Guidelines for vaccination in kidney transplant recipients

Kidney transplant recipients are at increased risk of developing infections, including vaccine-preventable diseases.[1] However, some of these vaccines may not be beneficial whereas others could even be harmful to kidney transplant recipients.[2] Under immunosuppression not only could live vaccine strains proliferate unchecked causing vaccine-induced diseases but also the immune response of recipients to the vaccines could be suboptimal, rendering vaccination ineffective, or even futile in certain situations.

The Kidney Disease Improving Global Outcomes (KDIGO) in 2009 brought out comprehensive, evidence-based guidelines for care of kidney transplant recipients including vaccination.[3] This chapter would attempt to endorse those guidelines with comments on the same or modify them if required, based on current literature to suit Indian scenario, with supporting rationale and evidence where available. For most of the supporting evidence for those guidelines adopted from the KDIGO guidelines, the readers are requested to refer to the original document.

1. Kidney transplant recipients should receive age-appropriate inactivated vaccinations as recommended for general population

   1. Hepatitis B Vaccination should be guided by anti-HBS titers, (measured at least 3 months after completion of vaccination and annually thereafter).

2. Kidney transplant recipients should not receive live vaccines. If a patient has received a live vaccine, the transplant should be delayed by at least 4 weeks since the time of administration

3. In general, it is best to wait until the first 3–6 months after kidney transplantation, the period of intense immunosuppression, before attempting vaccination. However, inactivated influenza vaccination can be administered as early as 1 month after kidney transplant to time it before onset of the flu season

4. Kidney transplant patients should receive ancillary inactivated vaccines based on the risk factors for the respective disease and the propensity to develop these rare infections, especially for vaccines that are neither routinely recommended for general population nor specifically in transplant recipients.

Rationale and Supporting Evidence

Response to vaccination has been shown to be suboptimal in transplant recipients.[1] The pretransplant vaccination history and the seroprotective status would affect the posttransplant vaccination strategies. Hence, detailed vaccination history should be obtained in all kidney transplant recipients at the first visit after kidney transplantation to plan the vaccination schedule if it is not already available.

Timing of vaccination after kidney transplant

Immune responses are suboptimal during the period of intense immunosuppression. The greater the degree of immunosuppression, the poorer is the response to vaccination. In this context, the degree of immunosuppression is best considered from the net state of immunosuppression rather than by the immunosuppressive drug doses and concentrations alone. Considering that the initial 3-6 months are a period of intense immunosuppression after kidney transplantation, it is preferable to avoid vaccinations during this time.[2] After 3-6 months, once maintenance immunosuppressive levels are reached, immunization could be undertaken.

If needed, some vaccines can be given after 2 months of kidney transplantation although the immune response is likely to be muted.[3,4]

Type of vaccine

Live attenuated vaccines pose considerable risk of unchecked vaccine strain proliferation and vaccine induced diseases in transplant recipients. Live virus vaccines should be administered as early in the course of chronic kidney disease (CKD) as possible. After administration of a live attenuated vaccine, a mandatory minimum waiting period of 4 weeks is necessary before using immunosuppression.[2]

Monitoring immune response to vaccination

Wherever possible, seroconversion should be documented after 4 weeks of completing the course of immunization to ascertain adequacy of protection, and determine need or additional boosters. While on ongoing immunosuppression, it may be prudent to monitor protective antibody levels to time booster doses appropriately.

Monitoring cellular immunity for protection against infections is under research.

Vaccination of health care workers and household contacts

Prevention of infections in kidney transplant should also involve a strategy to vaccinate household contacts and pets with vaccines for preventable diseases. Vaccine-preventable diseases such as Hepatitis B, pneumococcal disease, and especially influenza vaccine should be offered to household contacts of transplant recipients. In general, inactivated vaccines are preferred for vaccination of household contacts.

Administration of live vaccines to household contacts can result in viral shedding, which can potentially result in vaccine-induced infectious disease in the transplant recipient. Hence, care should be taken to avoid live vaccines for household contacts of transplant recipients. Of importance to India is the administration of oral polio vaccine to children in the recipient's household, which can result in virus shedding and potentially result in virus-induced disease in the kidney transplant recipient. However, so far, there have been no documented reports of vaccine-induced poliomyelitis among transplant recipients, possibly due to preexisting immunity against polio among the recipients.

In case only a live attenuated vaccine is available, viral shedding should be considered and preferably the household contacts who have received them should exercise precaution as well as infection prevention measures such as frequent hand-washing and limit contact with the transplant recipient for the first 2 weeks, when viral shedding is likely to be at its peak.

Vaccines of special interest in transplantation

A summary of the various vaccines used in kidney transplant recipients is given in Table 14.

Table 14.

Vaccines in kidney transplantation

Hepatitis B Vaccination

The ideal time to administer Hepatitis B vaccine is before the onset of End stage renal disease. However, many patients do not receive the complete course of vaccination before kidney transplantation.

Kidney transplant recipients who lack protective antibody titers (>10 IU/ml) should receive hepatitis B vaccination.[5,6,7,8] It is preferable that the vaccination be administered at a time of less intense immunosuppression, which is after the first 3 months of kidney transplantation. Protective response to hepatitis B vaccination post solid organ transplant varies widely from 17 to 89%.[9,10] In view of low immunogenic response, there has been interest in accelerated vaccination schedules[11,12] although they have not been studied in kidney transplant recipients.

Protective antibody titres against Hepatitis B (Anti HBS) show a rapid decline post kidney transplantation. Hence, Anti HBS titres should be checked every 6-12 months and booster doses should be administered either when the titres fall below 10IU/ml or when it is expected to fall below that level in the next 3-6 months. In addition, it is important to note that the response to booster doses in transplant recipients will be less intense than with general population.

Pneumococcal vaccination

Vaccination with both 23 valent polysaccharide vaccine (PPSV23) and 13 valent conjugate vaccine (PCV13) are safe in kidney transplant recipients.[13,14,15] The schedule of immunization with the vaccines is as per the recommended schedule for general adults. The ACIP guidelines suggest the following comprehensive approach for optimal vaccine efficacy among immunocompromised adults:[16]

• If a patient receives the first dose of PCV13, it should be followed by PPSV23 at about 8 weeks later

• If patient had received PPSV23 in the past, a PCV13 dose should be administered after at least a year only

• If a patient who has received PPSV23 requires further doses of PPSV23, it should be administered at least 5 years after the last dose of PPSV23.

For immunocompromised children:[17]

• Between 2 and 5 years age: Two doses of PCV13 administered 8 weeks apart, followed by the additional dose of PPSV23 should be administered at least 8 weeks after the last dose of PCV13

• 6-18 years age:

  1. The first dose of PCV13 should be followed by 8 weeks later a dose of PPSV23
  2. If patient had been administered PPSV23, PCV13 should be administered after 8 weeks later.

In the year 2014, ACIP recommended routine use of PCV13 among adults aged ≥65 years.[18] As per this recommendation, both PCV13 and PPV23 should be routinely administered in series to all adults aged ≥65 years. ACIP recommendations for use of PCV13 (high risk) in adults aged ≥19 years with immunocompromising conditions, functional or anatomic asplenia, cerebrospinal fluid leak, or cochlear implants remain unchanged. The ACIP recommendation was amended in 2015 to simplify the spacing between PCV13 and PPSV23 in adults >65 years.[19] The new recommendation states that the recommended interval for adults receiving PCV13 and PPV23 to be at least 1 year apart, regardless of sequence.

Influenza vaccination

Among the various flu vaccines, the injectable inactivated vaccine is safe in kidney transplant recipients whereas the nasal live attenuated vaccine is contraindicated in the immunocompromised.[20] If an ESRD patient received a live attenuated influenza vaccine, he/she should not be immunosuppressed preferably for the next 4-6 weeks, and at least for not <2 weeks.[20]

After kidney transplantation, routine annual inactivated influenza vaccine administration is recommended in all transplant recipients.[20,21,22,23,24,25,26,27,28,29,30] Immunogenicity of the influenza vaccine in kidney transplant recipients varies widely.[31,32] This variation could be attributed to the vaccine strain, the time after transplantation, the immunosuppressive regimen, as well as the net state of immunosuppression of the recipient.[1,31,33] For example, patients on MMF have a lower seroprotective rate.[31,32]

Concerns about influenza vaccine triggering an immune response and increase the risk of acute rejections[34,35] were not substantiated in large scale studies that demonstrated no increase in acute rejection episodes when influenza vaccine was used.[36,37] In large registry data, influenza vaccine use in transplant recipients was associated with lower rates of allograft loss and death.[27] However, use of adjuvanted Influenza vaccines has been shown to cause a rise in anti-HLA antibodies but not acute rejection episodes.[38,39] It is, therefore, advisable not to use adjuvanted influenza vaccines in kidney transplant recipients.[20]

Varicella vaccines

Being a live vaccine, this vaccine is contraindicated in kidney transplant recipients. It should be administered at least 4-6 weeks before kidney transplantation.[40] If transplant is emergently indicated in a patient who has received a varicella vaccine recently, he/she should receive peri-transplant prophylaxis with intravenous acyclovir or oral valacyclovir.[2] The Zoster vaccine, composed of a stronger dose of the live attenuated strain, is also contraindicated in kidney transplant recipients.[41]

Human papillomavirus vaccination

HPV vaccination should be completed prior to kidney transplantation. If the vaccination has been initiated pretransplant and could not be completed, additional doses could be administered after 3 months of kidney transplantation when the intensity of immunosuppression is less.[42] Serconversion after kidney transplant is around 50-70%. Unvaccinated kidney transplant recipients who satisfy the following criteria must receive HPV vaccination[43,44,45]

• 9-13 years age girls should be primary target of vaccination. Similar age boys could also be vaccinated

• Catch-up vaccination can be administered to those men and women between 11-26 years of age who have not been vaccinated previously.

The role of HPV vaccination among male and female kidney transplant recipients may expand in future.[46]

Hepatitis A vaccination

Hepatitis A vaccine is an inactivated subunit vaccine that can be administered in high-risk individuals or a potential to contract the viral infection from food, water, and body fluids of infected individuals. One study has shown reasonable seroprotective rates with the two-dose regimen among solid organ transplant recipient including kidney transplant recipients.[47]

Haemophilus influenzae vaccine

Pediatric transplant recipients are significantly susceptible to haemophilus influenza pneumonia. A study of the Haemophilus influenzae b (HiB) vaccine in adult kidney transplant recipients demonstrated 71% immunogenicity.[48]

Considering that splenectomized individuals and sickle cell disease (SCD) are at high risk of this infection,[45] it is reasonable to consider immunizing CKD patients with SCD and in those undergoing desensitization protocol or ABO incompatible transplantation.

In contrast, children should receive the vaccine as per routine schedule and the immunogenicity can be assessed by a follow up HiB antibody titer after 4 weeks of the vaccination.[2]

Meningococcal vaccine

Kidney transplant recipients at risk of developing meningococcal infection and those who undergo a desensitization protocol transplantation or ABO incompatible transplantation may be reasonably administered the vaccine.[2]

Tetanus vaccine

Among adults, immunization against tetanus with the inactivated tetanus toxoid vaccine should be kept updated. Following the general principles of immunization, adult kidney transplant recipients should undergo a similar updating of their vaccination status based on routine indications and recommendations as for adults.[2] The immunogenicity of tetanus vaccine and its safety in kidney transplant recipients have been supported by several studies.[39,40,41,42,43,44,45,46,47,48,49,50,51] Pediatric kidney transplant recipients should be vaccinated according to the regular pediatric schedule of immunization.[2]

Rabies vaccine

Rabies cell culture vaccines are safe in immunocompromised individuals, and kidney transplant recipients should receive rabies vaccine as per recommendations for general population.[2] Although kidney recipients can potentially acquire rabies from the organ donor through donation,[52,53] currently there is no evidence to recommend vaccination for all potential deceased donor kidney transplant wait-listed patients. While kidney transplant patients who have been bitten by a rabid dog must receive vaccination according to international guidelines, the protective effect may be inadequate[54] and it is prudent to monitor protective immunoglobulin levels and administer additional vaccine doses when indicated.[55,56]

Polio vaccine

Oral polio vaccine is contraindicated in kidney transplant recipients.[2] Pediatric transplant recipients below the age of 5 years should not participate in the pulse polio campaign to avoid oral polio vaccine strain induced poliomyelitis due to their immunocompromised state. Vaccine strain transmission has been documented from household contacts of immunocompromised individuals; therefore, household contacts of transplant recipients should also not receive oral polio vaccine.[57,58] Injectable inactive polio vaccine is safe and effective and pediatric kidney transplant recipients should be vaccinated according to the regular schedule of immunization for polio.[57]

Typhoid vaccine

Live oral typhoid vaccine Ty21a is contraindicated in transplant recipients and their household contacts.[4,59] Instead, killed Vi polysaccharide vaccine can be administered when indicated.[33] Typhoid vaccine is recommended as per routine indications in the country.

Cholera vaccine

Oral live cholera vaccine is contraindicated in kidney transplant recipients.[4,58] The new indigenous vaccine from India (VA 1.4) developed by the National Institute of Cholera and Enteric Diseases in Kolkata is a live oral vaccine that should not be used in transplant recipients.[60,61] The killed and subunit vaccine is considered safe in immunocompromised patients although its immunogenicity of the vaccine in transplant recipients in unclear.[62]

Yellow fever vaccine

The live attenuated Yellow fever vaccine is contraindicated in kidney transplant recipients.[2,4] Although a case series has suggested that there was no important side effects in that cohort of solid organ transplanted patients.[63] Travel to endemic regions is best avoided. If unavoidable, travelers should take precautionary measures and carry a letter from physician stating the contraindication to vaccination with the stamp of an approved yellow fever immunization center.[64] However, some countries may deny entry without immunization.85