Background
While COVID-19 vaccines are generally safe and efficacious, seroconversion rates after COVID-19 vaccination are significantly lower among immunocompromised patients [ [1] , [2] , [3] , [4] ]. Only 44–70 % of individuals treated with anti-CD20 therapies, 73 % of hematopoietic-cell transplant recipients, and 14 % of CAR-T cell recipients develop antibodies against SARS-CoV-2 spike protein following the administration of two doses of SARS-CoV-2 mRNA vaccination [ [5] , [6] , [7] , [8] , [9] , [10] ]. A third dose of SARS-CoV-2 mRNA vaccination increases immunogenicity in solid organ transplant recipients, but only from 40 % to 68 % [ [11] , [12] , [13] ]. Multiple immunosuppressants, immunomodulators, and chemotherapies impair humoral responses to SARS-CoV-2 mRNA vaccination, such as high dose steroids, venetoclax, Bruton's tyrosine kinase inhibitors, and anti-CD20 antibodies, conferring an increased risk of infection in patients receiving these agents [ [14] , [15] , [16] , [17] , [18] , [19] ]. Immunocompromised patients are also more likely to develop severe COVID-19 disease, highlighting the need for alternative approaches that prevent SARS-CoV-2 infection in this population [ 20 ]. Additionally, both vaccine and infection induced immunity wane over time, reinforcing the need for booster vaccination and sustained protective strategies in high-risk individuals [ 21 ] (see Fig. 1 )
Monoclonal antibodies (mAb) offer a targeted and adaptable approach to preventing and treating COVID-19, independent of the host immune response. In May 2021, sotrovimab obtained US Food and Drug Administration (FDA) Emergency Use Authorization (EUA) for the treatment of mild-to-moderate COVID-19 in adults and children (12 years of age and older, weighing at least 40 kg) with positive results of direct SARS-CoV-2 viral testing, at high risk of progression to severe COVID-19, including hospitalization and death [ 10 , 22 , 23 ]. The EUA for early treatment (500 mg IV dose) was deauthorized in April 2022 given reduced in vitro neutralization of sotrovimab against the BA.2 variant with unclear impact on efficacy.
In this study, we examined the safety and tolerability of sotrovimab administered in two sequential doses as prophylaxis in immunocompromised patients with impaired humoral immunity against SARS-CoV-2.
Methods
Trial design
We conducted a phase II open-label study examining the safety and tolerability of sotrovimab, administered as two sequential doses as prophylaxis in immunocompromised patients with impaired humoral immunity against SARS-CoV-2. The designation of impaired humoral immunity to SARS-CoV-2 was based on SARS-CoV-2 spike antibody testing performed within 28 days of enrollment.
The protocol was designed by the study investigators, in conjunction with representatives of the sponsor [10] . The study was conducted at the Dana-Farber Cancer Institute (DFCI), Massachusetts General Hospital, and Brigham and Women's Hospital, all in Boston, Massachusetts. The Office for Human Research Studies of the DFCI and Mass General Brigham approved the study. Written informed consent was obtained from all study participants.
Participants
Adult (≥18 years of age) patients weighing at least 40 kg who had an immunocompromising condition that increased their likelihood of having an impaired humoral immune response to SARS-CoV-2 vaccination and were at increased risk of SARS-CoV-2 infection or progression to severe COVID-19 were considered eligible for study inclusion [ 10 ]. Participants were required to have a negative or low-positive (<50 U/mL) SARS-CoV-2 spike antibody assay within 28 days of enrollment.
Individuals with active SARS-CoV-2 infections or a positive RT-PCR or antigen test result within 21 days prior to consent were excluded, along with individuals with symptoms suggestive of SARS-CoV-2 infection and/or close contact with individuals with COVID-19 in the 14 days prior to consent, based on clinical history and participant reports at screening visit [10] . Additional exclusion criteria were active enrollment on another interventional research study of any agent for the treatment or prophylaxis of SARS-CoV-2 infection, exposure to any other anti-SARS-CoV-2 mAb product for treatment of COVID-19 infection in the six months preceding enrollment or for prophylaxis against COVID-19 infection within the year leading up to enrollment. Please refer to the Supplement for a complete list of inclusion and exclusion criteria.
Interventions
Patients received a single 500 mg dose of intravenous (IV) sotrovimab at the start of the study (TD1) and a single dose of sotrovimab 2000 mg IV at a second timepoint 8–14 weeks after the first dose (TD2). The time between TD1 and TD2 was determined by PK modeling of the duration of expected efficacy of sotrovimab as antiviral prophylaxis against Omicron BA.2, given the emergence and spread of this variant during this period.
The first ten patients to receive both doses comprised an initial lead-in intensive PK sampling (one additional sample collecting time at day 59) cohort to evaluate the pharmacokinetics of sotrovimab. The first fifty patients, including these ten in the initial lead-in PK cohort, comprised a safety and tolerability lead-in cohort, with an assessment of infusion-related reaction (IRR) rates with a 30-min infusion of sotrovimab 500 mg and a 60-min infusion of sotrovimab 2000 mg. The remaining study subjects comprised an expansion cohort for further assessment of the safety and tolerability of the study drug in this patient population.
The 500 mg sotrovimab dose on TD1 was followed by a 1-h monitoring period while the 2000 mg dose on TD2 was followed by a 2-h monitoring period. The monitoring period on TD2 was later reduced to 1 h after no patients in the safety lead-in cohort developed an IRR greater than a grade 2 or serious adverse events (SAEs) potentially related to sotrovimab.
All study subjects followed a schedule of in-person and remote study visits, assessments, and sample collection points outlined in the protocol (Supplement) [ 10 ]. Patients had a remote/telephone end of study visit at 36 weeks/252 days after their final dose of sotrovimab, which corresponded approximately to 5 half-lives of sotrovimab after this dose. Serum anti-drug antibody (ADA) levels were collected pre-dose during the TD1 visit, at the day 29 visit, pre-dose during the TD2 visit, at the TD2+29 days visit, and at the end of treatment visit.
Patients who developed an IRR to the first infusion were pre-medicated with oral antihistamine agents (e.g. loratadine, famotidine diphenhydramine) and/or hydrocortisone 30 min prior to the second study drug dose or IV antihistamine agents 5 min before study drug infusion, according to the protocol.
Pharmacokinetic analysis
PK parameters were generated by a non-compartmental analysis (NCA) approach using the PKNCA package (version 0.10.2) in R (version 4.2.2). For four subjects with drug concentrations below the limit of quantification (LOQ), the data points were excluded from the calculation of pharmacokinetic parameters.
A population PK model was developed using Non-linear mixed effect modeling (NONMEM, version 7.3.0). Perl and Perl-speaks-NONMEM (PsN, version 4.6.0) were used for model evaluation and automatic covariate model-building. The estimation method was first-order conditional estimation with interaction (FOCE + I). Residual variability was accounted for as both proportional and additive in the structural model. R (version 3.2.5) was used for data visualization and result process and statistical analyses.
A two-compartment model with linear elimination best described sotrovimab PK and was used as the base model for the analysis [ 24 ]. The covariates evaluated in the analysis were: demographics (age, race, ethnicity, body weight, height, body mass index [BMI], sex), immunocompromised status type (exposure to anti-CD20 monoclonal antibodies; chronic lymphocytic leukemia, multiple myeloma, or Waldenström macroglobulinemia; solid organ transplantation; other), serum creatinine level, and eGFR calculated using the CKD-EPI equation [ 25 ]. Both serum creatinine level and eGFR were included as time-varying covariates, while the rest of the covariates were included as baseline values. Covariate relationships were explored using a stepwise covariate modeling approach (SCM). Various covariate relationships were tested including linear and non-linear (exponential, and power) relationships. Forward inclusion and backward exclusion steps were conducted with a cutoff of change in objective function value (ΔOFV) of at least 3.84 (P ≤ 0.05, for 1 degree of freedom) and 6.83 (P ≤ 0.01, for 1 degree of freedom), respectively. Scientific plausibility and clinical relevance of the covariates were also taken into account. Statistically significant covariate effects were included in the final model if the relationship was also considered clinically plausible. The final PK model was validated using visual predictive checks and goodness of fit plots. To further examine the clinical relevance of the identified covariate effects, simulations based on the final model were performed using virtual patients with only one covariate change at each time.
ADA treatment descriptions
For ADA analysis, TD1 baseline was defined as the latest pre-dose sample taken before the 500 mg IV dose and TD2 baseline was defined as the pre-dose sample taken before the 2000 mg IV dose. TD1 post-baseline was defined as an occurrence after the first dose of the 500 mg IV treatment and TD2 post-baseline was defined as an occurrence after the 2000 mg IV treatment.
The occurrence of treatment-induced ADA was defined as the de novo development of positive ADA with a negative or missing TD1 or TD2 baseline. Treatment-unaffected ADA was defined as the presence of positive ADA at baseline, with the post-baseline titer consistently remaining at or below 4 times the baseline titer.
Study objectives
Primary objectives were to evaluate the proportion of study subjects with grade 3–5 treatment-emergent adverse events (TEAEs), SAEs, and adverse events of special interest (AESIs) including infusion-related and hypersensitivity reactions, following the Division of AIDS (DAIDS) table version 2.1 for grading the severity of adult and pediatric adverse events [ 10 , 26 ]. We also evaluated the proportion of study subjects who developed ADA levels and evaluated the pharmacokinetics of sotrovimab in the study population.
Secondary objectives of this study were to describe rates of COVID-19 infection and quality-of-life outcomes in immunocompromised individuals receiving sotrovimab prophylaxis. We determined the proportion of study subjects developing COVID-19 over the study follow-up period, and the extent of symptoms assessed by the 8-point National Institute of Allergy and Infectious Diseases ordinal scale (NIAID-OS) at the end of hospitalization or 14 days after the diagnosis of COVID-19 [ 27 ]. We also evaluated health-related quality of life measures using the Short Form Health Survey (SF-36) instrument at baseline, 12 weeks and 24 weeks [ 28 ].
Safety assessment
We defined TEAEs as all adverse events occurring after the administration of the study drug, with assessment of AEs from the time of consent through the end of study visit. The causality of adverse events was determined by the investigator evaluating the event and all events that were clearly, likely, or maybe related to the study drug were reported as related to the study drug to the study sponsor and regulatory bodies. Given the immunocompromised nature of the study population, we collected only grade 3 or higher TEAEs, except for drug-related AEs and serious adverse events, which were collected regardless of grade [ 10 ].
Sample size
The planned sample size for this study was 200 participants, yet we terminated new participant enrollment prematurely and modified the study protocol after these 93 participants had received their first dose of sotrovimab 500 mg IV, given the increased proportion of COVID-19 cases caused by the BA.2 Omicron sub-variant of SARS-CoV-2 during this interval [ 29 ]. The study accrued 93 participants in two months, with the first 10 participants comprising a lead-in PK cohort. This enrollment plan was consistent with similar clinical studies of COVID-19 prophylaxis and justified by the relatively broad inclusion criteria for the study. Participants who discontinued their participation in the study prematurely were not replaced.
Statistical methods
No participant had incomplete data for the primary and secondary outcomes of interest. No formal hypothesis or significance tests were conducted for comparisons. The primary safety and tolerability outcomes of interest were presented through listings, frequency tables, summary statistics, and visualizations, where applicable. Statistical analyses were performed using SAS 9.3 or higher (SAS Institute Inc., Cary, NC), and R v2.13.2 (the CRAN project).
Optimal PK models were determined with statistical significance in NONMEM using the FOCE + I. The difference in the minimum OFV between hierarchical models was assumed to be Chi-square distributed with degrees of freedom equal to the difference in the number of parameters between models. The comparison of full versus reduced models using the log-likelihood criterion was considered as one major factor together with goodness of fit plots and visual predictive checks in the model selection process.
For secondary endpoints of interest, changes in self-reported quality of life from baseline to the study mid-point and baseline to endline, as assessed by the SF-36 instrument were analyzed descriptively (mean, SD and paired t -test, when appropriate).
RESULTS
Participants
Between February and April 2022, 204 subjects were assessed for study participation; ultimately, 93 patients were enrolled in the study.
All individuals enrolled received 500 mg of sotrovimab on TD1, and 81 of 93 received 2000 mg on TD2. Of the 12 subjects who received only the first dose of sotrovimab, 6 (7 %) were permanently discontinued from the study due to COVID-19 infections after the initial sotrovimab dose and prior to eligibility for the second dose. Two participants (2 %) terminated their participation early, one due to personal reasons prior to receiving the second dose of the study drug and one due to enrollment in a clinical trial of another investigational drug. Four participants (4 %) withdrew their participation from the study after the first sotrovimab dose due to the personal reasons specified in the Supplement.
Participant characteristics are presented in Table 1 . Median age was 66.4 (range 32.3, 93.7) years and 45 (48 %) study subjects were female. All participants were immunocompromised at baseline: 34 (37 %) due to receipt of anti-CD20 monoclonal antibodies, 27 (29 %) due to chronic lymphocytic leukemia, multiple myeloma, or Waldenström macroglobulinemia, 20 (22 %) due to solid organ transplantation, 6 (7 %) due to receipt of other immunosuppressive medications, 4 (4 %) due to allogeneic hematopoietic-cell transplantation, and 2 (2 %) due to chimeric antigen receptor (CAR) T-cell therapy.
Table 1
Participant characteristics.
Abbreviations: Chimeric antigen receptor, CAR; Chronic lymphocytic leukemia, CLL; Multiple myeloma, MM; Standard deviation, SD. a Other immunosuppressive medications included were specifically associated with a blunted humoral immune response to SARS-CoV-2 vaccination such as mycophenolate mofetil, azathioprine, methotrexate, Bruton tyrosine kinase inhibitors, ruxolitinib, venetoclax, or corticosteroids (prednisone >20 mg or equivalent daily for at least 14 days).
| Sotrovimab (500 mg IV) (N = 93) | Sotrovimab (2000 mg IV) (N = 81) | |
| Sex, N (%) | ||
| Female | 45 (48) | 40 (49) |
| Male | 48 (52) | 41 (51) |
| Age (years) | ||
| Mean (SD) | 64.3 (12.8) | 64.5 (12.6) |
| Median (Min, Max) | 66.4 (32.3, 93.7) | 66.1 (32.3, 93.7) |
| Ethnicity, N (%) | ||
| Hispanic or Latino | 3 (3) | 3 (4) |
| Not Hispanic or Latino | 85 (91) | 74 (91) |
| Not reported | 5 (5) | 4 (5) |
| High Level Race, n (%) | ||
| Asian | 2 (2) | 2 (3) |
| Black or African American | 3 (3) | 3 (4) |
| White | 85 (91) | 73 (90) |
| Other | 3 (3) | 3 (4) |
| BMI (kg/m2) | ||
| Mean (SD) | 28.3 (8.0) | 28.3 (8.1) |
| Median (Min, Max) | 27.1 (14.1, 61.5) | 27.1 (14.1, 61.5) |
| Immunocompromising condition, N (%) | ||
| Exposure to anti-CD20 monoclonal antibodies | 34 (37) | 27 (33) |
| CLL, MM, or Waldenström macroglobulinemia | 27 (29) | 25 (31) |
| Solid organ transplantation | 20 (22) | 18 (22) |
| Exposure to other immunosuppressive medications a | 6 (7) | 5 (6) |
| Allogeneic hematopoietic-cell transplantation | 4 (4) | 4 (5) |
| CAR-T cell therapy | 2 (2) | 2 (3) |
Eighty-three of 93 participants received pre-exposure prophylactic tixagevimab/cilgavimab at least 20 weeks after their 2000 mg sotrovimab dose, at a time when sotrovimab's protection against the Omicron BA.2 variant was anticipated to diminish.
Safety and tolerability
Five adverse events of special interest (AESIs) were reported within 24 h of study drug administration in three participants ( Table 2 ). Three (3 %) participants developed IRR or mild hypersensitivity skin reactions after the first dose of sotrovimab (500 mg). Two of these subjects developed a similar reaction with the second dose of sotrovimab (2000 mg) despite receiving prophylactic pre-medication with antihistamine agents. All AESIs were grade 2 per DAIDS grading criteria and all participants fully recovered shortly after study drug infusion [ 26 ]. One subject had a grade 2 headache that was considered possibly related to the study drug. The headache fully resolved within a day of the infusion. Therefore, the proportion of participants reporting drug-related adverse events after infusion was 4 %.
Table 2
Drug-related adverse event summary by body system.
Abbreviations: Adverse events, AE; Adverse events of special interest, AESI; Intravenous, IV. a (%) = 100∗(no. of patients with event/no. of patients in denominator). SOC are presented in alphabetical order. Patients are counted only once per system organ class (SOC) and once per preferred term within a SOC. For each patient, the highest grade of each event is tabulated.
| Sotrovimab (500 mg IV) (N = 93) | Sotrovimab (2000 mg IV) (N = 81) | |||||||
| System Organ Class Preferred Term | Grade 1 N (%) a | Grade 2 N (%) | Grade 3 N (%) | Total N (%) | Grade 1 N (%) | Grade 2 N (%) | Grade 3 N (%) | Total N (%) |
| ANY EVENTS | 0 | 4 (4) | 0 | 4 (4) | 0 | 2 (3) | 0 | 2 (3) |
| Total number of patients with an AESI | 0 | 3 (3) | 0 | 3 (3) | 0 | 2 (3) | 0 | 2 (3) |
| Total number of patients with a drug-induced AE | 0 | 1 (1) | 0 | 1 (1) | 0 | 0 | 0 | 0 |
| Injury, poisoning and procedural complications | ||||||||
| Any event | 0 | 3 (3) | 0 | 3 (3) | 0 | 2 (3) | 0 | 2 (3) |
| Infusion related reaction | 0 | 3 (3) | 0 | 3 (3) | 0 | 2 (3) | 0 | 2 (3) |
| Nervous system disorders | ||||||||
| Any event | 0 | 1 (1) | 0 | 1 (1) | 0 | 0 | 0 | 0 |
| Headache | 0 | 1 (1) | 0 | 1 (1) | 0 | 0 | 0 | 0 |
Five of 93 (5 %) subjects developed grade 3–5 TEAEs after the first dose of sotrovimab (500 mg) and 13 of 81 (16 %) after the second dose of sotrovimab (2000 mg). Serious adverse events (SAEs) developed in 5 of 93 (5 %) subjects after the first sotrovimab dose and in 12 of 81 (15 %) after the second dose ( Table 3 ). Notably, all TEAEs were also deemed SAEs, except for an incidental finding of grade 4 neutropenia (per DAIDS grading criteria) identified 64 days after TD1 during the TD2 infusion visit, prior to study drug administration. The neutropenia was not considered severe by the study investigators. Only one event resulted in death, occurring 240 days after TD1, after the participant was transferred to palliative care during hospitalization for respiratory failure. None of these events were considered related to the study drug, nor did they result in withdrawal of participants from the study.
Table 3
All grade 3–5 treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs).
Abbreviations: Serious adverse events, SAE; Treatment-emergent adverse events, TEAE; Intravenous, IV. a (%) = 100∗(no. of patients with event/no. of patients in denominator). SOC are presented in alphabetical order. Patients are counted only once per system organ class (SOC) and once per preferred term within a SOC. For each patient, the highest grade of each event is tabulated.
| Sotrovimab (500 mg IV) (N = 93) | Sotrovimab (2000 mg IV) (N = 81) | |||||||
| System Organ Class Preferred Term | Grade 3 N (%) a | Grade 4 N (%) | Grade 5 N (%) | Total N (%) | Grade 3 N (%) | Grade 4 N (%) | Grade 5 N (%) | Total N (%) |
| ANY EVENTS | 5 (5) | 0 | 1 (1) | 6 (7) | 21 (26) | 0 | 0 | 21 (26) |
| Total number of patients with TEAEs | 4 (4) | 0 | 1 (1) | 5 (5) | 12 (15) | 1 (1) | 0 | 13 (16) |
| Total number of patients with SAEs | 4 (4) | 0 | 1 (1) | 5 (5) | 12 (15) | 0 | 0 | 12 (15) |
| Blood and lymphatic system disorders | ||||||||
| Any event | 0 | 0 | 0 | 0 | 1 (1) | 1 (1) | 0 | 2 (3) |
| Febrile Neutropenia | 0 | 0 | 0 | 0 | 1 (1) | 0 | 0 | 1 (1) |
| Neutropenia | 0 | 0 | 0 | 0 | 0 | 1 (1) | 0 | 1 (1) |
| Cardiac disorders | ||||||||
| Any event | 1 (1) | 0 | 0 | 1 (1) | 2 (3) | 0 | 0 | 2 (3) |
| Heart Failure | 0 | 0 | 0 | 0 | 2 (3) | 0 | 0 | 2 (3) |
| Non-ST Elevation Myocardial Infarction | 1 (1) | 0 | 0 | 1 (1) | 0 | 0 | 0 | 0 |
| Gastrointestinal disorders | ||||||||
| Any event | 0 | 0 | 0 | 0 | 3 (4) | 0 | 0 | 3 (4) |
| Colitis | 0 | 0 | 0 | 0 | 1 (1) | 0 | 0 | 1 (1) |
| Pancreatitis | 0 | 0 | 0 | 0 | 1 (1) | 0 | 0 | 1 (1) |
| Upper GI Bleed | 0 | 0 | 0 | 0 | 1 (1) | 0 | 0 | 1 (1) |
| General disorders and administration site conditions | ||||||||
| Any event | 0 | 0 | 0 | 0 | 2 (3) | 0 | 0 | 2 (3) |
| Chest Pain | 0 | 0 | 0 | 0 | 1 (1) | 0 | 0 | 1 (1) |
| Non-Cardiac Chest Pain | 0 | 0 | 0 | 0 | 1 (1) | 0 | 0 | 1 (1) |
| Infections and infestations | ||||||||
| Any event | 3 (3) | 0 | 0 | 3 (3) | 9 (11) | 0 | 0 | 9 (11) |
| Empyema | 0 | 0 | 0 | 0 | 1 (1) | 0 | 0 | 1 (1) |
| COVID-19 infection | 0 | 0 | 0 | 0 | 1 (1) | 0 | 0 | 1 (1) |
| Pneumonia | 1 (1) | 0 | 0 | 1 (1) | 4 (5) | 0 | 0 | 4 (5) |
| Tracheobronchitis | 0 | 0 | 0 | 0 | 1 (1) | 0 | 0 | 1 (1) |
| Urinary Tract Infection | 1 (1) | 0 | 0 | 1 (1) | 0 | 0 | 0 | 0 |
| Viral Infection | 0 | 0 | 0 | 0 | 1 (1) | 0 | 0 | 1 (1) |
| Worsening Pneumonia | 1 (1) | 0 | 0 | 1 (1) | 0 | 0 | 0 | 0 |
| Wound Infection | 0 | 0 | 0 | 0 | 1 (1) | 0 | 0 | 1 (1) |
| Injury, poisoning and procedural complications | ||||||||
| Any event | 0 | 0 | 0 | 0 | 1 (1) | 0 | 0 | 1 (1) |
| Burn Scar in The Bronchus | 0 | 0 | 0 | 0 | 1 (1) | 0 | 0 | 1 (1) |
| Metabolism and nutrition disorders | ||||||||
| Any event | 0 | 0 | 0 | 0 | 1 (1) | 0 | 0 | 1 (1) |
| Dehydration | 0 | 0 | 0 | 0 | 1 (1) | 0 | 0 | 1 (1) |
| Renal and urinary disorders | ||||||||
| Any event | 1 (1) | 0 | 0 | 1 (1) | 0 | 0 | 0 | 0 |
| Hematuria | 1 (1) | 0 | 0 | 1 (1) | 0 | 0 | 0 | 0 |
| Respiratory, thoracic and mediastinal disorders | ||||||||
| Any event | 0 | 0 | 1 (1) | 1 (1) | 2 (3) | 0 | 0 | 2 (3) |
| Bronchial Obstruction | 0 | 0 | 0 | 0 | 1 (1) | 0 | 0 | 1 (1) |
| Hemoptysis | 0 | 0 | 0 | 0 | 1 (1) | 0 | 0 | 1 (1) |
| Respiratory Failure | 0 | 0 | 1 (1) | 1 (1) | 0 | 0 | 0 | 0 |
ADA
At TD1 baseline, 92 of 93 participants contributed to the ADA immunogenicity evaluation. Three (3 %) had baseline positive ADA, which remained treatment unaffected. In TD1 post-baseline, 91 of 93 participants contributed to the data. One subject (1 %) had treatment-induced ADA with a median titer value of 4.0. At TD2 baseline, 81 subjects (100 %) had baseline negative ADA. In TD2 post-baseline, 80 of 81 participants contributed to the data, with two (3 %) having treatment-induced ADA with a median titer value of 3.0 [range, 3–4]. One participant had persistent positive-ADA responses. None of the participants had a transient response only detected at TD1 baseline. None of the participants with ADA-positive results experienced TEAEs/SAEs/IRRs, including SARS-CoV-2 infections, which were recorded as adverse events in this study. Given that none of the ADA-positive participants experienced adverse events, the overall immunogenicity profile suggests that the ADA responses, whether transient or persistent, were not associated with clinically significant Safety or efficacy concerns in this population.
Pharmacokinetics of sotrovimab
At the 500 mg dose, sotrovimab exhibited a mean AUC 0-∞ of 6721.5 (SD 2371.7) μg ∗ day/mL, which substantially increased to 28865.3 (SD 9327.0) μg ∗ day/mL at the 2000 mg dose. Similarly, the mean C max increased from 169 (SD 56) μg/mL at the 500 mg dose to 731.3 (SD 185.9) μg/mL at the 2000 mg dose. The mean concentration at 28 days increased from 54 (SD 18.8) μg/mL to 218.5 (SD 66.9) μg/mL with dose escalation. Similarly, the mean C last increased from 29.4 (SD 18.0) μg/mL to 71.4 (SD 119.1) μg/mL at the higher dose level ( Table 4 ). Dose-normalized PK parameters suggest consistency across doses, which may indicate dose-proportionality ( Supplemental Table 1 ).
Table 4
PK parameters generated with a non-compartmental analysis approach.
Abbreviations: Area under the curve, AUC; Coefficient of variation, CV; Concentration at day 28 post-administration, C 28 ; Half-life, t ½ ; Last measurable concentration, C last ; Last timepoint of measurable concentration, t last ; Maximum concentration, C max ; Micrograms per day per milliliter, μg∗day/mL; Micrograms per milliliter, μg/mL; Pharmacokinetics, PK; Standard deviation, SD; Time to reach maximum concentration, t max. a Four subjects had drug concentrations below the limit of quantification at 0.8, 1.25, 1.17, 0.92 h post-administration. b One subject had only one timepoint collected at 1.1 h (0.05 day). c For three subjects, fewer than three data points were collected, preventing the calculation of their half-life. And another subject exhibited an abnormal concentration vs. time profile, rendering their half-life calculation inapplicable. d One subject had only one concentration measurement was collected after the end of infusion, which is insufficient to calculate the half-life.
| PK parameters | PK values | 500 mg IV | 2000 mg IV |
| AUC 0-∞ (μg∗ day/mL) | N | 89 | 80 |
| Mean (SD) | 6721.5 (2371.7) | 28865.3 (9327.0) | |
| Geometric mean (geometric %CV) | 6252.8 (35.3) | 27210.8 (32.3) | |
| Median | 6393.9 | 27221.3 | |
| Range (Min-Max) | 675.7–13925.7 | 4682.7–57760.9 | |
| C max (μg/mL) | N | 93 | 81 |
| Mean (SD) | 169 (56) | 731.3 (185.9) | |
| Geometric mean (geometric %CV) | 159.4 (33.2) | 708.4 (25.4) | |
| Median | 160.2 | 703.3 | |
| Range (Min-Max) | 35.5–338.3 a | 361.1–1365.7 | |
| t max (hours) | N | 93 | 81 |
| Mean (SD) | 16 (79.7) | 1.4 (0.2) | |
| Geometric mean (geometric %CV) | 1.2 (499.1) | 1.4 (15.2) | |
| Median | 0.9 | 1.5 | |
| Range (Min-Max) | 0.5–646.1 a | 1.0–1.9 | |
| C 28 (μg/mL) | N | 78 | 57 |
| Mean (SD) | 54 (18.8) | 218.5 (66.9) | |
| Geometric mean (geometric %CV) | 50.7 (34.8) | 185.0 (30.6) | |
| Median | 51.6 | 219.8 | |
| Range (Min-Max) | 7.7–127.1 | 0.0–384.7 | |
| C last (μg/mL) | N | 93 | 81 |
| Mean (SD) | 29.4 (18.0) | 71.4 (119.1) | |
| Geometric mean (geometric %CV) | 25.5(61.3) | 49.8 (166.9) | |
| Median | 26.8 | 49.2 | |
| Range (Min-Max) | 0.7–165.4 | 5.8–1050.9 | |
| t last (days) | N | 93 | 81 |
| Mean (SD) | 85.2 (31.4) | 155.5 (37.6) | |
| Geometric mean (geometric %CV) | 75.7 (36.8) | 136.6 (24.2) | |
| Median | 85.6 | 167.1 | |
| Range (Min-Max) | 0.05–260 b | 0.1–195.8 d | |
| t ½ (days) | N | 89 c | 80 d |
| Mean (SD) | 54.3 (18.6) | 57.3 (15.6) | |
| Geometric mean (geometric %CV) | 51.3 (34.3) | 54.9 (27.2) | |
| Median | 51.1 | 58.7 | |
| Range (Min-Max) | 13.4–123.8 | 16.3–99.6 |
A two-compartment population PK (popPK) model with central and peripheral compartments best fit the data. Body weight at baseline was a significant covariate on sotrovimab clearance and volume of distribution ( Table 5 ). Given the limited sample size, immunocompromised status (IS) was included as categorical covariate and defined as follows: Group 1 - exposure to an anti-CD20 agent; Group 2 - chronic lymphocytic leukemia/small lymphocytic lymphoma, multiple myeloma, Waldenström macroglobulinemia; Group 3 - solid organ transplantation; Group 4 - Other. Both immunocompromised status and serum creatinine were significant covariates on sotrovimab clearance ( Table 5 ).
Table 5
Parameter estimates and covariate effects.
Abbreviations: Central volume of distribution, V2; Clearance, Q; Coefficient of variation, CV; Elimination clearance, CL; Kilograms, Kg; Liters, L; Peripheral volume of distribution, V3.
| Parameter | Population mean | Inter-individual variability | |
| CL | Elimination Clearance in Participants of 78.1 kg (L/day) | 0.0668 | 24.7 % CV |
| Body Mass Effect (per kg) | 0.0091 | ||
| Immunosuppressed - Group2 | 0.0905 | ||
| Immunosuppressed - Group3 | 0.249 | ||
| Immunosuppressed - Group4 | 0.241 | ||
| Serum Creatinine level (mg/dL) | 0.0438 | ||
| V2 | Central Volume of Distribution in Participants of 78.1 kg (L) | 2.93 | 16.9 % CV |
| Body Mass Effect (per kg) | 0.0086 | ||
| Q | Distribution Clearance (L/day) | 0.436 | |
| V3 | Peripheral Volume of Distribution (L) | 3.58 | 20.5 % CV |
| Body Mass Effect (per kg) | 0.0093 | ||
| CCV Residual Variability Component | 0.0183 | ||
| Additive Residual Variability Component | 17.7 |
To examine the clinical relevance of the effects of these covariates on sotrovimab exposure, we conducted a series of simulations ( Supplemental Table 2 ). Immunocompromised subjects in group 1 with median body weight and serum creatinine at 1 mg/dL at baseline (scenario 2) were selected as a reference. An increase in body weight of 10 kg, an increase in baseline serum creatinine to 4 mg/dL or switching to IS-group 2 affected the expected half-life of sotrovimab, within a 10 % difference from the baseline assumption. An increase in baseline serum creatinine to 6 mg/dL or switching the immunocompromised status category to solid organ transplantation or other as the underlying immunocompromised status led to a 15–18 % change in the expected half-life of sotrovimab.
In terms of sotrovimab exposure, which was measured by the area under the curve (AUC) of simulated sotrovimab concentration from time 0 to week 12 after 2000 mg IV dosing, changes in significant covariates (scenario 3–9) resulted in changes of AUC 0–90day that were all within 10 % of the base scenario. We also included a non-immunocompromised subject scenario (scenario 1). In comparison to scenario 1, the reference immunocompromised participants had a 21 % increase in AUC. Even though scenarios 3–9 yielded lower AUCs than the reference scenario, all AUCs were still higher than AUCs in non-immunocompromised subjects.
COVID-19 incidence and extent
Twenty-four study participants (26 %) developed COVID-19 prior to the end of treatment (EOT) visit and 11 study participants (12 %) developed COVID-19 after the EOT visit and prior to the end of study (EOS) visit. Of these, 6 participants had infections after TD1 with a median time to infection of 59.5 days (interquartile range (IQR), 40.25–103.75) and 29 participants had infections after TD2 with a median time to infection of 138 days from TD2 (IQR, 128–203). One participant had a severe grade 3 COVID-19 infection, requiring hospitalization. The remaining COVID-19 infections were either mild (29 of 35) or moderate (5 of 35).
One study subject (3 %) had a maximal NIAID-OS score of 5 (hospitalized, requiring supplemental oxygen). One subject (3 %) had a maximal score of 2 (not hospitalized with limitations on activities and/or requiring home oxygen). Thirty-three study subjects (94 %) had a maximal score of 1 (not hospitalized, no limitation on activities). The majority of COVID-19 infections during the study period occurred when the Omicron BA.2 subvariant was predominant in the region; however, specific variant identification for each case was not performed.
Quality of life (QOL)
Baseline self-reported QOL measurements were collected from all participants at TD1, 82 participants provided reports at TD2 and 90 at EOS. Supplemental Table 3 shows mean and standard deviation scores for various scales in the SF-36 questionnaire from baseline to endline prior to TD1, TD2, and during EOS visits. Role limitations in physical health significantly increased from TD1 to TD2, with a mean difference of 5.57 (SD = 6.32), but this increase was not sustained at the EOS visit. Pain scores exhibited a statistically significant decrease from TD1 (mean, 76.21, SD = 22.34) to EOS (mean, 71.42, SD = 0.01), although there were no significant changes between TD1 and TD2. Other scales, including role limitations, emotional problems, energy fatigue, social functioning, emotional well-being, general health, and physical functioning, had no significant changes across the study. These fluctuations in scores are likely attributed to variations in the participants’ underlying disease conditions.
Discussion
We evaluated the safety and tolerability of sotrovimab as pre-exposure prophylaxis in immunocompromised adults with an impaired humoral immune response to SARS-CoV-2 vaccination. Sotrovimab doses of 500 mg and 2000 mg were generally well-tolerated, with a low incidence of drug-related adverse events and Grade 3–5 TEAEs following the administration of both doses. Comprehensive ADA testing suggested low rates of immunogenicity overall, with 1 % and 3 % of subjects developing treatment-induced ADA after the first and second sotrovimab dose.
Omicron BA.2 SARS-CoV-2 became the dominant variant causing COVID-19 cases shortly after this study opened for enrollment, and we terminated new participant enrollment prematurely and modified the study protocol after 93 participants had received their first dose of sotrovimab 500 mg. The protocol allowed participants to receive other available anti-SARS-CoV-2 monoclonal antibodies authorized for pre-exposure prophylaxis, such as tixagevimab/cilgavimab, at least 20 weeks after their 2000 mg sotrovimab dose, when sotrovimab-mediated protection against the Omicron BA.2 variant was expected to wane, and 11 COVID-19 events occurred after the end of treatment visit and prior to the end of study visit, with the emergence of the Omicron XBB.1.5 subvariant during this interval.
Sotrovimab exhibited dose-dependent exposure and linear pharmacokinetics at doses of 500 mg and 2000 mg, with proportional increases in both AUC 0-∞ and C max , which is consistent with observations of sotrovimab in non-immunocompromised individuals. Immunocompromised patients may experience weight fluctuations due to their underlying disease states or exposure to immunosuppressants or chemotherapeutic agents, which are often associated with decreased appetite, metabolic changes, and nausea. Variations in body weight can impact drug distribution and clearance, but the reported PK model simulations demonstrate that variations in body weight, serum creatinine, or immunocompromised status category have a non-clinically relevant influence on sotrovimab pharmacokinetics. Based on simulation results, sotrovimab exposures are shown to be higher in immunocompromised individuals compared to non-immunocompromised individuals. On the other hand, another study previously reported that sotrovimab exposures were significantly reduced in stem cell transplant recipients who developed diarrhea and lower gastrointestinal graft-versus-host disease post-transplant [ 30 ]. Hence studying the PK profile of sotrovimab in different immunocompromised groups to gain more information would be beneficial.
During the COVID-19 pandemic, we have experienced a rapidly evolving variant landscape. Ultimately, the PK profile and the shifting SARS-CoV-2 variant landscape both influence the clinical efficacy of a given mAb dose and dosing regimen. Because conducting a prophylaxis study requires a significantly longer duration of follow-up compared to an early treatment study, a key consideration is selecting an optimal dose that targets the predominant variant(s) not only at the beginning of the study but also those that emerge throughout the whole study period. Hence, including a lead-in cohort designed to study the PK of sotrovimab provides flexibility for determining the second dose level using PK modelling.
Strengths of this study included its prospective design, with standardized and consistent data collection, establishing a clear temporal relationship between sotrovimab exposure and the observed outcomes. The longitudinal nature of this study allowed for a comprehensive exploration of adverse effects and patient-reported quality of life scores. This broadened our understanding of the safety and tolerability of this mAb agent while mitigating potential recall bias, enhancing the robustness of our results.
Our study also had several limitations. We terminated new participant enrollment prematurely due to the spread of the Omicron BA.2 subvariant, with a reduction of our study population from our original target. We enrolled individuals with heterogeneous immunocompromising conditions and medication exposures, although the study population was reflective of the range of immunocompromised patients at risk for a limited humoral immune response to SARS-CoV-2 vaccination and severe COVID-19 disease. Additionally, the absence of a placebo arm limited our ability to directly compare the efficacy of the dual doses. Our study population was geographically confined to the Northeastern US and predominantly enrolled white, non-Hispanic individuals, potentially reducing the generalizability of our results. Future research endeavors could examine larger patient cohorts and conduct longitudinal assessments to validate the observed pharmacokinetic profile to optimize dosing strategies further.
In conclusion, this phase II open-label study demonstrated that sotrovimab was safe and generally well-tolerated when administered as pre-exposure prophylaxis in immunocompromised individuals at both doses, 500 mg and 2000 mg, with a low incidence of drug-induced adverse events and immunogenicity. Despite the rapid evolution of the spike protein of SARS-CoV-2, which has led to the FDA EUA withdrawal of all previously authorized COVID-19 mAbs (bamlanivimab plus etesevimab, casirivimab plus imdevimab, sotrovimab, tixagevimab/cilgavimab, and bebtelovimab). While sotrovimab's efficacy was impacted by emerging variants such as Omicron BA.2, these findings contribute to the body of evidence that mAbs against SARS-CoV-2 are safe, and a valuable part of the armamentarium for those unlikely to mount protective immune responses to SARS-CoV-2 [ [31] , [32] , [33] , [34] ].
CRediT authorship contribution statement
Isabel H. Gonzalez-Bocco: Writing – review & editing, Writing – original draft, Software, Formal analysis, Data curation, Conceptualization. Rayven Frierson: Writing – review & editing, Project administration, Data curation. Alyssa Cho: Writing – review & editing, Project administration, Data curation. Fabiola A. Reyes Curcio: Writing – review & editing, Data curation. Andres E. Franceschi: Writing – review & editing, Data curation. Chloe Lahoud: Writing – review & editing, Data curation. Dimitrios G. Moshovitis: Writing – review & editing, Project administration, Data curation. Katherine Beluch: Writing – review & editing, Project administration, Data curation, Conceptualization. Manu Balusu: Writing – review & editing, Data curation. C. Elizabeth Keleher: Writing – review & editing, Project administration, Data curation. Keri M. Sullivan: Writing – review & editing, Project administration, Data curation. Michael Dougan: Writing – review & editing, Resources, Project administration, Methodology. Qianwen Wang: Writing – review & editing, Writing – original draft, Validation, Methodology, Formal analysis. Jennifer H. Han: Writing – review & editing, Validation, Resources, Formal analysis. Ahmed Nader: Writing – review & editing, Validation, Resources, Formal analysis. Alicia Aylott: Writing – review & editing, Validation, Resources, Formal analysis. Wei Wang: Writing – review & editing, Writing – original draft, Formal analysis, Data curation. Brian T. Chan: Writing – review & editing, Supervision, Project administration, Investigation. Sarah P. Hammond: Writing – review & editing, Supervision, Project administration, Methodology, Investigation, Data curation, Conceptualization. Jennifer Manne-Goehler: Writing – review & editing, Supervision, Project administration, Methodology, Investigation, Conceptualization. Sophia Koo: Writing – review & editing, Writing – original draft, Supervision, Project administration, Methodology, Investigation, Funding acquisition, Conceptualization.
Ethical approval statement
The study protocol DFCI 21–755, IND Number: 159550, was reviewed by the Dana-Farber Office of Human Research Studies and by the Mass General Brigham Internal Review Board in the meeting of 01/25/22, with a date open for accrual on 01/26/22 and a date closed for accrual of 07/14/22.
Funding source
The study was funded by GlaxoSmithKline (GSK) and VIR Biotechnology. VIR Biotechnology provided the investigational product.
Declaration of competing interest
The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: The study was funded by GlaxoSmithKline (GSK) and VIR Biotechnology. VIR Biotechnology provided the investigational product. The study was designed in conjunction with representatives of the sponsor, and GSK employees analyzed PK data (Qianwen Wang) and ADA data (Alicia Aylott) and contributed to the interpretation and reporting of the study findings (Qianwen Wang, Jennifer Han, Alicia Aylott). Commercial disclosures of Dr. Sophia Koo, research funding from Merck Sharp & Dohme Corp, Scynexis, Inc, GlaxoSmithKline, Ansun BioPharma, Locus Biosciences. Consulting fees: Generate Biomedicines, Vertex Pharmaceuticals.
Footnotes
Supplementary data to this article can be found online at https://doi.org/10.1016/j.nmni.2025.101620 .
Supplementary data
The following is the Supplementary data to this article:
Multimedia component 1
References
1. Lee A.R.Y.B., Wong S.Y., Chai L.Y.A., Lee S.C., Lee M.X., Muthiah M.D., et al. Efficacy of covid-19 vaccines in immunocompromised patients: systematic review and meta-analysis. BMJ. 2022 doi: 10.1136/bmj-2021-068632.
2. Polack F.P., Thomas S.J., Kitchin N., Absalon J., Gurtman A., Lockhart S., et al. Safety and efficacy of the BNT162b2 mRNA covid-19 vaccine. N Engl J Med. 2020;383:2603–2615. doi: 10.1056/NEJMoa2034577.
3. Thomas S.J., Moreira E.D., Kitchin N., Absalon J., Gurtman A., Lockhart S., et al. Safety and efficacy of the BNT162b2 mRNA covid-19 vaccine through 6 months. N Engl J Med. 2021;385:1761–1773. doi: 10.1056/NEJMoa2110345.
4. Cheng H., Peng Z., Luo W., Si S., Mo M., Zhou H., et al. Efficacy and safety of COVID-19 vaccines in phase III trials: a meta-analysis. Vaccines (Basel) 2021;9:582. doi: 10.3390/vaccines9060582.
5. Vijenthira A., Gong I.Y., Fox T.A., Booth S., Cook G., Fattizzo B., et al. Outcomes of patients with hematologic malignancies and COVID-19: a systematic review and meta-analysis of 3377 patients. Blood. 2020;136:2881–2892. doi: 10.1182/blood.2020008824.
6. Severe outcomes among patients with coronavirus disease 2019 (COVID-19) Centers for Disease Control and Prevention; 2020.
7. Agha M., Blake M., Chilleo C., Wells A., Haidar G. Suboptimal response to COVID-19 mRNA vaccines in hematologic malignancies patients. MedRxiv. 2021 doi: 10.1101/2021.04.06.21254949.
8. Thakkar A., Gonzalez-Lugo J.D., Goradia N., Gali R., Shapiro L.C., Pradhan K., et al. Seroconversion rates following COVID-19 vaccination among patients with cancer. Cancer Cell. 2021;39:1081–1090.e2. doi: 10.1016/j.ccell.2021.06.002.
9. Malard F., Gaugler B., Gozlan J., Bouquet L., Fofana D., Siblany L., et al. Weak immunogenicity of SARS-CoV-2 vaccine in patients with hematologic malignancies. Blood Cancer J. 2021;11:142. doi: 10.1038/s41408-021-00534-z.
10. Gonzalez-Bocco I.H., Beluch K., Cho A., Lahoud C., Reyes F.A., Moshovitis D.G., et al. Safety and tolerability study of sotrovimab (VIR-7831) prophylaxis against COVID-19 infection in immunocompromised individuals with impaired SARS-CoV-2 humoral immunity. Pilot Feasibility Stud. 2023;9:100. doi: 10.1186/s40814-023-01325-y.
11. Kamar N., Abravanel F., Marion O., Couat C., Izopet J., Del Bello A. Three doses of an mRNA covid-19 vaccine in solid-organ transplant recipients. N Engl J Med. 2021;385:661–662. doi: 10.1056/NEJMc2108861.
12. Rozen-Zvi B., Yahav D., Agur T., Zingerman B., Ben-Zvi H., Atamna A., et al. Antibody response to SARS-CoV-2 mRNA vaccine among kidney transplant recipients: a prospective cohort study. Clin Microbiol Infection. 2021;27:1173.e1–1173.e4. doi: 10.1016/j.cmi.2021.04.028.
13. Hall V.G., Ferreira V.H., Ku T., Ierullo M., Majchrzak-Kita B., Chaparro C., et al. Randomized trial of a third dose of mRNA-1273 vaccine in transplant recipients. N Engl J Med. 2021;385:1244–1246. doi: 10.1056/NEJMc2111462.
14. Addeo A., Shah P.K., Bordry N., Hudson R.D., Albracht B., Di Marco M., et al. Immunogenicity of SARS-CoV-2 messenger RNA vaccines in patients with cancer. Cancer Cell. 2021;39:1091–1098.e2. doi: 10.1016/j.ccell.2021.06.009.
15. Herishanu Y., Avivi I., Aharon A., Shefer G., Levi S., Bronstein Y., et al. Efficacy of the BNT162b2 mRNA COVID-19 vaccine in patients with chronic lymphocytic leukemia. Blood. 2021;137:3165–3173. doi: 10.1182/blood.2021011568.
16. Greenberger L.M., Saltzman L.A., Senefeld J.W., Johnson P.W., DeGennaro L.J., Nichols G.L. Antibody response to SARS-CoV-2 vaccines in patients with hematologic malignancies. Cancer Cell. 2021;39:1031–1033. doi: 10.1016/j.ccell.2021.07.012.
17. Ollila T.A., Lu S., Masel R., Zayac A., Paiva K., Rogers R.D., et al. Antibody response to COVID-19 vaccination in adults with hematologic malignant disease. JAMA Oncol. 2021;7:1714. doi: 10.1001/jamaoncol.2021.4381.
18. Maneikis K., Šablauskas K., Ringelevičiūtė U., Vaitekėnaitė V., Čekauskienė R., Kryžauskaitė L., et al. Immunogenicity of the BNT162b2 COVID-19 mRNA vaccine and early clinical outcomes in patients with haematological malignancies in Lithuania: a national prospective cohort study. Lancet Haematol. 2021;8:e583–e592. doi: 10.1016/S2352-3026(21)00169-1.
19. Mairhofer M., Kausche L., Kaltenbrunner S., Ghanem R., Stegemann M., Klein K., et al. Humoral and cellular immune responses in SARS-CoV-2 mRNA-vaccinated patients with cancer. Cancer Cell. 2021;39:1171–1172. doi: 10.1016/j.ccell.2021.08.001.
20. Underlying medical conditions associated with higher risk for severe COVID-19: information for Healthcare Providers. Centers for Disease Control and Prevention; 2021.
21. Levin E.G., Lustig Y., Cohen C., Fluss R., Indenbaum V., Amit S., et al. Waning immune humoral response to BNT162b2 covid-19 vaccine over 6 months. N Engl J Med. 2021;385 doi: 10.1056/NEJMoa2114583.
22. GSK sotrovimab fact sheet for healthcare providers: emergency use authorization for sotrovimab. GSK. 2022 https://gskpro.com/content/dam/global/hcpportal/en_US/Prescribing_Information/Sotrovimab/pdf/SOTROVIMAB-EUA.PDF#nameddest=HCPFS
23. Gupta A., Gonzalez-Rojas Y., Juarez E., Crespo Casal M., Moya J., Falci D.R., et al. Early treatment for covid-19 with SARS-CoV-2 neutralizing antibody sotrovimab. N Engl J Med. 2021;385:1941–1950. doi: 10.1056/NEJMoa2107934.
24. Follmann D., O'Brien M.P., Fintzi J., Fay M.P., Montefiori D., Mateja A., et al. Examining protective effects of SARS-CoV-2 neutralizing antibodies after vaccination or monoclonal antibody administration. Nat Commun. 2023;14 doi: 10.1038/s41467-023-39292-w.
25. Inker L.A., Eneanya N.D., Coresh J., Tighiouart H., Wang D., Sang Y., et al. New creatinine- and Cystatin C–based equations to estimate GFR without race. N Engl J Med. 2021;385:1737–1749. doi: 10.1056/NEJMOA2102953/SUPPL_FILE/NEJMOA2102953_DISCLOSURES.PDF.
26. Division of AIDS (DAIDS) Table for grading the severity of adult and pediatric adverse events, corrected version 2.1. US department of health and human services, national institutes of health. National Institute Allergy Infect Dis Division AIDS. 2017
27. Sinha A., Deshwal H., Vashisht R. Safe Effect Use Baricitinib Remdesivir Hospital Patients Coronavirus (COVID-19) 2023
28. 36-Item Short Form Survey (SF-36) RAND Corporation; 2021.
29. FDA Updates sotrovimab emergency Use Authorization. 2022. FDA limits use of Sotrovimab to treat COVID-19 in some U.S. regions due to the BA.2 Omicron sub-variant.
30. Boonyaratanakornkit J., Wang Q., Nader A., Kimball L., Stevens-Ayers T., Levkova M., et al. The effect of gastrointestinal graft-versus-host disease and diarrhea on the pharmacokinetic profile of sotrovimab in hematopoietic stem cell transplant recipients. J Infect Dis. 2024 doi: 10.1093/INFDIS/JIAE236.
31. Soeroto A.Y., Yanto T.A., Kurniawan A., Hariyanto T.I. Efficacy and safety of tixagevimab‐cilgavimab as pre‐exposure prophylaxis for COVID‐19: a systematic review and meta‐analysis. Rev Med Virol. 2023;33 doi: 10.1002/rmv.2420.
32. Evering T.H., Chew K.W., Giganti M.J., Moser C., Pinilla M., Wohl D.A., et al. Safety and efficacy of combination SARS-CoV-2 neutralizing monoclonal antibodies Amubarvimab plus Romlusevimab in Nonhospitalized patients with COVID-19. Ann Intern Med. 2023;176:658–666. doi: 10.7326/M22-3428.
33. Self W.H., Sandkovsky U., Reilly C.S., Vock D.M., Gottlieb R.L., Mack M., et al. Efficacy and safety of two neutralising monoclonal antibody therapies, sotrovimab and BRII-196 plus BRII-198, for adults hospitalised with COVID-19 (TICO): a randomised controlled trial. Lancet Infect Dis. 2022;22:622–635. doi: 10.1016/S1473-3099(21)00751-9.
34. Li S., Wu X., Li N., Cao G., Wang J., Chen Y., et al. Safety, tolerability, pharmacokinetics, and immunogenicity of an anti-SARS-CoV-2 monoclonal antibody HFB30132A after single dose intravenous administration in healthy Chinese subjects: a phase 1, randomized, double-blind, placebo-controlled study. Front Pharmacol. 2023;14 doi: 10.3389/fphar.2023.1117293.