[CHALLENGES IN LIVER TRANSPLANT 2023].

INTRODUCTION: Liver transplantation improves the survival and the quality of life of patients with liver failure and primary liver carcinoma. Candidates for liver transplantation are thoroughly evaluated to rule out infectious and malignant conditions that might deteriorate following the immune suppression so that their cardiovascular and pulmonary function can sustain them through the surgical procedure. Poor nutritional status, sarcopenia and frailty portend a poor prognosis before and after the transplantation. Steatohepatitis (NASH) emerges as the most common indication for liver transplantation due to liver cirrhosis and liver tumors. NASH patients are often elderly and have comorbidities such as cardiovascular disease, renal failure and sarcopenia. Particular effort should be invested to ameliorate these conditions in order to minimize waiting list dropout and to improve the outcome after surgery. The Israeli Ministry of Health is responsible for the regulation of organ transplants in Israel - by law. It organizes the procurement and allocation of organs and supervises all the transplant activity. All the candidates are listed on the national waiting list and the priority is allocated according to the MELD-Na. Transplant candidates who carry EDI cards (expressing their advanced directive of consent to organ donation after death) receive additional points on the waiting list. Acute liver failure, hepatopulmonary syndrome and hepatocellular carcinoma patients are prioritized according to their condition, as their MELD score does not reflect their prognosis. To overcome the continuous shortage of organs new techniques have been adopted such as living donor liver transplantation, better management of marginal livers, be they from brain dead donors or donations after circulatory death. The main challenges after liver transplantation are the metabolic syndrome and its complications, renal failure and malignancy. An aggressive, early preventive approach is highly recommended to promote a healthy lifestyle, optimize medical therapy and screen for malignancy.

Nonalcoholic Fatty Liver Disease before Kidney Transplantation Correlates with New Onset Diabetes and Poor Metabolic Outcomes.

INTRODUCTION: Cardiovascular disease (CVD) is the leading cause of morbidity and mortality after kidney transplantation. Metabolic syndrome is common in renal transplant recipients and is associated with increased CVD risk in those patients. Nonalcoholic fatty liver disease (NAFLD) is considered to be the hepatic manifestation of a multi-system disorder, including CVD and metabolic syndrome. The data about prevalence of NAFLD before kidney transplantation and its consequences following transplantation are scarce. METHODS: A retrospective study of metabolic parameters and sonographic evidence of NAFLD, and an analysis of its metabolic outcomes, was performed in 341 consecutive kidney transplant recipients. RESULTS: One-hundred twenty-four (36.4%) kidney recipients had NAFLD before transplantation. The risk of NAFLD before kidney transplantation was independently and significantly related to diabetes (OR = 1.8), male gender (OR = 1.4), older age (every year of age increased the risk by 4%), higher BMI (every increase of 1 kg/m2 increased the risk by 15%), and higher triglycerides level. Mean levels of liver enzymes were similar in patients with and without NAFLD. Recipients with NAFLD before transplantation had a higher prevalence of new onset diabetes, even after adjustment to covariables. In addition, they had a higher increase in liver enzymes, triglycerides, and FIB-4 score, as an indication of liver fibrosis, after transplantation. Furthermore, NAFLD pre-transplantation was independently associated with cardiovascular mortality (HR = 4.4) following kidney transplantation. CONCLUSIONS: Sonographic evidence of NAFLD before kidney transplantation is associated with significant metabolic outcomes including de novo diabetes and cardiovascular mortality following transplantation and should be included as part of the assessment of kidney transplant candidate.

Reduced humoral response to mRNA SARS-CoV-2 BNT162b2 vaccine in kidney transplant recipients without prior exposure to the virus.

COVID-19 is associated with increased morbidity and mortality in transplant recipients. There are no efficacy data available regarding these patients with any of the available SARS-CoV-2 vaccines. We analyzed the humoral response following full vaccination with the BNT162b2 (Pfizer-BioNTech) in 136 kidney transplant recipients, and compared it to 25 controls. In order to exclude prior exposure to the virus, only participants with negative serology to SARS-CoV-2 nucleocapsid protein were included. All controls developed a positive response to spike protein, while only 51 of 136 transplant recipients (37.5%) had positive serology (p < .001). Mean IgG anti-spike level was higher in the controls (31.05 [41.8] vs. 200.5 [65.1] AU/mL, study vs. control, respectively, p < .001). Variables associated with null humoral response were older age (odds ratio 1.66 [95% confidence interval 1.17-2.69]), high-dose corticosteroids in the last 12 months (1.3 [1.09-1.86]), maintenance with triple immunosuppression (1.43 [1.06-2.15]), and regimen that includes mycophenolate (1.47 [1.26-2.27]). There was a similar rate of side effects between controls and recipients, and no correlation was found between the presence of symptoms and seroconversion. Our findings suggest that most kidney transplant recipients remain at high risk for COVID-19 despite vaccination. Further studies regarding possible measures to increase recipient's response to vaccination are required.

Low immunogenicity to SARS-CoV-2 vaccination among liver transplant recipients.

BACKGROUND & AIMS: Two SARS-CoV-2 mRNA vaccines were approved to prevent COVID-19 infection, with reported vaccine efficacy of 95%. Liver transplant (LT) recipients are at risk of lower vaccine immunogenicity and were not included in the registration trials. We assessed vaccine immunogenicity and safety in this special population. METHODS: LT recipients followed at the Tel-Aviv Sourasky Medical Center and healthy volunteers were tested for SARS-CoV-2 IgG antibodies directed against the Spike-protein (S) and Nucleocapsid-protein (N) 10-20 days after receiving the second Pfizer-BioNTech BNT162b2 SARS-CoV-2 vaccine dose. Information regarding vaccine side effects and clinical data was collected from patients and medical records. RESULTS: Eighty LT recipients were enrolled. Mean age was 60 years and 30% were female. Twenty-five healthy volunteer controls were younger (mean age 52.7 years, p = 0.013) and mostly female (68%, p = 0.002). All participants were negative for IgG N-protein serology, indicating immunity did not result from prior COVID-19 infection. All controls were positive for IgG S-protein serology. Immunogenicity among LT recipients was significantly lower with positive serology in only 47.5% (p <0.001). Antibody titer was also significantly lower in this group (mean 95.41 AU/ml vs. 200.5 AU/ml in controls, p <0.001). Predictors for negative response among LT recipients were older age, lower estimated glomerular filtration rate, and treatment with high dose steroids and mycophenolate mofetil. No serious adverse events were reported in either group. CONCLUSION: LT recipients developed substantially lower immunological response to the Pfizer-BioNTech SARS-CoV-2 mRNA-based vaccine. Factors influencing serological antibody responses include age, renal function and immunosuppressive medications. The findings require re-evaluation of vaccine regimens in this population. LAY SUMMARY: The Pfizer-BioNTech BNT162b2 SARS-CoV-2 vaccine elicited substantially inferior immunity in liver transplant recipients. Less than half of the patients developed sufficient levels of antibodies against the virus, and in those who were positive, average antibody levels were 2x less compared to healthy controls. Factors predicting non-response were older age, renal function and immunosuppressive medications.

Hepatitis C related cognitive impairment: Impact of viral and host factors and response to therapy.

Chronic hepatitis C virus (HCV) infection is associated with cognitive impairment via several suggested mechanisms including direct neurotoxicity and minimal hepatic encephalopathy. The prevalence of HCV-related cognitive impairment and whether it is reversed by anti-viral therapy is unknown. We aimed to assess predictors and reversibility of cognitive impairment of HCV-infected patients after successful treatment. Consecutive HCV patients treated during the EMERALD study (AbbVie 3D regimen for protease inhibitors failure) underwent neuropsychological (number connection test A [NCTA] and digital symbol test [DST]) and neurophysiological (critical flicker frequency [CFF]) tests at baseline and at 12 weeks post-treatment. Patient self-reported outcomes (PROs) were prospectively collected. Patients with a history of hepatic encephalopathy were excluded. Thirty-two patients underwent the cognitive tests at baseline. Seven of them had abnormal CFF test findings. Twenty-five (25/32, 78%) patients had repeated evaluations 3 months post-treatment. High viral loads were significantly associated with abnormal CFF across fibrosis levels (area under the ROC curve 0.817). CFF results significantly improved following viral eradication, from 40.9 (interquartile range 38.6-42.9) at baseline to 41.5 (39.8-44), p = .042, at follow-up. Both NCTA and DST results improved, but not significantly. There was improvement in the PROs of general health perception and vitality. The NCTA and DST results were more significantly associated with PROs than CFF. This prospective interventional study showed greater cognitive impairment in HCV patients with high viral load and demonstrated partial reversibility of HCV neurotoxicity and subsequent improvement in PROs following treatment.

Kidney transplant recipients vaccinated before transplantation maintain superior humoral response to SARS-CoV-2 vaccine.

Majority of transplant recipients did not develop an appreciable humoral response following SARS-CoV-2 vaccine, in contrast to dialysis patients and healthy individuals. We analyzed the serologic response to BNT162b2 (Pfizer-BioNTech) vaccine in a cohort of 19 kidney transplant recipients, vaccinated prior to transplantation, compare to 109 recipients vaccinated after transplantation, and to 39 healthcare workers, by determining the level of anti-spike antibodies after transplantation. All controls and 17 of 19 (90%) of recipients vaccinated before transplant were seropositive, while only 49 of 109 (45%) recipients vaccinated post-transplant had positive serology (P < .001). Median anti-spike IgG in the group of kidney transplant recipients vaccinated after transplantation (10.7 AU/ml, [IQR 0-62.5]) was lower than the patients vaccinated before transplantation (66.2 AU/ml [21.6-138]), which was significantly lower than in the controls (156 AU/ml [99.7-215.5]). Negative humoral response was associated with vaccination post transplantation (odds ratio 22.4), older age (OR = 1.04), and longer time on dialysis (OR = 1.02), while higher lymphocyte count at time of vaccination was protective (OR = .52). Our findings of sustained superior humoral response to SARS-CoV-2 vaccine in kidney transplant recipients vaccinated prior to transplantation strongly support the recommendations of SARS-CoV-2 vaccination of transplant candidates, especially those younger than 60 years.

Ombitasvir/paritaprevir/ritonavir & dasabuvir ± ribavirin following protease inhibitors failure - a prospective multi-centre trial.

BACKGROUND: Hepatitis C virus (HCV) infection is a leading cause of chronic liver disease and hepatocellular carcinoma. Treatment with first generation protease inhibitors (PI) + peg-interferon (pegIFN) and ribavirin (RBV) achieved sustained virologic response (SVR) rates of 65-75% but was associated with multiple side effects. The aim of this study was to evaluate safety and efficacy of Ombitasvir/Paritaprevir/Ritonavir and Dasabuvir (3D) ± RBV in HCV genotype 1 patients that failed previous treatment with first generation PIs. METHODS: An investigator-initiated, open-label, multi-centre clinical trial. HCV Genotype 1 patients who were previously null/partial responders or relapsers to telaprevir, boceprevir or simepravir+pegIFN/RBV and met eligibility criteria were included. 3D ± RBV were administrated for 12 or 24 weeks according to label. The primary outcome was antiviral response (SVR12); Secondary outcomes were patient reported outcomes, adverse events and resistance associated variants. RESULTS: Thirty-nine patients initiated treatment according to study protocol (59% men, age 54.0 ± 8.7 years, BMI 28.7 ± 4.5 kg/m2). Thirty-seven (94.9%) completed the study. Thirty-five patients had genotype 1b (9 cirrhotics) and 4 had genotype 1a (2 cirrhotics). Intention-to-treat SVR12 was 92.3% and per-protocol SVR12 was 97.3%. The rate of advanced fibrosis (FibroScan® score F3-4) declined from 46.2 to 25.7% (P = 0.045). Abnormal ALT levels declined from 84.6 to 8.6% (P < 0.001). Seven patients (17.9%) experienced serious adverse events (3 Psychiatric admissions, 1 pneumonia, 1 ankle fracture, 2 palpitations), and 12 patients (30.8%) experienced self-reported adverse events, mostly weakness. CONCLUSION: 3D ± RBV is safe and effective in achieving SVR among patients with HCV genotype 1 who failed previous first-generation PI treatment. TRIAL REGISTRATION: NCT02646111 (submitted to ClinicalTrials.gov, December 28, 2015).

Efficacy and safety of a two-drug direct-acting antiviral agent regimen ruzasvir 180 mg and uprifosbuvir 450 mg for 12 weeks in adults with chronic hepatitis C virus genotype 1, 2, 3, 4, 5 or 6.

Ruzasvir (MK-8408, an NS5A inhibitor) and uprifosbuvir (MK-3682, a nonstructural protein 5B nucleotide inhibitor) are highly potent direct-acting antiviral agents for the treatment of hepatitis C virus (HCV) infection. A phase III clinical trial evaluating the two-drug combination of ruzasvir 60 mg plus uprifosbuvir 450 mg suggested suboptimal efficacy in certain HCV genotypes (C-BREEZE 1; NCT02759315). The aim of the present study was to evaluate the efficacy and safety of ruzasvir in combination with uprifosbuvir administered at a higher dose than that assessed in the earlier study (C-BREEZE 2: NCT02956629/Merck protocol PN041). Treatment-naïve or interferon (with or without ribavirin)-experienced participants with or without compensated cirrhosis were enrolled. All participants received ruzasvir 180 mg plus uprifosbuvir 450 mg once daily for 12 weeks. The primary objectives were the proportion of participants with HCV RNA <15 lU/mL at 12 weeks after the end of study therapy (SVR12), and safety and tolerability of the study drug. Overall, 282 participants were enrolled. SVR12 (n/N) was 91.3% (42/46) in participants infected with HCV genotype (GT) 1a; GT1b, 96.7% (29/30); GT2, 91.5% (43/47); GT3, 73.8% (45/61); GT4, 98.2% (55/56); GT5, 100.0% (18/18); and GT6, 90.9% (20/22). Adverse events (AEs) were reported by 61.3% of participants; drug-related AEs were reported by 33.3%. The most frequent (≥5% of participants) drug-related AEs in all participants were fatigue (7.8%) and headache (7.4%). In conclusion, the two-drug combination of ruzasvir 180 mg plus uprifosbuvir 450 mg for 12 weeks was highly effective and well tolerated in participants infected with HCV GT1, GT2, GT4, GT5 and GT6, with a lower efficacy in GT3-infected persons.

Kidney transplantation in patients with inflammatory bowel diseases (IBD): analysis of transplantation outcome and IBD activity.

Inflammatory bowel diseases (IBD) is a systemic disorder with possible renal involvement, yet data regarding the outcome of kidney transplantation (KT) in those patients, and IBD course post KT, are scarce. In this retrospective analysis, we studied the outcome of 12 IBD kidney recipients (seven Crohn's disease, five ulcerative colitis; primary kidney disease was IgA nephropathy in five, polycystic disease in four), compared to two control groups: matched controls and a cohort of recipients with similar kidney disease. During a follow-up period of 60.1 (11.0-76.6) months (median, interquartile range), estimated 5-year survival was 80.8 vs. 96.8%, with and without IBD, respectively (P = 0.001). Risk of death with a functioning graft was higher with IBD (HR = 1.441, P = 0.048), and with increased age (HR = 1.109, P = 0.05). Late rehospitalization rate was higher in IBD [incidence rate ratio = 1.168, P = 0.030], as well as rate of hospitalization related to infection [1.42, P = 0.037]. All patients that were in remission before KT, remission was maintained. Patients that were transplanted with mild or moderate disease remained stable or improved with Infliximab or Adalimumab treatment. In conclusion, IBD is associated with an increased risk of mortality, hospitalization because of infection and late rehospitalization after KT. Clinical course of IBD is stable after KT.

Progression and new onset of nonalcoholic fatty liver disease in living kidney donors compared to healthy controls.

BACKGROUND: There is growing evidence linking nonalcoholic fatty liver disease (NAFLD) with reduced glomerular filtration rate (GFR). Living kidney donors do not have underlying kidney disease, but have reduced GFR as a result of nephrectomy. Whether kidney donation is associated with a higher risk for development or progression of NAFLD is currently unknown. METHODS: Retrospective evaluation of metabolic parameters and sonographic evidence of NAFLD were performed in 232 living kidney donors and 162 healthy controls. RESULTS: A total of 25 donors and 44 controls had NAFLD at baseline. During a mean follow-up of 6.8 years, 6 donors (24%) and 17 controls (38.6%) (P = .29) had a remission of NAFLD, related with decreased body mass index (BMI). The progression of NAFLD fibrosis score was similar in both groups. New onset of NAFLD was observed in 14 (6.8%) donors and 13 (11.01%) controls (P = .211), and was related to increased BMI and a higher baseline Fatty Liver Index score. Neither eGFR nor urine albumin excretion in the donors were related to new onset or progression of NAFLD. CONCLUSIONS: Reduced kidney function secondary to kidney donation is not associated with increased incidence or progression of NAFLD.

Living donor versus deceased donor liver transplantation: a surgeon-matched comparison of recipient morbidity and outcomes.

Informed consent for living donor liver transplantation (LDLT) requires that patients are provided with accurate information on the relative benefits and risks of this procedure compared with deceased donor liver transplantation (DDLT). There is strong evidence to suggest that LDLT facilitates timely transplantation to patients; however, information on the relative morbidity and death risks after LDLT as compared with DDLT is limited. A matched cohort comparison was performed matching recipients for age, MELD, date of transplant, gender, primary diagnosis, and recipient surgeon. A total of 145 LDLT were matched with 145 DDLT. LDLT had a higher overall rate of perioperative surgical complications (P = 0.009). Most of this difference was caused by a higher rate of biliary complications. However, the complications that occurred in the DDLT group tended to be more serious (P = 0.037), and these complications were strongly associated with graft loss in multivariate analysis. The 3- and 5-year graft and patient survivals were similar. In conclusion, DDLT and LDLT have different complication profiles, but comparable hospital stays and survival rates. In areas of deceased donor organ shortages, LDLT offers an excellent alternative to DDLT because it facilitates access to a liver transplant without compromising short- or medium-term recipient outcomes.

Embryonic pig pancreatic tissue for the treatment of diabetes in a nonhuman primate model.

Xenotransplantation of pig tissues has great potential to overcome the shortage of organ donors. One approach to address the vigorous immune rejection associated with xenotransplants is the use of embryonic precursor tissue, which induces and utilizes host vasculature upon its growth and development. Recently, we showed in mice that embryonic pig pancreatic tissue from embryonic day 42 (E42) exhibits optimal properties as a beta cell replacement therapy. We now demonstrate the proof of concept in 2 diabetic Cynomolgus monkeys, followed for 393 and 280 days, respectively. A marked reduction of exogenous insulin requirement was noted by the fourth month after transplantation, reaching complete independence from exogenous insulin during the fifth month after transplantation, with full physiological control of blood glucose levels. The porcine origin of insulin was documented by a radioimmunoassay specific for porcine C-peptide. Furthermore, the growing tissue was found to be predominantly vascularized with host blood vessels, thereby evading hyperacute or acute rejection, which could potentially be mediated by preexisting anti-pig antibodies. Durable graft protection was achieved, and most of the late complications could be attributed to the immunosuppressive protocol. While fine tuning of immune suppression, tissue dose, and implantation techniques are still required, our results demonstrate that porcine E-42 embryonic pancreatic tissue can normalize blood glucose levels in primates. Its long-term proliferative capacity, its revascularization by host endothelium, and its reduced immunogenicity, strongly suggest that this approach could offer an attractive replacement therapy for diabetes.

SARS-CoV-2 Vaccines: Safety and Immunogenicity in Solid Organ Transplant Recipients and Strategies for Improving Vaccine Responses.

Purpose of Review: While solid organ transplant (SOT) recipients are at the highest risk for severe complications and increased mortality from COVID19 disease, their vaccination against SARS-CoV-2 remains challenging due to fear of immune-mediated adverse events and suboptimal immune response. Our current review is aimed to summarize current knowledge about the safety and efficacy of SARS-CoV-2 vaccines, describe factors that are correlated with immune response, and discuss strategies to improve vaccine immunogenicity in SOT recipients. Recent Findings: SARS-CoV-2 vaccines are safe in SOT recipients and not related to rejection or other major adverse events. The immune response to two doses of vaccine is suboptimal and correlated to age and magnitude of immunosuppression. Administration of a third vaccine dose brings to significant amplification of immune response. Summary: This review strengthens the existing recommendation of vaccination by three doses of vaccine in all SOT recipients and completion of vaccination before transplantation if possible.

Hepatitis C Virus Prevalence, Medical Status Awareness and Treatment Engagement among Homeless People Who use Drugs: Results of a Street Outreach Study.

Background: Hepatitis C virus (HCV) infection is a primary health concern among people who use drugs (PWUDs). Homeless PWUDs that constitute a key population for HCV transmission remain underrepresented in many surveys. Objectives: We performed a proactive street outreach to evaluate HCV infection prevalence among homeless PWUDs in Tel Aviv, identify risk factors associated with HCV infection, awareness of disease status and linkage to care rate. Results: Thirty-eight percent of approached PWUD were willing to participate in the study. Out of 53 subjects who got tested for anti HCV by rapid test, 29 (54.72%) had a positive result, 20 of 29 anti-HCV positive (69%) patients had positive HCV PCR. Risk factors were investigated using structured questionnaires. Heroin use was reported significantly more frequently in the HCV-positive group (P = .05, CI 95%), whereas other established risk factors did not reach significance in our cohort. While 21 of 29 (72%) HCV-positive participants were aware of their condition, only 4 of 21 (19%) received treatment in the past, and 2 of 4 (50%) failed to achieve treatment goals, as assessed by HCV PCR. Conclusions: Our data indicate a high prevalence of HCV infection among homeless PWUDs. Importantly, despite relatively high awareness of HCV status in this population, we found strikingly low access to care. These findings motivate novel interventional approaches targeted at improving patient access, and compliance among homeless PWUDs, in an effort to reduce HCV transmission.

Hepatitis C Virus Elimination in Methadone-treated Patients: Implementation of Hepatology Clinic in a Methadone Treatment Program.

OBJECTIVES: Patient ignorance and bureaucratic obstacles prevent initiation of hepatitis C virus (HCV) treatment in patients participating in methadone treatment program. Despite high safety and efficacy of currently available oral medications, the rate of patient-initiated treatment remains low. We evaluated the impact of an interventional program on treatment success rate and factors associated with treatment engagement. METHODS: An intervention performed from 2018 to 2020 included an on-site Fibroscan and hepatologist evaluation, anti-viral HCV treatment initiation, and close support and follow-up by a dedicated team. Demographic and medical data were collected and comparison between patients who completed vs. patients who did not complete HCV treatment was done. RESULTS: Fifty-nine out of 74 HCV polymerase chain reaction-positive patients (79.7%) were willing and capable of undergoing on-site hepatologist and Fibroscan evaluations. Twelve (25%) of the participants had cirrhosis, 2 of whom were decompensated. Fifty of the 57 patients that got an anti-viral medication prescription (87%) initiated the treatment. Premature treatment discontinuation was rare (3 patients), intention-to-treat sustain virologic response (SVR) rate was 81% and per-protocol SVR rate was 97%. The rate of treatment initiation during the intervention was significantly higher than the patients' self-initiation rate (44 vs 12 patients). The main factors associated with successful completion of the care cascade was full abstinence from street drugs for 6 months before treatment initiation. CONCLUSIONS: Installing a hepatology clinic in an methadone treatment program center was associated with a 3-fold increase in the HCV treatment, with high adherence to treatment levels, and a high SVR rate. The main factor associated with low engagement to treatment was ongoing street drug use.

Barriers and Facilitators of Hepatitis C Care in Persons Coinfected with Human Immunodeficiency Virus.

Hepatitis C virus (HCV) and human immunodeficiency virus (HIV) are often co-transmitted. Viral coinfection results in worse outcomes. Persons who inject drugs (PWIDs) face barriers to medical treatment, but HCV treatment is indicated and effective even with ongoing active drug use. We aimed to assess access to HCV care and treatment results in patients coinfected with HIV-HCV. This is a real-world retrospective single-center study of patients followed in the HIV clinic between 2002 and 2018. Linkage to care was defined as achieving care cascade steps: (1) hepatology clinic visit, (2) receiving prescription of anti-HCV treatment, and (3) documentation of sustained virologic response (SVR). Of 1660 patients with HIV, 254 with HIV-HCV coinfection were included. Only 39% of them achieved SVR. The rate limiting step was the engagement into hepatology care. Being a PWID was associated with ~50% reduced odds of achieving study outcomes, active drug use was associated with ~90% reduced odds. Older age was found to facilitate treatment success. Once treated, the rate of SVR was high in all populations. HCV is undertreated in coinfected young PWIDs. Further efforts should be directed to improve access to care in this marginalized population.

The effect of a third-dose BNT162b2 vaccine on anti-SARS-CoV-2 antibody levels in immunosuppressed patients.

OBJECTIVES: The recent surge in coronavirus disease 2019 cases led to the consideration of a booster vaccine in previously vaccinated immunosuppressed individuals. However, the immunogenic effect of a third-dose severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine in immunosuppressed patients is still unknown. METHODS: This was an observational cohort study of 279 previously vaccinated immunosuppressed patients followed at a single tertiary hospital in Israel. Patients were administered a third dose of the Pfizer-BioNTech mRNA vaccine (BNT162b2) between July 14 and July 21, 2021. Levels of IgG antibodies against the spike receptor-binding domain of SARS-CoV-2 were measured 3 to 4 weeks after vaccination. RESULTS: Of the cohort of 279 patients, 124 (44.4%) had haematologic malignancies, 57 (20.4%) had rheumatologic diseases, and 98 (35.1%) were solid organ-transplant recipients. Anti-SARS-CoV-2 antibody levels increased in 74.9% of cases. Across the entire cohort, the median absolute antibody levels (expressed in AU/mL) increased from 7 (interquartile range (IQR), 0.1-69) to 243 (IQR, 2-4749) after the booster dose. The response significantly varied across subgroups: The transplant cohort showed the greatest increase in absolute antibody levels (from 52 (IQR, 7.25-184.5) to 1824 (IQR, 161-9686)), followed by the rheumatology (from 22 (IQR, 1-106) to 1291 (IQR, 6-6231)) and haemato-oncology (from 1 (IQR, 0.1-7) to 7.5 (IQR, 0.1-407.5)) cohorts. The χ2 test was 8.30 for difference in fold change (p = 0.016). Of the 193 patients who were seronegative at baseline, 76 became seropositive after vaccination, corresponding to a 39.4% (95% CI, 32.8%-46.4%) seroconversion rate. Transplant patients had the highest seroconversion rate (58.3% (95% CI, 44.3%-71.2%)), followed by rheumatology (44.1% (95% CI, 28.9%-60.5%)) and haemato-oncology (29.7% (95% CI, 22%-38.8%); χ2 = 11.87; p = 0.003) patients. DISCUSSION: A third dose of BNT162b2 is immunogenic in most immunosuppressed individuals, although antibody response may differ based on the type of disease and immunosuppression. The antibody level that correlates with protection is still unknown; thus, future studies are needed to evaluate clinical outcomes.