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Interpreting and addressing suboptimal immune responses after COVID-19 vaccination in solid-organ transplant recipients
Peter G. Stock,1 Timothy J. Henrich,2 Dorry L. Segev,3 and William A. Werbel4
1Department of Surgery and
2Department of Medicine, UCSF, San Francisco, California, USA.
3Department of Surgery and
4Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Address correspondence to: Peter G. Stock, University of California, San Francisco, 505 Parnassus Avenue, M-884, Box 0780, San Francisco, California 94143-0780, USA. Phone: 415.353.8617; Email: Peter.Stock@ucsf.edu.
Find articles by Stock, P. in: JCI | PubMed | Google Scholar
1Department of Surgery and
2Department of Medicine, UCSF, San Francisco, California, USA.
3Department of Surgery and
4Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Address correspondence to: Peter G. Stock, University of California, San Francisco, 505 Parnassus Avenue, M-884, Box 0780, San Francisco, California 94143-0780, USA. Phone: 415.353.8617; Email: Peter.Stock@ucsf.edu.
Find articles by Henrich, T. in: JCI | PubMed | Google Scholar
1Department of Surgery and
2Department of Medicine, UCSF, San Francisco, California, USA.
3Department of Surgery and
4Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Address correspondence to: Peter G. Stock, University of California, San Francisco, 505 Parnassus Avenue, M-884, Box 0780, San Francisco, California 94143-0780, USA. Phone: 415.353.8617; Email: Peter.Stock@ucsf.edu.
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Segev, D.
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1Department of Surgery and
2Department of Medicine, UCSF, San Francisco, California, USA.
3Department of Surgery and
4Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Address correspondence to: Peter G. Stock, University of California, San Francisco, 505 Parnassus Avenue, M-884, Box 0780, San Francisco, California 94143-0780, USA. Phone: 415.353.8617; Email: Peter.Stock@ucsf.edu.
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Werbel, W.
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Published June 18, 2021 - More info
J Clin Invest. 2021;131(14):e151178. https://doi.org/10.1172/JCI151178.
© 2021 American Society for Clinical Investigation
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Abstract
Novel mRNA-based vaccines have been proven to be powerful tools in combating the global pandemic caused by SARS-CoV-2, with BNT162b2 (trade name: Comirnaty) efficiently protecting individuals from COVID-19 across a broad age range. Still, it remains largely unknown how renal insufficiency and immunosuppressive medication affect development of vaccine-induced immunity. We therefore comprehensively analyzed humoral and cellular responses in kidney transplant recipients after the standard second vaccination dose. As opposed to all healthy vaccinees and the majority of hemodialysis patients, only 4 of 39 and 1 of 39 transplanted individuals showed IgA and IgG seroconversion at day 8 ± 1 after booster immunization, with minor changes until day 23 ± 5, respectively. Although most transplanted patients mounted spike-specific T helper cell responses, frequencies were significantly reduced compared with those in controls and dialysis patients and this was accompanied by a broad impairment in effector cytokine production, memory differentiation, and activation-related signatures. Spike-specific CD8+ T cell responses were less abundant than their CD4+ counterparts in healthy controls and hemodialysis patients and almost undetectable in transplant patients. Promotion of anti-HLA antibodies or acute rejection was not detected after vaccination. In summary, our data strongly suggest revised vaccination approaches in immunosuppressed patients, including individual immune monitoring for protection of this vulnerable group at risk of developing severe COVID-19.
Authors
Arne Sattler, Eva Schrezenmeier, Ulrike A. Weber, Alexander Potekhin, Friederike Bachmann, Henriette Straub-Hohenbleicher, Klemens Budde, Elena Storz, Vanessa Proß, Yasmin Bergmann, Linda M.L. Thole, Caroline Tizian, Oliver Hölsken, Andreas Diefenbach, Hubert Schrezenmeier, Bernd Jahrsdörfer, Tomasz Zemojtel, Katharina Jechow, Christian Conrad, Sören Lukassen, Diana Stauch, Nils Lachmann, Mira Choi, Fabian Halleck, Katja Kotsch
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Strategies for improving vaccine immunogenicity
The cellular response data described in the paper by Sattler et al. may be helpful in understanding the mechanisms of impaired vaccine immune response in immunosuppressed patients as well as potential strategies for altering immunosuppressive medications during the vaccination window or offering a different platform for a subsequent booster vaccination However, cellular assays to measure vaccine responses are not commercially available. Viral-specific helper CD4+ T cell responses have been shown to correlate with antibody levels and neutralization titers (20–22). Importantly, cutoffs for protective CD4+ or cytolytic CD8+ T cell responses have not been defined in any population. Cucchiari et al. (23) recently demonstrated that SARS-CoV-2–specific T cell responses can be observed in up to 50% of kidney transplant recipients who do not develop antibodies following vaccination. Unlike antibody responses, however, it is not yet known whether these T cell responses correlate with protection versus SARS-CoV-2 infection or attenuate disease severity, particularly in persons taking immunosuppressives explicitly tailored to blunt T cell activity (i.e., inhibit alloimmunity).
What are potential strategies for improving vaccine immunogenicity given the likelihood that COVID-19 will remain a world-wide threat to the health of transplant recipients (Figure 1 and ref. 24)? Alternative vaccination regimens, including additional doses of mRNA vaccines, are currently being assessed in clinical trials, including a Canadian trial of a third booster dose of Moderna COVID-19 vaccine in transplant recipients (25). The French Health ministry now routinely recommends a third dose of mRNA vaccines for recipients of bone marrow and solid organ transplants as well other immunosuppressed populations (26). There are also anecdotal reports (14) of third doses in the United States, including an antibody response to an adenoviral vectored vaccine after a failed response to two doses of mRNA vaccine in a transplant recipient (i.e., heterologous boosting). Indeed, there is some evidence that the Oxford-AstraZeneca adenovirus vaccine ChAdOx1 stimulates a more potent cellular response than BNT162b2 mRNA vaccine in elderly persons (27). Based on the report by Sattler et al., it will be important to prospectively study both the humoral and cellular responses using any alternative dosing strategies as well as associated modulation of immunosuppression regimens. In that way, approaches that are optimal in improving the broad impairment in effector cytokine production, memory differentiation, and spike-specific CD8+ T cell responses as noted in this study can be adopted into vaccination strategies.
Modulation of immunosuppressives is another potential strategy. The lack of an antibody response following completion of the mRNA vaccines has been strongly correlated with the utilization of the antiproliferative agent mycophenolic mofetil (MMF) in the immunosuppressive regimens of transplant recipients (5, 6). This has also been observed in influenza vaccination (8). All of the recipients in the Sattler study were maintained on immunosuppressive regimens, including a CNI and an MMF; hence, the impact of the antiproliferative agent could not be determined. One potential strategy for enhancing the immune response in transplant recipients could be to minimize or potentially hold the antiproliferative agent at the time of a vaccine booster in patients with a failed vaccine-mediated antibody response. Although not recommended by transplant societies at this time, this approach has been explicitly recommended for persons taking antiproliferative agents for control of autoimmune diseases (28). This strategy must be nuanced and individualized, as for example, recipients with recent transplantation and/or who are highly allosensitized could be at unacceptably high risk for rejection or other alloimmune events. Fortunately, to date, there is no strong evidence to support enhancement of the alloimmune response by COVID-19 vaccination in transplant recipients (29). For recipients that are deemed low risk by their transplant provider for developing an alloimmune complication in the context of antiproliferative agent minimization, for example, long-standing liver transplant recipients, the ability to modulate immunosuppression at the time of the vaccine booster may be a reasonable approach after individualized discussion of the risks and benefits.
In order to deliver optimal vaccine responses for our transplant recipients, it will be important to conduct careful, monitored clinical trials of vaccine boosters as well as modulation of immunosuppression regimens. Nonetheless, many transplant recipients do not have access to such clinical trials and deserve information in real time, particularly in regions suffering unchecked viral spread and in advance of anticipated seasonal coronavirus disease spikes. As with all management strategies for transplantation during the COVID-19 pandemic, any of the outlined approaches will have to be made in a relative data vacuum alongside individualized discussion between clinicians and transplant recipients, carefully integrating rapidly evolving observational and clinical trial results into that vague but important notion of clinical judgment. In the interim, appropriate testing for humoral responses following vaccination in transplant recipients would provide data for encouraging and reinforcing safe behavior and would identify the highest risk individuals who may benefit from these exploratory, but crucial interventions.
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ISSN: 0021-9738 (print), 1558-8238 (online)