Comparison of infected and vaccinated transplant recipients highlights the role of Tfh and neutralizing IgG in COVID-19 protection

Abstract

Transplant recipients, which receive therapeutic immunosuppression to prevent graft rejection, are characterized by high COVID-19-related mortality and defective response to vaccines. Having observed that previous infection by SARS-CoV-2 but not the standard 2 doses scheme of vaccination, provided complete protection against COVID-19 to transplant recipients, we undertook this translational study to compare the cellular and humoral immune responses of these 2 groups of patients. Neutralizing anti-Receptor Binding Domain (RBD) IgG were identified as the critical immune effectors associated with protection. Generation of anti-RBD IgG was dependent upon spike-specific T follicular helper (Tfh) CD4+ T cells, which acted as limiting checkpoint. Tfh generation was impeded by high dose mycophenolate mofetil in non-responders to vaccine but not in infected patients, suggesting that increasing immunogenicity of vaccine could improve response rate to mRNA vaccine. This theory was validated in two independent prospective cohorts, in which administration of a 3rd dose of vaccine resulted in the generation of anti-RBD IgG in half of non-responders to 2 doses.

Humoral Immune Response of SARS-CoV-2 Infection and Anti-SARS-CoV-2 Vaccination in Renal Transplant Recipients

“…In the present study, we observed that the seroconversion rate with Covishield and Covaxin is comparable, or relatively higher, to that of the mRNA-based vaccines. Infection with SARS-CoV-2 usually triggers the generation of high titers of protective neutralizing anti-spike IgGs in RTRs, similar to our observations [ 22 ]. A study also revealed that the main predictor of successful seroconversion after vaccination is a previous history of COVID-19 in RTRs.…”

Predictive factors of a viral neutralizing humoral response after a third dose of COVID-19 mRNA vaccine

“…However, only 25% (range: 2.5%–48%) of KTRs develop adequate antibody response after the “standard” two doses of COVID‐19 mRNA vaccine 6‐14 . These antibodies are responsible for the neutralization of the virus, that can be assessed using in vitro functional assay, which currently represents the best available correlate of protection against severe COVID‐19 for both the general population 15 and KTRs 16 . Accordingly the lack of adequate antibody response after vaccination in KTRs correlated with the occurrence of (sometime severe forms of) COVID‐19 in vaccinated patients 17‐19 …”

“…[6][7][8][9][10][11][12][13][14] These antibodies are responsible for the neutralization of the virus, that can be assessed using in vitro functional assay, which currently represents the best available correlate of protection against severe COVID-19 for both the general population 15 and KTRs. 16 Accordingly the lack of adequate antibody response after vaccination in KTRs correlated with the occurrence of (sometime severe forms of) COVID-19 in vaccinated patients. [17][18][19] Preliminary reports suggest that a third dose (D3) of vaccine improves the humoral response in transplant recipients.…”

Predictive factors of response to 3rd dose of COVID-19 mRNA vaccine in kidney transplant recipients

“…This vulnerable population has therefore been prioritized for vaccination. However, after the "standard" 2 doses of mRNA vaccine only few KTRs develop appropriate levels of anti-receptor binding domain of spike protein (RBD) IgG [6][7][8] , which are responsible for the neutralization of the virus and the protection against COVID-19 9 . Accordingly, we and others have reported cases of vaccinated KTRs with (sometime severe forms of) COVID-19 10,11 .…”