Several recent studies have reported that solid organ transplant (SOT) recipients have poor humoral responses to mRNA-based severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination.1-6 Several conclusions regarding vaccine responses in transplant recipients can be drawn from the existing literature. First, diminished responses should be anticipated from a single mRNA vaccine dose compared with those elicited in healthy controls; a potential exception being in patients with prior SARS-CoV-2 infection (although such data currently do not exist). Second, the absence or reduction in SARS-CoV-2 antibody responses in transplant recipients is associated with patient age or treatment with specific categories of immunosuppressants.1,3,6 Third, only 37%–59% of transplant recipients generate antispike Ab responses following their second vaccination with an mRNA vaccine.3,5,6 Of note, a recent study described especially concerning results in belatacept-treated patients following SARS-CoV-2 vaccination. Specifically, only 5% of patients developed antibody responses.7 Collectively, these data underscore that SOT recipients are a heterogeneous group of subjects whose immunologic risk, age, length of time posttransplant, and type of organ transplanted impact the intensity and type of immunosuppression they receive. Furthermore, alternative approaches to achieve vigorous antibody responses to SARS-CoV-2 vaccination need to be explored for this patient population. Possibilities include (1) additional vaccine doses beyond the standard 2-dose regimen, (2) increased vaccine dosage, (3) combinations of differing vaccine platforms (eg, mRNA, adenoviral-based, protein-based) in individual patients with/without additional adjuvants, (4) sequence optimization if multivaccine approaches are applied, (5) temporary dose reduction of selected immunosuppressants para-vaccination and 7–10 d postvaccination (acknowledging that such an approach would increase the risk of graft rejection), and (6) potential adjustment to long-term immunosuppressive therapy. Clinical trials to rigorously test these and other strategies to enhance immune responses to SARS-CoV-2 vaccination should be rapidly designed and initiated.
It is not particularly surprising that belatacept strongly inhibits SARS-CoV-2 antibody responses given the importance of the germinal center to humoral immunity. Mechanistically, belatacept disrupts germinal centers due to blockade of CD28:B7 interactions critical to T follicular helper/dendritic cell and B-cell interactions,8 thereby inhibiting humoral responses to COVID-19 vaccines. One potential strategy would be to convert patients to bi-monthly belatacept dosing9 and vaccinate 2 weeks before the next dose. Because recent evidence also indicates that antiproliferative agents such as mycophenolate mofetil (MMF) reduce antibody responses to SARS-CoV-2 vaccines,6 another alternative would be to discontinue belatacept or MMF and maintain patients on a calcineurin inhibitor until an adequate vaccine response was achieved. The collective experiences with belatacept and MMF are instructive to develop temporary immunosuppression reduction strategies designed to enhance immune responses to SARS-CoV-2 vaccination. Controlled trials with careful immune monitoring are clearly needed to determine the optimal vaccination strategies in our patient population.
It is critical that treating physicians know which SARS-CoV-2 vaccine a patient receives as well as the relative strengths and weaknesses of the various SARS-CoV-2 antibody tests. Currently, the US Food and Drug Administration has approved >50 SARS-CoV-2 antibody detection assays under emergency use authorization.10 These tests differ in platform, specificity, sensitivity, predictive value (positive and negative), immunoglobulin isotype, the targeted antigens, and detection of neutralizing antibodies. Moreover, most tests are qualitative rather than quantitative and limited to a single target antigen. Each of these factors must be considered when interpreting antibody testing data. As an example, the antibody tests used by Boyarsky and colleagues were ELISA-based and limited to immunoglobulin G directed against either the spike S1 or receptor-binding domain epitopes; the study did not assess antibodies directed against the SARS-CoV-2 nucleocapsid, which could have only resulted from a natural infection.1,6 In contrast, the study by Grupper et al5 excluded any participants with antibodies directed against the SARS-CoV-2 nucleocapsid and used a chemiluminescent assay for immunoglobulin G anti-SARS-CoV-2 S1/S2, which provided semiquantitative assessment rather than only a positive/negative result.5 Responses to the native (trimeric) form of the spike protein were not assessed in either of those studies. Multiplex assays that simultaneously evaluate multiple targets provide additional data that may be more informative.11 For example, by evaluating antibody responses to multiple viral proteins, different patterns of responsiveness may categorize patients with differing clinical presentations. Furthermore, multiplexed assays can be readily expanded to incorporate variant forms of the spike protein found in mutant strains of SARS-CoV-2, thereby addressing whether antispike protein antibodies to native virus crossreact with spike protein mutants.
The durability of immune responses to SARS-CoV-2 remains an unstudied issue for SOT recipients as well as larger populations of immunosuppressed patients including those with autoimmune disease and cancer. In immunocompetent subjects, some studies report that antibody responses to natural SARS-CoV-2 infection have shortened half-lives,12,13 although others indicate that antispike antibodies persist up to at least 8 mo postinfection.14 Protective antibody responses have been detected at least 6 mo after vaccination with mRNA-1273 vaccination.15 It would not be surprising to find that humoral immunity is less durable in the posttransplant setting. Depending on emerging details of antibody durability, routine testing for stability of antibody responses may become an important component for long-term patient management or timing of booster inoculations, particularly among patients with diminished immune function.
As with many vaccines, clinical studies have focused primarily on humoral responses to SARS-CoV-2 vaccines. Full protection, however, also requires intact innate and adaptive cellular immune responses. Unfortunately, T-cell responses are less commonly performed on a clinical scale to assess immune responses to vaccines as these tests16 are cumbersome, time consuming, manual, and not as easily adaptable to a clinical laboratory setting. In one report, the cellular response of transplant recipients to BNT162b2 mRNA vaccination (as measured by ELISPOT to a pooled mix of SARS-CoV-2 peptides) was detectable in only 56.25% of those patients.17 Furthermore, the number of spots per subject was substantially reduced compared with those of immunocompetent controls. These data suggest that SOT recipients have reductions in both arms of adaptive immunity in response to mRNA-based SARS-CoV-2 vaccination.
These concepts are important for herd immunity and ring strategy considerations in transplant populations. According to Centers for Disease Control statistics as of April 29, 2021, in the United States, 82% of people aged 65 years and older and 54.1% of US adults above the age of 18 received at least 1 SARS-CoV-2 vaccine dose. Although estimates of vaccinated population proportions requisite to achieve herd immunity vary based on infectivity (and this changes with emergence of new more infectious mutants), reasonable estimates are that approximately 67% of the total population will need to be fully vaccinated to achieve SARS-CoV-2 herd immunity.18 Until SOT recipients are effectively vaccinated, their risks are likely to be from unvaccinated adults and children below the age of 12, where SARS-CoV-2 vaccination outside of clinical trials is not being practiced. Ring strategies in which SARS-CoV-2-susceptible patients (such as transplant recipients) have their close contacts vaccinated and monitored for antibody responses would be reasonable (although requiring “buy in” from those close contacts) as would assiduous masking, social distancing, etc to minimize risk from SARS-CoV-2 infection until vaccine efficacy is achieved in transplant patients.
In summary, informative, comprehensive, and serial antibody testing should be an important component to evaluating SARS-CoV-2 immunity in immunosuppressed populations. Ongoing studies are needed to determine appropriate intervals and interpretation of antibody testing in transplant recipients. Patients will benefit when treating physicians fully understand the nuances of antibody testing and stay current not only with existing but emerging knowledge regarding SARS-CoV-2 vaccination and immunity. Considerable efforts are needed and should be implemented promptly to test the concepts outlined above.
1. Boyarsky BJ, Werbel WA, Avery RK, et al. Immunogenicity of a single dose of SARS-CoV-2 messenger RNA vaccine in solid organ transplant recipients. JAMA. 2021;325:1784–1786.
2. Yi SG, Knight RJ, Graviss EA, et al. Kidney transplant recipients rarely show an early antibody response following the first COVID-19 vaccine administration. Transplantation. 2021;105:e72–e73.
3. Marinaki S, Adamopoulos S, Degiannis D, et al. Immunogenicity of SARS-CoV-2 BNT162b2 vaccine in solid organ transplant recipients. Am J Transplant. [Epub ahead of print. April 17, 2021]. doi:10.1111/ajt.16607
4. Benotmane I, Gautier-Vargas G, Cognard N, et al. Weak anti-SARS-CoV-2 antibody response after the first injection of an mRNA COVID-19 vaccine in kidney transplant recipients. Kidney Int. 2021;99:1487–1489.
5. Grupper A, Rabinowich L, Schwartz D, et al. Reduced humoral response to mRNA SARS-Cov-2 BNT162b2 vaccine in kidney transplant recipients without prior exposure to the virus. Am J Transplant. [Epub ahead of print. April 18, 2021]. doi:10.1111/ajt.16615
6. Boyarsky BJ, Werbel WA, Avery RK, et al. Antibody response to 2-dose SARS-CoV-2 mRNA vaccine series in solid organ transplant recipients taking belatacept. JAMA. 2021;325:2204–2206.
7. Ou MT, Boyarsky BJ, Chiang TPY, et al. Immunogenicity and reactogenicity after SARS-CoV-2 mRNA vaccination in kidney transplant recipients taking belatacept. Transplantation. [Epub ahead of print. May 19, 2021]. doi:10.1097/TP.0000000000003824
8. Kim EJ, Kwun J, Gibby AC, et al. Costimulation blockade alters germinal center responses and prevents antibody-mediated rejection. Am J Transplant. 2014;14:59–69.
9. Badell IR, Parsons RF, Karadkhele G, et al. Every 2-month belatacept maintenance therapy in kidney transplant recipients greater than 1-year posttransplant: a randomized, noninferiority trial. Am J Transplant. [Epub ahead of print. February 14, 2021]. doi:10.1111/ajt.16538
10. Shuren J, Stenzel T. The FDA’s experience with Covid-19 antibody tests. N Engl J Med. 2021;384:592–594.
11. Bray RA, Lee J-H, Brescia P, et al. Development and validation of a multiplex, bead-based assay to detect antibodies directed against SARS-CoV-2 proteins. Transplantation. 2021;105:79–89.
12. Isho B, Abe KT, Zuo M, et al. Persistence of serum and saliva antibody responses to SARS-CoV-2 spike antigens in COVID-19 patients. Sci Immunol. 2020;5:eabe5511.
13. Long Q-X, Tang X-J, Shi Q-L, et al. Clinical and immunological assessment of asymptomatic SARS-CoV-2 infections. Nat Med. 2020;26:1200–1204.
14. Dan JM, Mateus J, Kato Y, et al. Immunological memory to SARS-CoV-2 assessed for up to 8 months after infection. Science. 2021;371:eabf4063.
15. Widge AT, Rouphael NG, Jackson LA, et al.; mRNA-1273 Study Group. Durability of responses after SARS-CoV-2 mRNA-1273 vaccination. N Engl J Med. 2021;384:80–82.
16. DiPiazza AT, Graham BS, Ruckwardt TJ. T cell immunity to SARS-CoV-2 following natural infection and vaccination. Biochem Biophys Res Commun. 2021;538:211–217.
17. Miele M, Busà R, Russelli G, et al. Impaired anti-SARS-CoV-2 humoral and cellular immune response induced by Pfizer-BioNTech BNT162b2 mRNA vaccine in solid organ transplanted patients. Am J Transplant. [Epub ahead of print. May 31, 2021]. doi:10.1111/ajt.16702
18. Tkachenko AV, Maslov S, Elbanna A, et al. Time-dependent heterogeneity leads to transient suppression of the COVID-19 epidemic, not herd immunity. Proc Natl Acad Sci USA. 2021;118:e2015972118.