Organ transplant recipients 'should not assume immunity' from COVID-19 vaccine
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Only 54% of solid organ transplant recipients demonstrate evidence of antibody development after receiving the COVID-19 vaccine, according to data in a pair of research letters published in JAMA.
“This study was important because transplant recipients and other immunocompromised people were excluded from the original vaccine trials,” Brian J. Boyarsky, MD, of the Johns Hopkins University School of Medicine, in Baltimore, told Healio Rheumatology. “We did not know how well these highly immunogenic vaccines would work in transplant recipients.”
To analyze the immunogenicity of mRNA vaccines among the immunocompromised, Boyarsky and colleagues conducted a pair of studies examining first, the quantified humoral response to the first dose of the COVID-19 vaccine, and subsequently, the antibody response after the second dose, among solid organ transplant recipients.
First Dose: Just 17% demonstrate antibody response
The first study included 436 transplant recipients, recruited from across the United States through social media, who received the COVID-19 vaccine between Dec. 16, 2020, and Feb. 5. None had previously tested positive for COVID-19.
Blood samples were collected either at home by the patient, using the TAPII blood collection device, or via standard venipuncture. TAPII samples were assessed using the EUROIMMUN anti–SARS-CoV-2 S enzyme immunoassay, which tests for antibodies to the S1 domain of the SARS-CoV-2 spike protein. Meanwhile, the venipuncture samples were tested using the Roche Elecsys anti–SARS-CoV-2 S enzyme immunoassay, which is designed to find antibodies against the receptor-binding domain of the SARS-CoV-2 spike protein.
Among the participants, the median age was 55.9 years, 61% were women and 89% were white. Fifty-two percent received the Pfizer-BioNTech vaccine, while the remaining 48% were inoculated with the Moderna vaccine. The median time since transplant procedure was 6.2 years, and the most common regimens for maintaining immunosuppression included tacrolimus, in 83%; corticosteroids, in 54%; and mycophenolate, 66%. Other regimens included azathioprine, in 9%; sirolimus, in 4%; and everolimus, in 2%.
According to the researchers, by a median of 20 days following the first dose, 17% of the included transplant recipients had demonstrated a detectable antibody response (95% CI, 14% to 21%). In addition, participants who were receiving anti-metabolite maintenance immunosuppression therapy were less likely to develop an antibody response than those not receiving such immunosuppression therapy — 37% compared with 63%, respectively (adjusted IRR = 0.22; 95% CI, 0.15-0.34). Older participants were also less likely to have an antibody response, with an adjusted IRR of 0.83 (95% CI, 0.73-0.93) per 10 years.
Patients who received the Moderna vaccine were more than twice as likely to develop an antibody response that those who received the Pfizer formulation — 69% compared with 31%, respectively (adjusted incidence rate ratio = 2.15; 95% CI, 1.29-3.57). According to the researchers, his findings was largely backed up in a sensitivity analysis, limited to 245 participants who were tested 14 to 21 days following vaccination (adjusted IRR = 2.29; 95% CI, 1.32-3.94).
Second Dose: Improved response but risks remain
The second study included 658 transplant recipients, all without prior confirmed COVID-19, who completed their two-dose vaccine series between Dec. 16, 2020, and March 13. All participants were followed through April 13. As with the first study, the researchers used semiquantitative anti-spike serologic testing with the Roche Elecsys anti–SARS-CoV-2 S enzyme immunoassay, using a positive cutoff of at least 0.8 U/mL, or the EUROIMMUN enzyme immunoassay, with a positive cutoff of at least 1.1 arbitrary units.
According to the researchers, at a median of 29 days following the second dose, 54% of participants registered a detectable antibody response (95% CI, 50% to 58%). Overall, 15% demonstrated measurable antibody response after both dose one and two, while 46% had no antibody response after either dose. Approximately 39% had no antibody response after dose one, but later demonstrated antibody response after dose two.
Median antibody levels among all participants following the second dose were 2.14 U/mL, for the Roche test, and 1.23 arbitrary units, for the EUROIMMUN immunoassay. Among the participants with an antibody response after dose two, median antibody levels were 142.1 U/mL and 6.48 arbitrary units, compared with 34.7 U/mL and 5.05 arbitrary units among those with no antibody response after dose one, and greater than 250 U/mL and 9.23 arbitrary units in those who registered a response after the first dose.
Among the 473 participants who were taking antimetabolites, 8% demonstrated an antibody response after doses one and two, and 57% had no antibody response after either dose, while 35% had an antibody response only after the second dose. Among the 185 participants who were not receiving antimetabolites, 32% had an antibody response after both doses, 18% had no response after either dose, 50% demonstrated a response only after the second dose.
Bottom Line: ‘Transplant recipients should not assume immunity’
“The big takeaway is that vaccinated transplant recipients should not assume immunity after vaccination,” Boyarsky said. “Even among those who had seroconverted, their antibody levels were relatively lower than what we see in people with competent immune systems.”
Despite these findings, Boyarsky said he still encourages transplant recipients to receive the COVID-19 vaccine. He also stressed the importance of inoculation among people who are close to those who are immunocompromised.
“The antibody response to vaccination is one part of the greater immune response to vaccination,” Boyarsky said. “In spite of relatively low antibody responses, we encourage transplant recipients to be vaccinated. It is also particularly important family members, friends and social networks of the immunocompromised get vaccinated to confer some level of protection to the most vulnerable.”
Perspective
Back to TopGordon K.W. Lam, MD, FACR, and Andrew J. Laster, MD, FACR
One of the major challenges for clinicians practicing through the COVID-19 pandemic is to determine the immunogenicity of the vaccines currently available in the context of our patients who are immunocompromised because of their underlying disease and/or drug therapy. We are just now beginning to see reports that hint at potential concerns in patients with heritable and acquired immunodeficiency diseases, lymphoproliferative disorders as well as solid organ transplants and patients with rheumatic and musculoskeletal diseases (RMD) who are being treated with immunomodulatory therapies.
To date, most of these studies are confined to documentation of quantitative antibody response to the S (spike) protein using readily available commercial assays. But what is the clinical significance of these reports in the absence of details regarding neutralizing antibodies or other measures of B- and T-cell function?
The ACR COVID-19 Vaccine Clinical Guidance Task Force cautions us not to “routinely order any lab testing to assess immunity to COVID-19 post-vaccination” as the expected response to vaccination is likely to be blunted in RMD. Thus, patients may not have the same protection as the participants in the vaccine clinical trials, who were healthy and immunocompetent.
Just as important, though, is our lack of understanding of the immunologic responses to vaccination that aren’t measured by an antibody assay, such as T-cell responses. Patient may still derive benefit from vaccination despite absent antibodies to the SARS-CoV-2 spike protein. Accordingly, our messaging to patients about their antibody results may be hindered by our limited context to date.
The task force has also offered recommendations regarding the dosing and timing of the immunomodulatory therapies that we as rheumatologists deploy. For the most part, these are based on educated guesses using available data from other vaccine platforms used to prevent other infectious diseases such as influenza, herpes zoster, viral hepatitis, and streptococcus pneumoniae, among others.
Critically, we currently lack any real data on the novel nucleic acid vaccine platforms for SARS-CoV-2 that use mRNA encapsulated in liposomes. Concerns have been raised about the potential effect of immunomodulatory therapies that directly alter T- and B-cell numbers and function, specifically rituximab, abatacept, mycophenylate and belimumab.
Questions abound. Do we need further guidance not just on the timing of rituximab after the last dose of the vaccine but also on the front end, how long should we wait after the last rituximab dose before we administer the vaccine? Is waiting 4 to 5 months or longer even feasible using the standard rituximab dose of 1000 mg given twice two weeks apart or should we consider giving only a single 1000 mg infusion? Is there potential value in using lymphocyte enumeration panels to determine whether CD19/CD20+ B cells have repopulated before giving the vaccine? Is 1000 mg/day of mycophenylate less likely to impede vaccine immunogenicity than 2000 mg/day or is 500 mg of abatacept infused monthly preferable to 1000 mg?
Additionally, for all of the suspect immunomodulatory therapies, are the Pfizer and Moderna mRNA vaccines with booster more immunogenic than the Johnson & Johnson single-dose adenovirus vaccine? Should we also be concerned about methotrexate and JAK inhibitors and adjust the dosing and/or timing of these drugs given the vaccine data we are aware of – including studies of influenza and H. zoster – or will immunogenicity be sufficient with the current SARS-CoV-2 vaccines that changes in dosing and timing are not necessary?
With increasing concerns that herd immunity may not be achievable, SARS-CoV-2 variants and mutations may arise that require modifications of the current vaccines, or immune protection afforded by the current vaccines may simply wane over time; thus, it seems plausible that we will require revaccination. In these circumstances, questions regarding not just dosing and timing of our immunomodulatory therapies but which drugs to select to treat our patients with RMD may assume even greater importance.
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Boyarsky BJ, et al. JAMA. 2021;doi:10.1001/jama.2021.4385.
Boyarsky BJ, et al. JAMA. 2021;doi:10.1001/jama.2021.7489.
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