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Background COVID-19 has disproportionately affected older adults. Frailty has been associated with impaired vaccine response in other vaccine types, but the impact of frailty on mRNA vaccine response is undefined. Methods Observational study of adults aged 55 and older from 1 U.S. health care system between January 22, 2021 and September 16, 2021 with self-reported Moderna or Pfizer COVID-19 mRNA vaccine and an electronic frailty index (eFI) score from their medical record (n = 1 677). Participants’ frailty status was compared with positive antibody detection (seroconversion) following full vaccination and subsequent loss of positive antibody detection (seroreversion) using logistic regression models. Results Of 1 677 older adults with median (interquartile range) age, 67 (62 and 72) years, and frailty status (nonfrail: 879 [52%], prefrail: 678 [40%], and frail: 120 [7.2%]), seroconversion was not detected in 23 (1.4%) over 60 days following full vaccination. Frail individuals were less likely to seroconvert than nonfrail individuals, adjusted odds ratio (OR) 3.75, 95% confidence interval (CI; 1.04, 13.5). Seroreversion was detected in 50/1 631 individuals (3.1%) over 6 months of median follow-up antibody testing. Frail individuals were more likely to serorevert than nonfrail individuals, adjusted OR 3.02, 95% CI (1.17, 7.33). Conclusion Overall antibody response to COVID-19 mRNA vaccination was high across age and frailty categories. While antibody detection is an incomplete descriptor of vaccine response, the high sensitivity of this antibody combined with health-system data reinforce our conclusions that frailty is an independent predictor of impaired antibody response to the COVID-19 mRNA vaccines. Frailty should be considered in vaccine studies and prevention strategies.

Background For cancer patients, rates of influenza-associated hospitalization and death are 4 times greater than that of the general population. Previously, we reported reduced immunogenicity to the standard-dose influenza vaccine in patients with central nervous system malignancy. In other poorly responding populations (eg, elderly patients), high-dose vaccination has improved efficacy and immunogenicity. Methods A prospective cohort study was designed to evaluate the immunogenicity of the Fluzone® high-dose influenza vaccine in brain tumor patients. Data on diagnosis, active oncologic treatment, and immunologic status (eg, CD4 count, CD8 count, CD4:CD8 ratio) were collected. All patients received the high-dose vaccine (180 µg). Hemagglutination inhibition titers were measured at baseline, day 28, and 3 months following vaccination to determine seroconversion (≥4-fold rise) and seroprotection (titer ≥1:40), which were compared to our prior results. Results Twenty-seven patients enrolled. Diagnoses included high-grade glioma (85%), CNS lymphoma (11%), and meningioma (4%). Treatment at enrollment included glucocorticoids (n = 8, 30%), radiation (n = 2, 7%), and chemotherapy (n = 9, 33%). Posttreatment lymphopenia (PTL, CD4 ≤ 200) was observed in 4 patients (15%). High-dose vaccination was well tolerated with no grade III-IV toxicity. Overall, seroconversion rates for the A/H1N1, A/H3N2, and B vaccine strains were significantly higher than in our prior study: 65% vs 37%, 69% vs 23%, and 50% vs 23%, respectively (all P < .04). Seroconversion was universally poor in patients with PTL. While seroprotection at 3 months declined in our prior study, no drop was observed following high-dose vaccination in this cohort. Conclusions The immunologic response to HD influenza vaccination was higher in this cohort than standard-dose influenza vaccination in our prior report. These findings mirror those in elderly patients where high-dose vaccination is the standard of care and raise the possibility of an immunosenescence phenotype.

Streptococcus pneumoniae (Spn) is a leading cause of community-acquired pneumonia, with infants and the elderly exhibiting significant susceptibility to the development of severe disease. A growing body of evidence supports the ability of Spn to negatively regulate the host response to infection, e.g. the capacity to induce death in numerous cell types. However, our understanding of the ability of Spn to directly impact lymphocytes remains limited. In this study, we tested the hypothesis that lymphocyte type and activation state influences the susceptibility to pneumococcus-mediated death. We show that in the resting state, CD4+ T cells exhibit a modestly increased susceptibility to Spn-induced death compared to CD8+ T cells or NK cells. In the presence of activating stimuli, the situation most reflective of what would occur in vivo during infection, all subsets demonstrated a significant increase in sensitivity to Spn-mediated death. Importantly, the activated subsets diverged dramatically in susceptibility with natural killer cells exhibiting an 8.6-fold greater sensitivity to pneumococcal components compared to the T-cell subsets. These results significantly expand our understanding of the capacity for pneumococcus to negatively regulate lymphocytes.

A previously unknown mechanism for the active negative regulation of function in effector T cells is described. CD8+ T cells play a critical role in the clearance of respiratory pathogens. Thus, it is surprising that functional inactivation of lung effectors has been observed in many models of viral infection. Currently, the molecular defect responsible for the shut-off of function in these cells is unknown. In the present study, we addressed this question using a model of respiratory infection with the paramyxovirus SV5. Nonfunctional cells were found to exhibit decreases in SOCE, resulting in reduced NFAT1 activation. Notably, function could be restored by the provision of increased levels of extracellular calcium. The reduced ability to mobilize calcium was associated with reduced expression of ORAI1, the CRAC channel subunit. These findings reveal a previously unknown mechanism for the negative regulation of function in effector T cells.

P18IIIB is a highly immunogenic peptide from the V3 loop of the HIV-1 gp160 envelope protein that is presented promiscuously by multiple class I MHC molecules. Understanding the molecular basis for promiscuous presentation may have many practical applications. As the highly prevalent HLAA2.1 class I molecule is known to present P18lilB for recognition by cytotoxic T lymphocytes (CTL) found in peripheral blood mononuclear cells of HIV + donors, a P18MIB-specific CTL line was generated from an HLA-A2 +, HIV~ donor in order to define the molecular basis for, and ultimately improve upon the binding of, this peptide to HLA-A2.1. The minimal epitope recognized by the line was a decamer, 110, with the sequence RGPGRAFVTI. Interestingly, this decamer is identical to the minimal epitope from P18IIIB seen by murine CTL restricted by H-2Dd. A panel of Ala-substitut ed peptides was employed in MHC-binding and T cell response studies to identify MHC- and TCRbinding residues. Notably, many of the agretopic and epitopic residues identified were identical to those involved in the corresponding interactions of 110 with the H-2Dd MHC molecule and murine 110-specific CTL. The 110 peptide does not contain the described HLA-A2.1 binding motif. Instead a Pro at P3, a Phe at P7 and an Me at P10 are utilized for MHC binding. Agretopic residue similarities with the hepatitis B nucleocapsid decamer suggest that these residues may comprise an alternative motif of anchors utilized by decamers for binding to HLA-A2.1.