COVID-19 Vaccination in Kidney Transplant Recipients: An Ounce Pre-Transplant is Worth a Pound Post-Transplant

The Coronavirus Disease 2019 (COVID-19) Vaccine FAQ sheet on the American Society of Transplantation (AST) website relays information on the current state of knowledge to transplant professionals and the community regarding the COVID-19 vaccine.¹ Last updated on August 13, 2021, this document includes the acknowledgment that “data on clinical efficacy of mRNA vaccines in solid organ transplant (SOT) recipients are incomplete.” In phase III clinical trials, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines generated robust titers of anti-spike1 protein (S1) IgGs that conferred >94% protection against severe COVID-19. Very shortly after their use was authorized, however, it became clear that the standard vaccination schedule is insufficient to elicit a protective response in over half of kidney transplant recipients on maintenance immunosuppression (IS), a population that was excluded from the initial clinical trials. Underlying this failure is the impaired generation of vaccine-specific helper T cells, plasmablasts, and memory B cells because of IS.^2,3 Such patients remain susceptible to severe COVID-19 despite vaccination and are in urgent need of an effective vaccination strategy.

The Food and Drug Administration authorized the administration of a third dose of SARS-CoV-2 mRNA vaccine to immunocompromised patients in August 2021, based on multiple small reports of efficacy. In this issue of JASN, Schrezenmeier et al. report their analysis of serological responses and vaccine-specific B- and T-cell immunity in 25 kidney transplant recipients without humoral response after two doses of BNT162b2 (BioNTech) vaccine who then received a third dose of either heterologous ChAdOx1 (AstraZeneca) or homologous BNT162b2 vaccine.⁴ Maintenance IS in this cohort is typical of the long-term kidney transplant population, with 84% being on a calcineurin inhibitor and all except one patient on mycophenolate mofetil (MMF). Thirty-six percent of the patients demonstrated positive anti-S1 IgG by day 27 after the third vaccination and this paralleled the neutralization capacity of their sera. Only three responders (12%) developed high anti-S1 IgG titers and one of them was the patient not on MMF. Those with a humoral response had significantly higher frequencies of viral spike protein receptor-binding domain specific B cells as well as spike-reactive CD4+ T helper cells compared with nonresponders.

An important finding of this study, similar to that of other recent reports⁵, is that while a third dose can boost the immune response in some kidney transplant recipients on IS, it is by no means a universal panacea, effecting a response in only one-third of recipients without a previous response. Indeed, one patient even in this small cohort developed severe COVID-19 10 days after the third dose, starkly illustrating the continuing threat to this population. The single patient in this study who was not on MMF and who developed high titer anti-S1 IgG after the third dose provides a glimmer of direction. Other groups have shown that MMF therapy significantly curtails the odds of a response to the vaccine and that the correlation is dose-dependent.⁶ Modulation of the IS regimen may be necessary to increase the probability as well as the magnitude of response to vaccination, at least in a subset of patients. Interruption of MMF treatment improved the antibody response to vaccination in patients with autoimmune disease⁷; the safety and efficacy of such an approach in transplant recipients is now being formally addressed in a prospective National Institutes of Health trial (NCT05077254).

In the general population, the durability of the humoral response and the effectiveness of subsequent vaccination is strikingly superior in those with previous infection compared with uninfected persons.⁸ Somewhat surprisingly, titers of neutralizing antibodies postinfection in kidney transplant recipients⁹ and the subsequent vaccination-induced boost in these antibody titers are comparable to those in nontransplant patients,¹⁰ showing that it is indeed possible to generate a strong protective response even in this group. Strategies to improve vaccine immunogenicity therefore remain critical to the effort to protect transplant patients from COVID-19. Schrezenmeier et al. did not find a statistically significant difference in the success of boosting with BNT162b2 (n=14) or ChAdOx1 (n=11) vaccine, although the latter group had a numerically higher response (45% versus 28%). A recent study of two-dose homologous or heterologous vaccine regimens in SOT recipients and healthy controls found that IgG and neutralizing activity were more pronounced after mRNA priming, whereas CD4 and CD8 T cell levels were higher after vector priming.¹¹ Interestingly, SOT recipients showed the strongest induction of antibodies and CD4 T cells with heterologous vaccination, in contrast to immunocompetent patients who had similar responses with either approach. This finding may explain the comparatively higher success rate (60%) seen after a dose of mRNA-1273 in a small cohort of nonresponders to BNT162b2.¹²

In line with previous reports, Schrezenmeier et al. observed a high degree of correlation between spike IgG antibody and neutralizing antibody titers. Measurement of anti-S1 IgG in transplant recipients may become a useful clinical aid to identify and counsel patients who remain serologically unresponsive after booster doses. It should be noted, however, that time since receipt of the vaccine dose, and possibly other factors, can modulate the relationship between anti-S1 IgG and neutralizing antibody levels, and routine use of anti-S1 IgG is not currently recommended by the AST. Finally, Schrezenmeier et al. demonstrated a strong correlation between vaccine-specific T cell frequencies and antibody titers after vaccination. The relative importance of humoral versus cellular immunity in vaccine-derived protection and the degree of concordance between the two in transplant recipients remains an area of active investigation. Ultimately, optimization of vaccine efficacy in this population will require a multipronged strategy that incorporates emerging information on host factors correlating with the strength and durability of protection after vaccination, as well as data from trials of new regimens of vaccine delivery. In the interim, the less than optimal immune response to a third dose of SARS-CoV-2 mRNA in post-transplant patients should provide the impetus for intensifying efforts to complete COVID-19 vaccination prior to transplant. Transplant centers need to combat vaccine hesitancy with education and ultimately vaccine mandates for waitlisted patients awaiting transplantation.

Disclosures

S. Chandran reports consultancy agreements with Everest Clinical Research and Bride Bio Gene Therapy; and research funding from Bristol-Myers Squibb and Genentech-Roche. The remaining author has nothing to disclose.

Funding

None.