Pillar 4
Functional Genomics & Structure-Function of VOCs

In 2022, Omicron replaced Wild-type and Delta virus strains as the dominant strain of SARS-CoV-2. During the emergence and establishment of Omicron variant, three doses of vaccine were recommended as the primary vaccine series for solid organ transplant recipients. Transplant recipients were recommended a 3rd dose of vaccine as part of their primary vaccine series because routine treatments with immunomodulators and immunosuppressants result in immunodeficiencies. Inducing immunodeficiency is important during organ transplantation to prevent rejection of the organ transplant by the patient’s normal immune system. Importantly, immunogenicity of vaccines containing wild-type spike antigens against the circulating Omicron strain was not well studied at the time of this report.

The main objective of this study was to determine if three doses of vaccine was sufficient to induce an immune response that can neutralise Omicron in transplant recipients. The study team recruited 60 solid-organ transplant recipients who received 3 doses of mRNA-1273 (Moderna).  Serum was isolated from the blood at 1-month and 3-months following third vaccinations. CoVaRR-Net researchers collaborated with the study team to measure the ability of antibodies to block (neutralize) Omicron virus entry into host cells.  Approximately 18.3% of transplant recipients had detectable neutralizing antibody responses to Omicron at 1 month and roughly 15.7% of transplant recipients had detectable neutralizing antibody responses to Omicron at 3 months following their primary vaccine series. Neutralizing antibody responses were compared between wild-type, Delta, and Omicron variants.  The proportion of patients with a detectable neutralization against Omicron was significantly reduced when compared to Delta or Wild-type variants.  For example, at 3 months, an approximate 18.8- fold reduction in neutralizing antibody response was detected for Omicron compared to Wild-type strains.

The receptor binding domain (RBD) of spike protein is important because during infection, this region mediates binding of SARS-CoV-2 virus to host receptors. The Omicron variant is a concern because it contains 37 spike mutations, of which 15 are RBD mutations, which may result in altered efficacy of vaccines or therapeutic treatments designed to target the RBD region.  To understand whether the anti-RBD antibodies generated in response to vaccination could have neutralizing capacity, the study compared anti-RBD antibody levels with the proportion of those who had neutralizing antibodies to Omicron.  Researchers observed that 70% of patients had detectable anti-RBD antibodies out to 3 months.  While most patients with Omicron-neutralizing antibodies had higher levels of anti-RBD antibodies, most patients (81.6%) did not have detectable neutralizing antibodies.  Those without neutralizing antibodies had lower anti-RBD antibody levels.  These results suggest that despite some overlap between anti-Omicron neutralizing antibody level and anti-RBD levels, we should not automatically assume that the same antibodies with RBD binding ability can neutralize Omicron.  Additionally, this study showed that three vaccine doses in transplant patients resulted in poor neutralizing responses to the Omicron variant.

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Neutralisation against Omicron variant in transplant recipients after three doses of mRNA vaccine. Deepali Kumar, Queenie Hu, Reuben Sampson, Victor H. Ferreira, Victoria G. Hall, Matthew Ierullo, Beata Majchrzak-Kita, William Hardy, Anne-Claude Gingras, Atul Humar. American Journal of Transplantation. 2022.08.22.00010-7; https://www.amjtransplant.org/article/S1600-6135(22)00010-7/fulltext