To the best of our knowledge, this is the first systematic review of the literature on vaccination response of currently licensed vaccines in SOT recipients.
The most important finding is that most clinical trials conducted and published over more than 30 years have all been small and highly heterogeneous regarding trial design, patient cohorts selected, patient inclusion criteria, dosing and vaccination schemes, follow up periods and outcomes assessed. The evidence base for vaccination recommendations for SOT recipients thus remains poor.
Our review had two main strengths: The systematic strategy and broad search terms used to identify studies in a wide range of databases and the rigorous methods used to extract and appraise the data. The main limitation of this review was the need to rely on studies that were largely observational. The potential for confounding and bias should therefore be considered when interpreting the results and the observed level of heterogeneity of the results.
The second most important finding is that the individual vaccines investigated have been studied predominately only in one group of SOT recipients, i.e. tetanus, diphtheria and polio in RTX recipients, hepatitis A exclusively in adult LTX recipients and mumps, measles and rubella in paediatric LTX recipients. There is a clear need to investigate all recommended vaccines across all SOT types. There is increasing concern about high individual and SOT-dependant variation in the response to immunosuppressive drugs in both paediatric and adult SOT recipients 
Most trials in SOT recipients included in this review have evaluated influenza vaccines. Variability of the response was very high and ranged from 0–100% in SOT recipients with corresponding high values of I-squared (all larger than 92%). Among other reasons (such as studies conducted over more than 30 years) the varying seasonal composition of influenza vaccines may play a role and makes comparisons between trials difficult. When comparing response rates of SOT recipients with controls, several studies showed a clear trend to a less pronounced response in SOT recipients with overall a 10% to 16% lower response rate in SOT recipients. The difference in response to control patients was in renal and lung transplant recipients somewhat less pronounced than in the other SOT groups. In some studies, however, the response rate in SOT recipients was even higher than in controls, which might reflect the play of chance or the fact that in some of these studies different vaccination schemes were used in the two groups (i.e. double dose for SOT recipients and single dose for controls) or highly differing pre-transplant antibody levels (higher in SOT recipients than in controls). Almost all trials, however, observed a measurable vaccine response at least in a subset of SOT recipients after single dose vaccination with a trend to lower response rates in SOT recipients compared to healthy controls in most of the trials, which is encouraging and is in accordance with findings from other authors 
. In contrast to other vaccinations, influenza vaccination is recommended annually to protect against the predicted seasonal strains; rapid decline of antibodies is, therefore, of marginal relevance. Given the susceptibility, morbidity and mortality associated with influenza infections in SOT recipients and the positive response found in most influenza vaccine trials, recommending annual influenza vaccination is encouraged by our review of published clinical trials. The benefit for accelerated vaccination schemes or multi dose vaccination to increase protection cannot be decided on the basis of available data.
Good evidence and encouraging results were found for vaccinating SOT recipients against tetanus, diphtheria and polio. Vaccination with tetanus toxoid in the post-transplant period elicits a high rate of responders in SOT recipients with conventional immunosuppression with no significant difference to healthy controls (p
0.96 on only two studies) while immunosuppression with anti-CD20
monoclonal antibody showed a decreased response rate compared to conventional immunosuppressive medication (p
0.043 in meta-regression). All studies with diphtheria vaccination in the post-transplant phase show comparable high response rates (I-squared
0%). From the data reviewed serological response to tetanus appears to be longer lasting than to diphtheria vaccination. Long-term response for tetanus showed persistence of antibodies without relevant decrease while the response for diphtheria had a 17% (95% CI: 7%–27%) decline over time in SOT recipients.
Response to polio vaccination also seems to be elicitable in SOT recipients, even though only one trial has investigated this vaccine. However, as polio eradication suffers from backlashes and international travel of SOT recipients is increasing, polio vaccination in SOT recipients is important and deserves further exploration.
Vaccination trials for viral hepatitis A and B have largely been conducted in LTX recipients and results can only be extrapolated to other SOT types with great care. Results for HAV vaccination show a high degree of heterogeneity (I-squared
97.7%), while one study shows high response rates for both RTX and LTX, others did not confirm this finding. Response rate to HBV after transplantation in adult SOT recipients is poor while in paediatric SOT recipients a 58% (95 CI: 37%–80%) higher response rate was seen (p
0.001 from meta-regression). The results of primary vaccination after SOT are disappointing as early response rates were low in almost all trials and long-term responses have not been assessed on a large scale. In one study, however, long-term response was assessed and antibodies for HAV were declining rapidly. The response for hepatitis A had a 41% (95% CI: 26%–57%) decline over time in SOT recipients.
In the light of this finding, the importance of hepatitis A and B vaccination prior to transplantation should be markedly stressed in pre-transplant assessment and counselling. The immunogenicity of both vaccines needs to be extended beyond LTX and should be evaluated in recipients of organs other than liver.
Vaccination against bacterial pathogens is of great importance for immunosuppressed recipients. Response rate in all Streptococcus pneumoniae
studies was above 50% with a summary estimate of 83% (95% CI: 83%–93%) with substantial heterogeneity (I-squared
81%), for Haemophilus influenzae vaccines (Hib)
a response rate above 50% in SOT recipients in both studies was observed as well as for Neisseria meningitides
Assessment of the response to pneumococcal vaccines is difficult due to the large numbers of serotypes included in the vaccines (conjugate vaccine with 7 serotypes and polysaccharide vaccine with 23 serotypes) and the unclear impact of the seroresponse measured on protection. The response rate assessed here might be overestimated as we accepted the serological response to a single antigen as positive response. However, even in healthy children and adults, vaccine-, serotype-, and population-specific differences in immune response is not readily understood 
. Most guidelines, nevertheless, recommend pneumococcal vaccines for SOT recipients. From current data it cannot be assessed if conjugate pneumococcal vaccines are superior to polysaccharide vaccines in SOT recipients.
Vaccines for protection of travel-related infections in SOT recipients have, with very few exceptions, not been studied so far. Due to increasing quality of life, SOT recipient are willing to travel and a thorough assessment of their vaccination status is therefore necessary 
. Also, it is important to note that some of these infections are highly endemic or epidemic in countries where SOTs are now also regularly performed. Rabies is an example. We could identify only a single and very small trial on rabies post-exposure prophylaxis. The summary response rate estimate seen in these nine SOT recipients was 89% (95% CI: 52%–100%). These results are encouraging for rabies vaccination in SOP recipients. From a global point of view research in this area is warranted.
Vaccination of SOT recipients with live-attenuated viral vaccines remains controversial and is clinical studies are currently limited to paediatric SOT recipients 
. Generally, live vaccines are contraindicated in immunocompromised recipients as there is a risk of vaccine-virus replication. As all other trials identified in our review, the trials investigating live vaccines are also underpowered to assess severe adverse events (SAEs) with appropriate accuracy. For live-attenuated varicella vaccination acceptable response rates were observed in all studies with an overall estimate of 73% (95% CI: 64%–83%) with little heterogeneity (I-squared
0%) in SOT recipients after post-transplantation vaccination are seen. For mumps, measles and rubella positive response rates were above 70% in all but one study conducted in 1993, resulting in a summary estimate of 85% (95% CI: 72%–99%) with substantial heterogeneity (I-squared
76%). Omitting the 1993 study reduced heterogeneity substantially (I-squared
36%). In terms of vaccination response, the trials presented here show encouraging results at least for paediatric recipients. The trials so far performed were very small, however, and do not allow to assess the risk-benefit ratio of vaccination vs. infections for e.g. measles or varicella. The underpowerment is a problem to accurately assess vaccine-related SAEs in SOT recipients in all trials conducted so far. On theoretical grounds the risk of SAE is expected to be less in inactivated compared to live-attenuated vaccines. On the basis of currently available evidence application of live vaccines should remain limited to carefully monitored trials until more data on safety are available. Instead, indirect protection of SOT recipients by vaccination of household contacts is stressed by all authors.
Vaccination aims for long-term protection after initial immunization. To which extent this can be achieved in SOT recipients is unclear. Only few studies assessed a long-term response after ≥12 months. Long-term response for tetanus showed persistence of antibodies without relevant decrease while response for diphtheria had a 17% (95% CI: 7%–27%) and the one for hepatitis A 41% (95% CI: 26%–57%) decline over time in SOT recipients. Based on this limited number of studies that assessed both short- and long-term response to vaccinations no recommendation on adaptation of general recommendations for booster intervals for SOT recipients can be given.
Limitations of our review are that, despite the use of systematic search strategies, some trials may have been missed, particularly since the search was limited to trials published in English. We did not assess the quality of the trials. All trials included in this review were, however, published in peer-reviewed journals. Only publications in which essential key data were missing were excluded. Since we did not restrict our search to a specific publication period, older trials using out-dated immunosuppressive regimens, which are no longer relevant, may have been included. We are aware that the type of immunosuppressive treatment impacts on the vaccine response. Stratification by type of immunosuppressive treatment would have, however, further fragmented the presentation of available data with the result of even smaller numbers per stratum. Equally, we did not exclude trials on the basis of the time period between SOT and vaccination despite the fact that the first 6 months after transplantation is regarded as the period during which immunosuppression is highest.
Additional potential sources of heterogeneity in positive response to vaccination were substantial loss to follow-up and often unknown and possibly varying levels of pre-transplant immunity to the infections covered in the respective vaccines. An unknown vaccination status of a SOT recipient represents, however, a situation frequently seen in clinical practice and requires a pragmatic approach.
With these caveats in mind, we believe that this review comprehensively presents the current knowledge on vaccination response in SOT recipients.
Vaccine-based prevention of infectious diseases is far from satisfactorily in solid organ transplant recipients. Despite the large number of vaccination trials preformed over the past decades, knowledge on vaccination response after SOT is still limited. Even though the protection, which can be achieved in SOT recipients through vaccination, appears encouraging on the basis of available data, current vaccination guidelines and recommendations for post-SOT recipients remain poorly supported by evidence. There is an urgent need to conduct appropriately powered vaccination trials with relevant endpoints in well-defined SOT recipient cohorts, as well as to increase the awareness of clinicians for timely pre-transplant vaccination.