LAUSR

We read with great interest the recent publication from Siegel and colleagues, reporting recommendations from an international consensus meeting for SARSCoV2 vaccination in patients with inflammatory bowel diseases (IBDs). Based on experiences with other vaccines, it is reported that several immunosuppressive agents are associated with suboptimal vaccine response in patients with IBD. We assessed the effect of immunosuppressive blood levels on the SARSCoV2specific immunogenicity of SARSCoV2 vaccination in liver transplant (LT) recipients vaccinated with two doses of the mRNA vaccines: BNT162b2 or mRNA1273 or the vector vaccine ChAdOx1 nCoV19. Excluded were patients with a history of a SARSCoV2 infection. A total of 476 LT recipients (476/795=59.9% of all alive recipients) were eligible for analysis between March and July 2021 at the Erasmus University Medical Centre (Rotterdam, the Netherlands). In total, 36 LT recipients had a history of a SARSCoV2 infection confirmed by PCR before vaccination, 128 LT recipients were not vaccinated and 155 LT recipients were not routinely seen at the outpatient clinic during the study period and, therefore, excluded from this analysis. Immunogenicity to vaccination was measured by using the Liaison SARSCoV2 TrimericS IgG assay (DiaSorin, Italy). Table 1 presents the demographical and clinical characteristics of the study population. Tacrolimus (TAC) was used in 88.2% of the LT recipients as main immunosuppressive agent. Mycophenolate mofetil (MMF) was used in 34% of the LT recipients, mainly in combination therapy with TAC. Seroconversion occurred in 79.0% (376/476) of our LT recipients (see online supplemental table 1 and online supplemental figure 1). Figure 1A shows the immunoglobulin G (IgG) SARSCoV2 antispike antibody response according to the type of vaccine and stratified by the use of MMF. The use of MMF reduced the median level of IgG SARSCoV2 antispike antibodies for all vaccines to below the manufacturer’s cutoff for considering reactive. We did not find any significant associations between the other used immunosuppressive agents and immunogenicity. Figure 1B,C shows the IgG SARSCoV2 antispike antibodies versus TAC and mycophenolic acid (MPA) trough levels including expected values from multivariable linear regression models (see online supplemental table 2). The median IgG SARSCoV2 antibody levels over the TAC trough concentration range were 1090 BAU/mL and TAC trough levels were not associated with an effect on the immunogenicity. The median IgG SARSCoV2 antibody levels over the MPA trough concentration range were below the cutoff considered reactive by the manufacturer. MPA trough levels were significantly associated with lower immunogenicity of SARSCoV2 vaccination. Overall, IgG SARSCoV2 antibody levels were low for recipients using MMF and even for MPA trough levels of ≤1 mg/L. These results complement data of several studies in immunocompromised patients showing an altered antibody response to SARSCoV2 vaccinations in relation to the immunosuppressive drugs used. MPA inhibits both T and B lymphocytes proliferation, thereby suppressing cellmediated immune responses and antibody formation. Other agents showing a significant effect on the differentiation of B lymphocytes are Janus Kinase (JAK) inhibitors and methotrexate, whereas TAC, corticosteroids and mechanistic target of rapamycin (mTOR) inhibitors deplete only the T lymphocytes and indirectly the B lymphocytes. Moreover, the duration of inhibitory effects of immunosuppressive agents on the T and B lymphocytes differs per agent. We suggest discontinuing MMF for at least 6 weeks prior to and after vaccination based on the pharmacodynamical effect of MMF on B lymphocytes as shown by Ganschow et al and our results shown in this cohort. Furthermore, avoiding other agents affecting B lymphocytes in immunocompromised patients is recommended to increase the immunogenicity to SARSCoV2 vaccines. Focusing on the mechanism of action and drug levels of immunosuppressive agents in relation to the immunogenicity is essential in the ongoing debate to select the right target population for additional vaccinations and to define the right moment for (booster) vaccination. The use of MMF, regardless the trough level, is associated with a very poor IgG SARSCoV2 antispike antibodies response to SARSCoV2 vaccination. As a consequence, lowering the dose of MMF has no beneficial effect. Midas B Mulder , Annemiek A van der Eijk, Corine H GeurtsvanKessel, Nicole S Erler, Brenda C M de Winter, Wojciech G Polak, Herold J Metselaar, Caroline M den Hoed Department of Hospital Pharmacy, Erasmus University Medical Center, Rotterdam, The Netherlands the Erasmus MC Transplant Institute, Erasmus MC Transplant Institute, Rotterdam, The Netherlands Department of Viroscience, Erasmus University Medical Center, Rotterdam, The Netherlands Department of Biostatistics, Erasmus University Medical Center, Rotterdam, The Netherlands Department of Epidemiology, Erasmus University Medical Center, Rotterdam, The Netherlands Department of Surgery, Division of HPB and Transplant Surgery, Erasmus University Medical Center, Rotterdam, The Netherlands Department of Gastroenterology and Hepatology, Erasmus University Medical Center, Rotterdam, The Netherlands