Vaccination for solid organ transplanted patients: Recommendations, efficacy, and safety

Abstract

Solid organ transplant recipients face unique challenges in managing their immunosuppressed status, making vaccination a critical consideration. This review aimed to comprehensively analyze current recommendations, evaluate the efficacy of vaccinations in this population, and assess safety concerns. We explored the latest evidence on vaccine types, timing, and potential benefits for transplant patients, highlighting the importance of individualized approaches for routinely used vaccines as well as coronavirus disease 2019 vaccines. By synthesizing available data, this review underscored the pressing need to optimize vaccination strategies, ensuring that transplant recipients can obtain the full protection against many pathogens while minimizing risks associated with their post-transplant immunosuppression.

Key Words: Vaccination; Solid organ transplant; Immunosuppression; Transplant recipients; Vaccine efficacy; Safety; COVID-19 vaccines; Immunization strategies; Post-transplant immunity; Clinical recommendations

Core Tip: Adapting vaccination strategies to the unique immunosuppressed status of solid organ transplant recipients is crucial. Individualized approaches, considering factors like transplant type, age, and immunosuppressive regimens, should guide clinicians in optimizing vaccine selection, timing, and dosing. As we bridge current recommendations with evolving evidence, personalized vaccination protocols will enhance protective immunity while minimizing risks of infections during immunosuppressive treatment, ensuring that transplant recipients receive optimal quality of life, overall wellbeing, and duration of life.

INTRODUCTION

Solid organ transplant (SOT) recipients encounter a delicate balance between the necessity for immunosuppression to prevent graft rejection and the imperative need for protective immunity against numerous infectious diseases, including opportunistic pathogens. Vaccination, a cornerstone of preventive medicine, becomes a critical challenge in this unique population characterized by immunosuppressed status[1]. Despite its vital role, a discernible gap exists in our understanding of optimal vaccination strategies for SOT recipients. The interplay between the immunocompromised state and the imperative need for immune response needs exploration, particularly regarding current recommendations, vaccine efficacy, and safety considerations. Existing guidelines provide a framework for vaccination in transplant recipients, but the complexity of vaccine response, duration of protection, and potential risks needs continuous investigation[2].

The limited data available on the effectiveness of vaccines in this specific cohort during clinical trials, coupled with concerns about adverse events and potential interactions with immunosuppressive medications, underscore the urgency to analyze real-world use of these vaccines[3]. This review critically examined current recommendations based on the efficacy and safety of vaccinations post-solid organ transplantation, with special attention paid on the coronavirus disease 2019 (COVID-19) vaccine data for SOT patients. We aimed to bridge existing knowledge gaps by synthesizing the latest evidence on vaccine types, optimal timing, and potential benefits specific to transplant patients. We also emphasized the importance of individualized vaccination approaches in this vulnerable population.

SOT patients are especially vulnerable to infectious diseases. Before the procedure, candidates may have organ insufficiency, but after the transplantation recipients develop immune suppression due to anti-rejection pharmacologic treatment. Therefore, healthcare professionals should be aware of these possible side effects and act according to the guidelines[4-10].

Vaccines are the first line of healthcare prevention. They are beneficial but must be used at the right time and dosage for the best possible protection and fewest side effects. In line with this, vaccinations after SOT that can be found in most guidelines are against: influenza, Streptococcus pneumoniae, hepatitis B virus, hepatitis A virus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), varicella zoster virus (VZV), meningococcal, human papilloma virus, measles mumps rubella (MMR), tetanus, tetanus diphtheria pertussis/tetanus diphtheria, Haemophilus influenzae type B, yellow fever, rabies, polio, rotavirus, tuberculosis-Bacillus Calmette-Guérin, smallpox, and cholera. We added the specific recommendations for lung, heart, kidney, and liver transplantation for pre-transplant and post-transplant patients in Table 1 as a comprehensive guide of recommended vaccines after SOT by organ type: Lung transplantation[11,12]; heart transplantation[13-17]; kidney transplantation[16-23]; liver transplantation[15,17,24-27].

Table 1 Recommended vaccines for solid organ transplant recipients.

Transplanted organ	Pre-transplant/candidate vaccines	Ref.	Post-transplant/recipient vaccines	Ref.
Lung	Influenza; Streptococcus pneumoniae; HBV; HAV; SARS-CoV-2; VZV; Meningococcal; HPV; MMR; Tetanus; Tdap/Td; Haemophilus influenzae type B; Rabies; Yellow fever; Polio; Smallpox; Cholera	Rubin et al[11]	Influenza; Streptococcus pneumoniae; HBV; HAV; SARS-CoV-2; Meningococcal; HPV; Tetanus; Tdap/Td; Haemophilus influenzae type B; Rabies; Polio	[12]
Heart	Influenza; Streptococcus pneumoniae; HBV; HAV; SARS-CoV-2; VZV; HPV; Tdap/Td; Haemophilus influenzae type B; Rabies; Tetanus	Rubin et al[11]; Kumar et al[13]	Influenza; Streptococcus pneumoniae; HBV; HAV; SARS-CoV-2; VZV; HPV; Tdap/Td; Haemophilus influenzae type B; Rabies; Tetanus	Rubin et al[11]; Kumar et al[13]; [14]; Anderson et al[15]
Kidney	Influenza; Streptococcus pneumoniae; HBV; HAV; SARS-CoV-2; VZV/RZV; Meningococcal; HPV; MMR; Tetanus; Tdap/Td; Haemophilus influenzae type B; Yellow fever; Rabies; Polio; Rotavirus; BCG; Smallpox; Cholera	Haddiya[16]; Ma et al[17]; Bonnel et al[18]; Krueger et al[19]; Babu and Kotton[20]; [21]	Influenza; Streptococcus pneumoniae; HBV; HAV; SARS-CoV-2; RZV; Meningococcal; HPV; MMR; Tetanus; Tdap/Td; Haemophilus influenzae type B; Rabies; Polio	Haddiya[16]; Ma et al[17]; Krueger et al[19]; Babu and Kotton[20]; Arora et al[22]; Danziger-Isakov et al[23]
Liver	Influenza; Streptococcus pneumoniae; HBV; HAV; SARS-CoV-2; VZV; Meningococcal; HPV; MMR; Tetanus; Tdap/Td; Haemophilus influenzae type B; Yellow fever; Rabies; Polio; Rotavirus; BCG; Smallpox; Cholera	Anderson et al[15]; Rubin et al[11]; Fagiuoli et al[24]; Fagiuoli et al[25]; Meites et al[26]	Influenza; Streptococcus pneumoniae; HBV; HAV; SARS-CoV-2; Meningococcal; HPV; MMR; Tetanus; Tdap/Td; Haemophilus influenzae type B; Rabies; Polio	Anderson et al[15]; Rubin et al[11]; Stucchi et al[27]

BCG: Bacillus Calmette-Guérin; HAV: Hepatitis A virus; HBV: Hepatitis B virus; HPV: Human papilloma virus; MMR: Morbilli parotitis rubella; RZV: Recombinant zoster vaccine (Shingrix); SARS-CoV-2: Severe acute respiratory syndrome coronavirus 2; VZV: Varicella zoster virus; Tdap/Td: Tetanus diphtheria pertussis/tetanus diphtheria.

Viganò et al[1] recommend healthcare providers to suggest vaccinations before the procedure and immunosuppression. Healthcare professionals should ask the future recipient’s vaccine history and provide the patient with all the missing and recommended vaccines before transplantation. Live-attenuated vaccines (LAVs) should be given ≥ 4 wk before immunosuppression and inactivated vaccines ≥ 2 wk before immunosuppression[17]. Close contacts involving humans and pets should undergo vaccination, except for vaccines that could cause transmission[1,22,28].

After transplantation and immunosuppression, LAVs should be avoided. Despite this warning, we may use some vaccines, such as MMR and VZV, but only if the patient complies with specific criteria. More frequent vaccinations should be done to achieve seroconversion in this case[29]. As far as strategies to prevent infections, vaccines are the most important, particularly when considering a future SOT where immunosuppression will increase the risk of infection and further reduce the immune system responsiveness. However, because of the compromised immune system, the immune response to vaccines in individuals with advanced stage of most chronic diseases may not be as effective as in healthy individuals[19,22]. Vaccines tend to be more effective when administered early in the progression of inflammatory or chronic diseases, although the optimal timing and schedules for vaccination are still under discussion. Therefore, the best course of action is to promptly ascertain the immunization status and response to prior vaccinations in all patients with advanced organ disease to close any potential immune protection failure[1].

In general, recipients of SOT should avoid LAVs, but this view has recently been questioned. Several studies were conducted on pediatric patients using the VZV and the MMR vaccine following SOT. These studies examined different timings, seroconversion patterns, and requirements for booster doses. Overall, the evidence indicated that LAVs are safe for selected SOT patients, with only mild side effects, comparable to those seen in healthy children, and with good seroprotection development. Still, repeated immunizations are required to ensure a sustained response.

Furthermore, there have been no reports of infections with the LAV strain[30-34]. In 2018, a consensus was reached that resulted in specific recommendations for administering MMR and VZV after SOT[29]. According to these recommendations, live MMR or VZV should only be administered in situations where all precautions have been taken or in situations where the risk of vaccination is expected to be lower than the opposite (that is, before an inescapable trip to an endemic risk area).

Notably, the risk of LAVs in recipients of SOT is associated with vaccine-mediated reactions. For example, vaccination with the yellow fever vaccine has been associated with acute antibody-mediated rejection of renal grafts[35]. In certain situations, if an equivalent inactivated vaccine is available, it should be used (e.g., typhoid vaccination). Regretfully, no information is available regarding the level of protection warranted against a primary varicella zoster infection by recombinant zoster vaccines. Despite this, family members and closest relatives of immunosuppressed patients with LAVs (primarily MMR and VZV) must be vaccinated.

In patients with organ failure awaiting transplantation, there is an increased risk of infections and acute decompensation, which results in increased rates of morbidity and mortality. In post-transplant recipients, immunosuppression is the primary factor predisposing them to infectious diseases, strongly impacting the rate and severity of the manifestation of the infection and the patient. These infections are well-known causes of morbidity and mortality in SOT recipients compared to immunocompetent individuals. Nevertheless, vaccination remains the most effective and cost-efficient method to prevent infectious diseases; however, its efficacy heavily relies on a fully functional immune system[1].

Additionally, vaccination strategies are critical in ensuring that people in close contact (family members, healthcare professionals, and pets) are adequately protected from infections. Members of this category should receive all recommended immunizations, particularly the annual influenza vaccine, preferably inactivated, and vaccinations against varicella and MMR to reduce the risk of exposure to wild-type viruses and SARS-CoV-2[36].

The “ideal” strategy is to promptly verify the vaccination status of all patients with advanced diseases to identify and resolve any potential immunity gaps before SOT, even though patients with end-stage organ disease may exhibit a diminished serological response to vaccines due to a compromised immune system as compared to healthy individuals. Vaccination demonstrates superior immunogenicity when administered earlier during the chronic disease. Vaccination is a crucial preventive strategy against specific infectious risks in these populations, particularly considering future SOT where immunosuppressive therapy will increase the risk of infections and further compromise the immune system responsiveness.

RECOMMENDATIONS FOR COVID-19 VACCINATION IN SOLID ORGAN TRANSPLANTATION

COVID-19 is associated with increased morbidity and mortality in SOT recipients because of decreased immune responses and seroconversion[37]. Organ rejection following vaccination is scarce; vaccination benefits outweigh this risk[38,39]. Overall, COVID-19 vaccines are safe for the SOT patients. Timing is essential for COVID-19 vaccination in SOT recipients and candidates. For candidates, we should wait for ≥ 2 wk to start the procedure, while for recipients, we have to wait at least 1 mo from the procedure and 3 mo if using T cell-depleting drugs[38,39]. We can vaccinate both before and after transplant, but it is widely recommended to perform it before[39].

Grupper et al[40] found that after the third booster dose, SOT recipients showed a substantial increase in seroconversion compared to those with only two doses. Recipients may or may not have had previous seroconversion. Health providers may have to consider changing non-responder patients to a different vaccine, as there are indications of better seroconversion[41] and suggest their patients consider other additional safety measures.

An international team of scientists in 2021 recommended administration of the vaccines against COVID-19 to all cancer patients, including those participating in clinical trials. Their view was that immunization against COVID-19 should be the norm, not the exception, for patients participating in cancer treatment trials. Scientists are prioritizing cancer patients for vaccination against the disease because patients with advanced, progressive cancer are on active treatment and typically make several visits to clinics and hospitals for procedures, potentially increasing their exposure to SARS-CoV-2 infection at multiple points[42].

The European Society for Medical Oncology recommends vaccination with mRNA vaccines against COVID-19 for people with cancer, and their application should be according to the current recommendations of the health authorities[43]. Data from studies have consistently demonstrated the efficacy and safety of SARS-CoV-2 vaccination in people with cancer. Cancer patients develop clinically significant seroconversion rates after complete vaccination against COVID-19[44-48].

The National Comprehensive Cancer Network in the United States and other cancer organizations urge cancer patients to get vaccinations against COVID-19 as well as booster shots[49]. The American Cancer Society recommends the following COVID-19 vaccines for cancer patients: (1) The Pfizer-BioNTech vaccine (under the brand name Comirnaty) for people 6 mo to 11 years of age and is approved for people 12 or older; (2) The Moderna vaccine for people ages 6 mo to 11 years and is approved (under the brand name Spikevax) for people ages 12 and older; and (3) The Novavax vaccine for people 12 years of age and older[50]. In Bulgaria, the recommendation of the medical authorities includes three doses of mRNA vaccines against COVID-19 for people with cancer, which was one more dose compared to the recommendations for people without cancer. By 2024, current recommendations include the administration of one dose of mRNA vaccine against Omicron XBB 1.5[51].

The Centers for Disease Control and Prevention recommend the 2023-2024 updated COVID-19 vaccines: Pfizer-BioNTech; Moderna; or Novavax. People aged 6 mo and older who are moderately or severely immunocompromised need at least one dose of a 2023-2024 updated COVID-19 vaccine. Depending on the number of doses they previously received, they may need more than one dose of the updated vaccine (e.g., unvaccinated patients should receive two or three doses of updated COVID-19 vaccine, patients with one previous Pfizer-BioNTech or Moderna COVID-19 vaccine should receive one or two doses of updated COVID-19 vaccine, and patients with two or more previous COVID-19 vaccines should receive one dose of updated COVID-19 vaccine)[52].

STRATEGIES TO IMPROVE IMMUNE RESPONSE IN COVID-19 AND OTHER VACCINES IN SOLID ORGAN TRANSPLANTATION

The challenges posed by immunosuppression in SOT recipients emphasize the urgency of optimizing immune responses to vaccinations, including those against COVID-19. Here, we discuss the innovative strategies to enhance vaccine efficacy in this vulnerable population with immune suppression. From personalized vaccination schedules to potential adjuvant use, we focused on the approaches designed to augment immune responses while maintaining the delicate balance of immunosuppression. Studies confirmed the extreme safety of COVID-19 vaccines. Theoretically, vaccination may lead to organ rejection[53-56] or the development of de novo anti-donor-specific antibodies[57,58], which has also been reported for the SARS-CoV-2 vaccine[59,60]. However, multiple studies of common vaccines have found no correlation between the two[61-66].

Given the high effectiveness of the SARS-CoV-2 vaccine and the severe clinical outcomes of COVID-19, the rare instances of rejection did not justify delaying vaccination in SOT recipients. In immunocompetent individuals, mRNA SARS-CoV-2 vaccines are known to cause mild-to-moderate side effects, such as headaches, fatigue, and local pain[67], with significant adverse events occurring infrequently[68-70]. SARS-CoV-2 vaccines were not linked to any unexpected short-term local and systemic side effects among recipients of transplant recipients.

Regarding efficacy, data about the immunological response to SARS-CoV-2 vaccinations has been rapidly collected over the past few months. Following two doses of mRNA SARS-CoV-2, the data consistently show that the transplant recipients’ humoral immune responses are suboptimal. Most patients receiving kidney and lung transplants did not develop a significant humoral immune response (seropositivity rates range from 8.2%-66.0% and 10.0%-47.4%, respectively). In contrast, recipients receiving liver and heart transplants had better responses (seropositivity rates between 37.5%-80.0% and 18.2%-62.0%, respectively).

Furthermore, there have been reports of T cell response impairments, including a reduced magnitude but high rate of spike-specific T helper cell response, limited production of effector cytokines in recipients of stem cells[71,72], and decreased generation of memory B cells and plasmablasts in response to the mRNA vaccine[73]. Cellular immunity may compensate for the lack of post-vaccination neutralizing antibodies in recipients of stem cells, as observed among 148 kidney transplant recipients, 35% of whom did not develop humoral or cellular responses after vaccination[74].

Growing evidence suggests that elapsed time following vaccination significantly affects breakthrough infection rates as immunity weakens and antibody levels decrease over time[75,76]. Bergwerk et al[76] reported SARS-CoV-2 breakthrough infections in a cohort of healthcare workers. They correlated these infections with declining neutralizing antibody titers in the peri-infection period, underscoring the clinical significance of this laboratory finding.

Experts, including the Food and Drug Administration, have recommended giving a booster (third) dose of the vaccine to immunocompromised people, including SOT recipients due to observations of waning immunity, as evidenced by decreased antibody levels in the general population after two doses of the vaccine[76] and breakthrough infections among vaccinated SOT recipients, including severe COVID-19 cases[77-83]. Additionally, there has been a suggested correlation between breakthrough infections and the time since the second vaccine dose.

Several countries have made similar recommendations. Reports on administering a third dose of the mRNA vaccine to SOT recipients have enhanced immune response following the third vaccine dose did not result in any immediate serious side effects. Administration of the third vaccine dose to SOT recipients effectively boosted immunoglobulin G anti-S levels, even among those who did not initially show detectable antibodies after two doses. The Centers for Disease Control and Prevention recommends that patients who are moderately to severely immunocompromised (including SOT recipients) should receive an additional dose of the mRNA COVID-19 vaccine at least 28 d after the second dose.

Sakuraba et al[84] conducted a systematic review and meta-analysis on COVID-19 vaccination and its serologic response on SOT recipients. They found that 9% of patients who received the first dose achieved seroconversion, 34% after the second dose, and 65% after the third dose. While the third dose increased the percentage of seroconversion by two-fold, they recommended searching for alternative protection measures, i.e. monoclonal antibodies.

Efros et al[85] evaluated in their systematic review and meta-analysis the third dose COVID-19 vaccine efficacy and safety in SOT recipients. They found that the third dose improved the immunogenic response and concluded that COVID-19 vaccination is safe. However, to make some strategies for improving the immune response towards vaccination in patients with SOT, we need to know the factors that impact this, mostly age and immunosuppression. With mounting evidence supporting the benefits of immunizing transplant candidates prior to transplantation, choosing the best timing for vaccination is one potential strategy to address the low response rate in SOT recipients. However, once transplantation has occurred, selecting the best timing for vaccination becomes more complex and should consider epidemiological data regarding the risk of SARs-Cov-2 contraction vs the desire to postpone vaccination for at least 1-3 mo following transplantation in light of a weakened immune response to the vaccine during this time.

Implementing a third (booster) dose currently represents the optimal strategy for enhancing immune response to the SARS-CoV-2 vaccine, and we possess ample evidence to recommend it for SOT recipients. Assessing the duration of this enhanced immune response will be crucial and could provide valuable guidance in deciding whether we need additional boosters in the future. Multiple studies have concluded that immunosuppression, particularly high-dose glucocorticoids and mycophenolate mofetil, harms the success of vaccinations. However, there is insufficient data to advise on adjusting immunosuppression in anticipation or preparation for immunization. Society guidelines do not recommend routinely modifying immunosuppression[86]. A further helpful tactic is suggested by promising findings from the most recent trial, which employed moving to a different vaccine platform in non-responders (e.g., viral vector-based vaccination after failure to produce a response after mRNA vaccination)[41].

FUTURE DIRECTIONS OF VACCINES IN SOT

As we navigate the intricate vaccination landscape in SOT recipients, several avenues for future research and clinical exploration emerge. One promising direction is the development of personalized vaccination strategies according to the unique immunological profiles of transplant recipients. This involves a deeper understanding of individual responses to specific vaccines, considering factors such as age, type of organ transplant, and underlying immunosuppressive regimens. Employing the potential of novel technologies, such as mRNA vaccines, may offer a paradigm shift in enhancing immunogenicity in this vulnerable population[87].

Additionally, investigations into the long-term durability of vaccine-induced immunity post-transplantation are critical. Longitudinal studies tracking antibody titers and immune memory will provide insights into the optimal timing for booster vaccinations. Collaborative efforts to establish registries for transplant recipients to track their vaccination history and outcomes can significantly contribute to evidence-based recommendations[88]. Additionally, the exploration of innovative vaccine adjuvants and formulations may enhance vaccine responses in immunosuppressed individuals. Understanding the interplay between immunosuppressive medications and vaccine efficacy will be crucial for guiding clinicians in optimizing immunization schedules without compromising graft function.

CONCLUSION

We focused on the complexities and challenges of vaccination in SOT recipients. Current guidelines, based on the vaccine efficacy and safety, recommend routine administration of vaccines against influenza, Streptococcus pneumoniae, hepatitis B virus, hepatitis A virus, SARS-CoV-2, VZV, meningococcal, human papilloma virus, MMR, tetanus diphtheria pertussis/tetanus diphtheria, Haemophilus influenzae type B, yellow fever, rabies, polio, rotavirus, tuberculosis-Bacillus Calmette-Guérin, smallpox, and cholera for SOT (i.e. heart, liver, lung, and kidney) before transplantation and immunosuppression. The continuous data gathering, research, and collaborative efforts will help optimize the balance between immunosuppression and protective immunity, ensuring SOT recipients can possess enhanced resilience against infectious agents while maintaining good quality of life and wellbeing.