Humoral and cellular immune responses to COVID-19 mRNA vaccines in immunosuppressed liver transplant recipients

Liver transplant recipients (LTRs) face a significantly elevated risk of severe COVID-19 due to immunosuppression and comorbidities. While mRNA vaccines have proven effective in the general population, their efficacy in LTRs is demonstrably lower compared to healthy individuals or other immunosuppressed patient groups. The precise mechanisms underlying this reduced responsiveness, particularly concerning the disruption of humoral (antibody-mediated) and cellular (T-cell mediated) immune memory responses, remain incompletely understood. This knowledge gap is critical because effective vaccination strategies are urgently needed to protect this vulnerable population. Previous studies have hinted at decreased antibody production and T cell responses in LTRs after vaccination, but a comprehensive longitudinal analysis examining both humoral and cellular immunity is lacking. This study aimed to address this gap by meticulously characterizing the immune responses (both antibody and T cell responses) to mRNA vaccination in LTRs, comparing them to those in healthy donors, and exploring how various immunosuppressive regimens influence vaccine efficacy. Understanding these nuances is paramount for developing tailored vaccination strategies to maximize protection in LTRs against COVID-19 and potentially other viral infections. The study aimed to not only investigate the effectiveness of the current vaccination protocols but also to offer guidance towards more effective strategies to enhance immune responses, ultimately reducing morbidity and mortality in LTRs.

Several studies have already highlighted the reduced immunogenicity of COVID-19 vaccines in liver transplant recipients. These studies reported lower antibody titers in LTRs compared to healthy donors after vaccination. However, these studies often lacked a detailed assessment of cellular immune responses, focusing mainly on antibody production. Furthermore, the impact of different immunosuppressive regimens on the immune response to the vaccine is not completely clear. Some research suggests that specific immunosuppressants might have a stronger negative impact on immune responses compared to others. This review aimed to expand on previous studies by adding a more thorough investigation of both humoral and cellular immunity, in addition to considering various immunosuppression regimens and using a more detailed analysis to look at these factors in relation to the vaccine response. This would lead to a better understanding of the relative contributions of humoral and cellular immunity following vaccination, and help to better tailor vaccination strategies to this at-risk population.

This prospective longitudinal study enrolled 98 participants: 44 healthy donors (HDs) and 54 liver transplant recipients (LTRs) from Osaka University, Japan. All participants received either the Pfizer-BioNTech (BNT162b2) or Moderna (mRNA-1273) COVID-19 mRNA vaccine. Peripheral blood mononuclear cells (PBMCs) and plasma samples were collected at multiple time points: before vaccination, and at 1, 3, and 6 months after the second dose, and 1 month after the third dose. Anti-receptor-binding domain (RBD) antibody levels were measured using ELISA. Spike-specific CD4⁺ and CD8⁺ T-cell responses were assessed using flow cytometry, including intracellular cytokine staining to determine the proportions of Th1 and Tfh cells. Neutralization assays were conducted to evaluate the plasma neutralizing activity against SARS-CoV-2. The characteristics of the subjects such as demographics (age, sex), time since transplantation, history of rejection, type of transplant (cadaveric vs. living-donor), eGFR (estimated glomerular filtration rate), and number of immunosuppressive drugs were meticulously recorded and analyzed. Statistical analyses included the Mann-Whitney U test, Wilcoxon matched-pairs signed-rank test, Spearman's rank correlation test, and multivariate logistic regression to determine the correlation between antibody and T cell response among subjects. The impact of different immunosuppressive regimens on the immune response were also investigated.

The study revealed that LTRs had significantly weaker anti-RBD IgG responses compared to HDs after both the second and third vaccinations. This difference was particularly pronounced in LTRs receiving multiple immunosuppressants compared to those on calcineurin inhibitors alone. The third vaccination improved antibody titers in LTRs, but the levels still remained lower than those observed in HDs after the second dose. Analysis of CD4⁺ T-cell responses showed that these were also weaker in LTRs, especially in those on multiple immunosuppressants. Similar to antibody responses, the third vaccination improved CD4⁺ T-cell responses in LTRs. However, spike-specific CD8⁺ T-cell responses were quantitatively limited in LTRs but without significant qualitative differences compared to HDs. Critically, no boosting effect was observed for CD8⁺ T-cell responses after the third dose, in either group. The correlation analysis revealed a positive association between CD4⁺ T-cell frequencies and antibody titers in both HDs and LTRs. The study also showed that the reduced antibody response in LTRs was associated with the number of immunosuppressive drugs they were taking. Neutralizing antibody activity was also significantly lower in LTRs compared to HDs. The induced antibodies were also less effective against Omicron sublineages, particularly BQ.1 and XBB. Importantly, while CD4+ T cell responses were elicited against various Omicron sublineages, there was no significant difference between HDs and LTRs after the third vaccination.

The findings of this study confirm the reduced immunogenicity of mRNA COVID-19 vaccines in LTRs, highlighting the importance of developing strategies to improve their immune responses to these vaccines. The observed weakness in both humoral and cellular immunity, particularly among those on multiple immunosuppressants, underscores the need for individualized vaccination approaches tailored to the specific immunosuppressive regimens of each patient. Although a third dose provided improved antibody and CD4⁺ T-cell responses in LTRs, further strategies are required to boost CD8⁺ T-cell responses, given their critical role in viral clearance. The study also highlighted the reduced effectiveness of the current vaccine against emerging variants of concern. Additional investigations are thus warranted to explore alternate vaccination strategies, including booster shots or multivalent vaccines, as well as potential immunomodulatory therapies to improve vaccine efficacy in LTRs. These strategies might enhance immune memory and provide broader protection against a wider range of SARS-CoV-2 variants. The study's strength lies in the detailed analysis of both humoral and cellular immune responses, alongside a consideration of diverse immunosuppressive regimens, providing valuable insights for future vaccine development and deployment in LTRs.

This study demonstrates that while mRNA vaccines can elicit both humoral and CD4⁺ T-cell responses in LTRs, the responses are weaker compared to HDs. A third dose can improve these responses, but further strategies are required to optimize CD8⁺ T-cell responses and broaden protection against emerging variants. Future research should focus on developing tailored vaccination strategies for LTRs, including investigating the potential benefits of booster doses, multivalent vaccines, and immunomodulatory therapies.

The study was conducted in a single center in Japan, limiting the generalizability of the findings to other populations and healthcare settings. The sample size, while substantial, could be increased for enhanced statistical power. The study did not directly investigate the clinical outcomes of COVID-19 infection in the participants, limiting the ability to establish a direct link between immune response and disease severity. Finally, the study focused on specific Omicron sublineages and additional variants might yield further insights.