Structural and energetic evidence for highly peptide-specific tumor antigen targeting via allo-MHC restriction.

Immunotherapies targeting peptides presented by allogeneic MHC molecules offer the prospect of circumventing tolerance to key tumor-associated self-antigens. However, the degree of antigen specificity mediated by alloreactive T cells, and their ability to discriminate normal tissues from transformed cells presenting elevated antigen levels, is poorly understood. We examined allorecognition of an HLA-A2-restricted Hodgkin's lymphoma-associated antigen and were able to isolate functionally antigen-specific allo-HLA-A2-restricted T cells from multiple donors. Binding and structural studies, focused on a prototypic allo-HLA-A2-restricted T-cell receptor (TCR) termed NB20 derived from an HLA-A3 homozygote, suggested highly peptide-specific allorecognition that was energetically focused on antigen, involving direct recognition of a distinct allopeptide presented within a conserved MHC recognition surface. Although NB20/HLA-A2 affinity was unremarkable, TCR/MHC complexes were very short-lived, consistent with suboptimal TCR triggering and tolerance to low antigen levels. These data provide strong molecular evidence that within the functionally heterogeneous alloreactive repertoire, there is the potential for highly antigen-specific "allo-MHC-restricted" recognition and suggest a kinetic mechanism whereby allo-MHC-restricted T cells may discriminate normal from transformed tissue, thereby outlining a suitable basis for broad-based therapeutic targeting of tolerizing tumor antigens.

Is vaccine confidence an unexpected victim of the COVID-19 pandemic?

Vaccines are among the safest and most effective primary prevention measures. Thanks to the synergistic global efforts of research institutions, pharmaceutical companies and national health services, COVID-19 vaccination campaigns were successfully rolled out less than a year after the start of the pandemic. While the unprecedented speed of development and approval of COVID-19 vaccines has been applauded as a public health success story, it also spurred considerable controversy and hesitancy even amongst individuals that did not previously hold anti-vaccination stances. This study aimed to compare pre- and post-pandemic vaccine confidence trends in different demographic groups by analysing the outcomes of two online surveys run respectively in November 2019 and January 2022 involving a total of 1009 participants. Non-parametric tests highlighted a statistically significant decline in vaccine confidence in the 2022 cohort compared to the 2019 cohort, with median Vaccine Confidence Score dropping from 22 to 20 and 23.8% of participants reporting that their confidence in vaccines had declined since the onset of the pandemic. While the majority of internal trends were comparable between the two surveys with regards to gender, graduate status and religious belief, vaccine confidence patterns showed considerable alterations with regards to age and ethnicity. Middle-aged participants were considerably more hesitant than younger groups in the 2019 cohort, however this was not the case in the 2022 survey. In both surveys White participants showed significantly higher vaccine confidence than those from Black backgrounds; in the 2022 cohort, unlike the pre-pandemic group, Asian participants showed significantly lower confidence than White ones. This study suggests that paradoxically, despite the success of COVID-19 vaccination campaigns, vaccine confidence has significantly declined since the onset of the pandemic; the comparison of a pre- and post-pandemic cohort sheds light on the differential effect that the pandemic had on vaccine confidence in different demographic groups.