Frailty impacts immune responses to Moderna COVID-19 mRNA vaccine in older adults.

BACKGROUND: Immune responses to COVID-19 mRNA vaccines have not been well characterized in frail older adults. We postulated that frailty is associated with impaired antibody and cellular mRNA vaccine responses. METHODS: We followed older adults in a retirement facility with longitudinal clinical and serological samples from the first Moderna mRNA-1273 vaccine dose starting in February 2021 through their 3rd (booster) vaccine dose. Outcomes were antibody titers, antibody avidity, and AIM+ T cell function and phenotype. Statistical analysis used linear regression with clustered error for antibody titers over multiple timepoints with clinical predictors including, age, sex, prior infection status, and clinical frailty scale (CFS) score. T cell function analysis used linear regression models with clinical predictors and cellular memory phenotype variables. RESULTS: Participants (n = 15) had median age of 90 years and mild, moderate, or severe frailty scores (n = 3, 7, or 5 respectively). Over the study time course, anti-spike antibody titers were 10-fold higher in individuals with lower frailty status (p = 0.001 and p = 0.005, unadjusted and adjusted for prior COVID-19 infection). Following the booster, titers to spike protein improved regardless of COVID-19 infection or degree of frailty (p = 0.82 and p = 0.29, respectively). Antibody avidity significantly declined over 6 months in all participants following 2 vaccine doses (p < 0.001), which was further impaired with higher frailty (p = 0.001). Notably, avidity increased to peak levels after the booster (p < 0.001). Overall antibody response was inversely correlated with a phenotype of immune-senescent T cells, CD8 + CD28- TEMRA cells (p = 0.036, adjusted for COVID-19 infection). Furthermore, there was increased detection of CD8 + CD28- TEMRA cells in individuals with greater frailty (p = 0.056, adjusted for COVID-19). CONCLUSIONS: We evaluated the immune responses to the Moderna COVID-19 mRNA vaccine in frail older adults in a retirement community. A higher degree of frailty was associated with diminished antibody quantity and quality. However, a booster vaccine dose at 6 months overcame these effects. Frailty was associated with an increased immune-senescence phenotype that may contribute to the observed changes in the vaccine response. While the strength of our conclusions was limited by a small cohort, these results are important for guiding further investigation of vaccine responses in frail older adults.

Frailty and Age Impact Immune Responses to Moderna COVID-19 mRNA Vaccine.

BACKGROUND: Immune responses to COVID-19 mRNA vaccines have not been well characterized in frail older adults. We postulated that frailty is associated with impaired antibody and cellular mRNA vaccine responses. METHODS: We followed older adults in a retirement facility with longitudinal clinical and serological samples from the first Moderna mRNA-1273 vaccine dose starting in February 2021 through their 3rd (booster) vaccine dose. Outcomes were antibody titers, antibody avidity, and AIM+ T cell function and phenotype. Statistical analysis used antibody titers in linear mixed-effects linear regression with clinical predictors including, age, sex, prior infection status, and clinical frailty scale (CFS) score. T cell function analysis used clinical predictors and cellular phenotype variables in linear regression models. RESULTS: Participants (n=15) had median age of 90 years and mild, moderate, or severe frailty scores (n=3, 7, or 5 respectively). After 2 vaccine doses, anti-spike antibody titers were higher in 5-fold higher in individuals with mild frailty compared to severe frailty and 9-fold higher in individuals with prior COVID-19 infection compared to uninfected (p=0.02 and p<0.001). Following the booster, titers improved regardless of COVID-19 infection or frailty. Antibody avidity significantly declined following 2 vaccine doses regardless of frailty status, but reached maximal avidity after the booster. Spike-specific CD4+ T cell responses were modulated by frailty and terminally differentiated effector memory TEMRA cells, and spike-specific TFH cell responses were inversely correlated with age. Additionally, an immune-senescent memory T cell phenotype was correlated with frailty and functional decline. CONCLUSIONS: We described the separate influences of frailty and age on adaptive immune responses to the Moderna COVID-19 mRNA vaccine. Though overall antibody responses were robust, higher frailty diminished initial antibody quantity, and all older adults had impaired antibody avidity. Following the booster, antibody responses improved, overcoming the effects of age and frailty. CD4+ T cell responses were independently impacted by age, frailty, and burden of immune-senescence. Frailty was correlated with increased burden of immune-senescence, suggesting an immune-mediated mechanism for physiological decline.

Frailty and COVID-19 mRNA Vaccine Antibody Response in the COVID-19 Community Research Partnership.

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.

Detection of Environmental Spread of SARS-CoV-2 and Associated Patient Characteristics.

Understanding transmission of severe acute respiratory syndrome coronavirus 2 informs infection prevention practices. Air sampling devices were placed in patient hospital rooms for consecutive collections with and without masks. With patient mask use, no virus was detected in the room. High viral load and fewer days from symptom onset were associated with viral particulate dispersion.

Mass-forming cholangiocarcinoma and adenocarcinoma of unknown primary: can they be distinguished on liver MRI?

PURPOSE: To determine MR features suggestive of mass-forming cholangiocarcinoma (CCA) or liver metastases of adenocarcinoma of unknown primary (AUP), and to compare the ability of two experienced radiologists to establish the correct diagnosis. MATERIALS AND METHODS: 61 patients with CCA or AUP, with MRIs were placed into two groups: population 1, 28 patients with certain diagnosis of either CCA or AUP; and population 2, 33 patients with uncertain diagnosis. Using population 1 with known diagnosis, two investigators formulated imaging criteria for CCA or AUP, which represented phase 1 of the study. In phase 2, two independent radiologists categorized the patients in populations 1 and 2 as CCA or AUP using the formulated criteria. This categorization was compared with the patient medical records and pathologist review. Findings were tested for statistical significance. RESULTS: In phase 1, solitary lesion, multifocal lesions with dominant lesion, capsule retraction, and porta hepatis lymphadenopathy were features of CCA; multifocal lesions with similar size, and ring enhancement were features of AUP. The number of lesions, capsule retraction, and early tumor enhancement pattern were observed to be significant features (P < 0.05). In phase 2, agreement between the two radiologists was good (k = 0.663). For population 1, the agreement was good (k = 0.659), and was fair for population 2 (k = 0.293). Concordance between the two radiologists, medical record, and the pathologist was found in 41/61 (67%) patients. CONCLUSION: Distinctive features of CCA and AUP are identifiable on MRI images, which may aid the radiologist to establish the correct diagnosis.

Identification of metabolic pathways influenced by the G-protein coupled receptors GprB and GprD in Aspergillus nidulans.

Heterotrimeric G-protein-mediated signaling pathways play a pivotal role in transmembrane signaling in eukaryotes. Our main aim was to identify signaling pathways regulated by A. nidulans GprB and GprD G-protein coupled receptors (GPCRs). When these two null mutant strains were compared to the wild-type strain, the ΔgprB mutant showed an increased protein kinase A (PKA) activity while growing in glucose 1% and during starvation. In contrast, the ΔgprD has a much lower PKA activity upon starvation. Transcriptomics and (1)H NMR-based metabolomics were performed on two single null mutants grown on glucose. We noted modulation in the expression of 11 secondary metabolism gene clusters when the ΔgprB and ΔgprD mutant strains were grown in 1% glucose. Several members of the sterigmatocystin-aflatoxin gene cluster presented down-regulation in both mutant strains. The genes of the NR-PKS monodictyphenone biosynthesis cluster had overall increased mRNA accumulation in ΔgprB, while in the ΔgprD mutant strain the genes had decreased mRNA accumulation. Principal component analysis of the metabolomic data demonstrated that there was a significant metabolite shift in the ΔgprD strain. The (1)H NMR analysis revealed significant expression of essential amino acids with elevated levels in the ΔgprD strain, compared to the wild-type and ΔgprB strains. With the results, we demonstrated the differential expression of a variety of genes related mainly to secondary metabolism, sexual development, stress signaling, and amino acid metabolism. We propose that the absence of GPCRs triggered stress responses at the genetic level. The data suggested an intimate relationship among different G-protein coupled receptors, fine-tune regulation of secondary and amino acid metabolisms, and fungal development.