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Research Highlights

Adigbli, George MRCS1; Berlin, Claudia MD1; Issa, Fadi DPhil, FRCS(Plast)1

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doi: 10.1097/TP.0000000000003937
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Randomized Trial of a Third Dose of mRNA-1273 Vaccine in Transplant Recipients

Hall VG, Ferreira VH, Ku T, et al. N Engl J Med. [Epub ahead of print. August 11, 2021]. doi:10.1056/NEJMc2111462

Vaccination is the most effective intervention for protection against severe illness from coronavirus disease 2019. Owing in part to the requirement for immunosuppressant medications, organ transplant recipients are at higher risk of contracting diseases prevented by vaccines and of not mounting optimal immune responses to vaccination.1 Recent trials have shown that as low as 17% of solid organ transplant (SOT) recipients mount positive antibody responses to an initial dose of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mRNA vaccines2,3 and 54% to 2 doses.4 In addition, infection and testing data from vaccinated transplant recipients identified rates of breakthrough infections to be 82 times higher than in the general public and rates of serious illness to be 485 times higher.5 As such, there is increasing concern about the vulnerability of transplant recipients who may become infected with SARS-CoV-2.

Adding to promising immune responses to third “booster” doses reported in nonrandomized studies of vaccinated SOT recipients,6,7 Hall et al8 present the results of a double-blind, randomized controlled trial evaluating the safety and immunogenicity of a third dose of Moderna mRNA-1273 vaccine. In the trial of 120 patients, the authors determined serological responses (primary trial outcome) to be positive when antireceptor binding domain antibody titers were >100 U/µL—a level correlating with 50% virus neutralization in vitro. Using this cutoff, a significantly greater proportion of patients had a positive response (55%) than patients given placebo (18%), corresponding with a mean fold change in antibody titer that was 75 times higher in the vaccination group. In addition to positive antibody responses, booster vaccinations were associated with greater numbers of SARS-CoV-2–specific CD4+ T cells, which demonstrated inducible interleukin-2 and interferon-γ production following stimulation with SARS-CoV-2 spike peptides.

These findings indicate that a third dose of the mRNA-1273 vaccine may induce greater protective immunity against coronavirus disease 2019 in SOT recipients than 2 doses alone. Local and systemic adverse effects were more frequent in vaccinated patients; however, these tended to be mild. Furthermore, neither severe adverse effects nor episodes of transplant rejection were reported. The limited reporting interval (1 mo after vaccination) and small study size mean that differences in clinical outcome cannot be conclusively inferred from this trial alone. In addition to determining the long-term efficacy and safety of this and other available vaccines, the potential influences of transplanted organ type and immunosuppression regimen on outcomes will likely be important considerations requiring further evaluation.

Gut Microbiota-derived Short-chain Fatty Acids Regulate IL-17 Production by Mouse and Human Intestinal γδ T Cells

Dupraz L, Magniez A, Rolhion N, et al. Cell Rep. 2021;36:109332.

The microbiome is intricately involved in human metabolism, immunity, and response to infection.1 In the gut, commensal bacteria profoundly shape the immune landscape, interacting with an array of innate and adaptive immune cells and influencing cellular differentiation and function through release of metabolites and other microbial products locally and systemically.1 Several strands of evidence suggest roles for the microbiome in the pathogenesis of inflammatory processes such as graft-versus-host disease2 and inflammatory bowel disease (IBD).3 The relationships between gut commensals and immune cells, such as dendritic cells and conventional αβ T cells, have been explored. γδ T cells demonstrate dichotomous inflammatory and regulatory properties in the gut, which could also relate to interactions with the microbiome4; however, these are less well understood.

In the present study, Dupraz et al investigate the relationships between gut microbiota and production of the inflammatory cytokines interleukin (IL)-17 and IL-22 by γδ T cells. Using cecal γδ T cells, they demonstrated repression of IL-17 production in mice harboring conventional microbiomes, which was associated with production of short-chain fatty acids (SCFAs) by intestinal commensals. The IL-17–repressed phenotype seen could be reversed by vancomycin-mediated inhibition of SCFA production. Propionate—the most potent SCFA to repress IL-17– and IL-22–producing γδ T cells—was found to mediate this effect through inhibition of histone deacetylase, which typically promotes an anti-inflammatory state.5 In γδ T cells from human IBD patients, SCFA-mediated repressed IL-17 production was similarly demonstrated in a histone deacetylase-dependent manner, suggesting regulatory potential of microbiota-derived metabolites in IBD.

These data highlight some of the mechanisms that regulate γδ T-cell function in the gut. For example, in the intestinal mucosa of IBD patients, IL-17–producing γδ T cells are abundant,6 and considering their pathological role, their control using SCFAs such as propionate offers an interesting therapeutic angle.

REFERENCES

1. Danziger-Isakov L, Kumar D; AST ID Community of Practice. Vaccination of solid organ transplant candidates and recipients: guidelines from the American Society of Transplantation Infectious Diseases Community of Practice. Clin Transplant. 2019;33:e13563.
2. Walsh EE, Frenck RW Jr, Falsey AR, et al. Safety and immunogenicity of two RNA-based Covid-19 vaccine candidates. N Engl J Med. 2020;383:2439–2450.
3. Jackson LA, Anderson EJ, Rouphael NG, et al.; mRNA-1273 Study Group. An mRNA vaccine against SARS-CoV-2—preliminary report. N Engl J Med. 2020;383:1920–1931.
4. Boyarsky BJ, Werbel WA, Avery RK, et al. Antibody response to 2-dose SARS-CoV-2 mRNA vaccine series in solid organ transplant recipients. JAMA. 2021;325:2204–2206.
5. Qin CX, Moore LW, Anjan S, et al. Risk of breakthrough SARS-CoV-2 infections in adult transplant recipients. Transplantation. [Epub ahead of print. July 23, 2021]. doi:10.1097/TP.0000000000003907
6. Kamar N, Abravanel F, Marion O, et al. Three doses of an mRNA Covid-19 vaccine in solid-organ transplant recipients. N Engl J Med. 2021;385:661–662.
7. Benotmane I, Gautier G, Perrin P, et al. Antibody response after a third dose of the mRNA-1273 SARS-CoV-2 vaccine in kidney transplant recipients with minimal serologic response to 2 doses. JAMA. [Epub ahead of print. July 23, 2021]. doi:10.1001/jama.2021.12339
8. Hall VG, Ferreira VH, Ku T, et al. Randomized trial of a third dose of mRNA-1273 vaccine in transplant recipients. N Engl J Med. [Epub ahead of print. August 11, 2021]. doi:10.1056/NEJMc2111462

REFERENCES

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