Prior vaccination promotes early activation of memory T cells and enhances immune responses during SARS-CoV-2 breakthrough infection.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection of vaccinated individuals is increasingly common but rarely results in severe disease, likely due to the enhanced potency and accelerated kinetics of memory immune responses. However, there have been few opportunities to rigorously study early recall responses during human viral infection. To better understand human immune memory and identify potential mediators of lasting vaccine efficacy, we used high-dimensional flow cytometry and SARS-CoV-2 antigen probes to examine immune responses in longitudinal samples from vaccinated individuals infected during the Omicron wave. These studies revealed heightened spike-specific responses during infection of vaccinated compared to unvaccinated individuals. Spike-specific cluster of differentiation (CD)4 T cells and plasmablasts expanded and CD8 T cells were robustly activated during the first week. In contrast, memory B cell activation, neutralizing antibody production and primary responses to nonspike antigens occurred during the second week. Collectively, these data demonstrate the functionality of vaccine-primed immune memory and highlight memory T cells as rapid responders during SARS-CoV-2 infection.

A Cluster of Neuroinvasive Adenovirus Infections on a College Campus: Case Series.

INTRODUCTION: We present six adenovirus cases that emerged from a cluster of respiratory illnesses within a college population. Two patients required intensive care with complicated hospital courses and experienced residual symptoms. Four additional patients were evaluated in the emergency department (ED) with two additional diagnoses of neuroinvasive disease. These cases represent the first known occurrences of neuroinvasive adenovirus infections in healthy adults. CASE SERIES: An individual presented to the ED with fever, altered mental status, and seizures after being found unresponsive in his apartment. His presentation was concerning for significant central nervous system pathology. Shortly after his arrival, a second individual presented with similar symptoms. Both required intubation and admission to a critical care setting. Over a 24-hour period, four additional individuals presented to the ED with moderate severity symptoms. All six individuals tested positive for adenovirus in their respiratory secretions. A provisional diagnosis of neuroinvasive adenovirus was made after consultation with infectious diseases. CONCLUSION: This cluster of cases appears to represent the first known reported diagnosis of neuroinvasive adenovirus in healthy young individuals. Our cases were also unique in demonstrating a significant spectrum of disease severity. Over 80 individuals in the broader college community ultimately tested positive for adenovirus in respiratory samples. As respiratory viruses continue to challenge our healthcare systems, new spectrums of disease are being discovered. We believe clinicians should be aware of the potential severity of neuroinvasive adenovirus disease.

Prior vaccination enhances immune responses during SARS-CoV-2 breakthrough infection with early activation of memory T cells followed by production of potent neutralizing antibodies.

SARS-CoV-2 infection of vaccinated individuals is increasingly common but rarely results in severe disease, likely due to the enhanced potency and accelerated kinetics of memory immune responses. However, there have been few opportunities to rigorously study early recall responses during human viral infection. To better understand human immune memory and identify potential mediators of lasting vaccine efficacy, we used high-dimensional flow cytometry and SARS-CoV-2 antigen probes to examine immune responses in longitudinal samples from vaccinated individuals infected during the Omicron wave. These studies revealed heightened Spike-specific responses during infection of vaccinated compared to unvaccinated individuals. Spike-specific CD4 T cells and plasmablasts expanded and CD8 T cells were robustly activated during the first week. In contrast, memory B cell activation, neutralizing antibody production, and primary responses to non-Spike antigens occurred during the second week. Collectively, these data demonstrate the functionality of vaccine-primed immune memory and highlight memory T cells as rapid responders during SARS-CoV-2 infection.

Human Invariant NKT Cells Induce IL-1ß Secretion by Peripheral Blood Monocytes via a P2X7-Independent Pathway.

The cytokine IL-1ß plays a central role in inflammatory responses that are initiated by microbial challenges, as well as in those that are due to endogenous processes (often called sterile inflammation). IL-1ß secretion that occurs independently of microbial stimulation is typically associated with the presence of endogenous alarmins, such as extracellular ATP (an indicator of cytopathic damage). In this study, we show that IL-2-activated human invariant NKT (iNKT) cells stimulate the secretion of IL-1ß protein by human peripheral blood monocytes in a manner that requires neither the presence of microbial compounds nor signaling through the extracellular ATP receptor P2X7 Monocyte IL-1ß production was specifically induced by iNKT cells, because similarly activated polyclonal autologous T cells did not have this effect. Secretion of IL-1ß protein occurred rapidly (within 3-4 h) and required cell contact between the iNKT cells and monocytes. Similar to IL-1ß production induced by TLR stimulation, the iNKT-induced pathway appeared to entail a two-step process involving NF-κB signaling and IL1B gene transcription, as well as assembly of the NLRP3 inflammasome and activation of caspase-1. However, in contrast to the classical inflammasome-mediated pathway of IL-1ß production, activation of monocytes via P2X7 was dispensable for iNKT-induced IL-1ß secretion, and potassium efflux was not required. Moreover, the iNKT-induced effect involved caspase-8 activity, yet it induced little monocyte death. These results suggest that IL-2-activated human iNKT cells induce monocytes to produce IL-1ß through a distinctive pathway that does not require the presence of microbial danger signals or alarmins associated with cytopathic damage.