regarding how this would be tolerated and the side effects associated with its use., Objectives: Our aim was to evaluate the safety and tolerability of Evusheld in patients with CVID from our tri-site institution., Methods: We performed an institutional review board-approved, retrospective chart review of patients with common variable immunodeficiency (CVID) who received Evusheld before March 26, 2022., Results: Of the 45 patients with CVID who received Evusheld, 41 (91%) received the recommended full dose of 600 mg. The majority of patients (39 of 45 [87%]) tolerated Evusheld without adverse events. The adverse events reported included immediate injection site pain, fatigue and cough, an episode of shingles, and chest pain., Conclusions: This is an initial report on the safety and tolerability of Evusheld injections in patients with CVID. The majority of patients tolerated the injections without adverse events. For patients with reported chest pain, the results of a subsequent cardiac workup were negative. The efficacy of Evusheld could not be evaluated owing to the short median follow-up of this study (19 days)., (© 2023 The Authors.)

Background: The Omicron era of the COVID-19 pandemic commenced at the beginning of 2022 and whilst it started with primarily BA.1, it was latter dominated by BA.2 and the related sub-lineage BA.5. Following resolution of the global BA.5 wave, a diverse grouping of Omicron sub-lineages emerged derived from BA.2, BA.5 and recombinants thereof. Whilst emerging from distinct lineages, all shared similar changes in the Spike glycoprotein affording them an outgrowth advantage through evasion of neutralising antibodies., Methods: Over the course of 2022, we monitored the potency and breadth of antibody neutralization responses to many emerging variants in the Australian community at three levels: (i) we tracked over 420,000 U.S. plasma donors over time through various vaccine booster roll outs and Omicron waves using sequentially collected IgG pools; (ii) we mapped the antibody response in individuals using blood from stringently curated vaccine and convalescent cohorts. (iii) finally we determine the in vitro efficacy of clinically approved therapies Evusheld and Sotrovimab., Findings: In pooled IgG samples, we observed the maturation of neutralization breadth to Omicron variants over time through continuing vaccine and infection waves. Importantly, in many cases, we observed increased antibody breadth to variants that were yet to be in circulation. Determination of viral neutralization at the cohort level supported equivalent coverage across prior and emerging variants with isolates BQ.1.1, XBB.1, BR.2.1 and XBF the most evasive. Further, these emerging variants were resistant to Evusheld, whilst increasing neutralization resistance to Sotrovimab was restricted to BQ.1.1 and XBF. We conclude at this current point in time that dominant variants can evade antibodies at levels equivalent to their most evasive lineage counterparts but sustain an entry phenotype that continues to promote an additional outgrowth advantage. In Australia, BR.2.1 and XBF share this phenotype and, in contrast to global variants, are uniquely dominant in this region in the later months of 2022., Interpretation: Whilst the appearance of a diverse range of omicron lineages has led to primary or partial resistance to clinically approved monoclonal antibodies, the maturation of the antibody response across both cohorts and a large donor pools importantly observes increasing breadth in the antibody neutralisation responses over time with a trajectory that covers both current and known emerging variants., Funding: This work was primarily supported by Australian Medical Foundation research grants MRF2005760 (SGT, GM & WDR), Medical Research Future Fund Antiviral Development Call grant (WDR), the New South Wales Health COVID-19 Research Grants Round 2 (SGT & FB) and the NSW Vaccine Infection and Immunology Collaborative (VIIM) (ALC). Variant modeling was supported by funding from SciLifeLab's Pandemic Laboratory Preparedness program to B.M. (VC-2022-0028) and by the European Union's Horizon 2020 research and innovation programme under grant agreement no. 101003653 (CoroNAb) to B.M., Competing Interests: Declaration of interests Funding bodies did not contribute to study design, data collection, data analysis or writing of the manuscript. Study design, data collection, data analysis and data interpretation was performed by the listed authors. Writing and review was performed by the listed authors. A.L.C. Participated on the AstraZeneca COVID-19 Advisory Board (2021), Seqirus COVID Advisory Board (2020) & CSL Seqirus APAC Advisory Council (2022). N.R., T.B., S.A.C., S.M., and T.H. are employees and shareholders of CSL LTD, a manufacturer of the polyclonal immunoglobulin preparations used as a reagent within the study., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Introduction: The effect of tixagevimab/cilgavimab (Evusheld™; AstraZeneca, UK) should be evaluated in the context of concurrent outbreak situations., Methods: For serologic investigation of tixagevimab/cilgavimab during the BA.5 outbreak period, sera of immunocompromised (IC) hosts sampled before and one month after tixagevimab/cilgavimab administration and those of healthcare workers (HCWs) sampled one month after a 3 rd shot of COVID-19 vaccines, five months after BA.1/BA.2 breakthrough infection (BI), and one month after BA.5 BI were investigated. Semi-quantitative anti-spike protein antibody (Sab) test and plaque reduction neutralizing test (PRNT) against BA.5 were performed., Results: A total of 19 IC hosts (five received tixagevimab/cilgavimab 300 mg and 14 received 600 mg) and 41 HCWs (21 experienced BA.1/BA.2 BI and 20 experienced BA.5 BI) were evaluated. Baseline characteristics did not differ significantly between IC hosts and HCWs except for age and hypertension. Sab significantly increased after tixagevimab/cilgavimab administration (median 130.2 BAU/mL before tixagevimab/cilgavimab, 5,665.8 BAU/mL after 300 mg, and 10,217 BAU/mL after 600 mg; both P < 0.001). Sab of one month after the 3 rd shot (12,144.2 BAU/mL) or five months after BA.1/BA.2 BI (10,455.8 BAU/mL) were comparable with that of tixagevimab/cilgavimab 600 mg, while Sab of one month after BA.5 BI were significantly higher (22,216.0 BAU/mL; P < 0.001). BA.5 PRNT ND 50 significantly increased after tixagevimab/cilgavimab administration (median ND 50 29.6 before tixagevimab/cilgavimab, 170.8 after 300 mg, and 298.5 after 600 mg; both P < 0.001). The ND 50 after tixagevimab/cilgavimab 600 mg was comparable to those of five months after BA.1 BI (ND 50 200.9) while ND 50 of one month after the 3 rd shot was significantly lower (ND 50 107.6; P = 0.019). The ND 50 of one month after BA.5 BI (ND 50 1,272.5) was highest among tested groups, but statistical difference was not noticed with tixagevimab/cilgavimab 600 mg., Conclusion: Tixagevimab/cilgavimab provided a comparable neutralizing activity against the BA.5 with a healthy adult population who were vaccinated with a 3 rd shot and experienced BA.1/BA.2 BI., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Yang, Won, Baek, Lee, Kim, Huh, Cho, Kang, Chung, Peck, Lee, Park, Yoon, Kim, Kim, Yim, Kim, Hyeon, Kim, Lee and Ko.)

Introduction: Direct-acting SARS-CoV-2 antiviral monoclonal antibodies have been an integral part of therapeutic strategies against COVID-19 pandemic. The monoclonal strategy was jeopardized by the emergence of new variants and resistant strains, making many monoclonal antibodies quickly obsolete. Nevertheless, a possible strategy consists in the use of antibody cocktails and the development of the cilgavimab + tixagevimab in combination is placed in this context., Areas Covered: In this review, we describe the development of the cilgavimab + tixagevimab cocktail, from pre-clinical to real-world evidence., Expert Opinion: The pre-clinical and clinical development of cilgavimab + tixagevimab followed a similar path to that of the antibodies developed in the earlier stages of the pandemic. Both antibodies have been developed from convalescent plasma and have been shown to be effective in clinical trials in prophylaxis and in early therapy. This cocktail has found its position in therapy especially in immunocompromised subjects for whom vaccine prevention is not feasible. The cocktail strategy, together with a more stable pandemic situation, could ensure a certain longevity to the drug against resistance, especially when compared with that of other antibodies. Recently emerged Omicron sub-lineages have demonstrated the ability to escape this cocktail's activity and so the future of this treatment could be compromised.