Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination has become the standard of care for the prevention of severe coronavirus disease 2019 (COVID-19), with a strongly positive impact in countries in which vaccination has been effectively promoted. Nevertheless, the emergence of variants of concern, such as B.1.617.2 (Delta), has contributed to a surge in cases across the globe, raising the question of the protection afforded by the vaccine. Even if BNT162b2 mRNA vaccine-induced immunity against SARS-CoV-2 infection appears to wane rapidly following its peak after the second dose, protection against hospitalization and death persists at a robust level for 6 months after the second dose (1). Kidney transplant recipients are at high risk of developing severe forms of SARS-CoV-2 infection (2), and vaccination with mRNA vaccine has been recommended rapidly through international guidelines, although they were excluded from “Phase 3 trial” vaccination studies. Unfortunately, the data reported to date in kidney transplant recipients are disappointing, with a low rate of seroconversion after two doses, while the occurrence of severe infection after vaccination is of concern (3). Many efforts have been made to enhance the immunogenicity of vaccine in kidney transplant recipients, such as a third dose of vaccine, but the level of protection against the Delta variants in kidney transplant recipient responders is still unknown. Recent reports have clearly demonstrated the importance of developing neutralizing antibodies (4), acting through binding to the spike protein of SARS-CoV-2, thereby eliminating extracellular viruses and preventing their entry into host cells. However, vaccine-induced antibodies have a reduced capacity to neutralize variants of concern (Beta and Delta) in healthy individuals (5). Until now, such data in kidney transplant recipients were not available.
In this issue of CJASN, Benning et al. (6) report the first study providing an in-depth characterization of the humoral responses to different variants of concern in kidney transplant recipients. From December 29, 2020 to June 21, 2021, they prospectively enrolled 173 kidney transplant recipients and 166 healthy controls undergoing SARS-CoV-2 vaccination. Anti-S1 IgG and neutralizing antibodies were measured in 73 and 135 kidney transplant recipients and in 115 and 134 healthy controls after the first and second vaccine (mostly mRNA) dose, respectively. Anti-S1 IgG antibody levels were significantly lower in kidney transplant compared with the healthy control cohort. A significantly lower antibody capacity of surrogate neutralization was observed in kidney transplant recipients after two-dose vaccination. After the second vaccine dose, 135 kidney transplant recipients, compared with 25 healthy controls matched for type of vaccine, sex, and age, showed significantly lower antibody reactivity against different spike protein domains (S1, S2, and RBD). The neutralizing activity against different variants of concern was measured on VeroE6 cells in 36 seropositive kidney transplant recipients, in comparison to 25 matched healthy controls. All seropositive kidney transplant recipients showed, in a VeroE6 cell neutralization assay, neutralizing activity against the B.1.1.7 (Alpha) variant with a median (interquartile range) ID50 (serum dilution that reduces infection of cells by 50%) of 80 (80–320), whereas only 23 out of 36 (64%) and 24 out of 36 (67%) of them showed neutralization activity against the variants of concern B.1.351 (Beta) and B.1.617.2 (Delta) with a median (interquartile range) ID50 of 20 (0–40) and 20 (0–40), respectively. In contrast, all matched healthy controls showed neutralizing activity against all tested variants, with significantly higher neutralization activity against the different variants of concern as compared with kidney transplant recipients.
Most of the studies published about the immunogenicity of two doses of mRNA vaccine in kidney transplant recipients draw the same conclusions: the seroconversion rate in kidney transplant recipients is poor and specific antibody titers are lower than in the general population. We know now that anti-S1 and anti-RBD IgG antibody levels correlate with the neutralization capacity of vaccine-induced antibodies, and vaccine efficacy, but may, however, be reduced toward new emerging SARS-CoV-2 variants. Benning et al. now demonstrate a reduced level of vaccine-induced antibodies in seroconverting kidney transplant recipients that may be insufficient to provide effective protection against the variants of concern. The study of Benning et al. thus strongly argues for a booster dose in immunocompromised patients such as kidney transplant recipients. A third dose of mRNA vaccine, as recommended for kidney transplant recipients since April 2021 in France, has afforded a dramatic increase in antibody titers to kidney transplant recipients already seropositive after the second dose and induced seroconversion in a significant proportion of seronegative patients (7). Hall et al. (8) also showed a 55% seroconversion rate after a third vaccine dose in 120 solid organ transplant recipients as compared with 18% in a placebo-treated control group, with 71% versus 13% virus neutralization in the mRNA-1273 and placebo group, respectively. In addition, spike-specific T cells numbers were greater in the mRNA-1273 group than in the placebo group.
The study of Benning et al. has some limitations. First, even if there is growing evidence for a strong correlation between neutralizing antibody levels and protection against severe forms of COVID-19, the exact cutoff level for protection is still unknown. This point might be explained by the fact that antibodies are just part of the immune response induced by the vaccine. In fact, the CD4+ and CD8+ T cell response should be taken into consideration to estimate the level of protection (9). Indeed, in kidney transplant recipients, the quality of T cell responses is known to be predictive of outcomes in the context of other infections, such as cytomegalovirus infection. Evaluation of the anti-SARS-CoV-2 T cell response is now feasible in current practice with different assays (Quantiferon and ELISPOT) and vaccine-induced T cell responses are probably less impaired than humoral responses in kidney transplant recipients (7). On the other hand, specific memory B cells against SARS-CoV-2 induced following immunization may persist despite waning antibody titers, but this cannot be easily assessed routinely (10). Therefore, the best evidence for the protection provided by SARS-CoV-2 vaccines remains decreased occurrence of clinical endpoints such as infection requiring hospitalization, need for intensive care unit, or SARS-CoV-2–related death. These kinds of data are terribly lacking in kidney transplant recipients, especially in the context of circulating variants of concern such as the Delta variant. Bestard et al. (11) recently reported that the incidence of SARS-CoV-2 infection markedly dropped during the 4 months following the vaccination campaign in kidney transplant recipients (March–June 2021) independently of the progressive reduction of infection rates observed over the same time in the general population. The reduction in COVID-19 incidence did also coincide with less restrictive community measures and a marked reduction in virus circulation. These observations suggest, on the one hand, the progressive generation of herd immunity (due to a generalized vaccination policy) and less viral infectivity, and, on the other hand, a likely protective role of vaccine-induced immunity in kidney transplant recipients with poor antibody responses.
The classic strategy of vaccination with mRNA vaccine used in the general population leads in kidney transplant recipients to lower seroconversion rates and in responders to reduced neutralizing capacity against emerging variants, and thus to reduced protection from severe forms of COVID-19 in responders and nonresponders. Kidney transplant recipient responders to two vaccine doses should receive a booster dose (third dose) to enhance the immune response and increase the level of neutralizing antibodies against variants of concern. The duration of protection (that is, the stability of neutralizing antibody titers overtime) is still undocumented and the crucial question of whether (and when) kidney transplant recipients will need boosters remains to be investigated. In nonresponders, this booster dose could be discussed and, in the absence of seroconversion, the use of anti-SARS-CoV-2 monoclonal antibodies might be the solution to protect this fragile population against the emergence of variants of concern.
All authors have nothing to disclose.
The content of this article reflects the personal experience and views of the author(s) and should not be considered medical advice or recommendation. The content does not reflect the views or opinions of the American Society of Nephrology (ASN) or CJASN. Responsibility for the information and views expressed herein lies entirely with the author(s).
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