Recipients of solid organ transplant recipients can mount significant T-cell responses to the BA.4/5 and XBB.1.5 Omicron variants following mRNA vaccination against ancestral SARS-CoV-2

A CITF-funded study, published in Transplantation, provided insights into the kinetics of variant-specific T-cell responses in recipients of solid organ transplants, with the aim of informing clinical and public health guidelines for immunocompromised populations. The study showed that mRNA vaccination against the ancestral strain of SARS-CoV-2 strongly induces T-cells that are also reactive (cross-reactive) to the BA.4/5 and XBB.1.5 Omicron strains. However, the magnitude of the response to the Omicron strains was significantly lower than the response to the ancestral strain. This study was led by Dr. Torin Halvorson (University of British Columbia) in collaboration with Dr. Deepali Kumar (University Health Network).

The researchers hoped to shed more light on the incompletely understood T-cell responses for recipients of solid organ transplants, who already display an impaired immune response to COVID-19 vaccination.

They conducted a prospective study and quantified circulating spike-specific CD4+ and CD8+ T-cells against ancestral SARS-CoV-2, Omicron BA.4/5, and XBB.1.5 in 42 kidney, lung, and liver transplant recipients across seven tertiary care transplant centres in Canada. Participants were enrolled at first dose of a monovalent COVID-19 mRNA vaccine from January 2021 and followed throughout a three- or four-dose ancestral Spike mRNA vaccination schedule.

Whole blood was drawn from the participants:

• Six months and one year* after the first dose;
• Within two weeks prior to the second dose;
• Three to six weeks after the second dose;
• And three to six weeks after the third dose.

*For a subset of patients, the one year post first dose sample collection was used as the post-fourth dose timepoint.

From these blood draws, T-cells were isolated and then stimulated with spike proteins from either the ancestral or Omicron strains of COVID-19 to assess and compare T-cell activation.

Key findings:

• COVID-19 vaccination induced significant and durable BA.4/5-specific T- cell responses, especially after second and third doses of the ancestral vaccine;
• The subset of patients who received a fourth dose of the ancestral vaccine showed a further increase in BA.4/5 T-cell responses;
• T-cell responses to Omicron BA.4/5 were lower in magnitude than responses to the ancestral strain;
• Lung transplant recipients receiving prednisone and older individuals had weaker T-cell responses;
• SARS-CoV-2-specific T-cell responses to ancestral and BA.4/5 strains correlated strongly with circulating anti-spike antibodies, with the strength of this correlation enhanced by a third dose;
• It required three COVID-19 vaccine doses to induce a significant T-cell response against the novel XBB.1.5 Omicron variant.

The study provided the first activation-induced marker (AIM) based characterization of COVID-19 vaccine induced T-cell responses in recipients of solid organ transplants, confirming studies showing that transplant recipients mount significant T-cell responses to mRNA vaccination. These persist over time and are enhanced by booster doses. However, the researchers show using AIM assays that BA.4/5 and XBB.1.5 cross-recognition is impaired in transplant recipients. AIM assays can detect rare populations of T-cells and generally have a high sensitivity, which makes them well-suited to detecting small differences.

The researchers were not able to draw any conclusions relative to the general population as the study did not include any healthy controls. Their sample size was also insufficient to assess whether AIM responses could predict subsequent infections or hospitalizations.