Vaccination strategy in liver transplantation – are we keeping up with global trends?
Zuzana Podmanická1, Světlana Adamcová Selčanová2, Eliška Lovratová3, Zuzana Krištúfková4, Ľubomír Skladaný5
+ Affiliation
Summary
Patients with advanced chronic liver disease (ACLD), those awaiting liver transplantation (LT), and post-transplant recipients face a high risk of infectious complications due to immune dysfunction. Vaccination is a key preventive strategy to protect this high-risk group from severe infections. The effectiveness of vaccines depends on the timing of administration – optimal vaccination occurs in the early stages of liver disease before transplantation when the immune response is strongest. Post-transplant vaccination is possible, but requires stabilization of immunosuppressive therapy. The administration of live vaccines after LT remains controversial, although recent research suggests their potential safety in specific cases. This paper summarizes recommended vaccination strategies in Europe and worldwide, evaluates the effectiveness of vaccination in this patient population, and highlights the need for further research to optimize immunization protocols for patients with chronic liver diseases and transplant recipients.
Keywords
advanced chronic liver disease, liver transplantation, vaccination, immune dysfunction, infectious complications, immunosuppressive therapy
Introduction
Advanced chronic liver disease (ACLD) is a condition frequently if not universally associated with the development of systemic inflammation and immune dysregulation, known as the cirrhosis--associated immune dysfunction syndrome (CAID) [1,2]. Development of this secondary immunodeficiency leads to, among other consequences, reduced immune defense against infections [2–5]. One of the preventive measures to protect high-risk patients from severe infections is vaccination. As many ACLD patients progress to end-stage liver disease (ESLD) or acute-on-chronic liver failure (ACLF), requiring consideration for liver transplantation (LT), they become particularly vulnerable [6–9]. Therefore, maximal efforts should be made to ensure they receive preventive vaccination [9–11].
According to available data, pre-LT vaccination should be administered at a time before LT when the patient still has the potential to develop sufficient immunity [12]. If vaccination is delayed until advanced disease stages, it becomes less effective or the full vaccination schedule may not be completed [13]. Vaccination can also be administered after LT, but this period carries many challenges which are subject of ongoing research. Current guidelines provide a good framework for management of patients with ACLD both before and after LT [13–15].
This paper aims to summarize the recommended vaccination strategies for these patient groups.
Recommended general vaccination strategies for high-risk groups in Europe and outside Europe
The fundamental principles of vaccination for both pediatric and adult populations, including high-risk groups, are summarized in the Centers for Disease Control and Prevention (CDC) guidelines, which are annually updated and published in collaboration with Advisory Committee on Immunization Practices (ACIP) in the United States [15–18]. Among the high-risk groups, patients with ACLD are also included [13,14].
The CDC recommendations classify patients with chronic liver diseases into two groups:
1. patients with chronic hepatitis [19,20];
2. patients with ACLD who are further categorized into:
- a) patients with portal hypertension;
- b) patients with functional asplenia;
- c) patients with immunodeficiency (CAID) [1,2,21,22].
Each group is assigned an appropriate vaccination schedule. Patients are recommended to receive vaccinations against 15 infectious diseases, including Influenza, Tetanus, Diphtheria, Pertussis, Measles, Mumps, Rubella, Varicella, Human papillomavirus (HPV), Streptococcus pneumoniae, Neisseria meningitidis, Haemophilus influenzae, Hepatitis A virus, and Hepatitis B virus. Vaccination is most effective when administered in the early stages of the disease (Tab. 1) [15].
Basic principles and timing of vaccination
The proper timing of vaccination in high--risk groups, specifically in the pre-transplantation and post-transplantation periods, has been a long-discussed topic. It has been proven that vaccination with inactivated (non-live) vaccines before transplantation is safe; however, in advanced stages of ACLD, it may be less effective [13,23]. In the case of live vaccines, it is recommended to maintain an interval of at least 4 weeks before LT [13].
After LT, recommendations for vaccination with inactivated vaccines vary among different authors, mainly regarding timing (2, 3, or 6 months after LT) [11,24,25]. The fundamental principle is that vaccination should take place when the dose of immunosuppressive therapy is stabilized and no longer in the induction phase [11,24,25]. In contrast to inactivated vaccines, vaccination with live (attenuated) vaccines has traditionally not been recommended in the adult population after LT [11,13]. However, recent data on efficacy and safety suggest that their use after solid organ transplantation (SOT) could be a viable strategy (Tab. 2) [25–31].
The primary consideration of administering live vaccines to severely immunocompromised individuals is the risk of dissemination of the vaccine strain and ensuing graft rejection [12,13,29]. Therefore, when considering their application, it is crucial to take into account the immunological profile of the patients, particularly the absolute count of CD4+ T-helper lymphocytes and the risk of infection with the so-called “wild” strain [12,30,32–36]. Vaccination with live vaccines is contraindicated in adult patients when CD4+ T-helper lymphocytes are below 15% (< 200 × 10⁶/L). In patients undergoing immunosuppressive therapy, an absolute CD4+ lymphocyte count of > 400 × 10⁶/L is recommended [30]. Besides the count and composition of lymphocytes, administration of live vaccines also depends on the dosage of immunosuppressive therapy, which is arbitrarily determined based on expert consensus [33]. However, contraindications and safe vaccination protocols are not yet sufficiently supported by literature for all immunosuppressive and biological therapies used in LT (Tab. 3) [33,37–39].
Given the above considerations, the preferred approach is to administer live attenuated vaccines at least 2–4 weeks before LT [15,30,33]. In cases where vaccination is contraindicated, risk assessment of an unvaccinated individual (patient) is recommended, and if at high-risk, focusing on a vaccinated milieu (e. g., family) is considered. This involves vaccinating close contacts (household members, healthcare personnel) following the so-called “cocoon” strategy [40].
Effectiveness of vaccination in a liver transplantation setting
The effectiveness and safety of vaccination depend on many factors. It is usually assessed based on the development of a protective antibody titer within 2–4 weeks post-vaccination [41]. However, this remains an area of ongoing research in high-risk patients with varying degrees of immune system impairment and those receiving immunosuppressive therapy [13,32]. One key factor influencing vaccination effectiveness is the timing of vaccination. The highest efficacy is observed in the early stages of chronic liver disease [14,15,18], while effectiveness decreases as liver damage progresses [2,14]. According to available studies, mild (non-protective) seroconversion is not significantly affected by gender and body mass index (BMI); of note, there are no differences between decompensated patients classified as Child-Pugh B and Child-Pugh C [42]. Studies from transplantation centers report a higher effectiveness of vaccination before LT [13]. However, successful immunization can still be achieved after LT [29]. Over the past 30+ years, numerous clinical studies have been published on patients after SOT. However, these studies are highly heterogeneous and predominantly focused on pediatric patients [41]. Findings indicate that while SOT patients are capable of mounting an immune response, their response to most vaccines is lower compared to the healthy population. The extent of this impaired immune response varies depending on the type of vaccine, transplanted organ, and patient’s age [43]. An overview of immune responses to certain non-live vaccines after LT is displayed in Tab. 4 [41].
We present a summary of vaccination effectiveness after live vaccines following SOT in the form of a review of available interventional studies, again predominantly based on the pediatric population (Tab. 5).
Protective antibody titers after vaccination
Most transplant centers monitor the effectiveness of vaccination through routine serological testing. In cases of insufficient serological response (absence of specific IgG antibodies in peripheral blood), revaccination – the administration of a booster dose – is indicated in most cases [41]. Available literature provides protective antibody titer data for 26 vaccines (Tab. 6) [42].
In the context of LT, multiple studies have focused on the effectiveness of Hepatitis B virus (HBV) vaccination, primarily due to the risk of developing de novo acquired hepatitis B, which may lead to graft failure [43,44]. In the general population, an anti-HBs titer > 10 mIU/ml is considered protective. However, in patients with advanced chronic liver disease (ACLD) and post--LT, authors suggest that a seroprotective titer should be defined as anti-HBs > 100 mIU/ml [43,44].
Revaccination – “booster” doses before solid organ transplantation
For patients awaiting SOT, it is optimal to complete all planned vaccinations well in advance of surgery to allow for the administration of the full vaccination protocol. If low peripheral levels of specific antibodies are detected before SOT, most transplant centers recommend revaccination (booster dose) [45]. According to available literature, in patients under 6 years of age, a booster dose may be administered at a minimum interval of 12 months after primary vaccination. In patients over 7 years and in adults with completed primary vaccination, booster doses are given as needed, such as reduced diphtheria toxoid vaccine (dTap), which should be administered at least 2 weeks before the planned transplantation [32]. For post-SOT patients, annual influenza vaccination is recommended, a 23-valent pneumococcal polysaccharide vaccine should be boosted every 2–5 years, a tetanus toxoid booster every 5 years, and a diphtheria toxoid booster every 10 years [13]. Circulating specific IgG antibodies following protein-based vaccines can be detected 3–4 weeks post-vaccination. A fourfold increase in antibody titers is considered a sufficient post-vaccination response. Although specific post-vaccination antibody levels in peripheral blood may decline, this does not indicate a lack of immunization. Upon re-exposure to the antigen, tissue memory cells (T and B lymphocytes) become reactivated, leading to a rapid antibody response [46–48]. Memory B and T cells can persist for several decades [13,49,50]. However, in the context of SOT, the lifespan of memory T lymphocytes has not yet been fully determined, nor is the effect of immunosuppressive therapy on immune memory cells completely understood [13,46,50].
Vaccination of close contacts
According to U.S. guidelines, vaccination of the SOT candidate alone is insufficient, and immunization of close contacts is also recommended [51]. Healthcare workers, especially caregivers, close contacts, and family members, should be fully immunized according to national vaccination schedules [30,51–54]. Healthy, immunocompetent individuals can receive both inactivated and live vaccines (Tab. 7) [55].
Vaccination of close contacts can prevent the transplanted patient from exposure to wild-type viruses [51].
Conclusion
Patients with advanced chronic liver disease (ACLD), those awaiting LT, and post-LT recipients face a high risk of infectious complications, which significantly contribute to increased morbidity and mortality. One of the fundamental preventive measures to protect these high-risk patients is vaccination, not only for the patients themselves but also for their close contacts. To date, standardized global criteria for vaccination before and after LT have not been established. According to available literature, timing is one of the key factors influencing vaccine effectiveness. The optimal period for vaccination appears to be the earliest-captured stage of liver disease before LT. In the post-LT period, the fundamental principle of vaccination is ensuring a stable immunosuppressive regimen. However, the use of live vaccines after LT remains the area of further research. A deeper investigation into this cohort of patients will allow the development of evidence-based recommendations, ensuring effective immunization and optimal protection for transplant recipients.
ORCID authors
Z. Podmanická 0000-0001-5683-3261,
S. Adamcová Selčanová 0000-0001-8181-1937,
Z. Krištúfková 0000-0003-1728-9659,
Ľ. Skladaný 0000-0001-5171-3623.
Submitted/Doručené: 25. 3. 2025
Accepted/Prijaté: 2. 4. 2025
Corresponding author
Svetlana Adamcová Selčanová, MD, PhD.
2nd Department of Internal Medicine
Div. HEGITO (Hepatology, Gastroenterology, and Transplantation Department)
Slovak Medical University Faculty of Medicine, Roosevelt University Hospital
Nám. L. Svobodu 1
975 17 Banská Bystrica
sselcanova@gmail.com
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