Researchers in Spain and Denmark reached different conclusions in two new randomized controlled trials comparing the effectiveness against hospitalization of the high-dose influenza vaccine with the standard-dose version among older adults, with one showing 44% better protection for the high-dose version against hospitalization for flu but not for flu or pneumonia, which goes against previous findings.
The findings of both studies were published in the New England Journal of Medicine.
Flu sample too small for statistical testing
Researchers at the Instituto de Investigacion Sanitaria de Santiago conducted a registry-based, open-label randomized controlled trial to compare the relative vaccine effectiveness (rVE) of the inactivated high-dose quadrivalent (four-strain) flu vaccine with the inactivated quadrivalent standard-dose version against poor outcomes among adults aged 65 to 79 years in Galicia, Spain, during the 2023-24 and 2024-25 respiratory virus seasons.
Sanofi funded the study, and its representatives helped design the trial, develop the protocol, and wrote and reviewed early versions of the manuscript but didn’t participate in conducting it.
The observed incidence of hospitalization for influenza or pneumonia seemed to be lower among those who received the high-dose vaccine than among those who received the standard-dose vaccine.
A total of 133,882 participants were randomly assigned in a 1:1 ratio to receive high-dose flu vaccine or the standard dose. The primary end point was a composite of hospital admission for flu or pneumonia from 14 days post-vaccination to May 31 of the next year. The average participant age was 72.3 years, and 53.6% were men.
“Traditional seasonal influenza vaccines prevent 30 to 50% of influenza cases, with lower effectiveness observed in older populations,” the authors note. “The high-dose inactivated influenza vaccine, which was developed to enhance protection in older adults, contains four times as much hemagglutinin antigen as is contained in the standard-dose vaccine.”
A total of 174 of 67,093 participants in the high-dose group were hospitalized for flu or pneumonia (absolute risk, 0.26%), as were 227 of 66,789 of standard-dose recipients (absolute risk, 0.34%; rVE, 23.7%; 95% confidence interval [CI], 6.6% to 37.7%).
Hospitalization for flu occurred in 63 of 67,093 participants in the high-dose group (absolute risk, 0.09%) and in 92 of 66,789 in the standard-dose group (absolute risk, 0.14%) (rVE, 31.8%; 95% CI, 5.0% to 51.3%). Of the 5,936 serious adverse events seen during the study, 49.7% occurred in the high-dose group and 50.3% took place in standard-dose recipients.
“Because of a lower-than-expected incidence of influenza, the number of cases needed to perform formal statistical testing was not reached,” the researchers wrote.
“However, the observed incidence of hospitalization for influenza or pneumonia seemed to be lower among those who received the high-dose vaccine than among those who received the standard-dose vaccine,” they added. “At the population level, such differences could translate into a meaningful effect on the health care system.”
High-dose: 44% higher protection against flu hospitalization
For the second study, a team led by investigators at Copenhagen University Hospital conducted an open-label randomized controlled trial among 332,438 older adults in Denmark during the 2022-23, 2023-24, and 2024-25 respiratory virus seasons to determine rates of flu or pneumonia hospitalization from 14 days post-vaccination to May 31 of the next year.
As in the first trial, Sanofi had a role but didn’t conduct the trial or work with the data.
The fact that the high-dose vaccine did not result in a significantly lower incidence of hospitalization for influenza or pneumonia or the individual component of hospitalization for pneumonia is inconsistent with previous data.
The researchers assigned adults aged 65 years and older to receive the high-dose (166,218) or standard-dose (166,220) inactivated flu vaccine and analyzed data from nationwide administrative health registries. The average participant age was 73.7 years, and 48.6% were women.
Hospitalization for flu or pneumonia occurred in 0.68% of the high-dose group and 0.73% of standard-dose recipients (rVE, 5.9%; 95.2% CI, -2.1% to 13.4%). Hospitalization for flu only and not pneumonia occurred in 0.06% of high-dose recipients and 0.11% of those in the standard-dose group (rVE, 43.6%; 95.2% CI, 27.5% to 56.3%).
A total of 0.63% and 0.63% high- and standard-use participants, respectively, were hospitalized for pneumonia (rEV, 0.5%; 95.2% CI, -8.6% to 8.8%).
Hospitalization for cardiorespiratory disease occurred in 2.25% and 2.38% of participants, respectively (rVE, 5.7%; 95.2% CI, 1.4% to 9.9%), while all-cause hospitalization occurred in 9.38% and 9.58% (rVE, 2.1%; 95.2% CI, -0.1% to 4.3%), and 0.67% and 0.66%, respectively died of any cause (rVE, -2.5%; 95.2% CI, -11.6% to 5.9%).
In total, 682 deaths occurred during the safety period; none were classified as vaccine-related. A blinded review of each serious adverse event determined that 132 events were vaccine-related (75 in the high-dose group and 57 among the standard-dose recipients).
“The fact that the high-dose vaccine did not result in a significantly lower incidence of hospitalization for influenza or pneumonia or the individual component of hospitalization for pneumonia is inconsistent with previous data,” the authors wrote.