Response to a third SARS-CoV-2 vaccine dose amongst immunocompromised

While the available COVID-19 vaccines have proven highly effective for most individuals, patients receiving immunosuppressive medication, such as those administered following an organ transplant, exhibit an inhibited immune response towards the vaccine, thus lowering their efficacy.

In an attempt to provide some level of immunity to these already high-risk patients, alternative vaccination schemes have been adopted, including the administration of a third dose.

In a research paper recently uploaded to the preprint server medRxiv* by Schrezenmeier et al. (August 12th, 2021) the potential benefit of three vaccine doses in either a homogenous or heterogeneous dosing regimen amongst kidney transplant patients is assessed, finding that the search for viable vaccination approaches amongst these patients remains an urgent medical need.

How was the study performed?

All 25 patients involved in the study had previously received the BioNTech mRNA vaccine within the proper dosing regimen: two doses, 21 days apart. Around half of the patients were then given either a third dose of the mRNA vaccine, on average 127 days after the first dose, or alternatively the AstraZeneca adenovirus vector-based vaccine, on average 90 days after the first vaccine.

All patients had failed to develop a sufficient anti-SARS-CoV-2 spike protein Immunoglobulin G (IgG) response before administration of the third vaccine, and all but one was presently receiving antimetabolite medication that has been demonstrated to diminish the immune response towards SARS-CoV-2.  

SARS-CoV-2 specific IgG and IgA were determined at multiple time-points for each patient by enzyme-linked immunosorbent assay, with just three of the 25 developing detectable levels one week following administration of the third dose, though another nine showed evidence of seroconversion at later time points.

SARS-CoV-2 specific IgG levels were only significant amongst three patients: two having received the mRNA vaccine and one the adenovirus vector-based vaccine. Anti-spike protein IgA levels and virus-neutralizing capacity peaked around three weeks after receiving the third dose in the majority of participants.

Three vaccinations remain inadequate for the immunocompromised

B- and T-cell responses were also evaluated one week after the second and third doses, and the group found that the relative proportion and number of SARS-CoV-2 spike protein receptor-binding domain-specific B-cells did not change, nor did the overall levels of circulating CD19. However, the number of patients with SARS-CoV-2 spike protein-specific T helper cell responses was high after both the second and third vaccinations.

The individuals that had undergone seroconversion from the third vaccine exhibited notably higher levels of such T-cells than those that had experienced little or no humoral response. There was also a significant drop in proliferating Ki67+ and activated PD1+ CD8 T-cells amongst all individuals after the third dose compared to the second, indicating that little ex vivo activation of T-cells took place was no change in specific memory/effector subset composition. However, responsive participants also showed higher levels of interleukin-2 and 4 secretion, indicating the maturation of T-cells or potentially the lowering of the IgG isotype switching threshold.

Vaccine-specific B- and T-cell immunity was not tracked amongst the patients due to the limited sample size, and nor were patients separated based on transplant type.

One participant within the study developed severe COVID-19 after having received the third dose, and given the barely sufficient humoral response levels developed amongst the few patients that did respond, the group cast doubt regarding the long-term efficacy of the vaccine amongst these individuals.

The authors suggest that prescribing antimetabolite medication such as mycophenolate mofetil in solid organ transplant patients should be avoided or reduced in the current climate of the COVID-19 pandemic, particularly in patients with stable transplants and no history of rejection, as the currently available vaccines induce a sufficient serological response in only a fraction of patients.

Alternative vaccines or vaccination protocols that provide protection to immunocompromised individuals are therefore in urgent need of development.

*Important Notice

medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.

Journal reference:
  • B and T cell responses after a third dose of SARS-CoV-2 vaccine in Kidney Transplant Recipients, Eva Schrezenmeier, Hector Rincon-Arevalo, Ana-Luisa Stefanski, Alexander Potekhin, Henriette Staub-Hohenbleicher, Mira Choi, Friederike Bachmann, Vanessa Pross, Charlotte Hammett, Hubert Schrezenmeier, Carolin Ludwig, Bernd Jahrsdoerfer, Andreia C Lino, Kai-Uwe Eckardt, Katja Kotsch, Thomas Doerner, Klemens Budde, Arne Sattler, Fabian Halleck, medRxiv, 2021.08.12.21261966; doi:,
Michael Greenwood

Written by

Michael Greenwood

Michael graduated from Manchester Metropolitan University with a B.Sc. in Chemistry in 2014, where he majored in organic, inorganic, physical and analytical chemistry. He is currently completing a Ph.D. on the design and production of gold nanoparticles able to act as multimodal anticancer agents, being both drug delivery platforms and radiation dose enhancers.


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