Withdrawing steroid treatment found to boost SARS-CoV-2 vaccine-induced immunity in kidney transplant recipients

In a recent study posted to the medRxiv* pre-print server, a team of researchers investigated the impact of the fourth dose of coronavirus disease 2019 (COVID-19) vaccine in kidney transplant recipients (KTRs), who had not mounted a humoral immune response to three doses of vaccine.

Study: Temporary hold of mycophenolate boosts SARS-CoV-2 vaccination-specific humoral and cellular immunity in kidney transplant recipients. Image Credit: PhotobyTawat/ShutterstockStudy: Temporary hold of mycophenolate boosts SARS-CoV-2 vaccination-specific humoral and cellular immunity in kidney transplant recipients. Image Credit: PhotobyTawat/Shutterstock

Past studies have produced evidence that steroid treatment impairs vaccine-induced humoral immunity in kidney transplant recipients (KTRs), resulting in high mortality rates among these patients after SARS-CoV-2 infection. More specifically, mycophenolate (MPA)-based treatments quantitatively and functionally affect antigen-specific B and T cell responses.

While two doses of the BNT162b2 COVID-19 vaccine remained ineffective in these at-high risk patients, findings of recent studies on autoimmune patients have shown that temporarily withdrawing MPA treatment could augment booster vaccination outcomes against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).

About the study

In the present study, the researchers examined the impact of short-term (5 weeks) MPA withdrawal on the vaccination outcome of a fourth COVID-19 vaccine dose in 29 KTRs who did not elicit a serological response after a three-dose vaccine protocol.

The study cohort included 14 homogeneously and 15 heterologously vaccinated KTRs. All the study subjects received a fourth dose of the BNT162b2 (BioNTech/Pfizer) vaccine, and the mean time interval between the third and fourth vaccination was 59.1 days.

All 29 KTRs were initially on antimetabolite treatment, 28 were on MPA, and one was on azathioprine (Aza). In addition, 25 of them received calcineurin inhibitors (CNI)-based medication and four received Belatacept. Antimetabolite treatment was stopped 4-7 days before administration of the 4th dose of the BNT162b2 vaccine and it remained paused until day 28-35 (day 32, taken as mean).

The authors observed seroconversion until day 32 after vaccination in 76% of patients, associated with the acquisition of virus-neutralizing capacity. KTRs were also closely monitored for kidney function, anti-human leukocyte antigen (HLA) antibodies, and donor-derived cell-free DNA (dd-cfDNA). The study also assessed vaccine-specific immunity of KTRs, including their B and T cell analyses, immunoglobulin G (IgG) and immunoglobulin A (IgA) levels, and neutralization capacity.

Study findings

The study results showed that at day 32, 84% of CNI-treated patients (21/25) and one out of four (1/4) belatacept-treated patients elicited humoral responses, together with an increase in neutralizing antibodies and occurrences of vaccine-specific B cells and plasmablasts. Further, at day 32, higher ex vivo activation of the spike (S)-specific T cells quantitatively correlated with S1 specific IgG were observed.

In conjunction with humoral responses, the receptor-binding domain (RBD)-specific B cells increased in counts and relative frequencies on day 7 after vaccination, along with RBD-specific CD27++ CD38+ plasmablasts.

The analysis also showed that overall proportions of S-reactive CD4+ T cells remained unaltered after the fourth vaccine dose, and their cellular frequencies positively correlated with specific IgG levels.

Notably, during the brief time of MPA withdrawal followed by re-vaccination, although antigen-specific Ki67+ and in vivo activated PD1+ T cells significantly increased, cytokine production and memory differentiation remained unaffected. MPA withdrawal, followed by re-vaccination, impacted all arms of immunity, with the strongest impact on B cell activation and differentiation, which boosted S-specific antibody production.

Interestingly, seroconversion did not change with the type of previous vaccines (mRNA, mixed mRNA, or vector-based vaccine). Subsequently, KTRs who received heterologous and homologous vaccinations exhibited similar seroconversion. Compared to 12% of KTRs who received the third vaccine dose under MPA treatment, seroconversion was already detectable on day 7 in 34.4% of KTRs, highlighting enhanced immune kinetics in the absence of steroids.

Conclusion

The study highlights that while immunosuppressive medication such as CNI, corticosteroids (CS), and steroids or MPA prevent acute rejections or impaired kidney function, these also adversely impact the outcome of SARS-CoV-2 vaccines. A majority of KTRs thus did not benefit from the third dose of a COVID-19 vaccine, highlighting the urgent need to modify vaccination protocols to achieve maximum protection against SARS-CoV-2 infections for this at-risk population. This potentially rapid vaccination strategy for at-risk patients under standard CNI-based immunosuppression treatment also warrants testing in larger cohorts.

In conclusion, temporarily withdrawing MPA treatment was safe, and augmented vaccine-induced immunity after booster vaccination. These findings suggest that it is feasible to accelerate and increase vaccine efficacy in KTRs, given that these patients are clinically stable. Clinically stable KTRs have stable graft function, no history of rejection episodes, increased anti-HLA antibodies, or dd-cfDNA plasma concentrations.

*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:
Neha Mathur

Written by

Neha Mathur

Neha is a digital marketing professional based in Gurugram, India. She has a Master’s degree from the University of Rajasthan with a specialization in Biotechnology in 2008. She has experience in pre-clinical research as part of her research project in The Department of Toxicology at the prestigious Central Drug Research Institute (CDRI), Lucknow, India. She also holds a certification in C++ programming.

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