Table 4.

Effect of COVID-19 vaccination in liver transplant recipients

Study	Aim	Study design	Vaccine brand	Number of patients	Main result
Boyarski et al. (Transplantation 2021)	To evaluate safety of the first dose	Participants completed a detailed online questionnaire 1 week following their first dose	Pfizer/BioNTech (50%) or Moderna (50%)	187 solid organ transplant recipients	No cases SARS-CoV-2, acute rejection, neurological diagnoses (Guillain–Barr syndrome, Bell’s Palsy, or neuropathy), or allergic reactions requiring epinephrine. Two cases of a new infection (acute-on-chronic pouchitis and influenza A) requiring treatment. Local site reactions included mild pain (61%), mild redness (7%), and mild swelling (16%). Systemic reactions such as fever and chills were uncommon (4% and 9%), although more-than-baseline fatigue was reported by 38%, headache by 32%, and myalgias by 15%
Boyarsky et al. (JAMA 2021)	To study the proportion of positive antibody response after a single dose	Antibodies to the S1 domain and anti-RBD of the SARS-CoV-2 spike protein at a median of 20 days after the first dose	mRNA (52% BNT162b2 vaccine and 48% mRNA-1273 vaccine)	436 solid organ transplant recipients	Antibody was detectable in 17% (95% CI 14–21%) of patients. Factors associated with lower response were anti–metabolite immunosuppression therapy (37% vs 63%; adjusted IRR 0.22; P < .001) and older age (adjusted IRR 0.83 per 10 years; P = .002). mRNA-1273 showed higher response than BNT162b2 (69%vs 31%; adjusted IRR 2.15; p = 0.003)
Timmermann et al. (Vaccines 2021)	To investigate the immune response alongside the influence of underlying diseases and immunosuppressive regimen	Anti-spike-protein-IgG testing at least 21 days after complete SARS-CoV-2 vaccination	BNT162b2 (n = 114), mRNA-1273 (n = 3) and JNJ-78436735 (n = 1)	118 liver transplant recipients	78% developed anti-spike-protein-IgG antibodies. Alcoholic liver disease before transplantation (p = 0.006) and mycophenolate mofetil-based regimen (p < 0.001) were associated with lower response rate. All patients weaned off immunosuppression were seropositive
Rashidi-Alavijeh et al. (Vaccines 2021)	Analyze immunogenicity	SARS-CoV-2 IgG against the Spike glycoprotein in a median of 15 days after receiving two doses of the vaccine	BNT162b2	43 liver transplant recipients and 20 healthcare workers as control group	79% liver transplant recipients developed antibodies (100% in the control group; p = 0.047). The median IgG titter was significantly lower in the liver transplant recipients (216 vs. > 2080 BAU/mL in controls, p = 0.0001). Mycophenolate mofetil was associated with a reduced response compared to the other liver transplant patients (45.5% vs. 90.6%, p = 0.004)
Rabinowich et al. (J Hepatol, 2021)	To asses vaccine immunogenicity and safety	SARS-CoV-2 IgG antibodies against the Spike-protein and Nucleocapsid-protein 10–20 days after receiving the second dose	BNT162b2	80 liver transplant recipients and 25 healthy controls	47.5% liver transplant patients presented positive serology (vs 100% in controls; 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 were older age, lower eGFR, high dose steroids and mycophenolate mofetil. No serious adverse events were reported in either group
Thuluvath et al. (J Hepatol, 2021) (29)	To asses vaccine immunogenicity and safety	Antibody responses to spike protein, 4 weeks after complete vaccination	2 doses of mRNA vaccines or after the single dose of Johnson & Johnson	62 liver transplant recipients	Antibody levels were undetectable in 11 patients and suboptimal (median titter 17.6, range 0.47–212 U/ml) in 27 patients. Liver transplantation, use of 2 or more immunosuppressive therapies and vaccination with Johnson & Johnson were associated with poor response. No patient had any serious adverse events
Boyarsky B et al. (JAMA 2021)	To asses antibody response after the second dose	Anti-spike serologic testing which tests for the receptor-binding domain of the SARS-CoV-2 spike protein at a median of 29 days after dose 2	mRNA	658 solid organ transplant recipients	Antibody was detectable in 54%. Among the 473 receiving antimetabolites, 8% had response after dose 1 and dose 2; 57% had no response after dose 1 or dose 2; and 35% had no response after dose 1 but subsequent antibody after dose 2. Among the 185 participants not receiving antimetabolites, 32% had response after dose 1 and dose 2; 18% had no response after dose 1 or dose 2; and 50% had no response after dose 1 but subsequent antibody after dose 2
Boyarsky B et al. (Transplantation, 2021)	To quantify the antispike antibody response to the Janssen vaccine and compare it to recipients of the mRNA series	Antibodies anti-RBD of the spike protein at 1 month after COVID-19 vaccine	Janssen (n = 12) and mRNA group (n = 725)	12 solid organ transplant recipients	Anti-RBD antibody was detectable in only 17% of participants who received the Janssen (vs 59% in mRNA series, P = 0.005), with lower odds (aOR0.11; P = 0.006) of developing anti-RBD antibodies than those who completed the mRNA series. Median anti-RBD Ig titers in the Janssen group were significantly lower than the mRNA group (2.39 versus 106.9 U/mL; P = 0.047)
Herrera et al. (Am J Transplant 2021)	To study cellular and humoral immune response	IgM/IgG antibodies and ELISpot against the S protein 4 weeks after receiving the second dose	mRNA-1273	58 liver and 46 heart recipients	64% developed IgM/IgG antibodies and 79% S-ELISpot positivity. 90% developed either humoral or cellular response (87% in heart and 93% in liver recipients). Factors associated with vaccine unresponsiveness were hypogammaglobulinemia and vaccination during the first year after transplantation. Local and systemic side effects were mild or moderate, and none presented donor-specific antibodies or graft dysfunction after vaccination
Kamar et al. (NEJM 2021)	To report the humoral response	Antibodies to SARS-CoV-2 spike protein in patients who were given three doses	BNT162b2	101 solid organ transplant recipients (78 kidney, 12 liver, 8 lung or heart, and 3 pancreas)	The prevalence of anti–SARS-CoV-2 antibodies was 0% before the first dose, 4% before the second dose, 40% before the third dose, and 68% 4 weeks after the third dose. Among the 59 patients who had been seronegative before the third dose, 44% were seropositive at 4 weeks after the third dose. All 40 patients who had been seropositive before the third dose were still seropositive 4 weeks later; their antibody titers increased from 36 to 2676 1 month after the third dose (P < 0.001). Patients who did not have an antibody response were older, had a higher degree of immunosuppression, and had a lower eGFR. No serious adverse events were reported, and no acute rejection episodes occurred
Guarino et al. (Clin Gastroenterol Hepatol 2022)	To evaluate immunogenicity and to identify factors associated with negative response	Anti-Spike protein IgG-LIAISON SARS-CoV-2 S1/S2-IgG chemiluminescent assay at 1 and 3 months after 2-dose vaccination	BNT162b2	492 liver transplant recipients and 307 controls matched by age and sex	Detectable antibodies were observed in the 75% of patients with a median value of 73.9 AU/mL after 3 months from 2-dose vaccination. Older age (> 40 years, p = 0.016), shorter time from liver transplantation (< 5 years, p = 0.004), and immunosuppression with antimetabolites (p = 0.029) were associated with non-response. Liver transplant recipients showed antibody titers lower than the control group (103 vs 261 AU/ml, p < 0.0001). Both in controls and transplant patients there was a trend of correlation between age and antibody titers (correlation coefficient: − 0.2023 and − 0.2345, respectively)
Toniutto (J Hepatol 2022)	To assess the long-term antibody response in liver transplant compared to controls	Anti-RBD IgG and anti-nucleocapsid protein IgG measurements at the one, four and six months after the second dose	Pfizer-BioNTech BNT162b2 vaccine	143 liver transplant and 58 controls	Among COVID-19 naïve, 66.4%, 77%, and 78.8% were anti-RBD positives at one, four and six months following the second dose, while 100% of controls were positive at 4 months (p < 0.001). The median anti-RBD titter at four months was significantly lower (32U/ml) in COVID-19 naïve than in controls (852 U/ml, p < 0.0001). Mycophenolate (p < 0.001), ascites (p = 0.012), and lower leukocyte count (p = 0.016) were independent predictors of anti-RBD negativity at six months

IRR incidence rate ratio, eGFR estimated glomerular filtration rate, anti-RBD Anti-receptor binding domain protein