Pillar 4
Functional Genomics & Structure-Function of VOCs

Immunocompromised patients are predisposed to severe symptoms of COVID-19.  Organ transplant recipients are typically treated with life-long immunosuppressants that can impair their immune responses to infectious pathogens.  In addition, preventative strategies such as vaccine boosters are less immunogenic, and the body of an immunosuppressed individual can serve as a permissive environment for the virus to replicate.  In this study, the authors compared antibody- and cell-mediated immune responses to Omicron BA.1 in organ transplant patients across a spectrum of organ transplant types, immunosuppressant medication regimens, and recovery from SARS-CoV-2 infections.  Four cohorts of study participants were recruited by the clinical team:  transplant recipients who were infected with Omicron BA.1 variant, transplant recipients who experienced an infection with a non-Omicron variant, uninfected transplant recipients who received 3 doses of an mRNA-1273 (Moderna) vaccine, and uninfected healthcare workers vaccinated with 3 doses of BNT162b2 (Pfizer) vaccine.  Blood was collected 1-3 months after symptom onset or a third dose of vaccine.  Serum was used for downstream antibody assays, whereas white blood cells were collected for T cell experiments.

Researchers in this study performed variant-specific neutralization assays for D614G, and Omicron-BA.1, -BA.2, and Delta variants to measure the ability of circulating antibodies to prevent viral variant entry into cells.   In these assays, synthetic virus-like particles (VLPs) with spike proteins from variants of concern and antibody-containing serum samples were incubated with lab-grown cells. Researchers observed that samples from partially or fully vaccinated transplant recipients who were infected with Omicron-BA.1 had greater BA.1 neutralizing antibody levels with the ability to cross neutralize BA.2 when compared to samples from those who were infected with non-Omicron variants.

The ability of T-cells to respond to Omicron-BA.1 and ancestral spike stimulation was also measured.  In these experiments, spike protein fragments (containing variant-mutations) were presented to T-cells, which were then allowed to mature, and the T-cells’ ability to produce immune factors was measured as a readout of a functional immune response.  Omicron-BA.1-infected transplant recipients showed the greatest BA.1-specific T-cell responses when compared to the other cohorts, at levels comparable to triple-vaccinated healthcare workers.

In summary, this study showed that unvaccinated transplant patients with prior non-Omicron SARS-CoV-2 infection, or patients vaccinated with three doses of mRNA vaccine, may be at risk for symptomatic or severe Omicron infection, due to their lower antibody and T-cell responses to Omicron BA.1.  In contrast, partially or fully vaccinated transplant recipients who recovered from Omicron-BA.1 infection developed potent neutralizing antibody and T-cell responses, similar in extent to triple-vaccinated immuno-competent controls. These include cross-reactive antibody responses to BA.2. This suggests that the risk for reinfection and severe disease may be comparatively reduced in this sub-group.

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Homotypic and heterotypic immune responses to Omicron variant in immunocompromised patients in diverse clinical settings. Victor H. Ferreira, Javier T. Solera, Queenie Hu, Victoria G. Hall, Berta G. Arbol, W. Rod Hardy, Reuben Samson, Tina Marinelli, Matthew Ierullo, Avneet Kaur Virk, Alexandra Kurtesi, Faranak Mavandadnejad, Beata Majchrzak-Kita, Vathany Kulasingam, Anne-Claude Gingras, Deepali Kumar, Atul Humar. Nature Communications. 2022. 08.04.32235; https://www.nature.com/articles/s41467-022-32235-x