Abstract Body (Do not enter title and authors here): Background and Aims:
The high-dose inactivated influenza vaccine (HD-IIV) results in a stronger serological response in older persons and in those with cardiovascular (CV) disease as compared with standard-dose vaccines (SD-IIV). The aim of this study was to evaluate the relative effectiveness of HD-IIV vs. SD-IIV on clinical respiratory and CV outcomes, in persons with or without pre-existing atherosclerotic cardiovascular disease (ASCVD).

Methods:
FLUNITY-HD comprised two pragmatic, open-label, individually randomized trials that compared HD-IIV vs. SD-IIV. DANFLU-2 was conducted in Denmark during the 3 most recent influenza seasons while GALFLU was conducted in Galicia, Spain during the 2 most recent influenza seasons. Both trials used the same harmonized protocol. The trials enrolled adults ≥65 years (65-79 in GALFLU), irrespectively of comorbidity, and randomized them 1:1 to HD-IIV or SD-IIV. Study data were obtained from registries. In each study season, participants were followed for outcomes from 14 days after vaccination through May 31 the following year. The primary outcome was the relative vaccine effectiveness (rVE) for HD-IIV vs. SD-IIV against hospitalization for pneumonia or influenza. Heterogeneity in rVE among participants with vs. without ASCVD was assessed using the Cochran-Mantel-Haenszel test. A two-sided p<0.05 was considered statistically significant.

Results:
A total of 466,320 participants (332,438 in DANFLU-2 and 133,882 in GALFLU) were randomized to HD-IIV (n=233,311) or SD-IIV (n=233,009); 56,886 (12.2%) had a history of ASCVD, i.e., 37,842 (8.1%) had ischemic heart disease, 19,460 (4.2%) had cerebrovascular disease, and 3,857 (0.8%) had peripheral artery disease. Baseline characteristics in participants with and without prevalent ASCVD are shown in Table 1. Persons with ASCVD were older, more often men, and had a higher prevalence of all reported comorbidities. The incidence of all reported outcomes was higher in participants with pre-existing ASCVD vs. those without (Table 2). However, the rVE for all outcomes were consistent regardless of ASCVD status, with no sign of heterogeneity (all p-interaction ≥0.05) (Figure 1).

Conclusions:
In this pooled FLUNITY-HD analysis comprising 466,320 individuals ≥65 years of age, HD-IIV reduced the incidence of a wide range of clinical CV and respiratory outcomes compared with SD-IIV, regardless of pre-existing ASCVD. Patients with ASCVD may potentially derive greater absolute benefits from HD-IIV.