Efficacy and Safety of Tixagevimab/Cilgavimab to Prevent COVID-19 (Pre-Exposure Prophylaxis): A Systematic Review and Meta-Analysis

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.


Introduction
Certain individuals may not benefit maximally from coronavirus disease 2019 (COVID- 19) vaccines compared to the general population in whom COVID-19 vaccination is the optimal method of pre-exposure prophylaxis (PrEP) [1,2]. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in people with moderate to severe immunocompromising conditions is associated with higher mortality compared to immunocompetent individuals, and immunocompromised individuals show an impaired anti-SARS-CoV-2 vaccine response even after four vaccine doses [3][4][5][6]. In this context, monoclonal antibody regimens (mAbs) providing passive immunization have been developed to enhance immunity against SARS-CoV-2 in immunocompromised patients [7]. In December 2021, tixagevimab-cilgavimab (TGM/CGM) received emergency use authorization (EUA) from the United States Food and Drug Administration (FDA) as PrEP in individuals aged 12 years or older (weighing at least 40 kg) who either are moderate to severely immunocompromised and cannot be vaccinated against COVID-19 or who may have an inadequate response to SARS-CoV-2 vaccination [7]. Subsequently, Europe approved TGM/CGM for PrEP in immunocompromised patients [8]. TGM/CGM is available as two separate injections given intramuscularly and given one after the other (Evusheld ® , AstraZeneca Pharmaceuticals LP, Wilmington, DE 19850, USA), and the recommended revised dosing by the United States FDA is 600 mg, consisting of 300 mg of tixagevimab and 300 mg of cilgavimab to ensure the neutralization of this mAb combination against the COVID-19 Omicron subvariants, administered as separate sequential injections at different sites in two different muscles, preferably in the gluteal muscles [7]. TGM/CGM are neutralizing mAbs directed against different epitopes of the receptor-binding domain (RBD) of the SARS-CoV-2 spike protein and have been associated with a lower risk of SARS-CoV-2 infection when used for PrEP (See Figure 1).
The randomized controlled trial that led to authorization of the TGM/CGM combination involved 5197 adults (≥18 years or older) who were not vaccinated against SARS-CoV-2 and never transmitted COVID-19, and were deemed to be at high risk for breakthrough and severe SARS-CoV-2 infection (old age ≥ 60 years and/or many medical comorbidities) [9]. Overall, serious adverse events in this trial mentioned above were balanced between the TGM/CGM versus placebo groups [9]. Given the potential for TGM/CGM as an mAb therapy to prevent COVID-19, the combination has been evaluated in several small clinical cohorts [10][11][12]. Therefore, we carried out this meta-analysis to identify, describe, evaluate,

Aim of the Study
This systematic review and meta-analysis aimed to assess the efficacy and safety of the monoclonal antibody combination TGM/CGM to prevent COVID-19 in patients at high risk for breakthrough and severe SARS-CoV-2 infection who might not benefit maximally from SARS-CoV-2 vaccination and for those who have a contraindication to SARS-CoV-2 vaccination in published research.

Data Extraction and Analysis
The screening of the papers was performed independently by four reviewers (Saad Alhumaid, Jalal Alali, Nourah Al Dossary, and Sami Hussain Albattat), by screening titles with abstracts using the selection criteria. Disagreements in the study selection after the full text screening were discussed, and if agreement could not be reached, a fifth reviewer was involved (Sarah Mahmoud Al HajjiMohammed). We categorized articles as case reports, case series, clinical trials, or cohort studies. The following data were extracted from the selected studies: authors; publication year; study location; study design and setting; age, gender, and sample size; details of study intervention and control therapies in addition to data on adverse events and treatment outcomes; time from TGM/CGM administration to first episode of symptomatic COVID-19; assessment of study risk of bias; and remarks on notable findings.

Risk of Biased Evaluation of Included Studies
Three tools were used appropriately to assess the quality of the studies included in this review: (1) Newcastle-Ottawa Scale (NOS) to evaluate cohort studies (scoring criteria: >7 scores = high quality, 5-7 scores = moderate quality, and <5 scores = low quality) [15]; (2) modified NOS to evaluate case report and case series studies (scoring criteria: 5 criteria fulfilled = good, 4 criteria fulfilled = moderate, and 3 criteria fulfilled = low) [16]; and (3) Revised Cochrane risk-of-bias tool (RoB 2.0) to evaluate randomized controlled trials (bias is assessed in five distinct domains and answers lead to judgments of "low risk of bias," "some concerns," or "high risk of bias") [17]. Quality assessment was conducted by three co-authors (Fatimah Saad Almuaiweed, Sukainah Mohammad Alshaikhnasir, and Maryam Radhi AlZaid) who separately evaluated the possibility of bias using these three tools.

Statistical Analysis
Because all of the data were continuous and dichotomous data, risk ratios (RRs) were used for estimating the point estimate, along with 95% confidence intervals (CIs). Taking a conservative approach, a random effects with the DerSimonian-Laird model was used [18], which produces wider CIs than a fixed effect model. Publication bias was evaluated using funnel plots and the Egger's correlation test, with p < 0.05 indicating statistical significance [19]. R version 4.1.0 with the packages metafor and meta was used to conduct all statistical analyses and generate forest plots. Figure 1 was created with BioRender.com (accessed on 11 August 2022) (agreement no. PW249QJYDR).
Diseases 2022, 10, 118 6 of 24 at high risk for breakthrough and severe SARS-CoV-2 infection appeared a on visual inspection, and Egger's tests confirmed symmetry by producing p (Figures 3-5).       No severe AEs were recorded for TGM/CGM in all patients.

Need for Oxygen Therapy
In the pooled analysis of two studies, the proportion of patients who needed oxygen therapy in the TGM/CGM-based treatment was lower than that of the control group

Need for Oxygen Therapy
In the pooled analysis of two studies, the proportion of patients who needed oxygen therapy in the TGM/CGM-based treatment was lower than that of the control group

Discussion
This is the largest meta-analysis on the efficacy and safety of TGM/CGM as mAb combination in patients at high risk for breakthrough and severe SARS-CoV-2 infection. This study involving 27,932 participants from 23 cohort, 5 case series, 1 case report, and 1 randomized clinical trial studies found that the majority of the patients treated with TGM/CGM as PrEP against COVID-19 were adults (100%), men (62.8%), and were mainly immunocompromised (66.6%) or high-risk patients for severe COVID-19 (e.g., obesity (BMI ≥ 30), hypertension, smoking, diabetes, or asthma (30.9%)). Our meta-analysis showed that the use of the TGM/CGM-based mAb combination in patients at high risk for breakthrough and severe SARS-CoV-2 infection significantly lowered the RT-PCR SARS-CoV-2 positivity rate and was associated with higher adverse effects (p < 0.05). The overall rates of COVID-19-related hospitalization, ICU admission, mortality, neutralization of COVID-19 Omicron variant, need for oxygen therapy, and severe and symptomatic COVID-19 were in favor of TGM/CGM regimens compared to an active comparator, placebo, or no intervention for PrEP against COVID-19. The findings of this review should

Discussion
This is the largest meta-analysis on the efficacy and safety of TGM/CGM as mAb combination in patients at high risk for breakthrough and severe SARS-CoV-2 infection. This study involving 27,932 participants from 23 cohort, 5 case series, 1 case report, and 1 randomized clinical trial studies found that the majority of the patients treated with TGM/CGM as PrEP against COVID-19 were adults (100%), men (62.8%), and were mainly immunocompromised (66.6%) or high-risk patients for severe COVID-19 (e.g., obesity (BMI ≥ 30), hypertension, smoking, diabetes, or asthma (30.9%)). Our meta-analysis showed that the use of the TGM/CGM-based mAb combination in patients at high risk for breakthrough and severe SARS-CoV-2 infection significantly lowered the RT-PCR SARS-CoV-2 positivity rate and was associated with higher adverse effects (p < 0.05). The overall rates of COVID-19-related hospitalization, ICU admission, mortality, neutralization of COVID-19 Omicron variant, need for oxygen therapy, and severe and symptomatic COVID-19 were in favor of TGM/CGM regimens compared to an active comparator, placebo, or no intervention for PrEP against COVID-19. The findings of this review should be interpreted carefully. We included 12 studies with small sample sizes which were conducted exclusively in two countries only (France and the United States) [6,20,[22][23][24][25][26]28,29,31,33,39], an issue that may limit the generalizability of our findings. Nevertheless, the heterogeneity regarding the clinical outcomes among 4 out of these 12 studies when combined with the other included studies was small, which could limit the bias in this meta-analysis [25,26,29,31].
Monoclonal antibodies are considered potential nonvaccine drugs to provide rapid protection against COVID-19 regardless of the recipient's immune system status [45,46]. The TGM/CGM mAb combination targeting the RBD of the SARS-CoV-2 spike protein is modified in the Fc regions to improve the half-life and decrease Fc effector functions [47]. If the results from this meta-analysis were confirmed in larger randomized trials, TGM/CGM would be an important preventive option against SARS-CoV-2. The injectable dosing, established safety profile, acceptable costs of production, and large-scale manufacture of TGM/CGM could allow rapid expansion to worldwide use in the prevention of COVID-19. However, the prophylactic efficacy of TGM/CGM is challenged by emerging immuneevasive SARS-CoV-2 variants [6,21,22,26,33,41,42], notably since the COVID-19 Omicron subvariants have emerged and become dominant worldwide with characteristics that allow them to evade PrEP from the mAb combination [48]. TGM/CGM is active against Omicron (B.1.1.529) lineage variants, but activity may be reduced depending on the sublineage (e.g., 12-to 30-fold decrease in susceptibility for BA.1 and 176-fold decrease for BA.1.1 [49], minimal change in susceptibility for BA.2 (5.4-fold decrease), and likely active (moderate reduction in susceptibility) for sublineages BA.4 and BA.5 [50,51]). With the relaxing of infection prevention and control measures across most countries, it is vital to protect patients at highest risk of serious COVID-19, whereas rates of Omicron subvariants' infection are still high. Immunocompromised patients are fatigued themselves to keep socially isolating, physically distancing, and avoiding others. Therefore, the use of TGM/CGM in these susceptible individuals may be a valued strategy to provide better protection against serious consequences from COVID-19. We should emphasize the need for additional prevention measures in people at high risk for breakthrough or severe COVID-19, such as masking and completing immunization series, while SARS-CoV-2 transmission remains high in the community. PrEP-reduced effectiveness of TGM/CGM justified the FDA's subsequent action to revise the TGM/CGM regimen and supports the necessity to give the TGM/CGM mAb combination at a dose higher than 150 mg/150 mg to ensure the neutralization of TGM/CGM against SARS-CoV-2 Omicron and its subvariants as variants of concern. However, there is a potential to intoxicate the patient, because high doses of TGM/CGM might have led to the very few reported cases of myocardial infarction, mild heart failure pericarditis, and mild/moderate cardia allograft rejection (n = 4) [9,10,42]. In a recent population-based propensity-matched cohort study, TGM/CGM use for PrEP against COVID-19 was not associated with increased risk of myocardial infarction, arrhythmias, or heart failure [52]. A causal relationship between TGM/CGM and these reported cardiovascular events has not been established. Risks and benefits before initiating TGM/CGM in individuals at high risk for cardiovascular events should be considered, and patients should be advised to seek immediate medical attention if they experience any signs or symptoms suggestive of a cardiovascular event. Hence, COVID-19 itself is strongly associated with arterial and venous complications [53][54][55][56], TGM/CGM can be hypothesized to lower the risk for myocardial infarction through the prevention of SARS-CoV-2 infection in select individuals at high risk of progression to severe COVID-19. Although evidence on the cost effectiveness of the use of TGM/CGM within its marketing authorization for preventing COVID-19 compared with the current standard of care is lacking, use of TGM/CGM mAbs in moderately to severely compromised patients as a PrEP may be cost effective by preventing severe outcomes and reducing hospitalization, thereby allowing patients a more rapid return to work. The use of TGM/CGM in suitable patients may improve quality of life by allowing patients to return to daily living activities with more confidence that include increased normal social interaction with others.

Limitation of the Study
We acknowledge that our study was not without some limitations. First, all of the evidence discussed was based on many cohorts and a few case series studies which were small in sample size, and most were performed within single centers. Second, most studies included in this review were retrospective in design which could have introduced potential reporting bias due to reliance on clinical case records. Third, we included two non-peerreviewed studies, and as such their effect on the final pooled treatment outcomes may be confounded. Fourth, the study population included adult patients only, and hence its results cannot be generalized to pediatric patients. Finally, the study was not registered in Prospero, an international prospective register of systematic reviews, as this might have added extra work and the merit was mostly limited to the avoidance of duplication.

Conclusions
For PrEP, there is a decrease in the development of COVID-19 related hospitalization, ICU admission, mortality, need for oxygen therapy, RT-PCR SARS-CoV-2 positivity, and severity and symptoms of COVID-19; however, there is a higher rate for all adverse effects with TGM/CGM. A higher rate of neutralization of COVID-19 Omicron subvariants was found with TGM/CGM use. TGM/CGM is active against Omicron (B.1.1.529) lineage variants but its activity may be reduced for BA.1, BA.1.,1 and BA.2, and likely maintains most of its activity against activity for sublineages BA.4 and BA.5. TGM/CGM higher than a 300 mg/300 mg dose may ensure more neutralization against SARS-CoV-2 Omicron and its subvariants in comparison to the TGM/CGM 150 mg/150 mg dose in immunocompromised patients; however, there is a higher potential to intoxicate the patient, particularly solid organ transplant recipients. 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.