Immunizations in solid organ transplant candidates and recipients

INTRODUCTION — Prevention of infection is of paramount importance to the increasing population of solid organ transplant recipients. Infection in these patients results in substantial morbidity and mortality, and antimicrobial therapy is often less effective than in the immunocompetent host. Although immunization appears to be an obvious way to prevent infection, immunocompromised patients are less likely to mount protective immune responses following vaccination. While concern had been raised that vaccination might trigger rejection, there does not appear to be a causal association between vaccination and organ rejection and transplant guidelines and programs support vaccination. Immunization with live virus vaccines is generally avoided in solid organ transplant recipients as it may result in adverse events from proliferation of attenuated vaccine strains.

Our approach to immunizing patients who are awaiting or have undergone solid organ transplantation will be reviewed here. Issues related to immunizations in patients who have had hematopoietic cell transplants, who have undergone chemotherapy for treatment of hematologic malignancies or solid tumors, who have human immunodeficiency virus (HIV) infection, patients with impaired splenic function, and in healthy adults are discussed separately. (See "Immunizations in hematopoietic cell transplant candidates and recipients" and "Immunizations in adults with cancer" and "Immunizations in persons with HIV" and "Standard immunizations for nonpregnant adults" and "Prevention of infection in patients with impaired splenic function".)

IMMUNOGENICITY — The risk of acquiring infection and the inability to prevent infection by immunization are directly related to the patient's "net state of immunosuppression." The greater the degree of immunosuppression, the less likely the patient is to respond to immunization. Factors contributing to immunosuppression in solid organ transplant recipients include the underlying disease (eg, renal or hepatic insufficiency), the post-transplant immunosuppressive regimen, the presence of allograft rejection, advanced age, and other comorbidities (eg, diabetes mellitus, asplenia).

Although vaccination is likely to provide benefit to the immunocompromised patient, an adequate vaccine response cannot be assumed [1-3]. Protection of the immunocompromised patient may require the use of vaccines and/or passive immunization (ie, intravenous immunoglobulin) as well as adjunctive measures, such as antiviral drug prophylaxis after influenza exposure.

While concern has been raised that vaccination might trigger rejection, numerous trials have shown no causal association between vaccination and organ rejection [4,5].

TIMING OF IMMUNIZATIONS

Pretransplant — Prior to transplantation, we review each patient's vaccination and exposure history in detail along with their serology results and administer any indicated vaccinations (table 1) [1,6] (see "Evaluation for infection before solid organ transplantation"). A programmatic approach to pretransplant vaccination has been shown to be beneficial and conveys better protection against infection [7]. Many transplant programs have initiated routine pretransplant vaccination programs. In general, updating COVID-19, pneumococcal, influenza, and tetanus immunizations, along with serology-based vaccine recommendations against measles, mumps, varicella/herpes zoster, hepatitis B virus, and hepatitis A virus, are key interventions.

Standard vaccines for children are summarized in the following figures (figure 1B and figure 1A). Standard vaccines for adults with medical conditions are summarized in the following figure (figure 1C). (See "Standard immunizations for nonpregnant adults" and "Immunizations in patients with end-stage kidney disease" and "Immunizations for patients with chronic liver disease" and "Standard immunizations for children and adolescents: Overview", section on 'Routine schedule'.)

The pretransplant period is an important window of opportunity to optimize protection against vaccine-preventable illness. Although vaccine responses may be diminished in some patients during this period, vaccine responses are generally even more attenuated post-transplantation when the patient is immunosuppressed [1-3]. Since vaccine immunogenicity is often diminished in the setting of organ failure, transplant candidates should be immunized as early in the course of their disease as possible [8,9]. In addition, live virus vaccines (eg, measles, mumps, rubella, varicella, and the intranasal influenza vaccine) are usually avoided post-transplantation. The Infectious Diseases Society of America recommends waiting a minimum of four weeks between live virus vaccine administration and subsequent transplantation [6].

Post-transplant — Optimal timing is important in maximizing the response to immunization following solid organ transplantation. It is common to wait at least 3 and often up to 12 months after transplantation before giving vaccines, once maintenance immunosuppression levels have been attained [6,8]. An exception is that during influenza outbreaks, it is reasonable to give the inactivated influenza vaccine as early as one month following transplantation [6]; most programs give influenza vaccine starting three months after transplant. Although there had been some concern about vaccine safety after transplant, multiple studies have shown that inactivated vaccines are safe and not associated with organ rejection following transplantation [10-16]. Live vaccines are generally contraindicated post-transplantation when patients are immunosuppressed.

The timing of vaccination may need to be modified when immunomodulatory treatment is given for rejection (eg, anti-CD20 antibodies, antithymocyte globulin). While specific timing will vary based on individual circumstance, we generally try to vaccinate when the effect of any immunosuppressive agents is at its nadir to maximize the likelihood of developing a protective immune response. We often avoid vaccination, other than seasonal influenza, for six months following treatment for rejection.

INACTIVATED VACCINES

Influenza — Annual administration of an inactivated seasonal influenza vaccine is indicated for all transplant candidates and recipients, including during the first year following transplantation [8]. When vaccinating, we generally prefer the high-dose influenza vaccine for adults because it increases the likelihood of developing a more robust immune response [17,18]; however, using the standard-dose vaccine is also reasonable.

We typically resume vaccinations for influenza approximately three to six months after transplantation once maintenance immunosuppression levels have been attained. In the United States, the Centers for Medicare and Medicaid Services have recommended that all patients, including transplant recipients, be immunized prior to discharge from the hospital. This may result in some patients being immunized very early following transplantation causing suboptimal immune responses to the vaccine. Revaccination of such patients three to six months following transplantation can be considered if there is still influenza activity. (See 'Timing of immunizations' above.)

Influenza is a common infection in solid organ transplant recipients and is associated with high morbidity and mortality [19]. In addition to the usual complications of influenza (eg, pneumonia), influenza infection may also be associated with rejection in solid organ transplant recipients [20]. Although the immune response to influenza vaccines is less robust and more heterogenous in solid organ transplant recipients when compared with healthy individuals, vaccination is still effective in preventing and reducing the severity of influenza infection [10,15,21-27]. As an example, in an observational study of lung transplant recipients who received one or two doses of an adjuvanted monovalent 2009 to 2010 pandemic H1N1 influenza vaccine versus no vaccine, documented influenza infection occurred in 2 of 148 vaccinated patients (1.3 percent) compared with 5 of 20 unvaccinated patients (25 percent) [28]. In a multicenter prospective observational study of 616 transplant recipients with confirmed influenza, prior vaccination during that season was associated with reduced rates of pneumonia (odds ratio [OR] 0.34, 95% CI 0.21-0.55) and admissions to the intensive care unit (OR 0.49, 95% CI 0.26-0.90) [26]. The degree of protection from vaccination likely varies based on circulating influenza strains, the intensity of the post-transplant immunosuppressive regimen, and time since transplantation [3,15,29,30].

Several strategies have been employed to augment vaccine immunogenicity in solid organ transplant recipients [31]. Among them, use of a high-dose inactivated influenza vaccine appears most efficacious. As an example, in one randomized trial evaluating 172 solid organ transplant recipients, seroconversion rates and postimmunization antibody titers were significantly higher among solid organ transplant recipients who were vaccinated with a high-dose influenza vaccine when compared with a standard-dose vaccine [17]. While rejection rates did not differ between groups, the study was not powered for this outcome. Booster dosing may also improve immunogenicity, though results among studies have varied [24,31,32]. Intradermal vaccination and adjuvanted standard-dose vaccination have not been shown to improve immunogenicity.

Use of inactivated influenza vaccines is considered safe following solid organ transplantation. While there is a theoretical concern that vaccination may trigger organ rejection [33,34], this association has not been reported in clinical trials [11,31,35-37]. By contrast, in a retrospective cohort study of 51,730 adult renal transplant recipients receiving Medicare, influenza vaccination during the first year after transplantation was associated with lower risk of subsequent allograft loss and death [16]. Like all live virus vaccines, the live attenuated influenza vaccine is contraindicated in solid organ transplant recipients. (See 'Live virus vaccines' below.)

Although vaccination against seasonal influenza appears effective and safe, protection is incomplete. Solid organ transplant recipients exposed to influenza or those who have inadvertently received a live formulation of the influenza vaccine are candidates for antiviral prophylaxis (see "Seasonal influenza in adults: Role of antiviral prophylaxis for prevention"). Transplant recipients who develop influenza are candidates for antiviral treatment, regardless of vaccine status. (See "Seasonal influenza in nonpregnant adults: Treatment".)

Pneumococcus — We agree with the United States Advisory Committee on Immunization Practices that all solid organ transplant candidates and recipients should be vaccinated against Streptococcus pneumoniae [38].

●Approach in adults – Adult solid organ transplant candidates and recipients should receive either of the following:

•The 20-valent pneumococcal conjugate vaccine (PCV20) alone or

•The 15-valent pneumococcal conjugate vaccine (PCV15) followed by the 23-valent polysaccharide pneumococcal vaccine (PPSV23) ≥8 weeks later [38].

Vaccine selection is based on availability and ease of dosing.

For patients who have already received either the PPSV23 or an older formulation of the pneumococcal conjugate vaccine (eg, 13-valent pneumococcal conjugate vaccine [PCV13], 10-valent pneumococcal conjugate vaccine [PCV10]) previously, the dosing schedule varies (algorithm 1). Some UpToDate contributors have a different approach to vaccine selection; this is discussed elsewhere. (See "Pneumococcal vaccination in adults", section on 'Approach to vaccination'.)

PCV15 and PCV20 are pneumococcal conjugate vaccines that are protective against additional pneumococcal serotypes compared with PCV13. Pneumococcal conjugate vaccines that contain a different number of serotypes (eg, the PCV10) are used in some countries in Europe and elsewhere; patients should be vaccinated against pneumococcus according to their national guidelines. (See "Pneumococcal vaccination in children", section on 'Conjugate vaccines'.)

Recommendations for revaccination (eg, booster dosing) with PPSV23 vary among experts and clinical practice guidelines. Revaccination with pneumococcal conjugate vaccines is not necessary. This is discussed in detail separately. (See "Pneumococcal vaccination in adults", section on 'General approach to revaccination'.)

●Approach in children – Pediatric solid organ transplant candidates and recipients should also be vaccinated against pneumococcus [39-41]. The following tables and algorithms summarize the recommendations for vaccination against pneumococcus in high-risk children (table 2A-B and algorithm 2A-B). (See "Pneumococcal vaccination in children", section on 'Conjugate vaccines'.)

●Safety and efficacy – Several small cohort studies have evaluated the immune response to pneumococcal vaccination in solid organ transplant recipients [42-46]. In most, organ transplant recipients developed measurable serologic responses to vaccination, but responses were lesser than those in immunocompetent patients. As an example, in one study, immunization with PPSV23 one year after heart transplantation was successful (defined as protective titers of >300 units/mL to eight of nine selected serotypes) in 75 to 100 percent of recipients [42]. However, only 50 percent of the transplant recipients developed protective levels to pneumococcal serotype 3, compared with a 91 percent response rate in healthy individuals. In trials comparing the 7-valent pneumococcal conjugate vaccine (PCV7) with PPSV23 in renal transplant recipients, there was no difference in immunogenicity between the vaccines [43,44]. Antibody response rates to each individual serotype were poor eight weeks following administration of each vaccine (13 to 40 percent with PPSV23, 17 to 50 percent with PCV7) [43]. Among patients who had adequate responses eight weeks following vaccination, responses to each serotype persisted in only 42 to 85 percent of individuals at three years [44].

PCV20 alone and PCV15 in series with PPSV23 have both been shown to be immunogenic and safe, although no studies have compared vaccine effectiveness of PCV20 alone or PCV15 combined with PPSV23 to the PCV13 combined with PPSV23 in solid organ transplant recipients [47,48].

Hepatitis B — Hepatitis B virus vaccination is indicated for all anti-hepatitis B surface antigen (anti-HBs)-negative solid organ transplant candidates [6]. There is no clear consensus on whether a specific vaccine formulation is superior; thus, any vaccine can be used. Because many transplant recipients do not mount an adequate antibody response to vaccination, we check an anti-HBs titer at least a month following a full vaccination series [49-52]. If a titer of ≥10 milli-international units/mL is not attained, revaccination is indicated. The complete high-dose vaccine series can be repeated; alternatively, one additional dose can be given and titers rechecked. Another alternative for revaccination is to give the CpG-adjuvanted recombinant hepatitis B vaccine (HEPLISAV-B); however, some experts have theoretic concerns about adjuvants in organ transplant recipients, as they could alter immunotolerance of the transplanted organ when used after transplant. (See "Hepatitis B virus immunization in adults", section on 'Patients on dialysis and immunocompromised hosts'.)

Since a transplant candidate may be offered an organ from a HBsAg-negative, core antibody-positive ("core-positive") donor, or sometimes even an HBsAg-positive donor, the vaccine series should be completed prior to transplantation whenever possible [53]. The response to hepatitis B vaccine administration after transplantation varies greatly, with ranges reported from 17 to 89 percent [54-56]. Unfortunately, titers decline more rapidly than usual, even in those who develop protective levels of antibody [54,57], and booster doses produce suboptimal responses [54]. These results underscore the value of pretransplant immunization, which generally results in a more robust and durable response, ideally done prior to the onset of advanced renal or liver failure. (See "Hepatitis B virus immunization in adults", section on 'Postvaccination testing'.)

The management of patients with chronic hepatitis B infection who undergo liver transplantation and of HBsAg-negative transplant recipients who receive a liver from a hepatitis B core antibody (anti-HBc)-positive donor is discussed in detail separately. (See "Liver transplantation in adults: Preventing hepatitis B virus infection in liver transplant recipients".)

Hepatitis A — Hepatitis A vaccine is indicated for all adult liver transplant candidates and recipients because of their increased risk of fulminant hepatic failure from hepatitis A virus (HAV) [58]. Hepatitis A vaccination is also indicated for all pediatric solid organ transplant candidates and recipients ≥12 months of age [6,8] and all nonliver solid organ transplant recipients who have additional risk factors for HAV transmission (eg, clotting factor disorder, travel to or residence in regions where hepatitis A virus is endemic) [8]. Monitoring titers is indicated only for individuals with an ongoing risk of exposure, such as planned travel to an endemic area [6].

Patients should be vaccinated as early as possible after the diagnosis of chronic liver disease because advanced liver failure blunts the immune response to the vaccine [59]. Several observational studies suggest that receipt of a complete vaccine series prior to solid organ transplantation engenders better immunity than when vaccines are given post-transplantation [60-63]. The duration of both natural immunity and vaccine-induced immunity is also reduced post-transplantation [60,64,65]. In one study of liver transplant recipients who acquired natural hepatitis A infection prior to transplantation, 4 of 22 patients (18 percent) and 7 of 24 patients (29 percent) became seronegative one and two years after transplantation, respectively [64]. While a combination hepatitis A-hepatitis B vaccine (Twinrix) may be efficient, some studies have shown that the combination vaccine is less immunogenic compared with monovalent vaccines [66].

Additional detail on hepatitis A vaccination is provided separately. (See "Hepatitis A virus infection: Treatment and prevention", section on 'Vaccination'.)

Human papillomavirus — Female solid organ transplant recipients with human papillomavirus (HPV) infection are at 20- to 100-fold increased risk of cervical intraepithelial neoplasia, and both male and female recipients are at risk for other anogenital cancers [33,67,68]. We recommend vaccinating solid organ candidates and recipients who meet the age-based indications for HPV vaccination [8,68]. (See "Human papillomavirus vaccination", section on 'Indications and age range'.)

Vaccination should be given prior to transplantation when possible. If all doses are not given prior to transplantation, the additional doses can be given beginning three to six months following transplantation. There are few data on the immunogenicity of the HPV vaccination in solid organ transplant recipients, but it should be safe to administer following transplantation since it is not a live vaccine. In one study, the quadrivalent HPV virus-like particle vaccine demonstrated poor immunogenicity in solid organ transplant recipients, with responses ranging from 53 to 68 percent against the four types included in the vaccine [69]. Factors associated with reduced immunogenicity included vaccination early after transplant, having a lung transplant, and having higher tacrolimus levels. At 12 months, there were significant declines in antibody titers to all four HPV types, although the number of patients who remained seropositive did not differ significantly.

There may be a role for HPV vaccine in both male and female transplant recipients outside the age-based indications to prevent anogenital warts, anal cancer, and HPV-associated skin cancers [68]. In a phase III single-arm study of 171 solid organ recipients aged 18 to 55 years who received the 9-valent HPV vaccine, seroconversion ranged from 46 to 72 percent (depending on HPV serotype) and there were no adverse effects [70]. We anticipate that there will be a future recommendation to broaden the indications for use of the HPV vaccine in transplant recipients, pending reporting of results of an ongoing study of the safety and efficacy of HPV in solid organ transplant recipients up to age 35 years.

Additional detail on HPV vaccination is provided separately. (See "Human papillomavirus vaccination".)

Meningococcus — The incidence of meningococcal disease after solid organ transplantation is unknown, and there is no information on the efficacy of meningococcal vaccines in patients with renal or liver failure or in solid organ transplant recipients. The quadrivalent meningococcal and serogroup B vaccines should be administered to solid organ transplant recipients and candidates who have a specific risk factor for invasive meningococcal infection (eg, asplenia, anticipated use of eculizumab) (table 3) [8,71].

A special transplant-related indication would be for those transplant recipients who are likely to receive or who have been given the terminal complement pathway inhibitor eculizumab. Guidelines suggest that for patients who will be starting eculizumab, when possible, vaccination should be completed at least two weeks in advance in order to provide adequate time for an immune response [8]. Many clinicians would still give antibiotic prophylaxis even after appropriate vaccination, as not all strains are covered and the immune response may not be as robust as needed. Some transplant programs give it to highly sensitized patients at higher risk of antibody-mediated rejection and who may need eculizumab.

Available formulations for quadrivalent meningococcal conjugate vaccine in the United States include MenQuadfi and Menveo. In addition, there are two serogroup B meningococcal vaccines (Trumenba, MenB-FHbp; Bexsero, MenB-4C) that have been approved for use in the United States. We generally vaccinate solid organ transplant recipients with specific indications, although the efficacy of these vaccines is not well studied in this population. Recommendations for vaccination are discussed separately. (See "Meningococcal vaccination in children and adults", section on 'Indications and schedules in the United States'.)

Haemophilus influenzae — Pediatric solid organ transplant recipients should receive the Haemophilus influenzae type b (Hib) conjugate vaccine according to the routine schedule for children (figure 1B and figure 1A). Hib titers should be checked at least four weeks after vaccine administration if serologic testing is available; a titer >0.15 mg/L is considered protective in the general population [8]. (See "Prevention of Haemophilus influenzae type b infection", section on 'Routine schedule'.)

Among adults, Hib is generally only recommended for individuals with impaired splenic function and following stem cell transplantation. (See "Prevention of infection in patients with impaired splenic function", section on 'Vaccinations' and "Immunizations in hematopoietic cell transplant candidates and recipients", section on 'Haemophilus influenzae'.)

Tetanus, diphtheria, and pertussis — The tetanus, diphtheria, pertussis (Tdap), the diphtheria, tetanus, pertussis (DTaP), and the tetanus, diphtheria (Td) vaccines should be given per the same indications and schedules as the general population (figure 1A-C).

Like other inactivated vaccines, these vaccines can be safely given post-transplantation when needed [33,72,73]. Observational data suggest that there is no increased risk of rejection following vaccination. However, the immune response to these vaccines may be blunted [72-75]. The American Society of Transplantation guidelines recommend monitoring tetanus titers in pediatric (but not adult) solid organ transplant candidates and recipients a minimum of four weeks following vaccination [8]. (See "Diphtheria, tetanus, and pertussis immunization in children 7 through 18 years of age" and "Diphtheria, tetanus, and pertussis immunization in children 6 weeks through 6 years of age", section on 'Schedules' and "Tetanus-diphtheria toxoid vaccination in adults".)

COVID-19 vaccine — SOT candidates and recipients should be vaccinated against coronavirus disease 2019 (COVID-19). This is discussed in detail elsewhere. (See "COVID-19: Vaccines" and "COVID-19: Issues related to solid organ transplantation", section on 'Vaccination'.)

ZOSTER VACCINES — There are two vaccine formulations available for the prevention of herpes zoster: the recombinant (nonlive) glycoprotein E vaccine (recombinant zoster vaccine [RZV]; sold as Shingrix) and the live attenuated vaccine (zoster vaccine live [ZVL] that is no longer available in the United States) [76].

We agree with the recommendations from the United States Advisory Committee on Immunization Practices to vaccinate immunocompromised (or soon to be immunocompromised) individuals ≥19 years old, such as solid organ transplant candidates and recipients, against herpes zoster with the recombinant zoster vaccine (RZV) [77].

●RZV as preferred option − RZV is administered in two doses spaced two to six months apart. However, in patients who are or will be immunosuppressed and would benefit from receiving the full vaccination series earlier, the second dose can be given as early as four weeks after the first dose. Like other vaccines, the vaccine should ideally be given before transplantation to help ensure maximal immune response. Vaccination with the RZV series should be completed at least two weeks prior to transplantation.

RZV appears to be effective and safe in solid organ transplant recipients. In a randomized trial in 264 adult renal transplant recipients, vaccination boosted cellular and humoral immune responses when compared with placebo, with higher responses seen in younger adults (<50 years old) [78]. There was no difference in graft rejection rates between the RZV and placebo groups. Small, observational studies have also demonstrated efficacy and safety of RZV in other solid organ transplant recipients [79].

RZV appears to be more effective than ZVL in the general health population and is not associated with a risk of disseminated disease. In a systematic network meta-analysis of randomized trials of healthy adults 60 years or older, ZVL was approximately half as effective in preventing zoster infection compared with RZV [80].

●ZVL as less preferred alternative − In settings where RZV is not available, ZVL is an alternative option for vaccination against herpes zoster. ZVL is administered as a single dose and should be given at least four weeks prior to transplantation. ZVL is contraindicated in solid organ transplant recipients post-transplantation because it is a live virus vaccine [8,81]. ZVL is not as effective as RZV; thus in patients who receive ZVL, consider revaccinating with RZV once it becomes available.

Additional detail on the vaccination of the prevention of herpes zoster is provided separately. (See "Vaccination for the prevention of shingles (herpes zoster)".)

LIVE VIRUS VACCINES — The Infectious Diseases Society of America (IDSA) recommends waiting a minimum of four weeks between live virus vaccine administration and solid organ transplantation [6]. Live organism vaccines are generally avoided following solid organ transplantation (or in those candidates who are immunosuppressed before transplant) given the potential for active infection. A list of live vaccines is provided in the following table (table 4).

The following caveats should be noted regarding the administration of live virus vaccines prior to transplantation [8]:

●The measles, mumps, and rubella (MMR) vaccine and the varicella vaccine can be administered on the same day, but if they are not given on the same day, the second live vaccine should be administered at least 28 days after the first.

●Live vaccines can interfere with the response to the tuberculin skin test (TST). A TST can be placed the same day as a live vaccine is given, but if it is not done on the same day, it should be delayed for four to six weeks. An alternative to the TST is the interferon-gamma release assay for tuberculosis, which may have higher sensitivity in patients with end-stage organ disease [82,83]. (See "Tuberculosis in solid organ transplant candidates and recipients", section on 'Screening'.)

●Intravenous immunoglobulin (IVIG) and antibodies transferred with blood products can bind vaccine and interfere with the immune response to live virus vaccines. Thus, administering MMR vaccine as well as the varicella vaccine should be delayed after receipt of IVIG and other blood products (table 5). Delay is not needed before the administration of inactivated vaccines (eg, recombinant zoster vaccine). (See "Overview of intravenous immune globulin (IVIG) therapy", section on 'Vaccination of patients receiving IVIG'.)

Measles, mumps, and rubella — Measles, mumps, and rubella infections are rare after solid organ transplantation, but the potential severity of these diseases is well recognized for nonimmunized individuals. All children should ideally receive a two-dose series of the MMR vaccine, with at least four weeks between doses [8]. In one study of children who were on dialysis when they received the MMR vaccine, 70, 50, and 80 percent developed protective titers against measles, mumps, and rubella, respectively, but only 30 percent were protected against all three infections [84]. Every effort should be made to immunize such transplant candidates at least one month prior to transplantation [6,41]. We suggest checking antibody titers after immunization prior to transplantation because of the variability in the vaccine response.

In order to immunize pediatric solid organ transplant candidates younger than one year of age prior to transplantation, the American Society of Transplantation (AST) and the IDSA state that the MMR vaccine can be given as early as six months of age in infants not receiving immunosuppression, although the vaccine is most effective after one year of age when maternal antibodies have waned [6,8]. Data suggest excellent immunogenicity in those infants with chronic renal failure and/or receiving peritoneal dialysis [85]. If transplantation has not occurred by one year of age, a second dose should be given, provided that a minimum of four weeks has elapsed since the previous dose. At least four weeks should elapse between live virus vaccine administration and transplantation. Several caveats are reviewed above. (See 'Live virus vaccines' above.)

Based upon the severe complications related to measles infection in transplant recipients and the experience of administering MMR in children infected with HIV [86], some transplant centers have started to use MMR after solid organ transplantation for children or others who have not completed the recommended series of MMR [87], primarily in those on low-dose immunosuppression [88]. However, this practice is not widespread and safety data are limited [89]. In one study, 7 of 17 seronegative pediatric liver transplant recipients developed protective titers against measles after immunization, and none developed clinical measles [90]. In another study, 44 pediatric liver transplant recipients who were ≥1 year post-transplantation on low-dose immunosuppression with lymphocyte counts ≥0.75 G/L were given MMR vaccine without any serious adverse events [88]. Vaccination was given a median of 6.3 years post-transplantation, and seroprotection was achieved in most patients following 1 to 3 doses of MMR. However, these limited data are inadequate to support a recommendation for post-transplant immunization with MMR in nonimmune individuals. Guidelines from the AST Infectious Diseases Community of Practice state "MMR and varicella vaccination are generally contraindicated post-transplant but may be administered in carefully selected patients with appropriate education and close follow-up" [8].

Nonimmune adult solid organ transplant candidates should receive MMR vaccination prior to transplantation. The optimal approach is not known. Some experts give a total of two MMR doses prior to transplantation while others give a single dose and test for a protective serologic response ≥4 weeks later. If seroconversion has not occurred, a second dose can be given prior to transplantation, if time permits. A key caveat is that the MMR is a live vaccine, which must be given at least four weeks prior to transplantation.

Nonimmune solid organ transplant recipients and those who are severely immunocompromised who have been exposed to measles should receive postexposure prophylaxis with intravenous immune globulin. (See "Measles, mumps, and rubella immunization in adults", section on 'Post-exposure prophylaxis'.)

Varicella — Given the risk of severe varicella infection (chickenpox) in nonimmune solid organ transplant recipients, we suggest immunization with the varicella vaccine at least four weeks prior to transplantation [6]. Because patients with end-stage organ disease have reduced seroconversion rates of approximately 60 percent to varicella vaccination [91-94], it is particularly important for such patients to receive two doses of the varicella vaccine, if feasible, with a minimum interval of four weeks between doses for individuals aged ≥13 years and a minimum interval of three months for individuals aged 1 to 12 years [6,81]. (See "Vaccination for the prevention of chickenpox (primary varicella infection)", section on 'Schedules in the United States'.)

Maternal antibodies interfere with the response to varicella vaccination, and the vaccine is most effective after one year of age when maternal antibodies have waned [8]. Infants awaiting transplantation may receive the vaccine as early as six months of age [6]. Varicella antibodies should be checked four weeks after the second dose of vaccine has been given [8]. If seroconversion does not occur, an additional dose can be given if time permits. Those who do not seroconvert are candidates for postexposure prophylaxis, should an exposure occur following transplantation. (See 'Postexposure prophylaxis' below.)

A potential concern for patients high on the waiting list is the possibility that transplantation could occur shortly after vaccination, subjecting a recently vaccinated patient to high-dose immunosuppression and the risk of proliferation of the attenuated strain. As noted above, transplant candidates should be vaccinated at least four weeks prior to transplant [6]. If transplantation is urgently indicated in a patient who has received the varicella vaccine within the previous month, peri- and post-transplant prophylaxis with intravenous acyclovir or oral valacyclovir or famciclovir should be given.

If the varicella vaccine is not administered pretransplant, we recommend against administration post-transplant in the majority of patients due to concern for disseminated varicella-zoster virus (VZV) infection. An exception is varicella-nonimmune pediatric renal or liver transplant recipients who are receiving minimal or no immunosuppression and who have had no recent allograft rejection; the IDSA has endorsed varicella vaccination post-transplant in this group of patients [6]. When indicated, the varicella vaccine should be given as the single antigen preparation rather than as part of the combined measles, mumps, rubella, and varicella vaccine.

Preliminary data are encouraging regarding the efficacy of varicella immunization for stable patients after liver, kidney, and intestinal transplantation [95-97]. As an example, in one study, 16 VZV-naïve pediatric renal and liver transplant recipients were immunized with the varicella vaccine during the late post-transplant period (range eight months to six years) [96]. Evidence of humoral immunity developed in 13 of 15 patients (87 percent) and cell-mediated immunity developed in 12 of 14 patients (86 percent). Following vaccination, four patients had fever and four developed vesicular rashes, three of whom received acyclovir. Subsequent VZV exposures in four patients, one of whom received varicella-zoster immune globulin, did not result in VZV infection. Case reports of disseminated VZV have been described following varicella vaccination in solid organ transplant recipients [98,99]; one case was proven to be caused by the vaccine strain [98].

Prior to widespread vaccination, varicella-zoster infection (chickenpox) occurred in up to 2 percent of pediatric renal transplant recipients in the first year after transplantation and was associated with significant morbidity and mortality [100]. Although adults are rarely susceptible to varicella, morbidity and mortality is high in those who acquire primary infection after transplantation. Although the recombinant shingles vaccine (Shingrix) is not licensed and has not been extensively studied for prevention of varicella in nonimmune subjects, early data demonstrate it can be a safe and effective option. In a small randomized study of 23 adult VZV-seronegative solid organ transplant recipients, 55 percent had a positive seroresponse four weeks after completing the vaccine series and no serious adverse effects were described [101].

Rotavirus — Rotavirus infection can lead to significant morbidity among solid organ transplant recipients and is particularly prevalent among pediatric solid organ transplant recipients [102]. Age-appropriate rotavirus vaccination is recommended for pediatric solid organ transplant candidates prior to transplantation but is not recommended following transplantation because it is a live vaccine [8]. Good infection control practices, including hand hygiene (especially after diaper changes), are recommended for immunocompromised household members of a recently vaccinated infant. (See "Rotavirus vaccines for infants", section on 'Schedule'.)

POSTEXPOSURE PROPHYLAXIS — Postexposure prophylaxis (PEP) may be warranted for selected immunocompromised patients who have been exposed to certain pathogens, including varicella-zoster virus (VZV), influenza virus, hepatitis B virus, measles virus, meningococcus, rabies virus, and tetanus. Although the decision to use PEP is usually individualized based on the type of exposure, timing of the exposure, and degree of immunosuppression, it is often prudent to provide PEP for patients who have not been vaccinated against the pathogen to which they were exposed and/or for those who are severely immunocompromised.

Varicella exposure — For nonimmune solid organ transplant recipients who have been exposed to a patient with VZV (varicella or herpes zoster) infection, we recommend prophylaxis with VariZIG and/or antiviral therapy. Solid organ transplant recipients with immunity to VZV (VZV IgG positive) do not require VZV prophylaxis following exposure to a patient with VZV infection.

In the outpatient environment, significant exposure is defined as exposure to a household contact or nontransient face-to-face contact indoors with a playmate or other contact [8,103]. In the hospital environment, significant exposure is defined as exposure in the same two- to four-bed room, face-to-face contact with an infectious staff member or patient, or a visit by a person deemed contagious. All transplant recipients should be monitored carefully after exposure, even if VariZIG or antiviral therapy is administered.

VariZIG is a purified human varicella-zoster immunoglobulin preparation [81,104]. When postexposure prophylaxis is indicated, VariZIG should be offered as soon as possible, but it may be given for up to 10 days following exposure. Immunoprophylaxis alone does not prevent all cases of varicella in immunocompromised patients, but it lessens the severity of infection [8]. For high-risk patients who have additional exposures to varicella-zoster virus ≥3 weeks after initial VariZIG administration, another dose of VariZIG should be considered. (See "Post-exposure prophylaxis against varicella-zoster virus infection".)

Use of antiviral agents (ie, acyclovir, famciclovir, valacyclovir) as postexposure prophylaxis has not been evaluated in randomized trials in immunocompromised patients, but it should be considered as adjunctive therapy in patients receiving immunoprophylaxis or in patients who were unable to receive immunoprophylaxis within 10 days following exposure. Although either oral acyclovir or valacyclovir can be used for postexposure prophylaxis, we prefer valacyclovir (1 g orally three times daily) given its superior bioavailability. The optimal prophylactic regimen is not known, and approaches vary among experts [81,103]. We typically give antiviral prophylaxis from days 3 to 28 after known exposure for patients who have been given immunoprophylaxis. The antiviral is started on day 3 following exposure because of the theoretical concern that VariZIG might prolong VZV's incubation period [105,106]. For patients who have not received immunoprophylaxis, we treat for 22 days following exposure.

All patients who have been exposed should also be monitored closely for any sign of active infection; intravenous acyclovir should be started immediately should this occur [107].

Other exposures — Other PEP regimens vary based on the pathogen and may include antimicrobial prophylaxis, vaccination, and/or passive immunization (ie, generic or pathogen-specific immune globulin). For immunocompromised patients, live vaccines recommended in some PEP regimens may need to be replaced or supplemented with immunoglobulin administration.

Specific PEP indications and recommendations are discussed separately for each pathogen:

●(See "Seasonal influenza in adults: Role of antiviral prophylaxis for prevention".)

●(See "Management of nonoccupational exposures to HIV and hepatitis B and C in adults", section on 'Exposure to hepatitis B virus'.)

●(See "Measles, mumps, and rubella immunization in adults", section on 'Post-exposure prophylaxis'.)

●(See "Treatment and prevention of meningococcal infection", section on 'Antimicrobial chemoprophylaxis'.)

●(See "Rabies immune globulin and vaccine", section on 'Post-exposure prophylaxis'.)

●(See "Infectious complications of puncture wounds".)

HEALTH CARE WORKERS AND CLOSE CONTACTS — Health care workers and close contacts (eg, family members) of solid organ transplant recipients should receive all recommended immunizations [6,8]. In particular, such individuals should be immunized against influenza annually, but they should also receive other indicated vaccines, including COVID-19. The following figures summarize routine vaccine recommendations for children (figure 1B and figure 1A), healthy adults (figure 2), and adults with medical conditions (figure 1C). (See "Seasonal influenza vaccination in adults" and "Seasonal influenza in children: Prevention with vaccines" and "Standard immunizations for nonpregnant adults" and "Immunizations for health care providers" and "Standard immunizations for children and adolescents: Overview", section on 'Routine schedule' and "COVID-19: Vaccines".)

With the exception of the smallpox vaccine and oral polio virus vaccines, there is little to no risk of transmission of vaccine viruses from vaccine recipients to their close contacts [8]. Nevertheless, health care workers and close contacts of solid organ transplant recipients should receive inactivated vaccines, especially COVID-19, when possible.

Specific issues in regard to certain live vaccines are discussed below.

●Influenza – The American Society of Transplantation (AST) favors the use of the inactivated influenza vaccine (IIV) for contacts of solid organ transplant recipients; they state that if the live attenuated influenza vaccine (LAIV) is the only available option, it can be given, but vaccine recipients should wash their hands frequently for two weeks following vaccination [8]. We agree with this approach. In contrast, the Infectious Diseases Society of America (IDSA) recommend either IIV or LAIV for contacts of solid organ transplant recipients; LAIV can be used in healthy nonpregnant individuals between 2 and 49 years of age [6]. (See "Seasonal influenza vaccination in adults" and "Seasonal influenza in children: Prevention with vaccines".)

●MMR – Nonimmune household and close contacts of solid organ transplant recipients should be immunized against measles, mumps, and rubella (MMR) to prevent transmission of wild-type viruses to transplant recipients [6,8,41]. (See "Measles, mumps, and rubella immunization in adults" and "Measles, mumps, and rubella immunization in infants, children, and adolescents", section on 'Measles, mumps, and rubella disease'.)

●Varicella – The use of the varicella vaccine in household contacts of transplant recipients has been the subject of much discussion. The American Academy of Pediatrics (AAP) recommends use of the varicella vaccine in household contacts but cautions that vaccinees who develop a rash should avoid contact with transplant recipients for the duration of the rash [103]. The AST and IDSA guidelines also support this view and recommend that close contacts and family members aged 12 months or older should be vaccinated against varicella if they have never received the vaccination, have no history of varicella or herpes zoster, and have no contraindications to vaccination [6,8]. Transplant recipients should be isolated from vaccine recipients who develop a rash. If isolation is not possible, then the nonvaricella-immune transplant recipient should be monitored for the development of a rash, and antiviral therapy (eg, valacyclovir or famciclovir) should be started in the unlikely event that a rash suggestive of varicella develops. (See "Vaccination for the prevention of chickenpox (primary varicella infection)", section on 'Contacts of immunocompromised hosts'.)

Similarly, the zoster vaccine should be administered to household contacts who have an indication to receive it. We generally prefer to use the recombinant zoster vaccine (RZV) for household contacts of solid organ transplant recipients rather than the live zoster virus vaccine because there is not risk of transmission of vaccine stain virus with RZV.

●Rotavirus – Rotavirus vaccines are given routinely to healthy infants and pose a theoretical risk of transmission since live virus may be shed in stool for two to four weeks following vaccination [6,108-110]. Highly immunocompromised patients (eg, solid organ transplant recipients within the first two months following transplantation) should avoid handling the diapers of infants who have received the rotavirus vaccine for four weeks following vaccination [6]. In addition, good handwashing practices should be adhered to among those who change the diapers of infants who received the rotavirus vaccine [8]. (See "Rotavirus vaccines for infants".)

Pets should also receive routine vaccines, including the live intranasal canine Bordetella bronchiseptica vaccine [8]. Transplant recipients should not be in the same room when this is administered, to avoid potential illness from this live attenuated vaccine [111].

LIVING DONORS — Living donors should be vaccinated according to recommendations for healthy individuals issued by the United States Advisory Committee on Immunization Practices (or, for those outside the United States, other national guidelines) [6]. Influenza vaccination is particularly important when transplantation occurs during influenza season. (See "Standard immunizations for nonpregnant adults".)

Live virus vaccines should be avoided within four weeks of organ donation (table 4) [6]. Vaccination of donors for the potential benefit of the recipient is not recommended.

IMMUNIZATIONS IN TRAVELERS — Immunizations in travelers are discussed separately. The use of the different vaccines must be considered in relation to the issues described above. (See "Travel advice for immunocompromised hosts", section on 'Routine vaccines' and "Travel advice for immunocompromised hosts", section on 'Travel vaccines'.)

GUIDELINES — In 2019, the American Society of Transplantation (AST) updated the guidelines for vaccination of pediatric and adult solid organ transplant candidates and recipients as well as health care workers, household contacts, and other close contacts of these patients [8]. In 2013, the Infectious Diseases Society of America (IDSA) published guidelines for vaccination of immunocompromised hosts, including solid organ transplant recipients [6]. The United States Advisory Committee on Immunization Practices (ACIP) also includes immunocompromised hosts in their recommendations (figure 1C) [112].

Our recommendations are generally in keeping with the AST guidelines, the IDSA guidelines, and the ACIP recommendations. Clinicians in other countries should consider referring to their national guidelines for recommendations regarding immunization of solid organ transplant candidates and recipients. (See 'Society guideline links' below.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Immunizations in solid organ transplant recipients".)

SUMMARY AND RECOMMENDATIONS

●Introduction − Vaccine-preventable infections cause substantial morbidity and mortality in solid organ transplant recipients. Thus, vaccination is an important part of care. (See 'Introduction' above.)

●Pretransplant evaluation − Prior to transplantation, we review each patient's vaccination and exposure history in detail and administer any needed vaccinations (table 1). (See 'Pretransplant' above and "Evaluation for infection before solid organ transplantation".)

●Timing of immunizations

•Vaccines should be administered as early in the pretransplant period as possible when the likelihood of developing a protective immune response is highest and when live vaccines can be given safely. Live vaccines should be given at least four weeks prior to transplantation in immunocompetent patients. With rare exception, live vaccines are contraindicated in immunocompromised patients and post-transplantation. (See 'Timing of immunizations' above and 'Live virus vaccines' above.)

•Post-transplantation, inactivated vaccines are considered safe, although their efficacy may be diminished. To maximize immune response, we generally wait at least 3 months and often up to 12 months post-transplant to give any needed inactivated (nonlive) vaccines. However, during influenza outbreaks, the inactivated influenza virus can be given as early as one month post-transplantation. (See 'Post-transplant' above.)

●Influenza vaccines − Vaccination against seasonal influenza virus should be given annually both pre- and post-transplantation. Post-transplantation, we suggest using the high-dose influenza vaccine for adults because it augments immune response and does not appear to increase the likelihood of rejection (Grade 2B). However, using the standard-dose vaccine is also reasonable. (See 'Influenza' above.)

●Pneumococcal vaccines − We vaccinate solid organ transplant candidates and recipients against pneumococcus with either the 20-valent pneumococcal conjugate vaccine (PCV20) alone or the 15-valent pneumococcal conjugate vaccine (PCV15) followed by the 23-valent polysaccharide pneumococcal vaccine (PPSV23) at least eight weeks later. For patients who have already received either the PPSV23 or an older formulation of the pneumococcal conjugate vaccine (eg, 13-valent pneumococcal conjugate vaccine [PCV13], 10-valent pneumococcal conjugate vaccine [PCV10]) previously, the dosing schedule varies (algorithm 1). (See 'Pneumococcus' above.)

●Hepatitis A and B vaccines − The hepatitis B virus vaccine series should be given to solid organ transplant candidates and recipients who are nonimmune to the virus based on serologic testing. Like the hepatitis A virus (HAV) vaccines, vaccination is particularly important for liver transplant candidates and recipients who are at increased risk of fulminant hepatic failure from these viruses. The HAV vaccine is also indicated for most pediatric solid organ transplant recipients and all nonliver solid organ transplant recipients with specific risk factors (eg, travel to or residence in a HAV-endemic area). (See 'Hepatitis B' above and 'Hepatitis A' above.)

●Herpes zoster vaccines − Vaccination against herpes zoster (shingles) is indicated for solid organ transplant candidates and recipients who are ≥19 years old. Vaccination should ideally be given pretransplantation to allow for maximal immunogenic response. For solid organ transplant recipients who are post-transplantation who have not received a herpes zoster vaccine, RZV should be administered; ZVL is contraindicated post-transplantation. (See 'Zoster vaccines' above.)

●COVID-19 vaccines − COVID-19 vaccination in SOT candidates and recipients is discussed separately. (See "COVID-19: Vaccines" and "COVID-19: Issues related to solid organ transplantation", section on 'Vaccination'.)

●Other vaccines − Additional vaccines may be needed for patients based on age, vaccination history, or other specific risk factors (eg, meningococcal vaccination for patients receiving eculizumab). (See 'Human papillomavirus' above and 'Haemophilus influenzae' above and 'Tetanus, diphtheria, and pertussis' above and 'Live virus vaccines' above and 'Meningococcus' above.)

●Postexposure prophylaxis − Following exposure to certain pathogens (eg, varicella-zoster virus, measles virus, or hepatitis B virus), passive immunization (eg, administration of immunoglobulin) and/or postexposure antimicrobial prophylaxis may be warranted for severely immunocompromised patients and/or for those who have not been vaccinated against these pathogens. (See 'Postexposure prophylaxis' above.)

●Health care workers and close contacts − We advise that close contacts of solid organ transplant candidates receive all recommended immunizations. When possible, live virus vaccines should be given prior to transplantation and/or the start of immunosuppression. (See 'Health care workers and close contacts' above.)