Unpacking the COVID-19 vaccine responses: Do we have what we need for a successful trip?

The SARS‐CoV‐2 pandemic has upended the world and the field of transplantation. With the introduction of COVID‐19 vaccines, we have entered a new phase; however, our understanding of vaccine responses and protection against infection in solid organ transplant recipients continue to evolve.

The current manuscript from Herrera et al. provides new insight into mRNA vaccine immune responses to mRNA‐1273 in COVID‐19 naïve liver and heart recipients. The authors evaluated safety, SARS‐CoV‐2 IgM/IgG antibody responses and spike‐specific cellular immune responses using an ELISpot assay 4 weeks following the second dose of the vaccine in 58 liver and 46 heart transplant recipients. Side effects mirrored those reported in the general population, and no breakthrough COVID‐19, no rejection or increase in HLA antibodies were detected. Antibody responses were consistent with previous reports for liver and heart recipients at 71% and 57%, respectively. Interestingly, 86% of liver and 70% of heart recipients showed ELISpot positivity. Overall, decreased responses were associated with vaccination within a year post‐transplant and hypogammaglobulinemia. The combined antibody or cellular responses reached 87% in the heart and 93% in liver recipients, which emphasizes the potential value of adding cellular immunity to estimates of overall response rates. Interestingly, a corresponding report in kidney transplant recipients recorded only 65% of patients with humoral or cellular immunity, which may in part be related to the inclusion of more patients within the first year after transplantation (29% kidney compared to 17% liver and 4% heart). In addition, this report excluded individuals with prior COVID‐19 by including assessment of humoral and cellular responses at baseline, whereas the heart and liver cohort only considered baseline serology. This may have overestimated cellular response rates to vaccination by potentially including previously infected but antibody negative individuals. Despite these differences, we may be able to gain additional insight into vaccine response. Receipt of anti‐thymocyte globulin occurred in 12.8% of kidney recipients but no heart or liver recipients, while lymphopenia was most common in the kidney cohort (28% compared to 21% liver and 9% heart). The impact of mycophenolate is less easily discerned with substantial proportions of both heart (72%) and kidney (61.5%) recipients receiving this agent.

The knowledge that a large percentage of infection‐naïve patients not only develop antibodies but also T cells after standard vaccine regimens are encouraging as antibodies including their neutralizing activity have been shown to protect from infection, and T cells are associated with the prevention of severe disease. Despite the high percentage of individuals with evidence of specific immunity, the studies are limited by the lack of a control group or further characterization of T cell functionality which precludes estimation as to whether antibody and T cell levels are equivalent to vaccine‐induced immune responses in immunocompetent controls, which is likely not the case. Although protection may be insufficient, natural exposure in the community may lead to a further boost in immunity. This is supported by reports including the kidney transplant study  showing transplant recipients mount both antibodies and T cells after SARS‐CoV‐2 infection, which can be substantially boosted after vaccination to an extent comparable to immunocompetent individuals. The question therefore remains whether a less pronounced vaccine‐induced immunity in patients is sufficient to protect from severe disease and mortality. In this regard, a study among 18215 vaccinated transplant recipients has identified 151 breakthrough infections with a mortality rate of 9.3%. Although this breakthrough infection rate is higher as compared to the general population, a large registry study including 48213 organ transplant recipients in the UK has found a higher rate of COVID‐19 in unvaccinated (51%) compared to fully vaccinated (0.3%) in addition to vaccine‐induced decrease in mortality from 12.6% in unvaccinated individuals and 12.0% in patients after the first vaccine dose, to 7.7% in patients after a full course of vaccination.

Despite the gain in understanding both cellular and humoral vaccine responses in solid organ transplant recipients, questions remain how to determine correlates of protection from infection and disease. Titers of IgG correlate with neutralizing activity towards the wildtype strain and may be a promising candidate for vaccine effectiveness. However, with the emergence of variant strains of concerns that variably escape from antibody recognition, higher titers of antibodies, which can be achieved by booster doses, may be necessary to compensate for this loss in activity. In support of this, antibody titers were low or absent in 24 out of 25 transplant recipients with breakthrough infections. While this clearly emphasizes that non‐responders to a standard course of vaccination may be most vulnerable, future studies should define correlates of protection including clinically relevant thresholds for both antibodies and T cells to guide further prevention strategies in transplant recipients. Given the recent FDA‐approval for booster doses in transplant recipients, this should also include research on how to best use available vaccines including heterologous regimens to improve immunogenicity.

DISCLOSURE

The authors of this manuscript have no conflicts of interest to disclose as described by the American Journal of Transplantation.