Sars-CoV-2 Antibody Response Before and After Third Dose of Homologous mRNA Vaccine in Liver Transplant Recipients

Purpose: Liver transplant (LT) recipients have a decreased response to 2 doses of SARS-CoV-2 vaccine compared to the general population, so we aimed to understand response to a third dose to inform vaccination strategies. Method(s): LT recipients in our observational cohort who received 3 homologous mRNA vaccines and available antibody levels pre- and post-dose 3 (D3) were identified. Those who reported a prior COVID-19 diagnosis or used belatacept were excluded. The peak anti-spike antibody level collected between the second (D2) and third dose (D3), was compared to the antibody level at 1 month post-D3. Samples were tested with Roche Elecsys Anti-Sars-CoV-2 enzyme immunoassay (EIA) (positive >=0.8 U/mL) or EUROIMMUN EIA (positive >=1.1 AU). Result(s): 146 participants completed 3 homologous doses of BNT162b2 (53%) or mRNA-1273 (47%) vaccines between 5/15/2021 - 11/8/2021. The median (IQR) time of peak pre-D3 antibody collection was 89 (31, 104) days post-D2. The median time of 1-month post-D3 antibody collection was 30 (23, 33) days. The median time between D2 and D3 was 168 (149-188) days. Overall, 125/146 (86%) were seropositive pre-D3, and 139/146 (95%) were seropositive post-D3 (Figure 1). There were no seroreversions post D3, and among the 21 seronegative recipients pre-D3, 14 (67%) seroconverted post-D3. Risk factors significantly associated with persistent seronegativity post-D3 were less time since LT (1.3 vs 6 years, p=0.042), mycophenolate use (100% vs 37%, p=0.001), BNT162b2 series (100% vs 50%, p=0.01), and pre-D3 seronegative status (86% vs 10%, p<0.001). Conclusion(s): Most LT recipients have excellent responses to a third homologous mRNA vaccine dose, greater than that seen in other transplant recipients. Persons seronegative after D2, however, show weaker response and may remain at high risk for SARS-CoV-2 infection despite D3.

SARS-CoV2 Antibody Kinetics and Durability Three and Six Months After Two-Doses of MRNA Vaccination in Liver Transplant Recipients

Purpose: nti-spike antibody response to SARS-CoV-2 vaccination is diminished in LT recipients compared to the general population so understanding durability for those that do respond is critical to mitigating risks of infection. We measured serial antibody titers in LT recipients for 6 months after two-dose mRNA vaccine series to describe kinetics and sero-reversion rates. Method(s): LT recipients without known prior COVID-19 had anti-spike antibody testing at 1, 3, and 6 months after the second dose of mRNA vaccine (D2) using two commercial assays (Roche Elecsys anti-receptor binding domain immunoassay (EIA) [positive >=0.8 U/mL] or EUROIMMUN anti-S1 EIA [positive >=1.1 AU]). We compared titer distributions over time and identified factors associated with sero-reversion. Result(s): 180 LT recipients received BNT162b2 (48%) or mRNA-1273 (52%) 2-dose series between 1/7/2021-5/7/2021. At 1 month post-D2 (n=173), 146 (84%) had positive antibody levels at a median (IQR) of 30 (28, 32) days post-D2. At 3 months post-D2 (n=164), 149 (91%) had positive levels at a median of 92 (90, 96) days post-D2. At 6 months post-D2 (n=73), 62 (85%) had positive levels at a median of 180 (176, 185) days post-D2. Among the 66 seropositive at 1 or 3 months post-D2, 58 (88%) remained seropositive by 6 months post-D2. Neither age, years since transplant, vaccine type, nor mycophenolate (MMF) use were associated with sero-reversion, though there was a trend toward more triple immunosuppressive use (25% vs 3%, p=0.07). Of those Roche-tested, the median anti-RBD levels were >=250 U/mL (14, >=250;n=120) at 1 month post-D2, >=250 U/mL (58, >=250;n=113) at 3 months, and >=250 U/mL (30, >=250;n=49) at 6 months . Of those EUROIMMUN-tested, the median anti-S1 levels were 7.25 AU (4.31, 8.71;n=53) at 1 month, 5.71 AU (1.27, 7.90;n=51) at 3 months, and 1.73 AU (0.76, 6.01;n=25) at 6 months. Conclusion(s): Overall, most LT recipients demonstrated 6 month durability of anti-spike antibody following vaccination, but a subset did sero-revert, potentially associated with heavier immunosuppression. Further investigation into clinical consequences of waning antibody levels is key to guide timing of additional vaccine doses.

B Cells Fit for Germinal Center Activity Predict Response to a Third Dose of SARS-CoV-2 Vaccine in Solid Organ Transplant Recipients

Purpose: While SARS-CoV-2 vaccination has dramatically reduced COVID-19 severity in the general population, fully vaccinated solid organ transplant recipients (SOTRs) demonstrate reduced seroconversion and increased breakthrough infection rates. Furthermore, a third vaccine dose only increases antibody and T cell responses in a proportion of SOTRs. We sought to investigate the underlying mechanisms resulting in varied humoral responses in SOTRs. Method(s): Within a longitudinal prospective cohort of SOTRs, anti-spike IgG, total and spike-specific B cells were evaluated in 44 SOTR participants before and after a third vaccine dose using high dimensional flow cytometry to assess immunologic and metabolic phenotypes. B cell phenotypes were compared to those of 10 healthy controls who received a standard two-dose mRNA series. Result(s): Notably, even in the absence anti-spike antibody after two doses, spikespecific B cells were detectable in most SOTRs (76%). While 15% of participants were seropositive before the third dose, 72% were seropositive afterward. B cells, however, were differentially skewed towards non-class switched B cells in SOTRs as compared to healthy control B cells. Expansion of spike-specific class-switched B cells in SOTRs following a third vaccine dose correlated with increased classswitched (IgG) antibody titers. Antibody response to a third vaccine dose was associated with expanded populations of germinal center-like (CD10+CD27+) B cells, as well as CD11c+ alternative lineage B cells with specific upregulation of CPT1a, the rate limiting enzyme of fatty acid oxidation and a preferred energy source of germinal center B cells. Conclusion(s): This analysis defines a distinct B cell phenotype in SOTRs who respond to a third SARS-CoV-2 vaccine dose, specifically identifying fatty acid oxidation as pathway that could be targeted to improve vaccine response such as through targeted immunosuppressive modulation. (Figure Presented).

Post-Acute Sequelae of Sars-Cov-2 Infection in Solid Organ Transplant Recipients

Purpose: Post-acute sequelae of SARS-CoV-2 infection (PASC) is an increasingly recognized phenomenon manifested by long lasting cognitive, mental, and physical symptoms. We aimed to estimate the prevalence of PASC symptoms in solid organ transplant recipients (SOTRs) in the short (1- 6 months) and long-term (> 6 months) periods after SARS-CoV-2 infection. We also compared the prevalence of these symptoms between those with SARS-CoV-2 infection requiring hospitalization and those not requiring hospitalization. Method(s): We surveyed 111 SOTRs with self-reported SARS-CoV-2 infection diagnosed more than 4 weeks prior to survey administration. The survey consisted of 7 validated questionnaires ("Quick Dementia Rating System (QDRS)", "Patient Health Questionnaire (PHQ9)", "Generalized Anxiety Disorder 7 (GAD-7)", "Impact of Events Scale (IES-6)", "EuroQol- 5 Dimension (EQ-5D)", "PROMIS global physical health scale (GHS) "and "Breathlessness, Cough and Sputum Scale (BCSS)"). Result(s): Of the 111 survey participants, 32 (33%) had been hospitalized and 35 (36%) had SARS-CoV-2 infection >6 months ago. Median (IQR) age was 58 years (46, 65). Median time from SARS-CoV-2 diagnosis was 167 days (138, 221). Cognitive impairment, anxiety, depression, insomnia, feeling of trauma, fatigue, pain, breathing problems, cough, abnormal smell, abnormal taste, and diarrhea were reported by 40%, 23%, 36%, 55%, 53%, 41%, 19%, 33%, 33%, 21%, 22%, and 32% of patients respectively. Hospitalized patients had poorer scores in cognition (QDRS survey score of 2 versus 0.75, p=0.048) (Figure 1), quality of life (EQ-5D survey score of 2 versus 1, p=0.043), physical health (PROMIS GHS survey score of 10 versus 11, p=0.013), respiratory status (BCSS survey score of 1 versus 0, p=0.056), and pain (Pain score of 3 versus 0, p 0.006). Among patients who had SARS-CoV-2 infection >6 months ago, abnormal breathing, cough, abnormal smell, abnormal taste, and diarrhea continued to be reported by 31%, 31%, 29%, 32%, and 32% of patients respectively. Conclusion(s): After SARS-CoV-2 infection, SOTRs had a high prevalence of PASC symptoms. Some of the symptoms are more severe in patients who had required hospitalization and persist beyond 6 months. Further studies are needed to understand the long term sequalae of SARS-CoV-2 infection in SOTRs and to develop an evidence-based multidisciplinary approach for caring for these patients beyond the acute phase. (Table Presented).

Covid-19 caseload and management practices vary by program-level factors: A multinational survey study

Purpose: During the pandemic, the COVID-19 patient caseload (CPC) is thought to be highly variable and likely dependant on the cumulative COVID-19 incidence (CCI) of the region. We aimed to capture this variability and COVID-19 treatment practices during the early months of the pandemic. Methods: From June-September 2020, we conducted a multinational survey of transplant physicians. Of 1,267 physicians contacted, 40.5% from 71 countries participated. CCI was calculated in person per million population (ppm) from March-July and divide into tertiles for the entire cohort (low: <2031ppm, medium: 2032-5400ppm, high: >5400ppm). The primary outcome of interest was a CPC of ≥5 transplant recipients. Logistic regression was used to conduct a comparative analysis. We also asked centers to report their treatment practices by patient symptoms, and rate the likelihood of recommending these treatments on a scale of 1-5 (1 being very unlikely and 5 being very likely). Results: 70.6% of programs reported seeing recipients with COVID-19 (31.0% <5, 16.2% 5-10, 13.5% 11-20, 6.4% 21-50, and 3.5% >50 cases). When compared with transplant programs from areas with low CCI, those from medium and high CCI areas had 7-and 10-times higher odds of ≥5 CPC, respectively. When compared with low/ lower-middle-income countries, upper-middle-income countries and high-income countries had 68% and 71% lower odds for this outcome. More importantly, performing a transplant during this time was associated with 54% lower odds of a higher COVID-19 caseload. In terms of treatments, while reducing immunosuppression was the mainstay, in patients with mild and moderate symptoms, supportive care only (59.3% vs. 23.2%), azithromycin (14.8% vs. 22.8%), and hydroxychloroquine/ chloroquine (11.3% vs.17.2%) were the top three choices. In patients with severe symptoms, a wide range of treatments was reported. Supportive care only (4.13±1.22) and Remdesivir (4.13±0.94) were strongly recommended by those that used them. Conclusions: The CPC is strongly associated with the CCI and income level of a region. But performing a transplant during the early days of the pandemic was not associated with seeing more patients with COVID-19. In transplant recipients with COVID-19, supportive care only and decreasing maintenance immunosuppression are the mainstays of therapy. Should there be a second wave of the pandemic, our findings may help guide clinical practice.

The impact of the COVID-19 pandemic on measures of transplant activity is higher in lower-income countries: A multinational survey study

Purpose: The COVID-19 pandemic has affected the field of solid organ transplantation due to the “ramp-down” of activity during the initial months. Impact on transplant activity may vary by baseline health system vulnerabilities. We aimed to analyze this by a country's cumulative COVID-19 incidence (CCI) and income-level. Methods: From June-September 2020, we conducted a multinational survey of transplant physicians. Of 1,267 physicians contacted, 40.5% from 71 countries participated. Income-level was assigned as per the World Bank Classification. CCI was calculated in person per million population (ppm) from March-July and divide into tertiles for the entire cohort (low: <2031ppm, medium: 2032-5400ppm, high: >5400ppm). Logistic regression was used to conduct a comparative analysis. Results: Overall, 75.2% of the programs reported a ramp-down phase, 76.8% performed transplants during this time, 69.6% reported fewer deceased donor offers, and 59.6% anticipate transplant volumes will be <75% of the norm in 2020. Compared with low/lower-middle income countries, transplant programs from highincome countries had 69% lower odds of a ramp-down phase and 50% lower odds of reporting fewer deceased donor offers. Also high income countries had higher odds of performing at least one transplant (OR=3.19, 95%CI: 1.55-6.60, p=0.002) and maintaining transplant volumes >75% (OR= 2.34, 95%CI: 1.20-4.58, p=0.01). CCI was not associated with any of these outcomes except fewer deceased donor offers in programs with moderate CCI. As shown in Table 1, kidney/pancreas transplant programs may be disproportionately affected during the pandemic. Conclusions: We report transplantation has incurred substantial collateral damage from the COVID-19 pandemic and measures of transplant activity during the initial months were significantly associated with the income-level of the country independent of the COVID-19 burden. It will take global effort from transplant leadership to rebuild disrupted transplant services, in particular in, countries that already have vulnerable health systems. (Table Presented).

Solid organ transplant recipient attitudes towards a SARS-CoV-2 vaccine

Purpose: An effective and widely-accepted SARS-CoV-2 vaccine could protect the community and vulnerable populations. We investigated the attitudes of solid organ transplant recipients (SOTRs) towards a SARS-CoV-2 vaccine and identified potential barriers to vaccination. Methods: We conducted a national survey of SOTRs between November 11 - December 2, 2020 through the network and social media platforms of the National Kidney Foundation. We studied 3 major domains: a) attitudes towards a vaccine, b) impact of the pandemic on daily life, and c) impact on mental health. Results: Among 1308 SOTRs, 783 (59.9%) were female and 1035 (79.1%) were White. Respondents were evenly distributed throughout the US and were largely college graduates (829, 63.4%) and married (830, 63.5%). Half (647, 49.5%) of SOTRs would be either unsure or unwilling to receive a SARS-CoV-2 vaccine once available (Table 1). Major concerns included side effects (537, 85.2%), lack of rigor in vaccine development (439, 69.7%), and incompatibility with organ transplant (482, 75.4%). However, 1135 (86.8%) SOTRs would be willing to receive a vaccine if recommended by a transplant provider. A small fraction (161 12.3%) were in self-isolation and severe anxiety related to the COVID-19 pandemic remained low (25, 1.9%). There were no significant differences in vaccine attitudes after the announcement of 94.5% efficacy in the mRNA-1273 vaccine (Moderna, Inc.). Conclusions: Transplant recipients expressed large amounts of skepticism in a potential SARS-CoV-2 vaccine, even after announcements of high vaccine efficacy. However, transplant providers may be the defining influence in vaccine acceptance due to the trust vested in them.

Safety of SARS-CoV-2 mrna vaccines in solid organ transplant recipients

Purpose: The safety of SARS-CoV-2 mRNA vaccines in solid organ transplant recipients (SOTRs) remains unknown. We investigated adverse events in SOTRs who received these mRNA vaccines. Methods: We studied SOTRs between 12/16/2020 - 2/10/2021 who received at least one dose of a vaccine. Vaccine reactogenicity within one week following the first or second dose was self-reported via an interactive, online platform. Results: A total of 790 SOTRs received either the Pfizer/BioNTech (49%) or Moderna (51%) vaccine. Most participants have, thus far, received only one dose, but 211 (27%) received both doses. The median (IQR) age was 58 (43-68), with 57% female, 90% White, and 81% college educated. Organs transplanted include kidney (56%), liver (20%), and heart (16%), with a median (IQR) of 6 (3-13) years since transplantation. There were no reports of new COVID-19 infection, acute rejection, anaphylaxis requiring epinephrine, or new neurological conditions such as Guillain- Barré or Bell's palsy. Overall, moderate to severe local and systemic adverse reactions remained low (Figure 1). Comparison between the first and second dose showed that moderate to severe systemic adverse reactions, while uncommon, were higher after the second dose, including fatigue (22% vs 12%, p<0.001), headache (14% vs. 8%, p<0.01), chills (6% vs. 2%, p<0.01), and fever (3% vs. 1%, p<0.001)(Table 1). Conclusions: In our observational cohort, there were no reports of new COVID-19 infection, acute rejection, anaphylaxis requiring epinephrine, or new neurological conditions following SARS-CoV-2 mRNA vaccination. While uncommon, moderate to severe systemic adverse reactions were higher after the second dose. Thus far, there are no large safety concerns for SARS-CoV-2 mRNA vaccines in SOTRs.

Limited immunogenicity of a single dose of SARS-CoV-2 MRNA vaccine in solid organ transplant recipients

Purpose: Given substantial challenges with vaccine allocation and evidence for short-term vaccine efficacy after a single dose of SARS-CoV-2 mRNA vaccines in clinical trials, some have proposed prioritizing first dose administration to reduce COVID-19 morbidity, potentially resulting in delays of second dose administration, or even purposefully withholding second doses for much longer intervals than evaluated in the clinical trials. However, this evidence is largely based off of the early vaccine trials which largely excluded immunocompromised patients. To better understand the immunogenicity of the available SARS-CoV-2 vaccines in immunocompromised individuals, we quantified the humoral response to the first dose of SARS-CoV-2 vaccine in solid organ transplant recipients (SOTRs). Methods: SOTRs who underwent SARS-CoV-2 vaccination were recruited to participate in this study. Participants underwent at-home blood sampling with the TAPIITM Blood Collection Device (7SBio, Medford, MA) or venipuncture. TapIITM samples were tested on the EUROIMMUN enzyme immunoassay (EIA) which tests for IgG to SARS-CoV-2 spike protein. Venipuncture samples were tested on the Roche Elecsys® EIA which tests for antibodies against the receptor binding domain of the SARS-CoV-2 spike protein. Both tests are semi-quantitative and consistent correlates of neutralizing immunity. Results: We studied 279 SOTRs between 12/29/20-2/12/21. None had a prior COVID-19. Median (IQR) age was 51 (40-65) years, 64% were female, 87% were white, and 6% Hispanic/Latino. Median (IQR) time since transplant was 6 (3-13) years;maintenance immunosuppression included tacrolimus (96%), steroids (53%), mycophenolate (74%), azathioprine (9%), sirolimus (4%), everolimus (4%). At a median (IQR) of 20 (15-23) days after the first dose, antibody was detectable in only 16% of participants (binomial exact 95% confidence interval 12-21%). Those not on anti-metabolite maintenance immunosuppression were 5.2 times (95% CI 3.1-8.7, p <0.001) more likely to develop an antibody response. Conclusions: The vast majority of participants did not mount appreciable antibody responses. However, those not on anti-metabolite maintenance immunosuppression were more likely to develop antibody responses. These results contrast dramatically with the robust early immunogenicity observed in mRNA vaccine trials. These findings are an important reminder that any individual with potential immune compromise should not assume they have achieved an immune response to the SARS-CoV-2 vaccine after a first dose.

Development and durability of SARS-CoV-2 antibodies among solid organ transplant recipients

Purpose: The response to SARS-CoV-2 may be blunted in transplant recipients, impacting reinfection risk, treatment selection, and vaccine protocols. We quantified antibody response and durability after COVID-19 in solid organ transplant recipients (SOTRs). Methods: SOTRs with PCR-confirmed COVID-19 were recruited through the EMR August 21-October 15, 2020. Participants underwent at-home blood sampling with the TAPTM Blood Collection Device, Second Edition (7SBio, Medford, MA). Serum samples were screened using Elecsys® anti-SARS-CoV-2 immunoassay (Roche), which uses a recombinant protein representing the nucleocapsid antigen. Confirmatory testing was performed using EUROIMMUN anti-SARS-CoV-2 enzyme-linked immuosorbent assay (ELISA) for semi-quantitative detection of IgG antibodies to spike protein (anti-S1-IgG), a likely correlate of neutralizing immunity. Results: Eighteen SOTRs were studied, for whom COVID-19 occurred at a median of 6 years (IQR 2-9) post-transplant. Median age was 56 years (IQR 42-63);56% were female;33% were Black and 11% were Hispanic. Most participants (89%) had experienced COVID-19 symptoms;72% were hospitalized. Among those hospitalized, 15% were admitted to the ICU and 8% were mechanically ventilated. COVID-19 convalescent plasma (CCP) was administered to 3 kidney and 2 lung recipients. At median 98 days (IQR 55-147) after COVID-19 diagnosis, 78% had reactive screening immunoassays (Table 1). Of the four patients with non-reactive immunoassays, 2 were the lung recipients treated with CCP and 1 was the kidney recipient receiving IVIg. Of those who screened positive, anti-S1-IgG was detectable in 83%. SOTRs who received CCP and/or IVIg were less likely to develop anti-S1- IgG and had lower antibody levels. Conclusions: We found antibody levels suggestive of neutralizing immunity in the majority of participants. However, those who were administered CCP and/or IVIg were less likely to mount a durable immune response. This raises the possibility that exogenous antibody preparations may blunt durable antibody formation. We observed a significant association between more severe disease and higher antibody levels. Seropositivity might decline over time;however, we were unable to distinguish between impaired production or rapid decrement. Our findings are important for individuals with compromised immune systems, whether deliberately for conditions like organ transplantation and cancer, or naturally in the elderly, frail, and autoimmune populations.

Response to a pandemic: The fall and rise of kidney transplantation in the us

Purpose: During the first wave of the COVID-19 epidemic in March-April 2020, waitlist registrations and living/deceased donor kidney transplants (LDKT/DDKT) dropped substantially. A second wave of infection peaked in August;a third wave began in late October and has not yet peaked. The effects on kidney transplantation in the US during the most recent waves have not yet been described. Methods: Using SRTR data, we compared observed waitlist registrations, waitlist mortality, LDKT, and DDKT 3/15/2020-10/31/2020 to expected events based on calculations from pre-epidemic data 1/2016-2/2020, overall and stratifying by statelevel COVID-19 incidence, while accounting for patient casemix. Results: New listings bottomed at 45% below expected in May (IRR = 0.520.550.57) but steadily recovered to 6% below expected by October (IRR = 0.910.940.97) (Table, Figure). Waitlist deaths peaked at 72% above expected in March/April (IRR = 1.601.721.85), bottomed at 7% above expected in June (IRR = 0.961.071.20), and have since risen only slightly to 16% above expected in August (IRR = 1.041.161.29);July/August waitlist mortality increases were restricted to states with the highest COVID-19 burden (August IRR = 1.051.191.36). DDKT was below expected through June in states with the highest COVID-19 burden (IRR = 0.640.800.99). Nationwide, DDKT peaked in July at 11% above expected (IRR = 1.061.111.17) and have since dropped only slightly to 5% above expected by October (IRR = 0.991.051.10). LDKT bottomed at 87% below expected in March/April (IRR = 0.100.130.15), peaked at 10% below expected in July (IRR = 0.820.900.98), before the second wave peaked, and then dropped slightly to 14% below expected during September and October (IRR = 0.790.860.94). Conclusions: Each successive wave had a lesser impact on transplant and waitlist mortality rates. New listings have approached pre-pandemic rates, suggesting that the medical system has successfully adapted to the challenges of COVID-19, despite occasionally high patient load caused by additional epidemic waves. Decreased mortality may reflect improved care, but may also indicate that true COVID-19 incidence during the first wave was substantially higher than detected.

Loneliness in adults awaiting liver transplantation at 7 u.s. transplant centers during the COVID-19 pandemic

Purpose: Loneliness, defined by the National Academy of Medicine as “a subjective feeling of being isolated”, has recently emerged as a strong predictor of adverse health effects and is of increasing concern given the COVID-19 pandemic. We aimed to characterize loneliness in patients with end-stage liver disease (ESLD) awaiting liver transplantation (LT). Methods: We surveyed adult ambulatory cirrhosis patients awaiting LT at 7 U.S. sites during the COVID-19 pandemic (May2020-Jan2021) using the validated UCLA Three-Item Loneliness Scale by phone or video. Participants were asked to report if they felt: 1) they lack companionship, 2) left out, or 3) isolated using a 3-point scale (1=hardly ever, 2=some of the time, or 3=often). Participants were classified as “lonely” if they reported a score of ≥2 in at least 1 category. Frailty was assessed with the Liver Frailty Index (LFI);“frail”=LFI≥4.4. Logistic regression was used to associate loneliness and other factors. Results: Of 454 participants, 36% were female, median age was 60 years (IQR 53-64), median MELDNa was 14 (IQR 10-19), and 14% were frail. 181 (40%) met criteria for “lonely” in at least 1 category;49 (11%) met criteria for “lonely” in all 3 categories. Compared to those who were not lonely, those who reported feeling lonely were younger (58 v. 61y) and more likely to be female (46% v. 29%), frail (19 v. 11%), or have hepatic encephalopathy (62 v. 50%). There were no differences by race/ethnicity, disease etiology, ascites, or MELDNa score. In univariable analysis, age (OR 0.97, 95% CI 0.96-0.99), female sex (OR 2.16, 95% CI 1.46-3.21), frailty (OR 1.88, 95% CI 1.09-3.2), and hepatic encephalopathy (OR 1.60, 95% CI 1.09- 2.35) were associated with loneliness. After multivariable adjustment, younger age (OR 0.97, 95% CI 0.95-0.99), female sex (OR 1.95, 95% 1.30-2.90), and frailty (OR 1.5, 95% CI 1.2-1.96), remained significantly associated with loneliness. Conclusions: During the COVID-19 pandemic, loneliness was prevalent in patients with ESLD awaiting LT (40%). This is similar to rates reported in the general population (20-50%) during the pandemic, despite LT candidates being a select subgroup in which social support is a criterion for listing. In our cohort, younger age, female sex, and frailty were independently associated with loneliness. These data lay the foundation for future work investigating the extent to which loneliness impacts health outcomes in LT patients, as it does in the general population, and how targeting loneliness in interventions may facilitate improvements in frailty.