By Stan Deresinski, MD, FACP
Clinical Professor of Medicine, Stanford University
SYNOPSIS: The apparent immunogenicity of available SARS-CoV-2 messenger ribonucleic acid vaccines is markedly reduced in solid organ transplant recipients, providing concern that they may not provide protection from symptomatic COVID-19 in many.
SOURCES: 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; Mar 15:e214385. doi: 10.1001/jama.2021.4385. [Online ahead of print].
Chavarot N, Ouedrani A, Marion O, et al. Poor anti-SARS-CoV-2 humoral and T-cell responses after 2 injections of mRNA vaccine in kidney transplant recipients treated with belatacept. Transplantation 2021; Apr 8. doi: 10.1097/TP.0000000000003784. [Online ahead of print].
Boyarsky and colleagues examined the antibody response to receipt of a COVID-19 messenger ribonucleic acid (mRNA) vaccine in 436 solid organ transplant recipients (SOT). Their median age was 55.9 years, 61% were women, and 89% were white. A median of 6.2 years after transplantation, approximately half of the patients received the BNT162b2 vaccine from Pfizer-BioNTech, while the other half of them received mRNA-1273 from Moderna. Eighty-three percent were taking tacrolimus, while 54% were taking corticosteroids, and 66% were taking mycophenylate. Less than 10% were taking azathioprine, sirolimus, or everolimus.
Serum antibody was tested a median of 20 days after administration of the first vaccine dose. The antibody tests used detected spike protein antigens and have been demonstrated to correlate with neutralizing activity. Antibody was detectable in only 76 subjects (17%; 95% confidence interval [CI], 14% to 21%). Older age and receipt of an antimetabolite immunosuppressant (mycophenylate or azathioprine) each were associated with reduced responses, as was receipt of BNT162b2 compared to mRNA-1273.
Chavarot and colleagues examined serological and cellular immune responses to vaccination with BNT162b2 of renal transplant recipients who had received, together with other immunosuppressives, abatacept, a monoclonal antibody directed at the coreceptor molecule CTLA4 — and found even poorer responses. Two-thirds of the 101 patients were men, and the median interval since transplantation was 59 months. The Abbott and Wantai tests were used, each at separate clinics. These detect antigens in the receptor binding domain of SARS-CoV-2 and have reported sensitivities of 97% and 90%, respectively. Antibody was detected in only two subjects (2.0%) 28 days after the first dose and in only two of 35 (5.7%) tested one month after the second dose. T-cell responses, as determined by an IFN- γ release assay by EliSpot in response to SARS-CoV-2 spike antigens, were observed in two of 40 patients (5.0%) at day 28, and seven of 23 patients (30.4%) at day 60.
These brief studies demonstrate that the available SARS-CoV-2 mRNA vaccines have markedly reduced immunogenicity in solid organ transplant recipients when compared to the general population cohorts in clinical trials in whom seropositivity has been reported to result in 100% of mRNA-1273 and BNT162b2 single-dose recipients by days 15 and 21, respectively. Perhaps more disturbing, in the study by Chavarot and colleagues, the second dose of BNT162b2 did not result in significantly improved antibody response rates, with only 5.0% being seropositive. Furthermore, in that same study, only 5.0% had evidence of T-cell immunity after the first dose, although this increased to 30.4% at two months. However, it must be kept in mind that the patients in that study differed from many other SOT recipients in that they were all receiving abatacept — although whether this was determinative is not known.
The immune response to natural SARS-CoV-2 infection in immunnosuppressed patients also is of interest, and some studies have found that antibody and cellular immune responses were similar to those of a non-immunosuppressed control group. In a study by the same group responsible for the paper reviewed here, SARS-CoV-2 infection resulted in the development of antibody to the viral spike protein in 78% after a median of 98 days.1 Favà et al found that solid organ transplant recipients had serologic and cellular immune responses similar to those of a control population, although with a delay in some.2 These results seem consistent with a number of reports that, despite their immunosuppressive therapy, the outcome of COVID-19 in solid organ transplant recipients is similar to that of patients not receiving such therapy. In fact, immunosuppressive agents (dexamethasone, baricitinib, and perhaps tocilizumab) have been demonstrated to provide clinical benefit in selected patients with COVID-19. We have a lot to learn.
Overall, the available data indicate that surviving COVID-19 in immunosuppressed patients is a potent immunizing event, while receipt of an mRNA vaccine is much less so. Whether these impaired measures of immunogenicity predict lack of protection against severe COVID-19, however, remains to be seen. But I think we should maintain a high level of concern and begin thinking about alternative protective strategies in these patients.
- Boyarsky BJ, Ou MT, Werbel WA, et al. Early development and durability of SARS-CoV-2 antibodies among solid organ transplant recipients: A pilot study. Transplantation 2021; Jan 19. doi: 10.1097/TP.0000000000003637. [Online ahead of print].
- Favà A, Donadeu L, Sabé N, et al. SARS-CoV-2-specific serological and functional T-cell Immune responses during acute and early COVID-19 convalescence in solid organ transplant patients. Am J Transplant 2021; Mar 23. doi: 10.1111/ajt.16570. [Online ahead of print].