Not just another shot: Tailoring vaccination in the era of modern liver transplantation

Abstract

Infections remain a leading cause of morbidity and mortality in patients with cirrhosis and liver transplantation (LT). Vaccination is underutilized despite proven benefits, and responses are often blunted by cirrhosis-associated immune dysfunction and post-transplant immunosuppression. This review synthesizes current evidence and recent advances in vaccination strategies for adult LT recipients, emphasizing optimal timing, novel vaccine platforms, and precision vaccinology. We discuss emerging data on coronavirus disease 2019, respiratory syncytial virus, and new pneumococcal and hepatitis B vaccines, highlight strategies to overcome immunogenicity gaps, and address implementation barriers. A practical roadmap and clinician-focused algorithms are proposed to integrate vaccination into the continuum of LT care.

Key Words: Vaccination; Liver transplantation; Immunosuppression; Precision vaccinology; Vaccine immunogenicity

Core Tip: Vaccination remains an underused preventive strategy in patients with cirrhosis and liver transplant recipients, despite a substantial burden of vaccine-preventable infections. Vaccine immunogenicity declines with advancing liver disease and is further reduced after transplantation due to immunosuppression, making early, pre-transplant immunization particularly important. Optimizing vaccine timing, formulation, and follow-up can support better integration of vaccination into standard liver transplant care. Novel vaccine platforms may improve immune responses in immunosuppressed patients, but their role in liver transplant recipients requires validation in dedicated clinical studies.

INTRODUCTION

Infectious complications remain a leading cause of morbidity and mortality in patients with cirrhosis and liver transplantation (LT) recipients[1,2]. Cirrhosis-associated immune dysfunction (CAID) results in heightened susceptibility to bacterial, viral, and fungal infections[3,4], while lifelong immunosuppression further increases this risk in LT recipients[1,2]. Despite advances in surgical techniques, immunosuppressive regimens, and antimicrobial therapies, the burden of infections in this population remains substantial.

Vaccination is a cornerstone of infection prevention in immunocompromised populations. For individuals with chronic liver disease (CLD) and LT recipients, vaccines against pathogens such as influenza, pneumococcus, hepatitis A, and hepatitis B have long been recommended[5]. However, vaccine uptake remains consistently suboptimal worldwide[6-8]. Importantly, while existing guidelines provide essential schedule-based recommendations, clinicians still face practical questions that are not fully resolved by guideline tables alone: Who is most likely to respond, which platform to choose, when to vaccinate across rapidly changing immune states, and how to individualize strategies under different immunosuppressive regimens?

The need to revisit vaccination strategies in modern LT is increasingly clear. Over the past decade, advances in vaccinology, including mRNA and recombinant protein platforms, have expanded available options and may offer improved immunogenicity and safety in immunocompromised populations. Concurrently, a more refined understanding of immune dysfunction across cirrhosis and post-LT has highlighted alterations in innate and adaptive immunity that are likely to influence vaccine responses[9]. Together, these developments challenge uniform, schedule-based vaccination approaches and underscore the value of precision vaccinology-tailoring vaccine selection and timing to patient-specific factors[10]. Recent shifts in the adult vaccine landscape (Supplementary Figure 1) further emphasize the need for an LT-specific, clinically grounded narrative.

In this review, we integrate immune biology with evolving vaccine technologies to provide a framework for vaccination in LT recipients. We focus on determinants of immunogenicity across disease stages, optimal timing, the influence of immunosuppressive regimens, vaccine safety including rejection concerns, and future directions toward individualized preventive care.

THE IMMUNOLOGICAL CONTINUUM: FROM CIRRHOSIS TO TRANSPLANTATION

CAID

Cirrhosis is characterized by CAID, a state marked by the coexistence of chronic systemic inflammation and immune paresis affecting both innate and adaptive immunity[3,4]. Increased gut permeability and dysbiosis promote sustained microbial translocation, which drives persistent immune activation followed by immune exhaustion and functional impairment[4]. As a result, key components of innate immunity-including Kupffer cells and hepatic macrophages-exhibit reduced phagocytic capacity and impaired antigen presentation and altered cytokine signaling, while adaptive immunity is compromised through T-cell exhaustion and impaired B-cell-mediated antibody production[3,5].

Clinically, these alterations translate into blunted and less durable vaccine responses, particularly in advanced cirrhosis. Seroconversion rates are reduced and antibody titers decline more rapidly, underscoring the importance of completing vaccination before decompensation whenever possible[5,11]. Because CAID affects both priming and durability, strategies such as early vaccination, timely boosting, and for selected vaccines post-vaccination serology can be considered to reduce the “immunogenicity gap”. Disease severity is a major determinant of immunogenicity: Higher model for end-stage liver disease (MELD) scores, prior infectious episodes, renal dysfunction, and hypersplenism are all associated with diminished vaccine responses[5,12]. For example, hepatitis B vaccine seroprotection falls to approximately 57% in Child-Pugh C cirrhosis, and MELD > 8 has been linked to impaired responses to coronavirus disease 2019 (COVID-19) vaccination[5,12].

Etiology appears to modify vaccine responsiveness, but its impact is generally smaller than that of disease stage and treatment intensity. Alcohol-related cirrhosis has been associated with lower responses in some studies, whereas metabolic dysfunction-associated steatotic liver disease typically shows preserved responses until cirrhosis develops; in autoimmune liver diseases, reduced responses are more strongly linked to concomitant immunosuppression than to liver disease itself[5,13].

Post-transplant immunosuppression

Following LT, vaccine responsiveness is primarily shaped by the intensity and composition of immunosuppression[14]. Calcineurin inhibitors (CNIs), the backbone of most maintenance regimens, suppress interleukin-2-dependent T-cell activation and are consistently associated with reduced vaccine immunogenicity[15]. Corticosteroids further impair antigen presentation and antibody production in a dose-dependent manner, with prolonged exposure linked to attenuated vaccine responses[16].

Emerging observational data suggest that mTOR-based regimens may be associated with preserved vaccine responses in some settings; however, evidence remains limited and confounded by indication[16,17]. Importantly, these findings should be interpreted as hypothesis-generating rather than an indication to modify immunosuppression solely to optimize vaccination. Agents such as basiliximab contribute to profound early post-transplant immunosuppression but are primarily relevant to the immediate peri-transplant period[15,17]. Of note, vaccine planning should account for the net state of immunosuppression, rather than any single agent in isolation.

Timing and the “immunization window”

Vaccine responsiveness follows a predictable temporal pattern across the transplant trajectory. The most favorable “immunization window” exists before advanced decompensation and before initiation of post-transplant immunosuppression, when immune competence is greatest (Figure 1)[4,11,15]. In contrast, vaccine responses are markedly impaired during the first 3-6 months after transplantation[15].

Figure 1 Dynamic immune dysfunction and vaccination responsiveness across cirrhosis and liver transplantation. ACLF: Acute-on-chronic liver failure; CAID: Cirrhosis-associated immune dysfunction; CNI: Calcineurin inhibitor; IS: Immunosuppression; LT: Liver transplantation; MASLD: Metabolic dysfunction-associated steatotic liver disease; MELD: Model for end-stage liver disease; MMF: Mycophenolate mofetil.

From a practical standpoint, inactivated vaccines should ideally be completed at least two weeks before transplantation, while live-attenuated vaccines require a minimum interval of four weeks and are contraindicated thereafter (Figure 2)[18,19]. When transplantation occurs before vaccination can be completed, immunization should be resumed once maintenance immunosuppression has stabilized, typically beyond the early post-transplant period[15,19]. These timing principles reinforce the need for early vaccination at evaluation or listing, rather than deferral based on anticipated waiting time[18,19].

Figure 2 Timing matters: When to vaccinate liver transplant candidates and recipients? HAV: Hepatitis A virus; HPV: Human papillomavirus; MMR: Measles, mumps, and rubella; LT: Liver transplantation; LAIV: Live attenuated influenza vaccine.

THE EXPANDING VACCINE LANDSCAPE

The next section emphasizes vaccines supported by the most robust evidence and associated with the highest clinical impact in CLD/LT populations [pneumococcus, influenza, COVID-19, hepatitis A/B, herpes zoster (HZ), respiratory syncytial virus (RSV)], while vaccines used less frequently or in specific circumstances (travel, outbreak control, region-limited availability) are discussed in a separate section.

Pneumococcal vaccination: Higher-valency conjugate vaccines and simplified adult schedules

Patients with CLD and LT recipients have a markedly elevated risk of pneumococcal disease, including increased rates of pneumococcal pneumonia and invasive pneumococcal disease, with substantial associated mortality[20,21]. Accordingly, pneumococcal vaccination is recommended for all patients with CLD and LT candidates[22]. Two vaccine classes are currently available: Polysaccharide (PPSV23) and conjugate vaccines (PCVs), which differ in serotype coverage and immunogenicity (Table 1). PPSV23 provides the broadest serotype coverage but induces short-lived, T-cell-independent immunity with poor durability in cirrhosis and rapid antibody decline after LT. Conjugate vaccines (PCV13, PCV15, PCV20, PCV21) elicit T cell–dependent responses, generate immunologic memory, and reduce nasopharyngeal carriage. Studies consistently show stronger and more functional antibody responses with PCVs compared with PPSV23. In LT candidates, PPSV23 responses are blunted compared with healthy controls, and after transplantation antibody levels decline rapidly[23]. In these patients, PCV13 induced higher antibody concentrations and opsonophagocytic activity than PPSV23, although titers declined post-transplant, but a second PCV13 dose partially restored responses[24]. Post-transplant seroprotection remains modest overall [approximately 40% in mixed solid organ transplant (SOT) cohorts][25]. Higher-valency conjugates (PCV15, PCV20, PCV21) extend coverage to emerging serotypes increasingly implicated in multidrug-resistant infections, although real-world LT data are still scarce. Given improved immunogenicity and expanded serotype coverage, recent guidelines recommend higher-valency PCVs for immunocompromised adults, using either a single dose of PCV20 or PCV21, or PCV15 followed by PPSV23 after ≥ 1 year (minimum 8 weeks in immunocompromised hosts), with no PPSV23 needed after PCV20/PCV21[22]. Vaccination before LT offers clearly superior immunogenicity; post-transplant vaccination is safe and generally initiated 3–6 months after LT once maintenance immunosuppression stabilizes[26].

Table 1 Characteristics of available pneumococcal vaccines.

Vaccine (brand)	Serotypes covered	Recommended adult use	Clinical notes in CLD/LT
PPSV23 (Pneumovax 23®, Merck)	1, 2, 3, 4, 5, 6B, 7F, 8, 9N, 9V, 10A, 11A, 12F, 14, 15B, 17F, 18C, 19A, 19F, 20, 22F, 23F, 33F	Adults ≥ 19 years with risk factors; given after PCV15 (≥ 1 year later; min 8 weeks if immunocompromised); not needed after PCV20/21	Broadest coverage but short-lived immunity and rapid titer decline post-LT. Used mainly to broaden coverage after conjugate vaccine
PCV13 (Prevnar 13®, Pfizer)	1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, 23F	Option if higher-valency PCVs unavailable	Early LT data showed better response than PPSV23, but immunity wanes quickly
PCV15 (Vaxneuvance®, Merck)	PCV13 + 22F, 33F	Adults ≥ 19 years: One dose, then PPSV23 ≥ 1 year later (min 8 weeks if immunocompromised)	Broader coverage and stronger immunogenicity than PCV13
PCV20 (Prevnar 20®, Pfizer)	PCV13 + 8, 10A, 11A, 12F, 15B, 22F, 33F	Adults ≥ 19 years: Single dose; no PPSV23 needed	Broadest coverage Preferred single-dose option for CLD/LT. Limited durability data post-LT
PCV21 (Capvaxive™, Merck)	PCV21 + 15A, 15C, 16F, 23A, 23B, 24F, 31, 35B

CLD: Chronic liver disease; LT: Liver transplantation.

Influenza vaccination: Prefer enhanced inactivated formulations in LT patients

The burden of influenza among LT recipients is significant, with high hospitalization rates and risk of severe complications[27,28]. Seasonal vaccination remains essential, using non-live platforms (inactivated or recombinant formulations), while live-attenuated influenza vaccine is contraindicated after LT and generally avoided in cirrhosis[29]. Three non-live influenza vaccine platforms are available: Inactivated influenza vaccines (IIV), recombinant hemagglutinin vaccines, and adjuvanted or high-dose formulations[30]. High-dose IIV (HD-IIV) contains four times more antigen, while adjuvanted IIV (aIIV3; MF59-adjuvanted) enhances innate and adaptive responses[30]. In randomized trials involving SOT recipients, both HD-IIV and MF59-adjuvanted vaccines produced significantly higher seroconversion rates than standard-dose IIV, without increasing rejection or liver-related adverse events[31,32].

Accordingly, a single annual dose is recommended, preferably high-dose or MF59-adjuvanted, administered before the influenza season (Table 2)[29,33].

Table 2 Recommended influenza vaccines in chronic liver disease patients/Liver transplantation recipients.

Vaccine (brand)	Recommended adult use	Clinical notes in CLD/LT
High-dose inactivated trivalent influenza vaccine (HD-IIV3) or adjuvanted inactivated influenza vaccine (aIIV3)	Adults ≥ 19 years should receive one dose before the onset of seasonal influenza epidemic. In case of planned LT, vaccine should be given at least 2 weeks prior to or at least one month following LT	Standard-dose inactivated trivalent influenza vaccine (IIV3) might be considered, although HD-IIV3 is preferred due to increased immunogenicity. Can be co-administered with other respiratory vaccines

CLD: Chronic liver disease; LT: Liver transplantation.

COVID-19 vaccination: Boosters to address attenuated responses

COVID-19 has had a disproportionate clinical impact on patients with CLD and LT recipients and vaccination remains the most effective intervention to reduce severe disease, hospitalization, and mortality in CLD and LT populations[34]. Current experience supports that widely used COVID-19 vaccines, particularly mRNA platforms, are safe and generally well tolerated in LT recipients, without a signal for increased allograft rejection (Table 3)[35]. However, vaccine-induced immune responses are attenuated in CLD and especially after LT, consistent with the broader “immunogenicity gap” under CNIs and antimetabolites[36]. Hence, booster doses are strongly encouraged by international societies, while acknowledging that no single “protective” antibody titer level is universally established for LT recipients[37]. Key remaining gaps include durability of protection under contemporary IS, effectiveness against evolving variants, and strategies for poor responders, including integrated assessment of cellular immunity[38].

Table 3 Coronavirus disease 2019 vaccines (adult)-recommended use and clinical notes in chronic liver disease/Liver transplantation.

Vaccine (brand)	Recommended adult use	Clinical notes in CLD/LT
Pfizer–BioNTech (Comirnaty®; mRNA)	Updated/seasonal dose(s) per national guidance for adults	Preferred platform for most CLD/LT due to strong effectiveness and safety experience. Responses may be attenuated and additional boosters often needed
Moderna (Spikevax®; mRNA)
AstraZeneca (Vaxzevria®; viral vector)	Where available/used: 2-dose primary series per local policy; boosters typically with an updated vaccine	Generally not first-line for immunocompromised patients. Heterologous boosting with mRNA may improve breadth of responses

CLD: Chronic liver disease; LT: Liver transplantation.

HZ vaccination: The era of adjuvanted recombinant vaccines

HZ poses a clinically relevant risk in both CLD and LT populations[39]. The recombinant zoster vaccine (RZV, Shingrix^®, containing recombinant glycoprotein E with the AS01B adjuvant) is the primary available option and is recommended for immunocompromised adults ≥ 19 years with evidence of prior varicella immunity (Table 4)[40,41]. RZV induces robust CD4⁺ T-cell responses and demonstrates superior efficacy and durability compared with the former live vaccine[42]. Evidence in CLD is limited but suggests vaccine effectiveness comparable to immunocompetent adults[43]. Data in LT recipients are currently lacking. RZV has shown an acceptable safety profile in immunocompromised populations[44]. Where feasible, the two-dose series should be completed pre-LT; otherwise, vaccination can be administered after immunosuppression stabilizes (typically ≥ 3-6 months post-LT)[45]. The need for booster dosing is not yet established.

Table 4 Vaccines approved for prevention of herpes zoster in chronic liver disease patients/Liver transplantation recipients.

Vaccine (brand)	Recommended adult use	Clinical notes in CLD/LT
LZV (Zostavax®, Merck)	Adults ≥ 50 years who are at increased risk for HZ a single intramuscular dose is given at least 4 weeks prior to LT	LZV is no longer available in the United States and EU. Contraindicated after LT. Not recommended for CLD patients
RZV (Shingrix®, GSK)	Adults ≥ 19 years who are at increased risk for HZ; two intramuscular doses (1 to 6, but ideally 1 to 2 months apart). Indicated for CLD patients with Child-Pugh scores B and C	Can be administered following LT, although vaccination should be timed > 3 months post-LT. Waning immunity warrants further investigation regarding the need of booster dosing

HZ: Herpes zoster; CLD: Chronic liver disease; LT: Liver transplantation; LZV: Live zoster vaccine; RZV: Recombinant zoster vaccine.

Hepatitis A vaccination: Optimizing protection in advanced liver disease

Although the overall incidence of hepatitis A is not higher in patients with CLD, outcomes are substantially worse with reported case-fatality rate 20-fold higher than in the general population[46]. This justifies routine hepatitis A virus vaccination for all seronegative CLD patients and LT recipients[47]. However, vaccination coverage remains low (< 15%)[48]. Immunogenicity strongly correlates with liver disease severity with seroconversion rates after the 2-dose schedule > 95% in patients with Child-Pugh A cirrhosis, whereas rates drop substantially in decompensated disease (≈ 37% in Child-Pugh B/C) or early post-LT[49,50]. Currently, two inactivated monovalent hepatitis A vaccines (Havrix and Vaqta) and one combined hepatitis A and B vaccine (Twinrix) are available (Table 5). Standard dosing consists of two doses 6-12 months apart, or three-dose schedule for high dose Twinrix doses[5]. Optional post-vaccination serological testing may be considered in high-risk individuals, with booster dose for patients with low antibody titers (< 20 IU/mL)[51].

Table 5 Currently recommended hepatitis A virus and hepatitis B virus vaccines in patients with chronic liver disease and liver transplantation recipients.

Vaccine (brand)	Recommended adult use	Clinical notes in CLD/LT
Hepatitis A
Havrix® (inactivated HAV)	2 doses: 0 and 6-12 months	Prefer pre-LT when feasible. Consider post-vaccination anti-HAV: Check ~1-2 months after dose 2; if anti-HAV < 20 mIU/mL, give an additional dose and recheck
Vaqta® (inactivated HAV)	2 doses: 0 and 6-18 months
Hepatitis B
Engerix-B® (recombinant HBsAg)	3 doses: 0, 1, 6 months	Consider double-dose 40 µg per dose and/or additional doses due to lower response. Prefer completion pre-LT; if post-LT, vaccinate once immunosuppression is stable. Check anti-HBs 1-2 months after last dose; if < 10 IU/L, revaccinate/boost
Recombivax HB® (recombinant HBsAg)	3 doses: 0, 1, 6 months
HBVaxPro® (recombinant HBsAg)	3 doses: 0, 1, 6 months
Fendrix® (HBsAg + adjuvant; “enhanced” vaccine)	4 doses: 0, 1, 2, 6 months	Often more immunogenic in poor responders. May be considered off-label for CLD/LT candidates depending on local policy
Heplisav-B® (CpG-adjuvanted; TLR9 agonist)	2 doses: 0, 1 month	Highly immunogenic and simplifies completion pre-LT. Availability varies by country/region
Hepatitis A and B combination
Twinrix® (HAV/HBV combination)	3 doses: 0, 1, 6 months (accelerated schedules exist)	Useful when both HAV and HBV vaccination are indicated

HAV: Hepatitis A virus; HBV: Hepatitis B virus; HBsAg: Hepatitis B surface antigen; CLD: Chronic liver disease; LT: Liver transplantation; Anti-HAV: Antibody to hepatitis A virus; Anti-HBs: Antibody to hepatitis B surface antigen; TLR9: Toll-like receptor 9.

Hepatitis B vaccination: Enhanced platforms and titer-guided boosting for hyporesponsive patients

Hepatitis B virus (HBV) infection can lead to severe disease in patients with CLD and may cause rapid graft dysfunction after LT, justifying routine vaccination of all seronegative CLD patients and LT candidates, including those with isolated anti-HBc positivity using titer-guided strategies[52,53]. However, as less than 30% of CLD/LT patients are vaccinated[48]. Vaccine response rates decline sharply with advancing liver disease; responses drop from approximately 88% in Child-Pugh A to 16%-33% in decompensated cirrhosis[54,55]. LT recipients show similarly poor outcomes; only 40% achieved protective anti-HBs after high-dose Engerix-B (40 µg), and only 17% of initial responders remained protected one year after vaccination[56]. Attempts to improve immunogenicity using higher doses or accelerated vaccination schedules have provided only modest and incomplete improvements[57,58]. Currently, second-generation recombinant HBV vaccines are most widely used due to their availability and safety profile (Engerix-B, Recombivax-HB, or Twinrix,), but newer platforms demonstrate superior immunogenicity (Table 5). Third-generation vaccines, which contain HBsAg together with preS1 and preS2 antigens, vaccines adjuvanted to stimulate the innate immune system through Toll-like receptor 9 (HEPLISAV-B), and double-adjuvanted formulations (Fendrix), have demonstrated enhanced immunogenicity in immunosuppressed patients and offer simplified two-dose schedules administered one month apart[54]. Current recommendations support vaccination early in the CLD course. For patients with decompensated cirrhosis, high-dose regimens or third-generation formulations are preferred. Post-vaccination anti-HBs titers should be assessed one to two months after the final dose, with a booster dose administered if titers remain < 10 IU/mL. When vaccination is not completed pre-LT, it should generally be delayed until ≥ 3-6 months post-LT when immunosuppression intensity is lower[54].

RSV vaccination: A new adult vaccine platform

RSV is increasingly recognized as an important cause of severe lower respiratory tract infection (LRTI) in older adults and individuals with chronic comorbidities, including CLD and LT recipients[59,60]. Three RSV vaccines are currently licensed as a single intramuscular dose for preventing severe RSV-LRTI: Abrysvo^® (RSVpreF; bivalent prefusion F subunit vaccine A/B), Arexvy^® (RSVPreF3 OA; AS01E-adjuvanted prefusion F subunit vaccine), and mRESVIA^® (mRNA-1345; mRNA encoding RSVpreF subtype A), as shown in Table 6[61]. In immunocompromised individuals, lower rates of vaccine effectiveness (65% to 72%) on RSV-associated hospitalizations were reported compared to immunocompetent individuals (75% to 83%)[62-64]. Approved vaccines are considered safe, with mostly local and self-limited systemic adverse events[65]. A single dose of RSV vaccine prior to RSV season should be administered to all patients aged 60 years or older, who are immunosuppressed or diagnosed with CLD[66]. Vaccine provides protection for at least two RSV seasons; booster strategies are not yet defined and co-administration with influenza and COVID-19 vaccines appears immunogenically acceptable[66].

Table 6 Currently approved respiratory syncytial virus vaccines in chronic liver disease patients/Liver transplantation recipients.

Vaccine (brand)	Recommended adult use	Clinical notes in CLD /LT
RSVpreF (Abrysvo®, Pfizer), RSVpreF3 OA (Arexvy®, GSK), mRNA-1345 (mRESVIA®, Moderna)	A single i.m. dose in adults with CLD aged 60-74 years prior to RSV season; a single intramuscular dose to adults undergoing LT at least 2 weeks prior to LT, or at least 6 months afterwards	No recommendations on booster dosing are yet available

RSV: Respiratory syncytial virus; RSVpreF: Respiratory syncytial virus prefusion F protein vaccine; RSVpreF3 OA: Respiratory syncytial virus prefusion F protein vaccine (adjuvanted, older adults formulation); CLD: Chronic liver disease; LT: Liver transplantation.

IMMUNIZATION BEYOND THE CORE: SPECIAL SITUATIONS AND SELECTIVE INDICATIONS

Beyond the core vaccines, most remaining immunizations in LT patients are risk-based and should be streamlined to avoid “one-size-fits-all” complexity. Human papillomavirus (HPV) vaccination is recommended as a three-dose series for HPV-naïve individuals, ideally completed pre-LT, through age 9-26 years (and selectively beyond, based on shared decision-making)[26]. This population has a significantly increased risk of persistent HPV infection and HPV-related malignancies due to long-term immunosuppression[26]. Meningococcal vaccination (MenACWY ± MenB) is indicated in those with specific epidemiologic or clinical risk and is preferably administered pre-LT (> 2 weeks before surgery), with booster strategies individualized based on age, ongoing immunosuppression, and local epidemiology[67]. Tetanus, diphtheria, and acellular pertussis (Tdap, DTaP, and Td) vaccines should be administered according to the same guidelines and schedules as in the general population[18]. Vaccines are non-live and safe, although responses may be attenuated after LT, supporting standard booster adherence[68,69]. Live-attenuated vaccines (e.g., measles, mumps, and rubella, varicella, yellow fever, oral Ty21a) should be administered only pre-LT and are contraindicated after transplantation, with outbreak management relying on rapid serologic assessment, passive prophylaxis when appropriate, and infection-control measures[26,70]. Travel vaccination should prioritize inactivated options (e.g., injectable typhoid, TBE where indicated) and strict vector precautions; live vaccines (notably yellow fever and live dengue vaccines) are generally contraindicated post-LT. Finally, hepatitis E vaccination remains an unmet need in many regions; while a recombinant vaccine (Hecolin, also referred to as HEV 239) is licensed in China and shows favorable efficacy and safety in available data, evidence in LT recipients is limited, supporting individualized risk assessment and prioritization of prevention strategies where vaccination is not accessible[71].

RISK OF GRAFT REJECTION AFTER VACCINATION IN LIVER TRANSPLANT RECIPIENTS

The possibility that vaccination could provoke immune pathways leading to allograft injury has long been discussed, although mostly on theoretical grounds. Several mechanisms have been proposed, including vaccine-related activation of T-cells or enhancement of humoral alloimmunity, either of which could, in theory, trigger rejection episodes[72,73]. However, across available clinical data, there is no consistent evidence linking vaccination to biopsy-proven rejection in LT recipients. Donor-specific antibody formation has been reported sporadically after vaccination, but is rarely associated with biopsy-proven rejection[74]. Decades of experience with influenza, hepatitis B, and pneumococcal vaccines have not demonstrated an increased rejection signal. A meta-analysis of 90 studies, including more than 15000 vaccinated SOT patients found an acute rejection rate of 2.1 percent, comparable to background rates reported in similar populations[74]. With severe acute respiratory syndrome Coronavirus 2 (SARS-CoV-2) vaccines, isolated case reports of rejection have been published, but such events remain rare relative to the large number of doses administered[73]. Most cases have recovered with standard immunosuppressive intensification and did not suffer permanent graft damage[73]. An open-label evaluation of the mRNA-1273 vaccine that included 77 LT recipients did not observe any biopsy-confirmed rejection events after vaccination[75]. Overall, evidence from case series[76,77], cohort studies[75,78], systematic reviews[73,79], and meta-analyses[74] supports vaccine safety in LT recipients, with no reproducible increase in acute rejection and any theoretical risk of rejection is outweighed by the well-established benefits of preventing severe infection in immunosuppressed patients. Accordingly, vaccination should not be deferred due to rejection concerns; routine post-vaccination clinical monitoring is sufficient in the absence of symptoms suggestive of graft dysfunction.

OVERCOMING THE IMMUNOGENICITY GAP

LT recipients exhibit attenuated humoral and cellular immune responses, as well as accelerated waning of protective immunity, resulting in suboptimal vaccine effectiveness. In practice, the most actionable strategies to mitigate this “immunogenicity gap” fall into three categories: (1) To increase the strength of immune priming; (2) Expand coverage and durability through additional antigen exposures; and (3) Identify and rescue non-responders with targeted revaccination (Figure 3).

Figure 3 Strategies to overcome the vaccine immunogenicity gap in liver transplant recipients. LT: Liver transplantation; MMF: Mycophenolate mofetil; IS: Immunosuppression; IGRA: Interferon-gamma release assay.

First, increasing “signal strength” with high-antigen-dose or adjuvanted formulations can partially offset impaired antigen presentation and improve serologic responses in SOT cohorts, with no consistent signal for rejection. HD-IIV and MF59-adjuvanted influenza vaccine are well-established examples. In the STOP-FLU randomized trial involving more than 600 SOT recipients, both the fourfold high-dose influenza vaccine and the MF59-adjuvanted formulation generated significantly increased serologic response rates (approximately 60%-66%) compared to standard-dose vaccination (approximately 42%)[32]. Mechanistically, higher antigen content and adjuvants enhance antigen presentation and T-helper activation, improving B-cell responses despite suppressive effects of CNIs and antimetabolites. Similar benefits have been reported with other adjuvanted recombinant vaccines, notably Shingrix (AS01_B adjuvant) and the CpG-adjuvanted hepatitis B vaccine, Heplisav-B[80,81].

Second, increasing “exposure” through additional doses and heterologous prime-boost regimens enhances response magnitude and coverage, as exemplified by sequential pneumococcal conjugate-polysaccharide strategies and booster-based schedules for respiratory viruses[24,82]. Where recommended, booster schedules should be followed closely in LT recipients, as incremental antigen exposures can partially compensate for reduced peak responses and faster waning.

Third, given the variability of vaccine responses, immune-guided revaccination—already established for hepatitis B and measles-can be extended to vaccines with validated serological correlates of protection, and cellular assays may be informative in selected high-risk setting where serology is discordant[83]. Commercial IFN-γ release assays, including those targeting SARS-CoV-2 or varicella, may identify vaccine-induced cellular immunity even in the absence of detectable antibodies, although their role as routine correlates of protection in LT recipients remains to be defined[84,85]. Research-grade immunologic methods-such as ELISPOT and multicolor flow cytometry-have similarly demonstrated T-cell activation despite absent circulating antibodies in a subset of SOT vaccine recipients.

Finally, timing vaccination to periods of lower “net” immunosuppression (e.g., after stabilization of maintenance regimens) is a pragmatic, evidence-consistent approach discussed above. In contrast, strategies that modify immunosuppression specifically to enhance vaccine responses (e.g., temporary antimetabolite interruption or regimen substitution) remain supported primarily by limited observational or pilot data and should not be undertaken routinely; if considered, they require individualized risk-benefit assessment in clinically stable recipients and close transplant-team oversight[86]. Early experiences, particularly in the context of COVID-19 vaccination, suggest improved immunogenicity with short-term MMF interruption in carefully selected, clinically stable transplant recipients[86]. Several experimental immunologic approaches are under evaluation, including transient administration of immune checkpoint inhibitors or cytokine-based immune stimulants as vaccine adjuvants[87]. While mechanistically compelling, these strategies remain investigational due to substantial safety considerations, particularly with respect to graft tolerance.

Overall, enhanced formulations, adherence to recommended booster schedules, and titer-guided rescue where validated offer the most practical tools to narrow the immunogenicity gap in routine LT care.

EMERGING VACCINES AND NOVEL PLATFORMS

Emerging vaccine technologies are reshaping preventive strategies for LT candidates and recipients. Among novel platforms, mRNA vaccines are currently the most clinically advanced. In LT recipients, mRNA SARS-CoV-2 vaccines have demonstrated acceptable safety and measurable immunogenicity, although responses remain attenuated compared with immunocompetent populations[88,89]. Beyond SARS-CoV-2, the mRNA platform is now extending to other adult vaccines: MRNA-1345 (mResvia)-an RSV mRNA vaccine has already received regulatory authorization[61]; mRNA-1010 has advanced through large phase 3 immunogenicity/safety evaluation as a seasonal influenza mRNA vaccine candidate[90], and CMV mRNA-1647 has shown acceptable safety and induction of antigen-specific immune responses in clinical studies[91].

Other next-generation approaches, including self-amplifying RNA and advanced protein/nanoparticle display vaccines with potent adjuvants are designed to enhance innate sensing and germinal center responses, potentially improving both magnitude and durability of immunity in poor responders[33]. By contrast, non-replicating viral vectors, such as adenoviral platforms, show reduced immunogenicity in LT recipients, likely due to pre-existing vector immunity and immunosuppression[36]. Precision antigen design, including epitope engineering and personalized vaccine approaches, may enhance vaccine efficacy in immunosuppressed patients by targeting conserved immunogenic regions, but evidence in LT recipients remains preliminary.

IMPLEMENTATION CHALLENGES AND OPPORTUNITIES

Persistently low vaccination rates among LT recipients, often below 50%, remain a global concern[92]. Barriers are multifactorial, including fragmented care delivery, misconceptions regarding vaccine safety and timing, lack of standardized protocols, limited access to immunization services within subspecialty clinics, and patient- and provider-related hesitancy[92-94]. Several pragmatic strategies have demonstrated measurable improvements and can be implemented without major structural change.

Electronic medical record–based interventions enhance communication between transplant teams and primary care providers, and have been associated with increased vaccine uptake and more complete immunization records[92,93,95]. Similarly, targeted communication and educational interventions such as personalized recommendation letters to patients and family physicians have been shown to significantly increase vaccination rates[93,96,97]. Sustained improvement requires active engagement of primary care providers.

Center-based vaccination pathways, such as dedicated transplant vaccination visits (often in partnership with infectious diseases), checklist-driven protocols at evaluation/Listing, and registry-based follow-up-can reduce missed opportunities and improve completion of recommended series[98]. Where validated correlates exist (e.g., hepatitis B), titer-guided approaches can identify patients who lose protection and may benefit from revaccination. Vaccinating household members and close contacts provides an additional protective layer. “Cocooning” strategies are particularly valuable when recipient responses are expected to be attenuated.

Accordingly, vaccination responsibility should be shared across the multidisciplinary transplant team, with transplant-center oversight and close collaboration with primary care providers, consistent with evidence and consensus guidance. A practical model is: Transplant center defines the protocol and timing windows, while primary care delivers routine vaccines with feedback to the transplant registry.

FUTURE DIRECTIONS: CLOSING EVIDENCE GAPS IN TRANSPLANT VACCINOLOGY

Adult LT recipients remain underrepresented in vaccine trials, underscoring the need for coordinated multicenter studies with harmonized protocols. Key priorities are: (1) Comparative effectiveness and safety of vaccine platforms and enhanced formulations (e.g., mRNA/recombinant and adjuvanted or high-dose products) in LT recipients under different immunosuppressive regimens; (2) Optimization of post-transplant timing and dosing, the value of additional doses, and the most effective booster intervals; and (3) Development of validated correlates of protection and response-stratification tools, integrating humoral and cellular immunity to identify poor responders. In parallel, implementation trials testing registry-based pathways, shared-care models, and cocooning approaches that might improve real-world vaccine uptake and completion are needed.

CONCLUSION

Vaccination remains essential for infection prevention in patients with CLD and LT recipients but is constrained by CAID and post-transplant immunosuppression. Vaccine responsiveness varies with disease severity, immunosuppressive intensity, timing relative to transplantation, and vaccine platform. Evidence supports early pre-transplant immunization, preferential use of high-immunogenicity and adjuvanted vaccines, heterologous and booster-based schedules, and serology-guided revaccination where validated correlates exist. Emerging platforms, including recombinant and mRNA vaccines, expand preventive options, while gaps persist for RSV, HEV, and travel-related infections. Coordinated, transplant-centered vaccination strategies are essential to reduce vaccine-preventable morbidity in this high-risk population.