Transplant patients are typically on chronic immunosuppression, making them automatically more vulnerable to infection with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the agent responsible for the loss of over three million lives in the current coronavirus disease 2019 (COVID-19) pandemic.
A new study, released as a preprint on the bioRxiv* server, discusses evidence for subnormal immune responses following COVID-19 in this population.
The history of transplant medicine has shown that these patients, being on high doses of immunosuppressive medication to ensure the survival of the transplanted organ, show poor responses to vaccination and an increased risk of severe viral infection.
*Important notice: bioRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.
Study aims
The current study focuses not only on humoral responses to the virus, but pre-existing T-cell immunity that was elicited by previous exposure to human coronaviruses (hCoVs). The latter are in wide circulation and are estimated to cause about 15% of seasonal flu.
The importance of cross-reactive pre-existing T cell immunity is its independent protective role against SARSd-CoV-2 infection, even when the antibody response is weak or ineffective. This may be the case not just in immunosuppressed individuals, but also when novel strains of the virus emerge that evade previously elicited antibodies by specific mutations on their receptor-binding domains (RBD).
The existence of T cell immunity is also the rationale behind the safe mingling of people who cannot safely or effectively take the vaccine but need to mix with others. The present paper deals with T cell immunity against SARS-CoV-2 in transplant recipients.
The researchers chose to use non-selected peptides from the viral spike protein, rather than immunodominant peptides, as is the practice in many recently described T cell assays. The reason for their choice is to avoid the hyperstimulation that is likely to occur in individuals with high-frequency HLA specificities with the sole use of peptides that bind with high affinities to these specificities.
In other cases, co-stimulatory peptides are used, which may also overstimulate the cognate T cells. A third objectionable practice is the use of counting methods that recognize only multi-marker cells to be reactive to the antigen, thus proving to be less than ideal for use with lymphopenic COVID-19 patients. This also requires advanced laboratory facilities.
Finally, findings from infected or convalescent non-transplant patients should not be simply extended to transplant patients, as the former are known to have higher frequencies of reactive T cells compared even to healthy or unexposed individuals, but very low numbers in case of critical illness.
Study details
The scientists chose a mixture of peptides containing the whole spike sequence with one marker of activation. The study population (n = 204) included both healthy unexposed transplant recipients on chronic immunosuppression, those with COVID-19 (mostly hospitalized), and non-transplant individuals (n = 130).
Of a total of 204 subjects, 101 were healthy, with 38 were non-white, 47 were male and with a median age of 41 years. Among the 103 COVID-19 patients, 83 were non-white, 60 were male, and the median age was 54 years. There were 74 transplant patients, 32 of whom had COVID-19.
CD154 was used as a marker for spike-reactive T cells, since they also expressed gamma-interferon (IFNγ), characteristic of cytotoxic T cells, and spike-specific B cells, which expressed interleukin (IL) -6.
What were the results?
The investigators found that both T and B cell responses dropped in transplant patients who were hospitalized with COVID-19, as well as those with severe COVID-19 infection, compared to healthy transplant patients.
Non-transplant recipients showed no difference with or without COVID-19, except for impaired spike-specific CD3 T cells in the latter.
Impaired RBD antibody responses were also seen in transplant patients with COVID-19, compared to non-transplant patients, but anti-spike immunoglobulin G (IgG) antibodies were comparable in both. Spike-reactive B cells were also fewer in COVID-19 patients compared to healthy subjects, without differentiation by transplant status.
Infection with cytomegalovirus (CMV) was more frequent in transplant patients, affecting over a third of them. While 11 had evidence of CMV in the blood, one had CMV hepatitis. T cell immunity specific to this virus was lower in transplant recipients with COVID-19, but not non-transplant patients with COVID-19. None of the latter developed CMV infection.
Spike-reactive T cells were present in pre-pandemic blood samples from transplant recipients in chronic immunosuppression, as has been earlier reported in the population at large. Healthy unexposed non-transplant subjects also had spike-reactive T cells in pre-pandemic samples.
The implications
The significant reduction in spike-reactive T cell frequencies in COVID-19 patients, relative to healthy unexposed subjects, observed in this study, is found in both transplant and non-transplant subjects, but more so in the former subset.
In transplant patients, the reduction in this subset of T cells was also progressive with increasing severity of disease, compared to those without COVID-19. In fact, with mild COVID-19, transplant patients showed the same frequencies as those without the infection. Thus, the reason for the lower spike-specific T cell frequencies seen among transplant patients with COVID-19 may be due to the severe profile of the whole transplant cohort, where most were hospitalized.
In non-transplant COVID-19 patients, the decrease was seen only in severe illness.
Some earlier studies have shown higher spike-reactive T cells in convalescence, but this may also be due to the use of selected peptides, as already discussed. The increased frequency of spike-reactive T cells in healthy naïve transplant recipients compared to non-transplant subjects is a matter for further research. One possible explanation is that chronic immunosuppression facilitates an enrichment of such cells.
The lower IgG antibody levels to the spike RBD may mean that COVID-19 vaccines may not be effective in transplant recipients. The current study also showed increased circulating myeloid-derived suppressor cells (MDSC) in COVID-19 patients, which is typically seen in lymphopenia and has a suppressive effect on T cells.
Surveillance of CMV viral loads during COVID-19 infection, and post-vaccination surveillance of antibody responses to confirm vaccine efficacy may be necessary in transplant recipients.”
*Important notice: bioRxiv 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.
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