Additive effects of booster mRNA vaccination and SARS-CoV-2 Omicron infection on T cell immunity across immunocompromised states

Abstract

Suboptimal immunity to SARS-CoV-2 mRNA vaccination has frequently been observed in individuals with various immunodeficiencies. Given the increased antibody evasion properties of emerging SARS-CoV-2 subvariants, it is necessary to assess whether other components of adaptive immunity generate resilient and protective responses against infection. We assessed T cell responses in 279 individuals, covering five different immunodeficiencies and healthy controls, before and after booster mRNA vaccination, as well as after Omicron infection in a subset of patients. We observed robust and persistent Omicron-reactive T cell responses that increased markedly upon booster vaccination and correlated directly with antibody titers across all patient groups. Poor vaccination responsiveness in immunocompromised or elderly individuals was effectively counteracted by the administration of additional vaccine doses. Functionally, Omicron-reactive T cell responses exhibited a pronounced cytotoxic profile and signs of longevity, characterized by CD45RA + effector memory subpopulations with stem cell–like properties and increased proliferative capacity. Regardless of underlying immunodeficiency, booster-vaccinated and Omicron-infected individuals appeared protected against severe disease and exhibited enhanced and diversified T cell responses against conserved and Omicron-specific epitopes. Our findings indicate that T cells retain the ability to generate highly functional responses against newly emerging variants, even after repeated antigen exposure and a robust immunological imprint from ancestral SARS-CoV-2 mRNA vaccination.

SARS-CoV-2 Variants Omicron BA.4/5 and XBB.1.5 Significantly Escape T Cell Recognition in Solid-organ Transplant Recipients Vaccinated Against the Ancestral Strain

“…Indeed, longitudinal analyses of immune-suppressed patients with diverse pathologies observe sharp declines in post-second dose responses, 29,51 whereas responses remain stable at similar magnitudes to healthy individuals following third and fourth doses. 28,51 Interestingly, although a fourth dose enhanced CD4 + responses compared with post-third dose levels, breakthrough infection did not further stimulate BA.4/5-specific T cells in patients who received a fourth dose, despite cases occurring during the Omicron wave of December 2021 to March 2022. However, these infections occurred >4 mo (IQR, 111-148 d) before 1-y sampling, thus the acute T cell response to infection was likely not captured.…”

“…The BA.4/5 and XBB.1.5 variants escape antibodymediated neutralization in individuals vaccinated against the ancestral strain. 13,[16][17][18][19][20]62 CD4 + and CD8 + T cell responses have thus far shown conserved cross-reactivity with Omicron 18,[26][27][28]63 including BA.4/5 in immune-compromised patients and SOTRs, 30,64 but no data existed for T cell responses to XBB.1.5. In contrast to previous research, we found small but significant decreases in T cell recognition of BA.4/5 relative to the ancestral strain.…”

“…25 Furthermore, memory T cells cross-recognize emerging variants, including Omicron and BA sublineages. 18,[25][26][27][28] However, SOTRs display poor cellular responses to vaccination, with lower Spike-specific CD4 + and CD8 + T cell frequencies compared with healthy controls 2 wks and 6 mo after 2-dose vaccination. 25,29 Although BA.4/5 and XBB.1.5 escape antibody neutralization, whether vaccination against the ancestral strain induces T cell responses cross-recognizing these variants is unclear in SOTRs.…”

Early antiviral CD4 and CD8 T cell responses and antibodies are associated with upper respiratory tract clearance of SARS-CoV-2

“…However, in the context of infection it is plausible that the relative importance of different compartments of the immune system shifts, and that viral control and clearance requires cellular immunity 15–19 . While there has been clear evidence of acute and memory T cell responses to SARS-CoV-2 infection 20–26 and COVID-19 vaccines 27–34 , studies on protective roles of T cells have been limited in humans, particularly in non-hospitalized cases, given the technical difficulties of conducting large scale studies examining acute antigen-specific T cell responses and viral loads concomitantly in non-hospitalized individuals 19,35–37 . There is evidence for cellular immunity contributing to SARS-CoV-2 protection in non-human primate models 18 .…”

Host-Microbe Multi-omic Profiling Identifies a Unique Program of COVID-19 Inflammatory Dysregulation in Solid Organ Transplant Recipients

“…Coronavirus disease 2019 (COVID-19) has resulted in an enormous societal burden, with a toll of millions of infections and deaths worldwide 1 . Immunocompromised patients who have undergone solid organ transplantation (SOT) are more susceptible to SARS-CoV-2 infection and produce less robust antibody responses following vaccination 2 , although they can achieve effective T cell responses with multiple vaccinations 3 . In addition, they are more likely to be hospitalized, experience adverse clinical outcomes, and have longer durations of infectiousness compared to the general population [4][5][6][7][8] .…”