tetano
Editor, Senior Moderator
Lancet Healthy Longev
. 2027 Aug 12:100894.
doi: 10.1016/j.lanhl.2026.100894. Online ahead of print.
Caroline Espersen 1 , Niklas D Johansen 1 , Daniel Modin 1 , Kira H Janstrup 1 , Matthew M Loiacono 2 , Rebecca C Harris 3 , Youjun Huang 4 , Carsten S Larsen 5 , Lykke Larsen 6 , Lothar Wiese 7 , Michael Dalager-Pedersen 8 , Brian L Claggett 9 , Katja V Bartholdy 1 , Katrine F Bernholm 1 , Julie I-M H Borchsenius 1 , Filip S Davidovski 1 , Lise W Davodian 1 , Maria Dons 1 , Lisa S Duus 1 , Frederik H Fussing 1 , Anne Marie R Jensen 1 , Nino E Landler 1 , Adam C F Langhoff 1 , Mats C H Lassen 1 , Anne B Nielsen 1 , Camilla I Ottosen 1 , Morten Sengeløv 1 , Kristoffer G Skaarup 1 , Scott D Solomon 9 , Martin J Landray 10 , Gunnar H Gislason 11 , Lars Køber 12 , Pradeesh Sivapalan 13 , Cyril J-M Martel 14 , Jens U S Jensen 13 , Kazumasa Harada 15 , Gaetan Gavazzi 16 , Tor Biering-Sørensen 17
Affiliations
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 332 438 randomised participants (mean age 73·7 years [SD 5·8]; 161 538 [48·6%] were female), 276 173 (83·1%) had low frailty risk, 52 395 (15·8%) had intermediate frailty risk, and 3861 (1·2%) had high frailty risk. The primary endpoint of hospitalisation for influenza or pneumonia occurred in 1424 (0·5%) of 276 173 participants with low frailty risk, 761 (1·5%) of 52 395 with intermediate frailty risk, and 163 (4·2%) of 3861 with high frailty risk (relative risk [RR] for intermediate vs low frailty risk 2·8 [95% CI 2·6-3·1]; RR for high vs low frailty risk 8·2 [7·0-9·6]). 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=0·020). The rVE was 0·2% (95% CI -10·8 to 10·2) among those with low frailty risk, 13·1% (-0·4 to 24·8) among those with intermediate frailty risk, and 19·9% (-10·3 to 42·1) among those with high frailty risk. No significant interaction was observed when HFRS was assessed according to the prespecified categorical frailty groups (pinteraction=0·17). The proportion of participants with at least one serious adverse event increased across frailty risk groups (13 366 [4·8%] of 275 795 for low frailty risk, 5475 [10·5%] of 52 315 for intermediate frailty risk, and 777 [20·2%] of 3850 for high frailty risk; p<0·0001), 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.
. 2027 Aug 12:100894.
doi: 10.1016/j.lanhl.2026.100894. Online ahead of print.
Effectiveness of high-dose versus standard-dose influenza vaccines against hospitalisation according to frailty risk: a prespecified analysis of the randomised trial DANFLU-2
Caroline Espersen 1 , Niklas D Johansen 1 , Daniel Modin 1 , Kira H Janstrup 1 , Matthew M Loiacono 2 , Rebecca C Harris 3 , Youjun Huang 4 , Carsten S Larsen 5 , Lykke Larsen 6 , Lothar Wiese 7 , Michael Dalager-Pedersen 8 , Brian L Claggett 9 , Katja V Bartholdy 1 , Katrine F Bernholm 1 , Julie I-M H Borchsenius 1 , Filip S Davidovski 1 , Lise W Davodian 1 , Maria Dons 1 , Lisa S Duus 1 , Frederik H Fussing 1 , Anne Marie R Jensen 1 , Nino E Landler 1 , Adam C F Langhoff 1 , Mats C H Lassen 1 , Anne B Nielsen 1 , Camilla I Ottosen 1 , Morten Sengeløv 1 , Kristoffer G Skaarup 1 , Scott D Solomon 9 , Martin J Landray 10 , Gunnar H Gislason 11 , Lars Køber 12 , Pradeesh Sivapalan 13 , Cyril J-M Martel 14 , Jens U S Jensen 13 , Kazumasa Harada 15 , Gaetan Gavazzi 16 , Tor Biering-Sørensen 17
Affiliations
- PMID: 42753782
- DOI: 10.1016/j.lanhl.2026.100894
Abstract
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 332 438 randomised participants (mean age 73·7 years [SD 5·8]; 161 538 [48·6%] were female), 276 173 (83·1%) had low frailty risk, 52 395 (15·8%) had intermediate frailty risk, and 3861 (1·2%) had high frailty risk. The primary endpoint of hospitalisation for influenza or pneumonia occurred in 1424 (0·5%) of 276 173 participants with low frailty risk, 761 (1·5%) of 52 395 with intermediate frailty risk, and 163 (4·2%) of 3861 with high frailty risk (relative risk [RR] for intermediate vs low frailty risk 2·8 [95% CI 2·6-3·1]; RR for high vs low frailty risk 8·2 [7·0-9·6]). 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=0·020). The rVE was 0·2% (95% CI -10·8 to 10·2) among those with low frailty risk, 13·1% (-0·4 to 24·8) among those with intermediate frailty risk, and 19·9% (-10·3 to 42·1) among those with high frailty risk. No significant interaction was observed when HFRS was assessed according to the prespecified categorical frailty groups (pinteraction=0·17). The proportion of participants with at least one serious adverse event increased across frailty risk groups (13 366 [4·8%] of 275 795 for low frailty risk, 5475 [10·5%] of 52 315 for intermediate frailty risk, and 777 [20·2%] of 3850 for high frailty risk; p<0·0001), 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.