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Clinical Factors Associated With Lack of Serological Response to SARS‐CoV‐2 Messenger RNA Vaccine in Liver Transplantation Recipients

Recent preliminary data report lower serological response to SARS-CoV-2 mRNA vaccines in solid organ transplant (SOT) recipients (1, 2). There are no data on factors associated with lack of serological response in SOT recipients - information that could guide recommendations regarding booster dose and closer follow up. We evaluated the serological response to SARS-CoV-2 vaccination in liver transplant (LT) recipients.

Comparisons used χ 2 testing for categorical variables and the t test or Mann-Whitney U test for continuous variables. Forward stepwise multivariate logistic regression analyses were used to determine covariates associated with the negative spike Ab. Model assumptions were checked for multicollinearity using a variance inflation factor for immunosuppression characteristics, and the final model performance was summarized by a concordance index of 0.75.

Results
In total, 74 LT recipients were enrolled, of which 5 were excluded as a result of a positive nucleocapsid Ab. Baseline clinical characteristics for LT recipients and comparisons based on spike Ab are in Table 1. Median time from first dose was 81 days (interquartile range [IQR], 72-90 days) and most were male (70%) and White (65%) as described in Table 1. Of the recipients, 48% (n = 33) had a positive spike Ab, of which onethird (n = 11) had a high Ab titer (>20).
Overall, we found that recipients with a negative spike Ab had a higher proportion with 2 or more immunosuppressive agents (56% to 36%), including prednisone (45% to 18%), within 1 year of LT (28% to 6%), leucopenia (19% to 6%), obesity (64% to 36%), and higher tacrolimus trough levels (6.6 versus 5.4 ng/mL) than those with positive spike Ab. In the multivariate model seen in Table 2, increase in tacrolimus trough levels, 2 or more immunosuppressive agents, and obesity were associated with negative spike Ab.
One recipient had mild biopsy-proven acute cellular rejection 2 months before first dose and had negative Ab. There were no significant differences in aspartate aminotransferase (AST), alanine aminotransferase (ALT), or alkaline phosphatase (ALP) levels between groups. A total of 5 patients had ALT or ALP more than 2 times the normal level; 3 patients had negative spike Ab. Of the recipients, 36 (52%) had HBs Ab titer within 1 year after LT and received hepatitis B vaccination after LT if the pre-LT serology was negative; only 21% (n = 8) had positive HBs Ab with a higher proportion seen in those with a positive spike Ab (41% versus 5%).

Discussion
We found that fewer than half of the LT recipients developed a serological response after receiving 2 doses of the mRNA SARS-CoV-2 vaccine, a concerning suboptimal response lower than previously reported. (2) These findings have several practical considerations for the management of LT recipients. Recipients within 1 year of LT are more likely to be on prednisone and are treated with multiple agents with frequent changes in immunosuppression; they represent a high-risk population that should be closely monitored for serologic response. Higher tacrolimus trough levels had lower responses, and reducing trough goals and avoiding supratherapeutic concentrations could be 1 potential strategy to improve the humoral response.
In recipients who received a hepatitis B virus vaccination series after LT based on pre-LT serology, only 33% had seropositivity within the first year after LT, further demonstrating the effect of high-intensity immunosuppression impairing the ability to develop a robust immune response to other vaccines as well. A recent report demonstrated that more than 90% of LT candidates were able to achieve a serologic response, which warrants further consideration for transplant centers to require those on the waiting list to complete a vaccination series prior to LT. In recipients who contract the SARS-CoV-2 infection, nearly one-quarter develop severe infection, with mortality rates of 17%. As the pandemic continues, LT recipients are at an increased risk, with nearly onequarter developing severe infection and with mortality rates of 17%. (4) Furthermore, the effects of severe SARS-CoV-2 infection on short-term and long-term allograft function is largely unknown. Because of this heightened risk and the low immune response after the second dose, a short delay for administering the third booster dose can improve the immune response in this vulnerable population. (5)(6)(7) Even with the recent Emergency Use Authorization (EUA) for a third dose in SOT recipients, there is a lack of data on its efficacy, optimal time between dosing, and longterm immunity. Given these unknown factors, optimizing immune response in waitlist candidates prior to LT can mitigate risk in the early post-LT period. The limitations of this study include the small sample size, short follow-up period, lack of controls, and the inability to assess for T cell response. As vaccination strategies to improve humoral response in this population are being considered, including EUA approval for a third booster dose, we identified several risk factors related to higher levels of immunosuppression and laboratory markers that can aid clinicians in identifying patients at risk for a negative serological response.