Transplant recipients are at risk for infectious complications secondary to lifelong immunosuppression. Vaccine-preventable infections (including influenza, measles, mumps, varicella, pneumococcus, meningococcus, human papillomavirus, rotavirus, Haemophilus influenzae, herpes zoster, pertussis, Hepatitis A, and Hepatitis B) are known to cause morbidity, mortality, and increased hospitalization costs for transplant recipients.1,2 Recent studies have demonstrated that even though vaccine-preventable infections are a common and significant problem after pediatric solid-organ transplant,1,2 the majority of pediatric transplant recipients are not receiving all immunizations that could potentially prevent or lessen the severity of these illnesses.3 The goals of this article are to provide an update on vaccine-preventable infections, to give a concise review of pre and posttransplant immunization recommendations, and finally, to discuss current immunization controversies in the transplant population.
Current State of Vaccine-Preventable Infections
In the general population, vaccine-preventable infections are occurring at epidemic rates, putting immunosuppressed transplant recipients at significant risk. Internationally, the World Health Organization reports a 300% rise in measles cases globally so far in 2019 as compared with the same period last year, with cases reported from over 170 countries.4 Although measles was declared eliminated in the United States in 2000,5 from January 1 to July 3, 2019, the Centers for Disease Control and Prevention (CDC) reported 1109 cases of measles in 28 states, the highest number of cases in the United States since 1994 (Figure 1A and B).6 Outbreaks in the state of New York have continued for 8 months, the longest lasting outbreak since measles was declared eliminated from the United States in 2000.
Cases of mumps, pertussis, meningococcus, Hepatitis A, and human papiloma virus (HPV) are also occurring across the country. Although mumps cases have decreased by 99% with the introduction of the 2 dose measles, mumps, and rubella (MMR) vaccination program in 1989, since 2006 there has been an increase in cases and outbreaks approximately every 5 years. In the first 6 months of 2019, 44 states and the District of Columbia reported over 1400 cases of mumps7 (Figure 1C and D). Since the 1980s, there has been an increase in the number of reported cases of pertussis (whooping cough) each year, with a peak in 2012 of >48 000 cases.8 Hepatitis A outbreaks began in 2016, and since then, 29 states have reported >23 000 cases resulting in over 14 000 hospitalizations and over 200 deaths.9 HPV is so common that 14 million new people become infected each year, and HPV is responsible for over 33 700 cancers in the United States annually.10
Pediatric solid-organ transplant patients are at increased risk for vaccine-preventable infections due to lifelong immunosuppressive medications needed to prevent graft rejection. Nearly 1 in 6 pediatric transplant recipients (16%) is hospitalized with a vaccine-preventable infection in the first 5 years following transplant, and many more are treated for these infections in the outpatient setting.1,2 Compared with the annual rates of hospitalization in the general pediatric population, the rate of hospitalization in the pediatric solid-organ transplant population is 50 times higher for influenza, 6 times higher for respiratory syncytial virus, and 2 times higher for pneumococcus (Figure 2).2 Risk factors for being hospitalized with a vaccine-preventable infection posttransplant included age <2 at time of transplant and receiving a heart, lung, intestine, or multi-visceral transplant.1 This is consistent with the fact that children who receive transplants before their second birthday are less likely to have received a full set of immunizations by the time of transplant, and heart, lung, multi-visceral, and intestinal transplant recipients require higher levels of immunosuppression posttransplant to prevent graft rejection than liver and kidney recipients. Vaccine-preventable infections continue to be a significant hindrance to optimal outcomes posttransplant, resulting in significant morbidity, mortality, and increased costs. Transplant hospitalizations complicated by vaccine-preventable infections are longer (median 55 versus 16 days; P < 0.001) and are more expensive (median $268,626 versus $148,128; P < 0.001).1
In the past, transplant recipients were afforded some degree of protection from vaccine-preventable infections secondary to “herd immunity” in which immunization of a significant portion of the healthy population provides some degree of protection for those members of society who have not or cannot develop immunity.11 With rising rates of vaccine hesitancy (a delay in acceptance or refusal of vaccines despite vaccine services12) among the general population, herd immunity no longer effectively protects nonimmune individuals such as transplant recipients. According to data from the 2017 National Immunization Survey, the percentage of children in the United States <24 months of age who had received no vaccines at all had risen to 1.3%, up from 0.3% in the 2001 survey.13 Likewise, for the third year in a row, the CDC observed a rising rate of vaccine exemptions due to personal beliefs from school vaccination among children entering kindergarten.14 As of June 2019, 45 states and the District of Columbia granted religious exemptions for school immunization requirements and 15 states allowed for nonmedical exemptions due to philosophical or personal beliefs.15 In a study using information from the 2016 to 2017 school year, a significant inverse association was found between the rate of nonmedical exemptions and the rates of MMR vaccination. States that did not allow for nonmedical exemptions (California, Mississippi, and West Virginia) had the highest MMR vaccine uptake and the lowest incidence of vaccine-preventable infections.16 Also concerning is the fact that nonmedical vaccination exemptions are geographically clustered in certain regions of the United States, making these communities at risk for outbreaks of vaccine-preventable diseases that can then spread into the larger population.16-20
Pretransplant Immunization Recommendations and Controversies
The American Society of Transplantation and the Infectious Diseases Society of America have both published recommendations that “solid organ transplant candidates receive all age-appropriate vaccines based on the CDC’s annual schedule for immunocompetent persons.”21,22 Furthermore, the Infectious Diseases Society of America states that “solid-organ transplant candidates who are aged 6–11 months can receive the MMR vaccine and the varicella vaccine in an accelerated fashion (before their first birthday) if transplantation is not anticipated within 4 weeks”21 (Figure 3). Despite these recommendations for vaccination pretransplant, under-immunization remains a major problem in the transplant population with the majority of transplant recipients under-immunized for age-appropriate immunizations at the time of transplant. In a recent multicenter study of patients from 34 pediatric liver transplant centers across North America, <30% of transplant recipients were up-to-date on age-appropriate immunizations at the time of transplant. This study also demonstrated that published accelerated vaccine schedules allowing for early administration of live vaccines pretransplant are not being utilized. Of 52 children transplanted at 6–11 months of age and eligible for accelerated live vaccines, only 15% had received a varicella immunization and only 25% had received the MMR vaccine before transplant.3 Surprisingly, immunization rates in pediatric transplant recipients, who are at high risk for infection given life-long immunosuppression, were significantly lower than immunization rates in the overall general pediatric population.3
It is crucial for immunizations to occur pretransplant for several reasons. First, immunosuppression greatly increases the risk of vaccine-preventable infections, as detailed above. Second, vaccines are more immunogenic before immunosuppressive therapies are initiated posttransplant.23 Third, administration of vaccines pretransplant increases the immunogenicity of vaccines posttransplant.24,25 Finally, live vaccines are not routinely recommended posttransplant due to the risk of causing vaccine strain-related disease in an immunocompromised host (although there are certain centers that are allowing this in certain patients on low-dose immunosuppression).21 Consequently, administration of live-vaccines pretransplant is the only way to attempt to offer protection from acquiring measles, mumps, rubella, and varicella posttransplant.
With respect to liver transplantation, a counterargument to the administration of vaccines pretransplant relates to immune dysfunction in chronic liver diseases. In the setting of cirrhosis, immune dysfunction affecting multiple innate and adaptive immune pathways is known as the cirrhosis-associated immune dysfunction syndrome (CAIDS). Specific to vaccine responses, CAIDS entails defective antigen presentation functions of dendritic cells, macrophages, and B cells, with subsequent low level of activation of vaccine-related memory T cells and B cells.26 Therefore, the impaired humoral immunity (lack of protective antibody formation) and cellular immunity (lack of antigen-specific T cell memory responses) could result in low/negligible vaccine responses and may be seen as futile. Abundant literature pertaining to the immune response to Hepatitis B vaccination in the setting of CAIDS suggests that protective immunity is significantly diminished in cirrhosis. In a recent meta-analysis of 11 studies involving adults with CAIDS (n = 961), the seroprotective response rates to HBV averaged 38% with standard dosing and 53% with double dosing; far below the >90% seroprotection observed in healthy individuals.27 Limitations to this type of analysis include the fact that only the antibody response was measured and no data on the memory T cell responses that are just as important for adequate vaccine immunity were provided. In addition, the initial “hyporesponsiveness” to the vaccine may still be sufficient to educate a subset of memory T and B cells so that upon reexposure of the antigen through vaccination posttransplant, a robust seroprotective response is possible. Finally, data regarding the response rate to vaccinations in infants and children with CAIDS in unknown and should be an area for future research.
In the face of decreasing herd immunity and ongoing national and international measles outbreaks, several pertinent pretransplant questions arise. First, is a 4-week waiting interval truly necessary between administration of live vaccines and transplant? This waiting period of 4 weeks was chosen based on the latest time for developing skin lesions post vaccination, concern for a period of viral replication (viremia) and thought that several weeks were necessary to mount an immunologic response.21 However, there are few data to support this timing. In a study of 22 healthy children who received the vaccine, no varicella zoster virus was detected in the blood or oropharynx 3 days after immunization.28 Nevertheless, 75% of pediatric hepatologists report strict adherence to the 4-week waiting period and will not list a child for transplant until 4 weeks after administration of live vaccines.29 Further studies are necessary to understand if vaccine-strain virus truly remains in the body for 4 weeks, necessitating this waiting interval.
Second, what is the earliest age at which live vaccines can be administered with successful achievement of protection? In healthy children, live vaccines are not recommended until a child’s first birthday at which point maternal antibody has waned and a good immune response can be mounted. There are data, however, that children can mount adequate seroprotection even before the age of 1 year.30-36 In a recent Swiss cohort study of children before and after liver transplant, 5 subjects who were immunized with MMR before 9 months of age demonstrated seroprotection after transplant.36 As live vaccines administration before a child’s first birthday is not standard practice for primary care providers, targeted educational interventions about the safety and efficacy of acceleration in the pretransplant population may be a needed area for focused future intervention (Figure 3).
Most importantly, should age-appropriate immunizations be mandated for nonemergent transplant? We believe it is time for transplant organizations such as the United Network of Organ Sharing to institute universal national policies requiring immunization of all nonemergent transplant candidates.37 Vaccine mandates would uphold several clinical and ethical goals, including minimizing harm and increasing beneficence to the transplant recipient. Vaccine mandates would enhance herd immunity to protect the overall community, including other transplant recipients. Finally, vaccine mandates would ensure allocation of a scarce resource (ie, liver donation) to those recipients who have proactively maximized the health of their new organ by getting immunized pretransplant.
Posttransplant Immunization Recommendations and Controversies
After transplant, the Infectious Diseases Society of America recommends that “vaccination should be withheld from solid organ transplant recipients during intensified immunosuppression, including the first 2-month posttransplant period, because of likelihood of inadequate response.”21 They do specify that “inactive influenza vaccine can be administered ≥1 month after transplant during a community influenza outbreak.”21 However, there is wide practice variation about when to re-initiate age-appropriate immunizations posttransplant. In a survey of 73 pediatric hepatologists, 10% recommended giving inactive vaccines at 1-month posttransplant, 34% waited 2–5 months posttransplant, 22% waited at least 6 months, 22% specifically waited until the child was off all steroids, and 11% waited until the child was only on single-agent immunosuppression.29 For a child undergoing transplant during influenza season, 29% of hepatologists recommended influenza immunization before being discharged from the hospital, 14% recommended vaccination in the first outpatient visit, and 57% recommended waiting a minimum of 1 month posttransplant.29 Future research is needed to understand what time period and what level of immunosuppression allows for adequate immune-response to immunizations.
Likewise, there is no consensus on when and how to monitor seroprotection. Most licensed vaccines confer seroprotection by stimulating the patient’s B cells to produce pathogen-specific IgG antibodies. Other measures of effectiveness include cell culture studies of antibody-mediated cytotoxicity or vaccine antigen-induced T cell responses. A novel technique that is currently being researched entails next generation sequencing (NGS) of the antibody repertoire. NGS of the antibody repertoire after vaccination can provide a detailed assessment of the antigen-specific sequences and the breadth of the response; however, it remains to be determined if NGS of the antibody repertoire will stand alone as a cost-effective and accurate measure of vaccine immunogenicity.38 We know that immune protection likely wanes over time in normal individuals and even more so in patients on immunosuppressive medications.36 But how to monitor protection (antibodies, T cell function, etc) and then under what circumstances to administer a booster vaccine remain unclear. In the same study of immunization practices among pediatric transplant hepatologists, the majority of hepatologists rarely/never checked antibody titers for protection against hepatitis A, hepatitis B, pertussis, and pneumococcus posttransplant.
The most controversial posttransplant immunization decision is whether live vaccines can ever be safely administered posttransplant. Current recommendations state that live vaccines should generally not be administered posttransplant due to concern that (1) administration of live vaccines to an immunocompromised patient could result in life-threatening infection with the viral-strain pathogen and (2) immunosuppression could prevent development of a protective immune response.21 In the survey study of pediatric hepatologists, 74% reported that they never recommend live vaccines posttransplant.29 There is, however, strong anecdotal evidence and published studies that suggest that certain transplant recipients who are on minimal immunosuppression can safely and effectively receive live vaccines.36,39-42 In a recent prospective interventional cohort study of 44 pediatric liver transplant recipients who received live attenuated MMR vaccine after liver transplant, no serious adverse events were reported and seroprotection rates were high (98%) and similar to that seen in the healthy population.36 The study did show that 38% of patients lost protection within 1 year, and then responded to booster dose(s), demonstrating the importance of monitoring protection and administering boosters when needed posttransplant. In an era of epidemic measles outbreaks, it may be time to change official recommendations to encourage live vaccines to be administered to certain transplant recipients without evidence of immunity who are a year or more out from transplant, on low-dose immunosuppression, and with no recent episodes of rejection. Large multicenter studies are needed to help define specific levels of immunosuppression that allow transplant recipients to safely and effectively receive live vaccines posttransplant.
Finally, as increased numbers of solid organ transplant (SOT) recipients are traveling internationally; concerns arise about endemic infections and need for travel-related vaccination. Several studies have shown that many SOT recipients are insufficiently counseled, immunized, and prophylaxed before their travel, and as a result many become ill during their journey.43-45 Depending on the region of travel and recipient’s age, level of immunosuppression, and degree of immunity, additional travel vaccines may be needed against Hepatitis A, Hepatitis B, Salmonella typhi, polio (inactive only), meningococcus and Japanese encephalitis. Full recommendations for travel vaccines in SOT recipients can be found in the American Society of Transplantation's Infectious Diseases Community of Practice 2019 recommendations.46
In an era of national and international outbreaks of vaccine-preventable infections, it is time to prioritize immunizations as part of routine pre and posttransplant care. Across the general population, national legislation is needed to prevent or limit nonmedical exemptions for school immunizations. Among the transplant community, stronger national immunization polices are needed to encourage and require immunizations for nonacute liver failure transplant candidates. Hepatology and transplant outpatient clinic visits should be viewed as potential opportunities to provide needed immunizations. Specific consensus recommendations should be developed to outline for which patient live vaccines should be given posttransplant. Finally, future research is needed to understand how to optimally monitor vaccine-related immune responses and seroprotection in the transplant population.
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