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Review 1: "Cellular and humoral immunogenicity of a SARS-CoV-2 mRNA vaccine in patients on hemodialysis"

Published onApr 14, 2022
Review 1: "Cellular and humoral immunogenicity of a SARS-CoV-2 mRNA vaccine in patients on hemodialysis"
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key-enterThis Pub is a Review of
Cellular and humoral immunogenicity of a SARS-CoV-2 mRNA vaccine in patients on hemodialysis
Description

AbstractBackgroundPatients with chronic renal insufficiency on intermittent hemodialysis face an increased risk of COVID-19 induced mortality and impaired vaccine responses. To date, only few studies addressed SARS-CoV-2 vaccine elicited immunity in this immunocompromised population.MethodsWe assessed immunogenicity of the mRNA vaccine BNT162b2 in at risk dialysis patients and characterized systemic cellular and humoral immune responses in serum and saliva using interferon γ release assay and multiplex-based cytokine and immunoglobulin measurements. We further compared binding capacity and neutralization efficacy of vaccination-induced immunoglobulins against emerging SARS-CoV-2 variants of concern B.1.1.7, B.1.351, B.1.429 and Cluster 5 by ACE2-RBD competition assay.FindingsPatients on intermittent hemodialysis exhibit detectable but variable cellular and humoral immune responses against SARS-CoV-2 and variants of concern after a two-dose regimen of BNT162b2. Although vaccination-induced immunoglobulins were detectable in saliva and plasma, both anti-SARS-CoV-2 IgG and neutralization efficacy was reduced compared to controls. Similarly, T-cell mediated interferon γ release after stimulation with SARS-CoV-2 spike peptides was significantly diminished.InterpretationQuantifiable humoral and cellular immune responses after BNT162b2 vaccination in individuals on intermittent dialysis are encouraging, but urge for longitudinal follow-up to assess longevity of immunity. Diminished virus neutralization and interferon γ responses in face of emerging variants of concern may favor this at risk population for re-vaccination using modified vaccines at the earliest opportunity.FundingInitiative and Networking Fund of the Helmholtz Association of German Research Centers, EU Horizon 2020 research and innovation program, State Ministry of Baden-Württemberg for Economic Affairs, Labor and Tourism.Research in the contextEvidence before this studyPatients on dialysis tend to have a reduced immune response to both infection and vaccination. We searched PubMed and MedRxiv for studies including search terms such as “COVID-19”, “vaccine”, and “dialysis” but no peer-reviewed studies to date assessed both SARS-CoV-2 specific B- and T-cell responses, mucosal immunoglobulins, and considered the impact of SARS-CoV-2 variants of concern in this at risk population.Added value of the studyWe provide a comprehensive functional characterization of both T- and B-cell responses following a two-dose regimen of BNT162b2 in at risk patients on maintenance hemodialysis. More importantly, to the best of our knowledge, we assess for the first time binding and neutralization capacity of vaccination-induced circulation and mucosal antibodies towards emerging SARS-CoV-2 variants of concern in an immunocompromised population.Implications of all the available evidencePatients on maintenance hemodialysis develop a substantial cellular and humoral immune response following the BNT162b2 vaccine. These findings should encourage patients on intermittent hemodialysis to receive the vaccine. However, we suggest continuing additional protection measures against variants of concern in this at risk population until longevity of the vaccine response is fully evaluated.

RR:C19 Evidence Scale rating by reviewer:

  • Reliable. The main study claims are generally justified by its methods and data. The results and conclusions are likely to be similar to the hypothetical ideal study. There are some minor caveats or limitations, but they would/do not change the major claims of the study. The study provides sufficient strength of evidence on its own that its main claims should be considered actionable, with some room for future revision.

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Review:
The work by Strengert et al. offers new insight into COVID-19 vaccine response in hemodialysis patients, as no other publication to date focused on SARS-CoV-2 specific B- and T-cell responses, mucosal immunoglobulins, and the impact of variants of concern (VOC) in a hemodialysis population. 

The authors found a significantly reduced IgG response in vaccinated dialysis patients, which is in line with previous findings. A novelty is the measurement of antibody response in saliva and in line with the response observed in plasma samples, the specific antibody response was diminished. In accordance with findings in the general population, the authors could find a reduced antibody binding to B.1.351 in comparison to the UK or LA variants.

This study is the first to extend the pure description of humoral response in patients on hemodialysis, as most only measured IgGs in comparison to a non-matched control cohort. The control group is not-matched either but the authors clearly state this as a limitation in the Discussion. The need to follow these patients longitudinally is clearly highlighted and potentially informs us about the re-dosing of hemodialysis patients.

This study found that saliva IgG antibodies are comparably diminished as compared to antibody levels measured from blood samples. More importantly, the T-cell response strongly correlated with the impaired humoral response and the plasma RBDWTACE2 neutralization.

As shown by the authors, the response towards variants of concern, especially the SA variant and probably also the Indian variant, is specifically diminished. This is concerning as shown in a diminished plasma RBD ACE2 neutralization which might indicate some form of “protection”. Specific strategies to boost vulnerable patient cohorts against VOC might be necessary, and strategies such as administration of a third (“booster”) dose of COVID-19 vaccine (either the same vaccine or another vaccine platform) should be considered as the Indian variant is becoming the dominant variant and raises concern in most countries with a high rate of vaccinations.

Lastly, the authors report that patients on hemodialysis were not only older but also had more co-morbidities. Importantly, more information would be necessary as these baseline characteristics already point towards a diminished immune response. Of their hemodialysis cohort, a high proportion of patients (> 10%) received immunosuppression. Again, more information on this population would be desirable, as patients receiving glucocorticoids or for example B-cell depletion with rituximab have a significantly impaired humoral and likely cellular immune response. Moreover, information about underlying kidney diseases leading to end-stage kidney disease is missing and should be added.

In conclusion, this single-center study from a major university hospital in Germany further underlines that the humoral vaccine response of hemodialysis patients is good, but IgG response is diminished in comparison to a non-matched cohort. The authors provide evidence that antibodies measured in saliva are similarly diminished as plasma IgG levels. Moreover, T-cell response correlates with the number of circulating antibodies and titers of a neutralizing assay, indicating that patients without a humoral response are likely also not exhibiting cellular immunity and may not be protected from SARS-CoV-2 infections. The work also shows that response to VOC is further reduced, and the development of specific strategies to obtain more robust protection against these variants is warranted.

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