Patient-Reported Outcomes after Tixagevimab and Cilgavimab Pre-exposure Prophylaxis among Solid Organ Transplant Recipients: Safety, Effectiveness, and Perceptions of Risk

Abstract

Background

Tixagevimab and Cilgavimab (T+C) is authorized for pre-exposure prophylaxis (PrEP) against 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 post injection, 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 (0.3%) reported a myocardial infarction. Breakthrough COVID-19 occurred in 9%, 16–129 days after receiving full dose (300mg/300mg) T+C, including 2 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.

Introduction

Tixagevimab and Cilgavimab (T+C) is a monoclonal antibody combination that binds distinct epitopes of the receptor binding domain of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), resulting in viral neutralization.¹ The US Food and Drug Administration authorized T+C as adjunctive pre-exposure prophylaxis (PrEP) against Coronavirus Disease 2019 (COVID-19) in moderate-to-severely immunocompromised populations including solid organ transplant recipients (SOTRs) in December 2021, based on effectiveness among unvaccinated, immunocompetent adults in the pre-Omicron era.^2,3 Over 1 million doses of T+C have since been distributed in the US.⁴

Reported safety and tolerability data of T+C in largely immunocompetent populations have been reassuring, though post-hoc analysis of the PROVENT trial noted a numerical imbalance in cardiovascular events (0.6% T+C vs 0.2% in placebo) among persons with prior cardiovascular disease (CVD). Given the high burden of CVD in SOTRs, dedicated evaluation of T+C safety in SOTRs is necessary.⁵ Furthermore, emerging in vitro and real-world data have indicated variable effectiveness of T+C against Omicron sublineages, including the dominant U.S lineages BA.4 and BA.5.^6,7 Breakthrough rates of 5–10%, particularly in recipients of 150/150mg T+C dosing during the BA.1 and BA.2 waves, have been reported at the single-center level.⁸ In the context of these findings, and based on pharmacological modeling data, the FDA doubled the recommended dosing of T+C in February 2022 from 150/150mg to 300/300mg, for which data are more limited.⁹

In general, patient-reported safety and effectiveness outcomes among SOTRs following T+C injection are lacking, particularly over longer post-injection follow-up during which events such as alloimmune complications or breakthrough infections might present. Additionally, amid this uncertainty, it has not been reported whether T+C administration might affect risk tolerance and behaviors among SOTRs. To address these knowledge gaps, we sought to describe patient-reported reactogenicity and safety following T+C injection in SOTRs, in addition to quantifying the rates of breakthrough infection. Furthermore, we framed these data by assessing attitudes among SOTRs toward changes in risk behaviors throughout ongoing waves of the COVID-19 pandemic.

Materials and Methods

Study Population

SOTRs previously enrolled in a parent nationwide, prospective observational study of COVID-19 vaccination in immunocompromised persons (IRB00248540) were queried whether they planned to receive T+C in the community. In the parent cohort, participants reported baseline demographics, clinical characteristics, vaccine information (number, type, and date of doses), and COVID-19 diagnoses, while undergoing serial antibody surveillance, as previously described.¹⁰ All participants who reported planned receipt of T+C were approached to join this substudy, and serial digital surveys were administered using REDCap electronic data capture tools hosted at Johns Hopkins University.¹¹ The date, dosage amount (150mg/150mg or 300/300mg) and number of doses of T+C were recorded for each participant during follow up. The dose of T+C was primarily determined by the date of drug administration: doses reported between December 8, 2021, and February 23, 2022, were recorded as 150/150mg dosing (original FDA authorized dose), whereas those on or after February 24, 2022 (date of FDA dosing update) were recorded as 300/300mg dosing unless otherwise specified by the participant via free text entry or independent communication with the study team. For those receiving 150mg/150mg doses, only those who went on to obtain a second 150mg/150mg dose were included to reflect currently recommended dose exposure.

Adverse Events

Participants were surveyed 7 days after the first reported injection (of any dose) for development of local (pain, redness, swelling) or systemic adverse reactogenicity (fever, fatigue, headache, chills, vomiting, diarrhea, myalgia) and hypersensitivity reactions. A second T+C-specific survey was administered 3 months following the first dose to assess for incident adverse cardiovascular events (myocardial ischemia/infarction, arrhythmia, or pulmonary embolism), acute organ rejection, infectious complications, and hospitalizations. Participants were provided a free text entry field to provide further details about adverse events.

Incident COVID-19

As part of the parent study, participants are encouraged to report COVID-19 diagnoses or adverse events via multiple opportunities including scheduled post-vaccination follow-up surveys and telephone or email communications with the study team. Additionally, within this substudy, targeted queries for incident COVID-19 diagnosis (by antigen or PCR testing) were administered as scheduled 7-day and 3-month post T+C surveys. Breakthrough COVID-19 was defined as incident COVID-19 diagnosis reported ≥14 days after receipt of a total of 300/300mg T+C (i.e., either following the second 150/150 injection or one 300/300mg injection).

Changes in Risk Behaviors

In the 3-month survey, participants were also queried about whether they felt that receiving T+C decreased their risk of risk of developing COVID-19 (“yes”, “no”, or “unsure”), which (if any) personal activities (grocery shopping, dining in a restaurant, dinner party at home with friends, air travel, in-person doctor visits, socializing without a mask in public, going back to work in person) they were more likely to perform after receiving T+C, and whether they were likely to get a booster vaccine when eligible.

Statistical Analysis

Clinical characteristics and differences in the frequency of adverse events and breakthrough COVID-19 were compared between T+C dosing groups using Wilcoxon rank-sum test for continuous variables and Fisher’s exact test for categorical variables. All analyses were performed using Stata 14.0 for Windows (College Station, Texas).

Results

3.1. Population Characteristics

392 SOTRs responded to the 3-month post-T+C survey, of whom 361 (92%) had also responded to the one-week survey. Approximately half of participants, 189/392 (48%) received an initial dose of 150/150mg T+C followed by a second 150/150 mg dose a median (interquartile range, IQR) 35 (25–50) days apart, while 52% (203/392) received a single dose of 300/300mg T+C. The median age was 64 (54–69) years, 59% were female, and 9% self-identified as non-white. There were 214 (55%) kidney, 105 (27%) thoracic, 53 (14%) liver, and 32 (8%) multi-organ recipients. The median time since transplant was 5.8 (2.8–11.2) years and 179 (46%) of respondents were on three-drug immunosuppression (Table 1). The cohort was highly vaccinated; participants reported receiving two (0.8%), three (29.4%), four (63.2%), or more (6.6%) vaccines prior to the first dose of T+C. Ninety percent of participants had received mRNA vaccines for the first, second, and third dose.

Table 1.

Characteristics of solid organ transplant recipients who received Tixagevimab and Cilgavimab.

	Total n=392	Two Doses (150/150mg) n=189	One Dose (300/300mg) n=203
Age (IQR)	64 (54–69)	64 (54–69)	64 (54–70)
Female (%)	228 (59.2)	113 (60.4)	115 (58.1)
Non-White race (%)	35 (9.1)	15 (8.0)	20 (10.1)
Hispanic/Latino ethnicity (%)	11 (2.9)	11 (5.9)	0 (0.0)
Organ received (%)
kidney	214 (54.6)	103 (54.5)	111 (54.7)
liver	53 (13.5)	18 (9.5)	35 (17.2)
lung	54 (13.8)	34 (18.0)	20 (9.9)
heart	38 (9.7)	17 (9.0)	21 (10.3)
multi-organ	32 (8.2) a	17 (9.0) b	15 (7.4) c
Years since transplant (IQR)	5.8 (2.8–11.2)	4.8 (2.5–8.9)	6.9 (3.5–13.4)
Triple immunosuppression (%)	179 (45.7)	99 (52.4)	80 (39.4)
Positive anti-RBD pre-T+C (%)	272 (70.5)	112 (59.9)	160 (80.4)
Adverse cardiac events (%)	7 (1.8)	5 (2.7)	2 (1.0)
Allergic reaction requiring epi-pen (%) d	0/361 (0)	0/175 (0)	0/186 (0)
Acute rejection (%)	4 (1.0)	3 (1.6)	1 (0.5)
Breakthrough COVID-19 (%) e	36 (9.2)	20 (10.6)	16 (7.9)
Days between T+C and breakthrough COVID-19 (IQR)	81 (62–101)	84 (63–115)	73 (61–94)
Hospitalized (%)	2/36 (6)	1/20 (5)	1/16 (6)
Treated (%)	21/36 (58)	11/20 (55)	10/16 (63)
Monoclonal antibodies	17/36 (47)	9/20 (45)	8/16 (50)
Remdesivir or other antiviral treatment	2/36 (6)	1/20 (5)	1/16 (6)
Other unspecified therapy	2/36 (6)	1/20 (5)	1/16 (6)

^a12 kidney-pancreas, 7 kidney-liver, 8 kidney-heart, 1 kidney-lung, 1 kidney-pancreas-lung, 1 heart-lung, 1 lung-intestine, 1 lung-unspecified other organ

^b8 kidney-pancreas, 3 kidney-liver, 2 kidney-heart, 1 kidney-pancreas-lung, 1 heart-lung, 1 lung-intestine, 1 lung-unspecified other organ

^c4 kidney-pancreas, 4 kidney-liver, 6 kidney-heart, 1 kidney-lung

^dQuestion was asked in the one-week initial survey, for which sample size was n=361

^e≥14 days after 300/300mg T+C

3.2. Adverse Events

One week after receiving a first dose of T+C (150/150mg or 300/300mg), 18.6% (67/361) of SOTRs reported one or more local reactions (pain, swelling, or redness at an injection site) and 37.7% (136/361) reported one or more systemic reactions. Common reactions were fatigue (29.2%), headache (20.0%), and pain at the site (17.7%). Any severe reactogenicity that prevented daily activity was reported by 2.2% (8/361) of all survey respondents. Recipients of 300/300mg T+C more frequently reported localized reactions (22.6% vs. 14.3%, p=0.057), but this difference did not reach statistical significance (Figure 1).

Figure 1.

Local and systemic reactogenicity following Tixagevimab and Cilgavimab, stratified by dosage

Local and systemic adverse events were rated on an ordinal scale by participants: none, mild (does not interfere with activity), moderate (some interference with activity), and severe (prevents daily activity).

Statistical significance was not observed for incidence of any local reaction (p=0.06) or systemic reaction (p=0.45) between 150/150mg T+C group and 300/300mg T+C group. None of the sub-criteria were statistically significantly different between T+C dose groups except for fatigue (higher in 300/300 group; p=0.044).

Over 3 months of follow-up, 4 SOTRs (1%) reported acute rejection at 43 days (heart), 86 days (lung), 90 days (heart), and 104 days (kidney) after T+C. All 4 were <3 years from transplant date, and all had received 3 or more mRNA vaccines prior to T+C. All 4 included details of biopsy results in the free text entry field, but these were not confirmed by the study team via medical record review. One heart transplant recipient reported grade 1R/2 rejection on a 2-year post-transplant biopsy. The other heart transplant recipient reported that rejection was diagnosed during the process of switching to Belatacept from Tacrolimus; with a grade R2 rejection on biopsy. The kidney transplant recipient reported that they underwent a renal biopsy in the setting of a drug resistant urinary tract infection, which showed “kidney rejection”. Finally, the lung transplant recipient reported “mild lymphocytic bronchitis grade A2-3” without further context. Six SOTRs (2%) reported cardiac events; one was a kidney recipient with a history of stented coronary artery disease who reported a diagnosis of non-ST elevation myocardial infarction 9 days following T+C. The other five SOTRs who reported cardiac events described them as palpitations (n=1), tachycardia (n=2), bradycardia (n=1) or premature ventricular contractions (n=1, Table 2). Additionally, the study team was informed of one death during follow up (approximately two months post T+C), though the cause of death was not provided by the reporter apart from specification that it was not due to COVID-19; as per exclusion criteria, this person was excluded from primary analysis due to incomplete data.

Table 2.

Characteristics of serious events following Tixagevimab and Cilgavimab

Age (decade) Sex	Organ	Years Since SOT	IS1 regimen	T+C Dose	Time From 300/300mg T+C	Description
Any Severe Reaction (n=11)
60/F	kidney	3	tacrolimus	150/150	0 days	myalgia, swelling, pain
60/F	kidney	7	tacrolimus steroid	150/150	< 7 days	headache, dizziness
40/M	lung	17	triple IS	150/150	< 14 days	diarrhea
60/F	kidney	< 1	triple IS	150/150	< 21 days	fatigue
70/F	liver	22	triple IS ustekinumab	150/150	< 21 days	myalgia
40/F	kidney	8	triple IS	150/150	< 30 days	headache
40/M	lung	17	triple IS	150/150	< 30 days	diarrhea
40/F	kidney	2	steroid belatacept MMF	150/150	< 30 days	headache
60/F	lung	5	triple IS	300/300	0 days	headache
60/M	kidney	3	tacrolimus	300/300	< 7 days	fatigue
40/F	kidney	4	triple IS	300/300	< 14 days	headache
Any Cardiovascular Events or Symptoms (n=6)
50/F	heart	1	triple IS	150/150	unspecified	bradycardia, junctional rhythm
70/M	kidney	3	triple IS	150/150	< 14 days	NSTEMI2
50/F	kidney	4	triple IS	150/150	2 months	tachycardia
60/M	lung	7	triple IS	150/150	2–3 months	PVCs3
704	lung	8	MMF	300/300	unspecified	tachycardia
60/F	kidney	3	MMF tacrolimus	300/300	< 7 days	hypertension, palpitation
Any Alloimmune Complication (n=4)
60/M	lung	1	steroid tacrolimus	150/150	3 months	rejection, treated (steroids)
40/F	heart	2	MMF tacrolimus	150/150	3 months	rejection, treated (steroids)
60/F	kidney	2	triple IS	150/150	3–4 months	rejection, treated (steroids, hospitalization)
60/F	heart	3	MMF tacrolimus belatacept	300/300	1–2 months	rejection, treated (steroids)

¹IS: immunosuppression; triple IS includes tacrolimus, mycophenolate, and steroids

²NSTEMI: non-ST elevation myocardial infarction

³PVC: premature ventricular contractions

⁴Sex not reported

3.3. Breakthrough COVID-19

Breakthrough COVID-19 (defined as occurring ≥14 days after a participant received a total of 300/300mg T+C) was reported by 36 SOTRs (9%) at a median (IQR) 81 (62–101) days post-T+C, ranging from 16–129 days after completing full-dose T+C. More breakthrough infections occurred in 150/150mg recipients (20/189, median [IQR] 84 [63–116] days post-T+C) than the 300/300mg recipients (16/203, median [IQR] 73 [61–94] days post-T+C), but the difference in incidence rates between these two groups was not statistically significant (p=0.39). The time between the first and second dose of T+C for the 150/150mg group was 35 (25–50) days in those without breakthrough COVID-19 (n=169), and 40 (30–56) days in those with breakthrough COVID-19 (n=20); this difference was not statistically significant (p=0.29). Infections occurred between mid-March 2022 to early August 2022, including 28/36 (78%) during periods of BA.2.12.1 and BA.4/5 US predominance.¹² Specifically, of those with breakthrough COVID-19, 2/36 (6%) reported hospitalization during the BA.4/5 wave; none required supplemental oxygen. 21/36 (58%) received treatment with monoclonal antibodies or remdesivir, whereas the remainder reported no directed therapies (Table 1).

3.4. Perceptions and Behaviors

Of 392 survey responders, 65% reported belief that T+C had reduced their risk of developing COVID-19, whereas 3% did not feel that T+C reduced their risk and 33% responded that they were “unsure”. Many SOTRs stated that they were likely to change certain behavior patterns since receiving T+C; specifically, 76% felt that they were more likely to attend an in-person doctor visit, see friends or family in public (70%) or go grocery shopping (67%). Changes in other behaviors included more willingness to dine in a restaurant (42%), have a dinner party at home with friends (40.8%), travel on an airplane (36%), though few were comfortable going back to work in person (19.9%) or ceasing wearing a mask in public (15%). Interestingly, 40% reported they were less likely to receive a monovalent booster vaccine (when eligible) after receiving T+C.

Discussion

Herein we report 3 months of patient-reported outcomes following T+C PrEP, including safety and breakthrough rates, as well as changing attitudes and perceptions about COVID-19 risk. Encouragingly, T+C was generally well tolerated, with few severe adverse events. In keeping with prior reported studies of SOTRs, acute rejection was uncommon (1.1% >1 month post T+C), while reported CVD events were largely comprised of later-onset arrhythmias of uncertain relation to injection. There was, however, one episode of myocardial infarction among the nearly 400 participants, which occurred relatively soon after T+C in a participant with known coronary disease, albeit of uncertain causal relation.

Overall, breakthrough COVID-19 occurred in 8.9% of this population over 3 months of follow up that predominately overlapped a period of BA.2 and BA.4/5 sublineage predominance in the United States. These rates are similar to post-vaccination breakthrough rates previously reported in our cohort during the BA.1 wave among those who did not receive T+C, albeit more frequent than rates observed during Alpha and Delta predominance.¹³ Recent work by Al Jurdi et al. reported a relatively similar post-T+C infection rate (5%) among SOTRs during the BA.1 and BA.2 waves, which was significantly lower than COVID-19 incidence in the control group (14%).¹⁴ Regardless, in our highly vaccinated cohort receiving full-dose T+C, there were only two hospitalizations and no episodes of severe disease during a later Omicron era (i.e., BA.4/5 circulation), suggesting the combination of passive and active immunoprophylaxis showed real-world effectiveness.

Strengths of this study included nesting within a large parent study that maintains longitudinal follow up of a highly engaged SOTR cohort, affording a unique opportunity to assess patient-reported outcomes including participant attitudes and behaviors surrounding T+C. Such assessments are rarely available in clinical trials yet are important to understanding real-world impact of new drugs. Within this construct, it was notable that the majority of SOTRs reported willingness to raise their risk tolerance for common social and healthcare interactions following T+C. This identified an opportunity for framing risk discussions with SOTRs including changes safety precautions with their transplant teams, best suited to address risk-benefit calculus within the current variant climate. It was reassuring to note that most SOTRs did not plan to cease central protective measures such as mask wearing.

Limitations of this study predominately relate to its observational design and focus on patient report, which may impact reporting of serious adverse events. For example, seriously ill SOTRs might be less likely to respond to digital surveys. Nevertheless, there was excellent medium-term follow-up and high survey response rates (93%) in this motivated cohort. Furthermore, we did receive major vital status updates during the study from engaged family members. Without scheduled surveillance testing, we may also have underreported pauci-symptomatic infections during follow up. This, however, may have been partially counterbalanced by inclusion of home testing results in our COVID-19 ascertainment which are less typically captured in research studies. As demonstrated, another consideration in interpreting breakthrough rates is potential changes in risk behavior following T+C, which may have led to increased exposure to SARS-CoV-2 and infections among those receiving PrEP (i.e., downward bias in drug effectiveness during follow up versus maintenance of “standard” behavior patterns). This, and the lack of a formal control group, and the fact that our parent cohort includes vaccinated SOTRs may limit the generalizability of reported breakthrough incidence rates to non-recipients of T+C and unvaccinated SOTRs, although we were able to reference breakthrough rates among fully vaccinated SOTRs within the parent cohort during Omicron predominance who had not received T+C prophylaxis, and SARS-CoV-2 vaccination is universally accepted and recommended by transplant centers in the United States.¹³ In our T+C population, 99% of SOTRs had received three or more SARS-CoV-2 vaccines prior to T+C, and 70% were seropositive for antibodies against the spike protein prior to receiving T+C, which is generally reflective of the target population (SOTRs) for whom T+C is recommended. Additionally, our study population, and the source cohort from which it was derived, is predominantly White, and thus these findings may not be generalizable to the general SOTR population. Recently, Tian and colleagues reported that type 2 diabetes, kidney disease, and older age were associated with hospitalization for COVID-19, and that after adjusting for covariates, there was evidence of racial disparities in COVID-19 outcomes that cannot be explained by age, sex, socioeconomic status, and other comorbidities alone. ¹⁵ Targeted efforts to study and improve access and outcomes among minority populations are certainly needed among US adults, SOTRs and non-SOTRs alike.

In summary, our study suggests that T+C PrEP is a generally safe and well-tolerated when used among fully vaccinated SOTRs in the modern variant era. Future steps to determine CVD risk after T+C in the post-EUA setting remain necessarily, particularly framed versus the well-recognized risk of CVD morbidity due to COVID-19, itself, among a population with high baseline CVD comorbidities.¹⁶ Uncertainties remain regarding real-world effectiveness in the modern Omicron sublineage era, though the lack of severe disease in T+C recipients including among those infected during the BA.4/5 wave is encouraging. Given that some SOTRs may change their risk behavior after receiving T+C, it remains important for transplant providers to counsel high-risk SOTRs regarding the potential for breakthrough infection and need for maintenance of safety measures. Further evaluation of longitudinal safety and effectiveness of T+C with comparison to well-matched, fully vaccinated SOTRs is necessary to ascertain true relative rates of COVID-19.

Abbreviations:

150/150mg T+C

150mg Tixagevimab and 150mg Cilgavimab

300/300mg T+C

300mg Tixagevimab and 300mg Cilgavimab

COVID-19

Coronavirus Disease 2019

IQR

interquartile range

PrEP

pre-exposure prophylaxis

SARS-CoV-2

severe acute respiratory syndrome coronavirus 2

SOTRs

Solid Organ Transplant Recipients

T+C

Tixagevimab and Cilgavimab

DATA STATEMENT

The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.