A Review of Humoral and Cellular Immune Responses to SARS-CoV-2 Vaccination Following Solid Organ Transplantation

Background

The first year of the COVID-19 pandemic resulted in a sharp decrease in the number of transplantations performed, both from deceased and living consenting donors. When comparing the number of transplantations carried out in the world year-on-year, the year 2020 saw a 17.5% decrease in the number of transplantations. This mostly involved kidney transplants (KTx) (decreased by 20.9%), pancreas transplants (decreased by 16.2%), lung transplants (decreased by 12.7%), liver transplants (LTx) (decreased by 11.3%), and heart transplants (decreased by 8%) [1]. In the United States, this resulted in an increase in patient mortality of up to 170% in patients awaiting transplantation, especially of the kidneys and lungs [2,3]. In Spain, the world leader in organ transplantation, the daily number of organ donations in the pandemic decreased from 7.2 to 1.2, and the number of transplantations performed decreased from 16.1 to 2.1 [4]. In Poland, in the beginning of the pandemic, the number of potential organ donors decreased by 43%, which resulted in a 60% reduction in the number of kidney and liver transplants performed [5]. The substantial decline in the number of transplantations was due to several factors. Firstly, there was concern about the life and health of patients from transplant waiting lists, as well as organ and bone marrow recipients, when exposed to SARS-CoV-2 infection. Transplantation centers in many countries recorded high mortality rates (up to 30%) caused by COVID-19 in this group of patients [6–11]. Secondly, limited access to intensive care units, where transplant patients would stay postoperatively and organ donors would be hospitalized. Moreover, for logistical reasons, constant testing for COVID-19 of both recipients and donors to monitor their infectious status was much more difficult [4,12–14]. To counter these very unfavorable tendencies, international transplant societies and transplantation centers developed guidelines to enable the continuation of organ transplantation. These activities, along with vaccinations against COVID-19 that began at the end of 2020, and gradually improved the situation [13–21]. The currently approved SARS-CoV-2 vaccines are BNT162b2 (Pfizer BioNTech) and mRNA-1273 (Moderna) containing mRNA encoding the S-glycoprotein (spike) of the virus [22,23] and 2 vector vaccines (ChAdOx1 nCoV-19 vaccine (AZD122) AstraZeneca and Ad26.COV2.S Janssen) containing replication-defective adenovirus (vector) with an integrated fragment of SARS-CoV-2 genetic material encoding the S-glycoprotein [24,25]. Although transplant recipients can safely receive any type of inactivated anti-SARS-CoV-2 vaccine, mRNA preparations are preferred for vaccination against COVID-19 in people with severe or moderate immunodeficiency [26]. Introduced at in 2021, COVID-19 mRNA vaccines BNT162b2 (Pfizer BioNTech) and mRNA-1273 (Moderna) offer 90–100% humoral and cellular immunity, preventing the acute form of the disease [22,23]. However, this does not apply to immunocompromised patients, including transplant recipients on immunosuppression. Therefore, this review aims to provide an update on the humoral and cellular immune responses to SARS-CoV-2 vaccination following solid organ transplantation.

Vaccinations in Solid Organ Transplant Recipients

In 2 consecutive papers published in March and May 2021 in JAMA, Boyarsky demonstrated that on day 20 after the first dose of COVID-19 vaccination, antibodies were found in 17% of the examined transplant recipients, and on day 29 after the second dose of vaccination, antibodies were present in 54% of transplant recipients (48% of kidney transplants, 80% of liver transplants, 56% of heart transplants, 39% of lung transplants, and 20% of pancreas transplants). Thus, 46% of transplant recipients did not produce antibodies after 2 doses of mRNA vaccines [27,28]. Other researchers have also confirmed a worse response to vaccination in transplant patients, both in terms of humoral and cellular response. Immune response to 2 doses of vaccination was insufficient [21,29–32]; no immunity to infection was found in more than 40% of transplant recipients [21,29–32], especially in patients over 60 years of age, in whom the humoral response was only in 4.8% of the study participants [31]. In a study by Hall, involving 127 examined transplant patients, antibodies were found only in 5% of patients after the first dose and in 34.5% of patients after the second dose of mRNA-1273 (28.5% of kidney transplants, 72.7% of liver transplants, 12.5% of heart transplants, 41.4% of lung transplants, and 38.9% of pancreas with kidney transplants). Cellular response was found in 47.9% of patients [32]. In the author’s opinion, it may be the case that despite receiving 2 doses of vaccination, a significant proportion of transplant recipients will not produce a level of antibodies sufficient to protect themselves against infection, and in this group of patients an alternative treatment should be considered [32].

Vaccinations in Patients Awaiting Transplantation

A reduced response rate to vaccination was observed not only in organ recipients but also in patients awaiting transplantation: those receiving dialysis for renal failure and those with cirrhosis [33–36]. The dialysis patients and cirrhotic patients had a much weaker response to vaccination compared to the healthy general population, but better than those after KTx and LTx. As Crespo et al reported, positive response was obtained in 96.6% of healthy patients, 89.3% of patients on peritoneal dialysis, 77.6% of patients on haemodialysis, and 61.3% of KTx patients. The combined humoral and cellular immune response was 100% in healthy patients, 95.4% in dialysis patients, and 78.8% in kidney transplant patients [34]. As Bertrand noted, SARS-CoV-2 vaccination is more efficient in patients on dialysis therapy than KTx recipients, indicating that vaccination should be first recommended for those registered on a waiting list for kidney transplant [37]. In yet another study, a similarly positive response was found among patients awaiting liver transplant: 100% for healthy patients, 65.4% for cirrhotic patients, and 36.6% for LTx patients [33]. Thuluvath and colleagues found that 24% of those with chronic liver diseases had undetectable or suboptimal antibody responses, and 61.3% of liver transplant recipients had a poor response. Antibody levels were completely undetectable in 17.8% of liver transplant recipients, in 3.8% of those with cirrhosis, and in 4.3% of those with chronic liver diseases without cirrhosis [38] (Table 1).

The humoral immune response after 2 doses of the COVID-19 vaccine in 30–50% of KTx patients and 80–95% of dialysis patients was insufficient [28,33,39], and, according to French authors, it is an indication for the administration of a third dose of the vaccine [36]. De Belo presented the results of a study on 396 transplant patients in whom the administration of the third dose increased the humoral response rate from 46.3% to 67.9%. In addition, in more than 40% of patients in whom there was no seroconversion despite the second dose, the third dose resulted in a humoral response [40]. Numerous authors have reported an improvement in the humoral response in organ recipients after the third dose of the vaccine [41–45], but it was also reported to be ineffective by others [32,33,46]. In view of this, Hall’s proposal of alternative treatment in patients without established seroconversion, despite vaccination, may be legitimate [32]. Possibly, the introduction of the fourth and fifth doses of vaccination in these patients might also be a solution [47,48].

Factors Influencing Response to Vaccination

STATUS POST-COVID-19 INFECTION:

It has been observed that after the first dose of the vaccine, post-transplant patients who recovered from COVID-19 had antibody levels similar to the healthy, immunocompetent population [31,49–51]. This pattern was noted in both renal and hepatic transplant patients as well as in dialysis patients awaiting transplantation [31,49–52]. The humoral immune response was better in patients after a full-blown symptomatic course of infection and was found in 68.4% of patients, whereas seropositive results after a mild or asymptomatic course of infection were found in 9.4% and 4.6% of patients, respectively [31]. Despite the increase in immunity among organ recipients who recovered from COVID-19, most researchers agree that for the level of humoral response to be sufficient, 2 doses of the SARS-CoV-2 vaccine are required [49–51].

TYPE OF VACCINE USED AND PATIENT AGE:

The available recommended COVID-19 vaccines – BNT162b2 (Pfizer BioNTech) and mRNA-1273 (Moderna) – are highly effective in preventing acute course of the disease [22,23]. Nevertheless, more recent studies of a healthy population have revealed a slightly higher effectiveness of the Moderna vaccine [53,54]. Similar results have been obtained in a study of lung transplant patients, in whom the humoral response after 2 doses of vaccination was slightly higher after the use of mRNA-1273 compared to the BNT162b2 vaccine [55]. The serological response to vaccination is also related to patient age. When examining a group of healthcare workers vaccinated with 2 doses, Richards found significantly lower levels of antibodies in people over 50 years of age than in the younger group after use of the mRNA-1273 and BNT162b2 vaccines [56]. A similar pattern was observed after vaccination of kidney, liver, and other organ recipients [31,32,46,57].

TYPE OF ORGAN TRANSPLANT AND IMMUNOSUPPRESSION USED:

It is believed that the liver is more immunologically privileged than other organs, thus it requires slightly less immunosuppression and develops a better response to vaccination. Herrera reported cellular and humoral responses in 90% of 56 liver transplant recipients who received 2 doses of the Moderna vaccine [58]. In a study by Nazaruk, humoral response was found in 88.9% of 61 LTx patients vaccinated with 2 doses of the Pfizer vaccine [57]. However, in a study by Ruether and Rabbinowich on the effect of vaccination in LTx patients, a humoral response was found only in 36.6% and 47.5% of cases, respectively [33,59]. According to most researchers, recipients of other organs, especially the kidneys and lungs, develop a weaker response to vaccination. Humoral response does not usually exceed 30–60% in KTx patients [29,34,36,57] and 25% in lung transplant patients [55]. Although research points to a lower effectiveness of vaccination in kidney and lung recipients [29,31,34,36,55], it is known that vaccination effectiveness depends on a variety of factors. In addition to older patient age [31–33,46,57], research shows the importance of other pathologies reducing vaccine effectiveness of vaccines in patients with hypogammaglobulinemia [58], abnormal function of the transplanted organ [45], a white blood cell count lower than 1500 cells [46], diabetes, antithymocytic globulin treatment in the year preceding vaccination [60], and hypertension [33]. The vast majority of researchers claim that the use of immunosuppressants has had the greatest impact on the recorded vaccination failure. Mycophenolate mofetil [45,46,61] and belatacept [46,61] significantly reduce the serological response to vaccination. The latter, when used after kidney transplantation, reduces response to vaccination to 5%, while in kidney recipients who were not administered this medication, the response was as high as 50% [36,46,62]. In addition, vaccination in the first year after transplantation [58], administration of high doses in triple immunosuppressive regimens [46,63], or administration of steroids [61] significantly reduce the serological response to vaccination. There have been attempts to modify immunosuppression, mainly through discontinuation of mycophenolate mofetil, in those organ recipients in whom due to the lack of response to the third dose of the vaccine, the administration of a fourth or even fifth dose is considered [47,48]. Netti reported a positive effect, improving the humoral and cellular response, of m-Tor inhibitors used in immunosuppression in kidney recipients [64].

POST-VACCINATION ADVERSE EVENTS:

There is no information available on severe post-COVID-19 vaccination-associated complications in transplant patients [40,44,46,47,58,60,61,65,66]. There have been no cases of the presence of donor-specific antibodies (DSA) that could damage the transplanted organ [58,60,67,68]. In a literature review on the efficacy and safety of the administration of the third dose of the vaccine based on data from 835 organ recipients, Efros did not report any cases of anaphylactic shock or other life-threatening complications. Typical adverse effects were mild or moderate pain at the injection site, headache, and short-term general weakness. In 1 case, mild rejection symptoms, not requiring intensification of immunosuppression, were observed on day 7 after the third dose of vaccine. According to the researchers, the relationship between this incident and vaccination is only hypothetical [44,46].

It is widely known that patient immunity after the second dose of vaccine is insufficient [28,33,39]; hence, the introduction of the third dose, also not always effective [32,33,46]. In view of this, Hall’s proposal of alternative treatment in patients without established seroconversion, despite vaccination, may be legitimate [32]. Possibly, the introduction of the fourth and fifth doses of vaccine in these patients might also be a solution [47,48].

Conclusions

The aim of the above is to review the available literature on the impact of the SARS-CoV-2 pandemic on organ transplantation worldwide. The introduction of vaccines preventing a severe course of COVID-19 is particularly important in immunocompromised patients, among whom organ recipients and patients awaiting transplantation constitute a large group. The fact that there appeared so many scientific papers based on post-transplant research in such a short period of time contributed to transplantation safety. However, the suboptimal response to vaccinations in this group of patients is a major challenge for both doctors and the patients themselves. Further prospective studies assessing the response to vaccination, antibodies levels, or COVID-19 incidence despite vaccination will certainly bring new data and provide answers to many questions.