The Covid-19 pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has a widespread impact on health, including a substantial mortality among older adults and patients with pre-existing health conditions [1]. Solid organ transplant recipients are considered a group at increased risk: although not associated with a higher infection rate, maybe due to high adherence to self-care measures preliminary data suggest an increased risk of severe disease and death in case of infection [2‐5].

Vaccination has emerged as a key tool for controlling the pandemic health crisis by preventing severe disease and mortality and by increasing population immunity.

Four vaccines have been approved by the European Medicines Agency (EMA) on base of the phase 3 clinical efficacy studies showing good safety and immunogenicity [6‐9] However, immunocompromised patients have been excluded from these studies.

In spite of lacking data about the novel concept of mRNA vaccines in organ transplant recipients, national and international transplant societies have recommended earliest possible vaccination for all recipients > 3–6 months post-transplant (unless recently treated with lymphocyte-depleting agents) and national vaccination strategies have suggested prioritized treatment for this potentially vulnerable group [10‐12].

The immune response to other types of vaccines have been shown to be blunted in immunosuppressed patients [13, 14].

To gain more insights in the immunogenicity of mRNA vaccines under immunosuppressive therapy, we analysed the antibody as well as the T-cell response after the first and second dose of the BNT162b2 vaccination in cardiothoracic organ transplant recipients.

This study demonstrates a lack of immunogenicity of the completed prime-boost vaccination with the mRNA SARS-CoV-2 vaccine BNT162b2 in cardiothoracic transplant recipients even 3 weeks after the second dose, strongly suggesting that immunosuppressed cardiothoracic organ transplant recipients are left immunologically unprotected against COVID-19 infection.

Reduced immune responses to conventional vaccination concepts following organ transplantation [13, 14] or in general, for patients under immunosuppressive therapy [17] have been reported before. However, the extent of missing humoral and cellular immune response following vaccination appears unexpected.

First insights into the immunogenicity of the BNT162b2 vaccine in an immunocompromised patient population have been reported as interim results from the SOAP-trial on cancer patients: the immune response following the prime dose was low in solid cancer patients (< 40%) and very low in haematological cancer patients (< 15%). However, in their population efficacy was greatly increased by boosting after 21 days [18].

There have been recent reports on poor anti-spike (S) antibody responses to mRNA vaccines in renal [19] and liver [20] transplant patients as well as in a mixed cohort of single organ transplant recipients [21] all of which had included patients over a wide range of years post-transplant, with reported semiquantitative serologic testing only. We present more detailed data on B-cell as well as specific T-cell responses in an uniform group of thoracic organ transplant recipients, all in their 2nd–3rd year post-transplant.

In our study, all participants have completed a full two-dose vaccination regimen, the doses being exactly 21 days apart: it demonstrates no seroconversion following the completed two-dose vaccination strategy in the vast majority (90%) of tested cardiothoracic organ recipients. These results contrast with the robust immunogenicity in the control group, who already exhibited a 98% seroconversion following the prime dose (although with a wide scatter of antibody titres), followed uniformly by a significant, on average > tenfold increase of IgG as well as neutralizing antibodies after the boosting.

In contrast to the healthy control group, evidence for a specific T-cell response (as determined by IFN-γ release of whole blood stimulated by spike antigens SARS-CoV-2 peptides) was also lacking in the majority of transplant recipients. However, in a subgroup of transplant recipients—with no detectable humoral response—a small IFN-γ release could be observed. Although cross-reactivity with a former Corona Virus-infection cannot be ruled out as a possible explanation [16], it might give evidence for a weak specific T-cell response in this subgroup of patients. The detection of specific T-cell responses in individuals lacking detectable circulation antibodies has also been described in convalescents after asymptomatic to mild COVID-19 infections [22]. The authors conclude that seroprevalence as an indicator may underestimate the extent of adaptive immune responses against SARS-CoV-2. The importance to combine analysis of B- and T-cell immunity has been emphasized elsewhere [23, 24]. In spite of growing insights into the persistence and decay of antibody responses both following infection [25] and vaccination, [9, 26] we do not yet know the exact correlates of immunity neither regarding the levels of required antibody titres nor whether suboptimal B-cell responses combined with T-cell responses might still protect from severe COVD-19.

Considering the time-dependent and distinct immunosuppressive regimens after single organ transplantation, it seems obvious that doses and composition of different immunosuppressive strategies may impact on the immunogenicity after mRNA vaccination against SARS-CoV-2.

Our findings focussed on cardiothoracic patients in their first three years post-transplant, most of them being on triple immunosuppressive therapy including a calcineurin inhibitor, mycophenolate-mofetil as well as corticosteroids. The relative high-maintenance immunosuppression might explain why our finding of poor humoral response was even more pronounced than recent reports by others: in a small group of 23 renal patients, the five patients with (low) detectable antibodies were on average 18 years post-transplant [19]; in a cohort of 80 liver transplants (median of 5 years post-transplant, 47% with (low-titre) detectable antibodies) maintenance immunosuppression was lower compared to our study group, with anti-metabolite agents included in only 50% of patients, and only 21% of patients being on triple immunosuppressive therapy [20]. In a larger mixed cohort of solid organ transplant recipients poor humoral response was associated with older age, cardiothoracic transplant organ, first years post-transplant, maintenance immunosuppression regime including anti-metabolites [21]—all factors holding true for our study population.

Larger scale analyses have to elucidate whether long-term thoracic organ transplant recipients under lowered maintenance immunosuppression may confer better vaccination effects. Future studies will also have to focus on age per se. In fact, we observed mild antibody responses to BNT162b2 in younger transplant recipients.

Our sobering results on the poor response to the mRNA BNT162b2 vaccine in transplant recipients prompt further questions on dosing of the vaccine. The preliminary data by Boharsky et al. suggest that the mRNA-1273 SARS-CoV-2 vaccine by Moderna with a higher concentration per dose may confer immune responses in a larger percentage of transplants [21], but this certainly needs deeper investigation.

To gain adequate protection against other potentially threatening infections augmenting vaccination strategies such as higher doses per vial or additional boosting have been suggested for transplant recipients before [13, 27, 28]./ Considering the beneficial data on safety and adverse local and systemic events of the BNT162B2 vaccine in immunocompromised cancer [18] and transplant [29] patients, additional booster dose(s) could be considered, at least in those transplant patients showing at least some detectable B- or T-Cell-response to the first two doses. Of course, additional information on the effectiveness of other COVID-19 vaccines, e.g. vector-based vaccines, is needed.

In summary, given the globally poor antibody- and T-cell response of our transplant patients to a completed two-dose regimen with the mRNA BNT162b2 vaccine our findings mandate an urgent review of vaccination strategies for organ transplant recipients. As there may be relevant differences in immune responses among immunosuppressed patients depending on age, time since transplant, immunosuppressive regimen etc., post-vaccination testing for both, B- and T-cell responses is advisable for best medical care.

As long as transplant recipients are left unprotected, adherence to all public health measures in place, such as social distancing and shielding even after vaccination is mandatory. Creating herd immunity around these patients using a strategy of “ring vaccination” should be an additional safety measure.