key: cord-0703714-2mjvn4vh authors: Rabinowich, Liane; Grupper, Ayelet; Baruch, Roni; Ben-Yehoyada, Merav; Halperin, Tami; Turner, Dan; Katchman, Eugene; Levi, Sharon; Houri, Inbal; Lubezky, Nir; Shibolet, Oren; Katchman, Helena title: Low immunogenicity to SARS-CoV-2 vaccination among liver transplant recipients date: 2021-04-21 journal: J Hepatol DOI: 10.1016/j.jhep.2021.04.020 sha: ab9f1cc710839254d1cc1b39e0c9a5d1a01178f7 doc_id: 703714 cord_uid: 2mjvn4vh BACKGROUND AND 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 for 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 eGFR, and treatment with high dose steroids and MMF. No serious adverse events were reported in both groups. CONCLUSION: LT recipients developed substantially lower immunological response to Pfizer-BioNTech SARS-CoV-2 mRNA-based vaccine. Factors influencing serological antibodies response include age, renal function and immunosuppressive medications. The findings require re-evaluation of vaccine regimens in this population. LAY SUMMARY: Liver Transplant recipients had a substantially inferior immunity to the Pfizer-BioNTech BNT162b2 SARS-CoV-2 vaccine. Less than half of the patients developed sufficient levels of antibodies against the virus, and in those who were positive, average antibody levels were two times less compared to healthy controls. Factors predicting non-response were older age, renal function and immunosuppressive medications. Affiliations: 1-Organ Transplantation Unit, Division of Surgery, Tel-Aviv Sourasky Medical Center, and Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel. Medical Center, and Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel. Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel. Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel. Background and 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 for 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% Two novel mRNA technology based SARS-CoV-2 vaccines, developed by Pfizer and Moderna are currently approved, with efficacy reaching 94-95% in clinical trials [1, 2] . Solid organ transplant (SOT) recipients were excluded from those trials, thus, the vaccine's immunogenicity in this population is unknown. Despite the lack of data, vaccination of Liver Transplant (LT) recipients was recommended by professional societies [3, 4, 5] . We assessed immunogenicity and safety of two doses of the Pfizer-BioNTech BNT162b2 SARS-CoV-2 vaccine among LT recipients. From December 2020, prioritized vaccination of SOT recipients was launched in Israel with the Pfizer-BioNTech BNT162b2 SARS-CoV-2 vaccine, administered in two doses given 3 weeks apart. The trial design included a study group of LT recipients followed in our SOT outpatient clinic, and a control group of healthcare workers with no major co-morbidities. All participants completed the full vaccination schedule. Exclusion criteria included age <18, inability to provide informed consent, and pregnancy. Participants signed a written informed consent. The Study was approved by the Tel-Aviv Sourasky Medical Center Institutional Review Board. Participants filled in a questionnaire on early 7 days post-vaccination side effects: local (pain, redness, swelling, and lymphadenopathy) and systemic (fever, chills, headache, fatigue, myalgia, arthralgia, nausea and vomiting, diarrhea) on a scale (0-4). Clinical data was obtained from patients' medical records and routine blood tests up to 3 months prior to the date of the first vaccination. Estimated glomerular filtration rate (eGFR) was calculated with the MDRD formula and adjusted to body surface area (Mosteller calculation) [6] . Chronic Kidney Disease (CKD) categories were defined according to KDIGO recommendations [7] . Blood samples were taken 10-20 days after the second vaccination. LIAISON SARS- Data is displayed as mean (standard deviation (SD)) for the continuous variables and All the patients and controls were negative for SARS-CoV-2 N-protein IgG serology test. Protective levels of SARS-CoV-2 S1/S2 IgG antibodies were detected in all the controls. Only 38/80 LT recipients (47.5%) had positive serology (p<0.001). Comparison of the clinical and laboratory data for the LT recipients with positive and negative SARS-CoV-2 S1/S2 IgG serology is presented in In a multivariate analysis, factors related significantly to negative serologic response were older age, use of high dose prednisone in the past 12 months, MMF and triple therapy immunosuppression. Use of low dose steroids showed a trend towards reduced immunogenicity but was not statistically significant. Higher eGFR was inversely related to a negative response ( Figure 1 ). The vaccine was well tolerated and no major adverse events occurred in any Treatment with MMF or high dose steroids in the year prior to vaccination had a significant effect on immunogenicity as previously shown in vaccination studies in SOT recipients [10, 11] . Other factors related to an inferior serological response were older age and reduced eGFR. This is also in line with other recent preliminary reports regarding the impact of older age on COVID-19 vaccine response [10, 12] . We reported no major adverse events to the vaccine and no event of graft rejection. Our study included only LT recipients, and thus does not necessarily reflect immunogenicity among other SOT recipients (i.e. lung, kidney) that are known to have lower post-vaccination response [9, 11] . Study limitations include a small sample size and short follow-up period. We did not test for the T-cell mediated response. The clinical outcomes regarding COVID-19 morbidity and mortality following the vaccination, in view of lower immunogenicity and lower antibody titers, requires further studies. Our findings raise a concern regarding the vulnerability of vaccinated LT recipients to COVID-19 infection, and define a recipient group at highest risk for immunization failure (older age, intense immunosuppression and kidney failure). Currently, effective measures to improve immunogenicity to the COVID-19 vaccine in this population remain unknown and are urgently needed. For the time being, our results support current recommendations that emphasize the importance of vaccinating patients pre-transplant. Finally, the reduced immunity must be taken into account when counseling patients with regards to practicing personal protective measures. Coronavirus  Neutralizing antibody was detected in only 47.5% of patients following vaccination.  Antibody titers were significantly lower compared to the control group.  Age, renal function and immunosuppression were associated with lower immunological response. J o u r n a l P r e -p r o o f C4591001 Clinical Trial Group. Safety and Efficacy of the BNT162b2 mRNA Covid COVE Study Group. Efficacy and Safety of the mRNA-1273 SARS-CoV-2 Vaccine EASL position paper on the use of COVID-19 vaccines in patients with chronic liver diseases, hepatobiliary cancer and liver transplant recipients AASLD COVID-19 Vaccine Working Group. AASLD Expert Panel Consensus Statement: Vaccines to Prevent COVID-19 Infection in Patients with Liver Disease A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. 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