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Study Reinforces Effectiveness of HD-Trivalent Influenza Vaccines


High-dose trivalent flu vaccine was associated with a reduced risk of hospitalization and emergency department visits for pneumonia or influenza in adults aged 65 and above, according to a recent study.

A recent study compared the efficacies of standard-dose (SD) trivalent, high-dose (HD) trivalent, SD-quadrivalent, and adjuvanted trivalent influenza vaccines at reducing the risk of hospitalization and emergency department (ED) visits for pneumonia or influenza in adults aged 65 and above.

The research, published in npj Vaccines, reinforces previous findings that HD-trivalent vaccines are statistically more effective than other types at reducing hospitalizations and ED visits.

The authors said their findings may provide evidence to policy makers to recommend HD-trivalent vaccines to older adults first, supplies permitting. Older adults are disproportionately affected by influenza. In the 2019-2020 flu season, they made up 43% of hospitalizations and 62% of deaths (overall, there were 38 million influenza cases, with 22,000 deaths and 400,00 hospitalizations).

Comparative studies between the potency of HD-trivalent vs. SD-quadrivalent specifically were also scarce in the literature prior to this research, with only marginal support for HD-trivalent’s effect at reducing influenza risk.

Previous research has consistently shown older adults have lower uptake of flu vaccination compared with younger adults, even though it is vital to increase vaccination rates in an aging population. In addition, the ongoing threat of the COVID-19 pandemic, which has stressed health care systems, also points to the need to reduce health utilization burdens by maintaining and increasing influenza vaccinations.

To arrive at their results, researchers analyzed data from individuals in the IBM MarketScan Medicare Supplemental Databases from 6 influenza seasons from January 2011 to December 2018.

The number of subjects ranged from 211,536 in 2017/2018 to 533,616 individuals aged 65 and older in 2012/2013. Individuals received SD-trivalent, HD-trivalent, SD-quadrivalent, or adjuvanted trivalent vaccines between September and August.

The 2 outcomes were hospitalization or ED visit from pneumonia or influenza; 55% of patients were female. The main comorbidities were diabetes (26.2%) and chronic obstructive pulmonary disease (16.2%).

Over the study duration, influenza cases resulted in hospitalizations 66.7% of the time and ED visits 33.3% of the time. Pneumonia mostly led to hospitalizations (91%) and less often to the ED (9.1%).

Multivariable Cox models showed the risk of hospitalization/ED visits increased in some demographics, particular for those who were older, male, urban residents, and having baseline indicators of other conditions like congestive heart failure.

Results showed statistically significant differences between rates for subjects taking the various vaccines by noting the overall likelihood ratio test (LRT) (P <.004) for each outcome.

SD-trivalent and SD-quadrivalent both possessed a higher risk of influenza-related hospitalization/ED visit (aHR, 1.16; 95% CI, 1.06–1.27) and hospitalization/ED visit for pneumonia (aHR,1.07; 95% CI, 1.05–1.10) than HD-trivalent.

The proportional hazards hypothesis stayed valid for any vaccine each season, showing no decline in relative effectiveness 1 year out from vaccination.

The study’s results differed from other international and domestic cohort studies on the effectiveness of cell-cultured quadrivalent and adjuvanted trivalent vaccines compared with SD-trivalent. The authors believe it may be a result of the studies using different base populations, influenza seasons, or outcome definitions.

Several limitations were present in the study:

Hospital International Classification of Disease codes were used to define cases of pneumonia and influenza, which by their nature may only capture more urgent cases.

  • The parameters of the data gathered did not allow the authors to determine how effective the vaccines were to different influenza types and subtypes.
  • Calendar issues had the potential to introduce confounding into pooled analyses if different types of vaccines were administered at higher rates between 2 years.
  • The possibility for confounding by indication was also present, though the researchers mitigated this by adjusting for patient characteristics like comorbidities and frailty of health.

Overall, the authors said the large sample size of vaccinated older adults over 6 influenza seasons tracking the various vaccine types lends statistical precision and power to their findings. Other strengths of the study included using 2 methods to estimate comparative effects, a time-to-event ratio and a rate ratio.

More research is needed to expand applicable knowledge to future influenza seasons, the researchers noted.


Machado MAÁ, Moura CS, Abrahamowicz M, Ward BJ, Pilote L, Bernatsky S. NPJ Vaccines. Relative effectiveness of influenza vaccines in elderly persons in the United States, 2012/2013-2017/2018 seasons. Published online August 24, 2021. doi:10.1038/s41541-021-00373-w.

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