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Soluble Immune Checkpoint Protein and Lipid Network Associations with All-Cause Mortality Risk: Trans-Omics for Precision Medicine (TOPMed) Program.

Annabelle Rodriguez·Chaojie Yang·Wenqi Gan·Keaton Karlinsey·Beiyan Zhou·Stephen S Rich·Kent D Taylor·Xiuqing Guo·Jerome I Rotter·W Craig Johnson·Elaine Cornell·Russell P Tracy·J Peter Durda·Robert E Gerszten·Clary B Clish·Thomas Blackwell·George J Papanicolaou·Honghuang Lin·Laura M Raffield·Jose D Vargas·Ramachandran Vasan·Ani Manichaikul
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Abstract

Adverse cardiovascular events are emerging with the use of immune checkpoint therapies in oncology. Using datasets in the Trans-Omics for Precision Medicine program (Multi-Ethnic Study of Atherosclerosis, Jackson Heart Study [JHS], and Framingham Heart Study), we examined the association of immune checkpoint plasma proteins with each other, their associated protein network with high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C), and the association of HDL-C- and LDL-C-associated protein networks with all-cause mortality risk. Plasma levels of LAG3 and HAVCR2 showed statistically significant associations with mortality risk. Colocalization analysis using genome wide-association studies of HDL-C or LDL-C and protein quantitative trait loci from JHS and the Atherosclerosis Risk in Communities identified TFF3 rs60467699 and CD36 rs3211938 variants as significantly colocalized with HDL-C; in contrast, none colocalized with LDL-C. The measurement of plasma LAG3, HAVCR2, and associated proteins plus targeted genotyping may identify patients at increased mortality risk.

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Annabelle Rodriguez, Chaojie Yang, Wenqi Gan, Keaton Karlinsey, Beiyan Zhou, Stephen S Rich, Kent D Taylor, Xiuqing Guo, Jerome I Rotter, W Craig Johnson, Elaine Cornell, Russell P Tracy, J Peter Durda, Robert E Gerszten, Clary B Clish, Thomas Blackwell, George J Papanicolaou, Honghuang Lin, Laura M Raffield, Jose D Vargas, Ramachandran Vasan, Ani Manichaikul. 2025-01-09. Soluble Immune Checkpoint Protein and Lipid Network Associations with All-Cause Mortality Risk: Trans-Omics for Precision Medicine (TOPMed) Program.. https://doi.org/10.1101/2025.01.08.25320225

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Effectiveness of high-dose versus standard-dose influenza vaccines against hospitalisation according to frailty risk: a prespecified analysis of the randomised trial DANFLU-2.

BACKGROUND: Frailty is a major risk factor for influenza-related complications and can influence vaccine effectiveness. We aimed to assess the relative vaccine effectiveness (rVE) of high-dose (HD-IIV) versus standard-dose inactivated influenza vaccine (SD-IIV) in older adults aged 65 years or older according to frailty risk. METHODS: This study was a prespecified analysis of DANFLU-2, an open-label, individually randomised trial, conducted in Denmark during three consecutive influenza seasons (2022-23, 2023-24, and 2024-25). Adults aged 65 years or older were randomised (1:1) to the HD-IIV or SD-IIV group. The primary endpoint was hospitalisation for influenza or pneumonia. Frailty was defined according to the validated Hospital Frailty Risk Score (HFRS) based on ICD-10 codes within 10 years before randomisation. Participants were stratified into three HFRS categories, namely low (<5 points), intermediate (5-15 points), and high (>15 points) frailty risk. The rVE of HD-IIV versus SD-IIV against the primary endpoint was assessed across prespecified HFRS categories and treating HFRS as a continuous variable. Pearson's chi-square test was used to compare safety events across frailty risk groups and randomisation groups. FINDINGS: Among 332&#x2009;438 randomised participants (mean age 73&#xb7;7 years [SD 5&#xb7;8]; 161&#x2009;538 [48&#xb7;6%] were female), 276&#x2009;173 (83&#xb7;1%) had low frailty risk, 52&#x2009;395 (15&#xb7;8%) had intermediate frailty risk, and 3861 (1&#xb7;2%) had high frailty risk. The primary endpoint of hospitalisation for influenza or pneumonia occurred in 1424 (0&#xb7;5%) of 276&#x2009;173 participants with low frailty risk, 761 (1&#xb7;5%) of 52&#x2009;395 with intermediate frailty risk, and 163 (4&#xb7;2%) of 3861 with high frailty risk (relative risk [RR] for intermediate vs low frailty risk 2&#xb7;8 [95% CI 2&#xb7;6-3&#xb7;1]; RR for high vs low frailty risk 8&#xb7;2 [7&#xb7;0-9&#xb7;6]). HFRS as a continuous variable significantly modified the effect of HD-IIV versus SD-IIV against the primary endpoint with higher rVE estimates with increasing HFRS (pinteraction=0&#xb7;020). The rVE was 0&#xb7;2% (95% CI -10&#xb7;8 to 10&#xb7;2) among those with low frailty risk, 13&#xb7;1% (-0&#xb7;4 to 24&#xb7;8) among those with intermediate frailty risk, and 19&#xb7;9% (-10&#xb7;3 to 42&#xb7;1) among those with high frailty risk. No significant interaction was observed when HFRS was assessed according to the prespecified categorical frailty groups (pinteraction=0&#xb7;17). The proportion of participants with at least one serious adverse event increased across frailty risk groups (13&#x2009;366 [4&#xb7;8%] of 275&#x2009;795 for low frailty risk, 5475 [10&#xb7;5%] of 52&#x2009;315 for intermediate frailty risk, and 777 [20&#xb7;2%] of 3850 for high frailty risk; p<0&#xb7;0001), with similar proportions of serious adverse events in the HD-IIV and SD-IIV groups for each frailty risk group. INTERPRETATION: Among adults aged 65 years or older in Denmark, frailty risk might modify the effects of HD-IIV versus SD-IIV against hospitalisation for influenza or pneumonia, with higher rVE estimates with increasing frailty risk. These findings might support considering high-dose influenza vaccines for frail older adults. However, effect modification was not evident when frailty was assessed using prespecified categorical subgroups, and subgroup-specific estimates were imprecise, with 95% CIs crossing the null. These results should be considered exploratory, warranting further investigation. FUNDING: The DANFLU-2 trial was funded by Sanofi.

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