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Clin Transplant Res 2024; 38(4): 247-256

Published online December 31, 2024

https://doi.org/10.4285/ctr.24.0062

© The Korean Society for Transplantation

SARS-CoV-2 vaccine-elicited immune responses in solid organ transplant recipients

Euri Seo1 , Eui-Cheol Shin1,2 , Min Kyung Jung1

1The Center for Viral Immunology, Korea Virus Research Institute, Institute for Basic Science (IBS), Daejeon, Korea
2Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Korea

Correspondence to: Min Kyung Jung
The Center for Viral Immunology, Korea Virus Research Institute, Institute for Basic Science (IBS), 55 Expo-ro, Yuseong-gu, Daejeon 34126, Korea
E-mail: mkjung@ibs.re.kr

Received: November 20, 2024; Revised: December 18, 2024; Accepted: December 18, 2024

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Solid organ transplant recipients (SOTRs) are considered a high-risk group for coronavirus disease 2019 (COVID-19). The adaptive immune responses generated by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination include humoral and cellular immune responses. Most studies on the SARS-CoV-2 vaccine have focused primarily on humoral immunity, but cellular immunity is vital for effectively controlling progression to severe COVID-19. In SOTRs, the vaccine-induced adaptive immune response is significantly attenuated compared to the response in healthy individuals. Nevertheless, vaccinated SOTRs exhibit a reduced rate and severity of SARS-CoV-2 infection. This review aims to provide a concise overview of the current understanding of SARS-CoV-2 vaccine-induced immune responses in SOTRs.

Keywords: Solid organ transplant recipients, SARS-CoV-2 vaccine, Humoral immune responses, Cellular immune responses

HIGHLIGHTS

  • Adaptive immune responses to severe acute respiratory syndrome coronavirus 2 vaccines are attenuated in solid organ transplant recipients (SOTRs) compared to healthy controls.

  • Additional booster vaccinations have improved vaccine-induced immunity, although SOTRs exhibit lower immune responses than healthy controls.

INTRODUCTION

The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection significantly impacted global public health after its emergence in December 2019 [1,2]. In response to this urgent public health crisis, SARS-CoV-2 vaccines targeting the spike protein of the original Wuhan-Hu-1 strain underwent unprecedented development and were administered to large populations globally. SARS-CoV-2 vaccines have been shown to prevent original Wuhan-Hu-1 infection and protect against severe disease from other SARS-CoV-2 variants, including Omicron [3–7].

SARS-CoV-2 vaccines provide protection by inducing both virus-specific humoral and cellular immune responses. Humoral immune responses are mediated by B cells and antibodies, including neutralizing antibodies (nAbs) that interfere with the entry of SARS-CoV-2 into host cells, and are considered to be key for host protection. However, the levels of nAbs decline with time after SARS-CoV-2 vaccination [8]. Moreover, continuously emerging SARS-CoV-2 variants escape nAbs elicited by vaccination [9]. Consequently, protection from infection itself decreases dramatically, which caused the global spread of Omicron in late 2021 [7]. Another immune response induced by vaccination is the T cell-mediated immune response. The virus-specific T cell response is crucial for controlling disease severity by eliminating infected host cells and reducing viral load. Although the infection rate of Omicron increased, protection from severe disease has remained high among vaccinated or convalescent individuals. This has been due, in part, to maintenance of cross-reactive immunity by T cell responses, as targeted epitopes are largely conserved between original SARS-CoV-2 (Wuhan-Hu-1) and variants, including Omicron [10,11].

Solid organ transplant recipients (SOTRs) are a high-risk group for COVID-19 due to their use of immunosuppressant medications and associated clinical complications. Several studies have demonstrated that humoral immune responses elicited by SARS-CoV-2 vaccines in SOTRs are impaired compared to normal healthy individuals. Despite a weak antibody-mediated immune response to vaccination in SOTRs, vaccinated SOTRs have reduced infection and mortality rates compared to unvaccinated SOTRs [12–14]. A few studies have reported on the cellular immune response elicited by SARS-CoV-2 vaccination in SOTRs. Similar to the antibody response, the cellular immune response following SARS-CoV-2 vaccination is lower in SOTRs compared to healthy individuals. Although repeated booster vaccinations have enhanced the virus-specific T cell response in SOTRs, these patients exhibit higher rates of COVID-19 breakthrough infections than healthy individuals due to a reduced SARS-CoV-2-specific immune response upon vaccination [15].

In this review, we summarize the current understanding of SARS-CoV-2 vaccine-induced humoral and cellular immunity in SOTRs. In addition, we discuss the impact of SARS-CoV-2 vaccination on the outcome of allograft by understanding the immunological characteristics induced by the SARS-CoV-2 vaccine in SOTRs.

HUMORAL RESPONSE TO SARS-COV-2 VACCINATION IN SOLID ORGAN TRANSPLANT RECIPIENTS

Vaccine-induced SARS-CoV-2 antibody responses are attenuated in SOTRs [16]. Several studies have reported that various SOTRs, including kidney, heart, and lung transplant recipients, have a limited humoral response to the first and second doses of the SARS-CoV-2 vaccine [17–19]. Although the first dose of vaccine does not elicit a response and results in generally low antibody levels, the second dose induces a humoral response among SOTRs with detectable antibody responses [18]. Despite poor seroconversion (<50%) after two-dose SARS-CoV-2 vaccination [20,21], vaccination was associated with reduced mortality and morbidity from COVID-19 compared to unvaccinated SOTRs [12,13,22].

Immunization with booster doses, such as the third or fourth dose of an mRNA vaccine, increases the levels of humoral immune responses in SOTRs, as well as in healthy individuals (Table 1) [23–27]. A study of SOTRs found that a third dose of the SARS-CoV-2 vaccine increased the seropositive rate for anti-RBD and antispike more than twice over the levels before the third dose. Despite these increases, the median anti-RBD and antispike immunoglobulin G (IgG) values remained significantly lower in SOTRs than in healthy controls. The analysis of 50% neutralization titer (NT50) showed that the third dose of SARS-CoV-2 vaccine enhanced the NT50 against the original Wuhan-Hu-1 and Delta variant of concern (VOC). However, 32% of SOTRs still had nondetectable nAbs against Delta after the third vaccination compared to 100% for healthy individuals, indicating that SOTRs had significantly lower neutralization activity than healthy controls even after the third dose [16]. A third dose of the SARS-CoV-2 vaccine to liver transplant recipients resulted in a significantly increased frequency of anti-RBD IgG (56%–98%) and NT50 (from 7.0–21.0 to 262.5–1,608). Most patients developed sufficient levels of humoral immune responses, except for older patients and those on mycophenolate mofetil medications [28].

Table 1. Summary of SARS-CoV-2 vaccine-induced immune responses among solid organ transplant recipients

StudyTransplanted organVaccineBoosting numberOutcomeDemographic
Age (yr)a)Male (%)
Humoral response
Del Bello et al. (2022) [23]Kidney, liver, heart, lung, pancreas, combinedBNT162b3rdAnti-SARS-CoV-2 Ab: 67.9% positive rate 4 weeks after the 3rd dose59±1565.0
Hall et al. (2021) [24]Kidney, liver, heart, lung, pancreas, combinedmRNA-12733rdAnti-RBD Ab: 55% positive rate 4 months after the 3rd dose66.9 (64.0–71.8)61.7
Memenga et al. (2023) [25]HeartBNT162, mRNA-12733rdAnti-SARS-CoV-2 IgG: 62.9% positive rate 1 month later the 3rd dose55 (48.5–61)69.0
Davidov et al. (2022) [28]LiverBNT162b3rdAnti-RBD IgG: 98% positive rate 5 months after the 3rd dose65 (52–70)57.4
Perrier et al. (2022) [29]Kidney, liver, heart, lung97% BNT162b3rd, 4thAnti-RBD IgG: 67.6% positive rate 4 months after the 3rd dose and 76.2% positive rate 1 months after the 4th dose61.2 (50.9–69.3)66.7
Peled et al. (2022) [30]HeartBNT162b4thAnti-RBD IgG Ab: 67.6% positive rate 2 weeks after the 4th dose57.2±13.868.9
McAteer et al. (2024) [31]Liver, kidney, heartBNT162b3rdAnti-SARS-CoV-2-Spike IgG: 100% positive rate 6 months after the 3rd dose and 94% positive rate 1 year after the 3rd dose16 (13.8–17.0)59.6
T cell response
Hall et al. (2021) [24]Kidney, liver, heart, lung, pancreas, combinedmRNA-12733rdIncreased SARS-CoV-2 specific T cell counts at 4 months after the 3rd dose with minimal polyfunctional CD8+ T cell response66.9 (64.0–71.8)61.7
Davidov et al. (2022) [28]LiverBNT162b3rdIncreased SARS-CoV-2 spike-specific T cell count 5 months after the 3rd dose65 (52–70)57.4
Müller et al. (2023) [32]Liver, kidney, pancreasBNT162b3rd, 4thIncreased Omicron spike-reactive CD4+ and CD8+ T cell responses after the 3rd and f4th doses with enriched TEMRA subset of CD8+ T cellNA51.0
Harberts et al. (2022) [33]LiverBNT162b, mRNA-12733rd, 4thSARS-CoV-2 spike-specific T cell response: 72% positive rates 2 weeks after the 3rd dose and 60% positive rates 2 weeks after the 4th dose59.0 (51.0–68.3)60.4
Schrezenmeier et al. (2022) [34]KidneyBNT162b4thCellular responder with spike-specific CD4+ T cell response: 85% positive rates 1 month after the 4th dose59.8±14.858.6

SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; Ab, antibody; IgG, immunoglobulin G; NA, not available.

a)Mean±standard deviation or median (interquartile range).

A large cohort study of the fourth dose of SARS-CoV-2 vaccine in 825 SOTRs suggested that the detectable humoral responses were significantly higher after the fourth dose than after the third dose (47% vs. 22%). Among the enrolled patients, liver transplant recipients more frequently had a strong humoral response with repeated vaccinations up to the fourth dose. In kidney transplant recipients, belatacept treatment was associated with a lower rate of detectable humoral responses [29]. In another study of heart transplant recipients, the fourth dose resulted in an enhanced level of anti-RBD IgG antibodies and a higher neutralization efficiency against the original Wuhan-Hu-1 and VOCs, such as Delta and Omicron (B.1.1.529). However, the neutralization efficiency was lower against the B.1.1.529 Omicron variant than against the Delta variant [30].

To improve the suboptimal SARS-CoV-2 vaccine response in SOTRs, various vaccine regimen strategies have been investigated. Kidney transplant recipients who did not respond to the first two doses of SARS-CoV-2 vaccine were further vaccinated with several vaccine regimen options, including one dose of mRNA vaccine (mRNA-1273), two doses of mRNA vaccine (mRNA-1273), or one dose of adenoviral vector-based SARS-CoV-2 vaccine (Ad26.COV2.S). All three regimens achieved an antispike antibody response rate of approximately 68%. This study proposed that repeated booster vaccination is needed to achieve an improved humoral immune response but did not find a significant difference between vaccine regimens [35]. However, another group suggested that SOTRs without an antibody response after two doses of mRNA vaccine may benefit from a heterologous boosting with adenoviral vector-based SARS-CoV-2 vaccine (Ad26.COV2.S) compared to an homologous boosting with mRNA vaccine (BNT162b2/mRNA-1273) [36].

The durability of the vaccine-induced antibody immune response is an important point regarding vaccine strategies. According to a study of SOTRs, antibodies induced from the second vaccine remained stable for up to 6 months [37], and the third dose of vaccine-elicited antibody-mediated immune responses lasting up to 6–12 months [31]. We need to consider the durability in future studies of the antibody response induced by booster vaccination and various vaccine platforms.

The prolonged COVID-19 pandemic and continued emergence of VOCs have led to the development of a bivalent vaccine. The new bivalent mRNA-1273.214 vaccine targeted both original Wuhan-Hu-1 and BA.4/BA.5 and has shown better immune responses against Omicron variants than previously developed SARS-CoV-2 vaccines (mRNA-1273). A fifth dose of the bivalent vaccine significantly improved neutralization against VOCs (BA.1, BA.2, BA.4, and BA.5) and reduced breakthrough infections among SOTRs [38,39].

T CELL RESPONSE TO SARS-COV-2 VACCINE IN SOLID ORGAN TRANSPLANT RECIPIENTS

A few studies have reported the cellular immune response, whereas most studies of vaccine-induced immune responses in SOTRs have focused primarily on evaluating the humoral response to SARS-CoV-2 vaccines. The representative advantage of T cell-mediated cellular immunity is its preserved function against mutated viruses through cross-reactivity, offering prolonged protection against inexperienced VOCs [40,41]. Memory T cells induced by SARS-CoV-2 vaccines targeting original Wuhan-Hu-1 substantially recognize VOCs, including various Omicron subvariants [42–44].

Several studies investigating cellular immunity following SARS-CoV-2 vaccination have indicated that SOTRs, such as kidney, liver, lung, or heart transplant recipients, have lower cellular immune response rates compared to healthy individuals, similar to antibody studies (Fig. 1) [45–47].

Figure 1. SARS-CoV-2 vaccine-induced T cell responses in SOTRs. T cell response to SARS-CoV-2 vaccines is significantly weaker in SOTRs than in healthy controls. Additional booster vaccinations have increased the frequency of virus-specific T cells, CD45RA+ effector memory (TEMRA) subpopulations, and cytokine-producing capacity, although SOTRs exhibit lesser T cell responses compared to healthy controls. Boosting vaccinations might contribute to lower breakthrough infection rates and reduced disease severity of coronavirus disease 2019 (COVID-19). SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; SOTRs, solid organ transplant recipients.

Gao et al. [48] studied how immunodeficiency in SOTRs (liver, kidney, pancreas) and other immunocompromised groups affects vaccine-induced SARS-CoV-2-specific T cells following their first and second doses of the SARS-CoV-2 vaccine. Notably, SOTRs exhibited the lowest T cell responses as measured by interferon (IFN)-γ enzyme-linked immunosorbent spot (ELISPOT) assays, not only when compared to healthy controls, but also when compared to individuals with primary immunodeficiencies and those with human immunodeficiency virus infection [48]. Further experiments revealed that the SOTR group had reduced frequencies of spike-specific CD4+ T cells 6 months after the second dose of the vaccine [48]. In a functional analysis of virus-specific CD4+ T cells, these spike-specific CD4+ T cell responses were significantly lower in strength in SOTRs [48]. The other group found consistent results, as the spike-specific CD4+ T cells from kidney transplant recipients also produced decreased levels of effector cytokines, such as IFN-γ, tumor necrosis factor (TNF), and interleukin (IL)-2. Moreover, kidney transplant recipients had significantly lower levels of polyfunctional spike-specific CD4+ T cells (IFN-γ+TNF+IL-2+) compared to healthy controls [48,49]. These findings were supported by transcriptome analysis with RNA sequencing, which indicated a decrease in several features related to cellular activation in kidney transplant recipients [49]. A study by Schmidt et al. [50] suggested that heterologous vaccine regimens, which involve a combination of different vaccine types alongside the mRNA vaccine (BNT162b2 or mRNA1273) and adenoviral-based vaccine (ChAdOx1 nCoV-19), were more effective in inducing CD4+ T cell responses compared to homologous mRNA vaccine regimens in SOTRs.

In the analysis of CD8+ T cells in SARS-CoV-2-vaccinated SOTRs, the rate of responders (i.e., individuals with detectable virus-specific CD8+ T cells) was notably reduced among kidney transplant recipients compared to healthy controls 1 month after the second vaccine dose [49]. In addition, SOTRs had reduced frequencies of virus-specific CD8+ T cell populations 6 months after the second dose of SARS-CoV-2 vaccine [48]. According to these reports, the reduced frequency of virus-specific CD8+ T cells in SOTRs compared to healthy controls persists after approximately 6 months. Müller et al. [32] reported that booster vaccination effectively induced enhanced and diversified Omicron-reactive T cell responses in immunocompromised individuals, including SOTRs. Functionally, Omicron-reactive CD8+ T cell responses induced by vaccination exhibited a pronounced cytotoxic profile and signs of longevity, characterized by CD45RA+ effector memory (TEMRA) subpopulations with stem cell-like properties and increased proliferative capacity. These implied the presence of minimal signs of antigenic sin or T cell fatigue, even after repeated antigen exposure and strong immunological imprint from original Wuhan-Hu-1-based vaccines [32]. Some groups have also reported the impaired T cell response after the second vaccination and enhancement of T cell response with further booster vaccinations in liver transplant recipients but to a lesser extent than in healthy controls (Table 1) [24,28,33,34].

CLINICAL OUTCOMES OF BREAKTHROUGH INFECTION IN SOTR

As mentioned above, SARS-CoV-2 vaccine-induced immunogenicity appears to be significantly impaired in SOTRs, and the risk of breakthrough infection is higher in these individuals. SOTRs have been reported to have a higher rate of breakthrough infection after two doses of vaccine compared to healthy individuals [51,52].

A growing number of reports have studied the effects of SARS-CoV-2 vaccination on clinical outcomes of breakthrough infection in SOTRs. Kidney transplant recipients had a breakthrough infection rate of 16% after two doses of vaccine, compared to 22% in unvaccinated recipients [53]. In another study, SOTRs with two doses of SARS-CoV-2 vaccine exhibited a reduced risk of death compared to SOTRS with one dose or unvaccinated SOTRs, with death rates of 7.7% vs. 12.0%–12.6% [22]. A significantly lower mortality rate was reported for kidney, liver, or heart transplant recipients vaccinated with two doses compared to unvaccinated recipients [49,54]. However, one study showed that disease severity outcomes, including mortality, oxygen requirement, and mechanical ventilation, were similar among SOTRs regardless of vaccination status.

The third dose of SARS-CoV-2 vaccine in SOTRs provides significant protection against breakthrough infection, with an 8% infection rate compared to 26% in unvaccinated SOTRs. It also reduces hospitalization rates (3% vs. 10%) and mortality (<1% vs. 8%) [55]. During the Delta-dominant period, kidney and liver transplant recipients with three doses of the SARS-CoV-2 vaccine had lower hospitalization and mortality rates [56]. SOTRs with three or more doses of the SARS-CoV-2 vaccine also had reduced severity of Omicron breakthrough infections [57–60]. SOTRs with four doses of the vaccine showed better protection against breakthrough infection-associated hospitalization and death during the Omicron era compared to SOTRs with three doses [61] or unvaccinated SOTRs [62]. Thus, booster doses of the SARS-CoV-2 vaccine in SOTRs are considered to reduce the rate of infection and reduce the severity of breakthrough infections.

ALLOGRAFT OUTCOMES OF mRNA VACCINATION

The risk of allograft rejection and allosensitization after vaccination is a significant concern in SOTRs. Many reports on rejection after SARS-CoV-2 vaccination are case studies, making it challenging to accurately assess the associated risk of rejection.

A systematic review and meta-analysis evaluated the rejection rates in SOTRs after SARS-CoV-2 vaccination. Among the rejections reported following the first or second dose were 11 liver transplants, six kidney transplants, and one pancreas transplant [63]. One patient experienced an incident of acute rejection following the second dose of vaccine [64]. Another patient had incident heart rejection 7 days after receiving the Janssen vaccine as the third dose following two mRNA vaccines, though this was not deemed to be related to the vaccine type [65]. Four cases of liver rejection were reported after the third dose of mRNA-1273, none of which were vaccine-related [66].

A recently published systematic review indicated that the number of mRNA vaccine doses may have little to no impact on the risk of rejection [67]. Kidney transplant recipients who had previously received a second dose of mRNA vaccine did not present with acute rejection after receiving either a single booster dose or two booster doses of COVID-19 mRNA vaccine [68]. Furthermore, Natori et al. [69] reported that administering the mRNA vaccine (BNT162b2) as a third dose in SOTRs did not lead to any new onset rejection during the follow-up period. In addition, Hall et al. [24] found that immunization with a third dose of the mRNA vaccine (mRNA-1273) to SOTRs resulted in no acute rejection, indicating that booster doses of the SARS-CoV-2 vaccine were well-tolerated and safe.

In a study of kidney transplant recipients, the third dose of the mRNA vaccine (BNT162b2) promoted the appearance of donor-specific antibodies in seven out of 45 patients (15.5%). However, this occurrence had no clinical consequences [70]. In addition, one patient awaiting kidney transplantation developed de novo donor-specific antibodies 18 days after receiving the first dose of the mRNA vaccine [71].

The risk of rejection associated with SARS-CoV-2 vaccination remains unclear, but it is likely low considering the number of vaccine doses administered. Although several studies in kidney or heart transplant recipients have reported no allosensitization following vaccination in SOTRs, vaccination may act as a nonspecific trigger for developing de novo donor-specific antibodies or anti-human leukocyte antigen antibodies [54,68,72].

CONCLUSION

SOTRs are particularly vulnerable to COVID-19 due to immunosuppressive medications taken to prevent organ rejection. SARS-CoV-2 vaccination generates essential immune responses, including both antibody-mediated humoral immunity and T cell-mediated cellular immunity. Boosting vaccination elicits an immune response in individuals who did not respond to the priming vaccine and can extend the duration of the vaccine-derived immune response. Though studies often focus on humoral responses, cellular immunity is crucial for controlling disease severity.

Published studies on the SARS-CoV-2 vaccine-induced adaptive immune responses in SOTRs have some limitations. Key aspects, such as the detailed phenotype, functionality, and epitope repertoire of T cells, remain unclear. Further studies are needed to optimize vaccination strategies that elicit strong and long-lasting immune responses in the high-risk group of SOTRs. A comprehensive understanding of SARS-CoV-2-specific immune responses induced by vaccines may have implications by providing important clues to future clinical strategy for better management of SOTRs.

ARTICLE INFORMATION

Conflict of Interest

Eui-Cheol Shin is an editorial board member of the journal but was not involved in the peer reviewer selection, evaluation, or decision process of this article. No other potential conflict of interest relevant to this article was reported.

Funding/Support

This work was supported by the Institute for Basic Science (IBS), Korea, under project code IBS-R801-D2.

Author Contributions

All the work was done by Euri Seo, Eui-Cheol Shin and Min Kyung Jung. All authors read and approved the final manuscript.

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